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📇 文献索引
 
🥷
天使的珊瑚： ICC国际临床委员会FOP分会（INTERNATIONAL CLINICAL COUNCIL ON FIBRODYSPLASIA OSSIFICANS PROGRESSIVA）汇聚了众多全球知名的FOP专家，旨在针对FOP这种超级罕见病提出有效可行的临床诊断、处置管理的方案。ICC成员在全球范围内，整理甄选大量FOP的相关文献，进行研究总结，汇编成这套《FOP临床管理指南》。文档前后翻译3次，第1~2版已经发布于知乎频道。2024年6月ICC发布第3版，本次通过Ai-ChartGPT和人工翻译校对，希望对患者，家属，医疗工作者、科研人员，以及关注FOP的人们能有所帮助。

编者序

2024年6月16日
亲爱的FOP社区成员们，
我们代表 FOP 国际临床委员会 （ICC） 及其 21 名成员、2 名名誉成员和 6 名顾问，很高兴地推出 2024 版
INTERNATIONAL CLINICAL COUNCIL ON FIBRODYSPLASIA OSSIFICANS PROGRESSIVA（也称为FOP治疗指南） 国际医师学会（ICC）坚持不懈地投入到这份指南的工作中，这代表了许多专家学者们的巨大努力。本报告包含了许多最新的更新，以及此前报告中您认为大受裨益的部分，希望这些内容能够为您有所帮助。 您将会注意到第二章《关键实践要点的执行摘要》。这部分写的相对谨慎、在提供丰富信息的同时，保持观点的平衡，以此获得了更为详尽的报告支持和阐述。 我们在此强调，本文件反映了作者对缓解症状药物的各类讨论和不同种类药物的经验和观点，仅此作为这种具有限循证信息的超级罕见病FOP治疗领域中的指南。 尽管每个FOP患者都有共同的身体特征，但个体之间存在着生理差异，这可能会影像本文所讨论的任何药物或药物类别的潜在收益或风险。使用或拒绝使用特定药物的决定最终必须由个体患者及其医生决定。 随着FOP药物在美国、加拿大和澳大利亚等地获得批准，正在进行中的世界各地临床试验，以及即将推出的更多新药的临床试验，我们预计本指南未来将会经常更新。 我们真诚地希望第3版FOP治疗指南能够帮助到全球相关的FOP患者、家庭、医生、牙医、医务人员和护理人员。
 
敬上， Frederick S. Kaplan，医学博士;宾夕法尼亚大学，宾夕法尼亚州费城 Robert J. Pignolo，医学博士、哲学博士; 梅奥诊所，明尼苏达州罗切斯特
通讯作者
 
原文
July 16, 2024
Dear Members of the FOP Community,|
On behalf of the International Clinical Council on FOP (ICC) and its 21 members, 2 emeritus members, and six consultants, we are pleased to introduce the 2024 edition of
(also known as The FOP Treatment Guidelines).
The ICC has worked assiduously on this document which represents a monumental effort on the part of many. This report contains many new sections that we hope you will find useful, as well as completely updated sections that you found useful in the past.
You will notice the Executive Summary of Key Practice Points (Section II). It is conservative, informative, and balanced – supported by the detailed exposition of the larger report.
We emphasize that this document reflects the authors’ experience and opinions on the various topics and classes of symptom-modifying medications and is meant only as a guide to this area of therapeutics for the ultra-rare condition of FOP for which evidence-based information is limited.
Although there are common physical features shared by every person who has FOP, there are physiological differences among individuals that may alter the potential benefits or risks of any medication or class of medications discussed here. The decision to use or withhold a particular medication must ultimately rest with an individual patient and his or her physician.
With an approved medication in the US, Canada, and Australia and ongoing clinical trials throughout the world and additional ones on the horizon, we anticipate that this document will be updated frequently.
We sincerely hope that this 3 rd edition of The FOP Treatment Guidelines will be useful and relevant to FOP patients, families, physicians, dentists, medical personnel and caregivers worldwide.
Sincerely,
Frederick S. Kaplan, M.D.; The University of Pennsylvania, Philadelphia, PA
Robert J. Pignolo, M.D., Ph.D.; The Mayo Clinic, Rochester, MN
Corresponding Editors
正文
THE MEDICAL MANAGEMENT OF FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: CURRENT TREATMENT CONSIDERATIONS
进行性骨化性纤维发育不良（FOP）医学管理：当前的治疗注意事项
(官方指南，2024第3版)
notion image
作者：Frederick S. Kaplan, Mona Al Mukaddam, Genevieve Baujat, Alberto Hidalgo Bravo, Matthew Brown, Amanda Cali, Tae-Joon Cho, Corrie Crowe, Carmen L. De Cunto, Patricia Delai, Robert J. Diecidue, Maja Di Rocco, Elisabeth M.W. Eekhoff, Lisa Friedlander, Clive Friedman, Zvi Grunwald, Nobuhiko Haga, Edward C. Hsiao, Richard Keen, Joseph Kitterman, Charles Levy, Vrisha Madhuri, Rolf Morhart, J. Coen Netelenbos, Christiaan Scott, Eileen M. Shore, Michael A. Zasloff, Keqin Zhang, Robert J. Pignolo
通讯作者 | Corresponding Editors:
Frederick S. Kaplan, M.D.
Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine Director, Center for Research in FOP & Related Disorders The Perelman School of Medicine - The University of Pennsylvania Department of Orthopaedic Surgery 3737 Market Street – Sixth Floor Philadelphia, PA 19104, USA Tel: (office) 215-294-9145 Fax: 215-222-8854 Email: [email protected]
Robert J. Pignolo, M.D., Ph.D.
Chair, Division of Geriatric Medicine & Gerontology Robert and Arlene Kogod Professor of Geriatric Medicine Mayo Clinic College of Medicine 200 First Street SW Rochester, MN 55905, USA Tel: 507-293-6988: Secretary: 507-293-0813 Fax: 507-293-3853 Email: [email protected]
Cite: [Kaplan FS, et al. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP 3: 1-159, 2024]

目录

编者序目录第一章. 概述第二章. 关键实践要点的执行摘要方法总体建议治疗用药第三章. FOP的临床与基础科学背景1. 引言2. FOP的经典临床特征3. FOP的其他骨骼异常4. FOP的放射学特征5. FOP病变的病理学6. FOP的实验室研究7. FOP的病因和病理8. FOP中大脚趾畸形的发育分子生物学9. 变异型FOP10. 免疫系统与FOP11. FOP的流行病学、遗传学和环境因素12. 基因检测与FOP13. FOP的动物模型14. FOP的预后15. FOP治疗评估的挑战第四章. 基于病理学与病理生理学的FOP治疗1. 简介2. 皮质类固醇3. 环氧合酶-2（COX-2）抑制剂和非甾体抗炎药（NSAIDs）4. 局部镇痛药5. 肥大细胞抑制剂6. 双磷酸盐7. 管理FOP炎症的非标签强效药物8. 肌肉松弛剂9. 化疗药物与放疗10. 骨髓移植11. 其他药物与治疗方法12. 支持性疗法13. 确切的FOP治疗靶点14. FOP的临床试验结果第五章. FOP的特殊医学考虑事项1. 简介2. FOP的创伤预防3. FOP的头皮结节4. FOP的脊柱畸形5. FOP的心肺功能6. FOP的呼吸健康7. FOP患者的其他疾病免疫接种（不包括流感和COVID-19）8. FOP的流感疫苗接种9. 新冠病毒（COVID-19）的预防措施与FOP患者及其家庭的指导10. FOP的急性和慢性疼痛管理11. FOP的神经问题12. FOP的发育性关节病和退行性关节病13. FOP的髋关节疼痛鉴别诊断14. FOP的肢体肿胀15. FOP患者的压疮16. 皮肤病与FOP17. FOP的趾甲内生（嵌甲）18. FOP的骨折19. FOP的颞下颌关节半脱位20. FOP的营养、钙和维生素D指南21. FOP的预防性口腔保健22. 拔出智齿23. 正畸与FOP24. FOP下颌下的急性发作25. 吞咽与FOP26. FOP的牙科麻醉27. FOP的全身麻醉28. FOP可接受/低风险的医疗处置29. FOP的听力障碍30. FOP的胃肠道问题31. 肾结石与FOP32. FOP的康复问题33. 辅助工具、助行器具和适应措施（AADAs）34. FOP群体中的女性健康35. FOP的怀孕问题36. 变异型FOP37. FOP对患者及其家庭的影响38. FOP的未满足需求第六章. 当前治疗考虑事项第七章. 药物类别（表1）第八章. 紧急救援人员、医生和牙医的急救指南第九章. 结论第十章. 致谢第十一章. 披露事项第十二章. 作者联系信息图1. FOP的靶点与潜在疗法
此版本的FOP指南由英文编写，是ICC审查和认可的唯一版本。ICC允许本文自由翻译为其他语言，但不保证任何此类翻译的准确性。在有条件的情况下，FOP指南的任何翻译都应由拟使用翻译的国家/地区的双语医学专家进行并审查。
原文
This version of the FOP Guidelines, written in English, is the only version reviewed and endorsed by the ICC.
The ICC acknowledges that this document may be freely translated into other languages but does not guarantee the accuracy of any such translations.
To the extent possible, any translation of the FOP Guidelines should be performed and reviewed by bilingual medical experts from the country where the translation is intended to be used.

第一章. 概述

进行性骨化纤维发育不良 (FOP) 是一种罕见的致残性遗传疾病，其特征是先天大脚趾畸形和特定解剖模式下的进行性异位骨化（HO）。FOP是人类中最为严重的异位骨化疾病。FOP的急性发作(Flare-ups)是偶发性的；身体受限是累积性的。
在所有散发性和家族性具有典型FOP表现的病例中，基因中均存在一种激活素A I型（ACVR1，也就是ALK2）突变，编译一种骨形态发生蛋白I型受体（BMP）。
预估有97%的FOP患者具有这种复发性突变，其他大约有3%的受影响个体具有ACVR1的变异突变，然而，所有已知的FOP个体，均含有ACVR1的突变基因。
FOP致病基因的发现为解读FOP奠定了重要的里程碑，它揭示了BMP信号通路中高度保守的治疗靶点，并且推动了开发以ACVR1介导的BMP信号通路的新型抑制疗法。虽然FOP的有效治疗方法可能会基于调节过度活跃的ACVR1信号传导，或者采取阻断特定的出生后异位骨化（HO），但是目前的治疗管理更应该侧重于早期的诊断、竭力避免损伤或医源性伤害、改善急性发作的疼痛症状，以及优化现有的身体机能。
本文中，我们简要地回顾了临床和FOP背后的基础科学、针对各类药物使用的科学依据、特殊的医学考量，以及结合当前理解下的缓解FOP症状的指南。本文并非旨在介绍管理FOP症状的特定方法，而是为了展示作者的观点，陈述和建议，基于此为面对类挑战的人提供有限的帮助。
未来，更为进一步的治疗将基于该疾病的分子和细胞层面机制的理解、改进后的临床药试用的基因动物模型，以及严格的临床试验，用来评估创新的和新兴的治疗方法与预防策略。
原文
I. ABSTRACT
Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. FOP is the most catastrophic disorder of HO in humans. Flare-ups are episodic; immobility is cumulative.
A common mutation in the activin receptor IA (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor, exists in all sporadic and familial cases with a classic presentation of FOP.
An estimated 97% of individuals with FOP have this recurrent mutation. Approximately 3% of affected individuals have different pathogenic variant mutations in ACVR1. However, all known individuals with FOP have mutations in the ACVR1 gene.
The discovery of the FOP gene established a critical milestone in understanding FOP, revealing a highly conserved therapeutic target in the BMP signaling pathway, and propelling approaches for the development of novel inhibitors of ACVR1-mediated BMP pathway signaling. While effective therapies for FOP will likely be based on interventions that modulate overactive ACVR1 signaling or specifically block postnatal HO, present management is focused on early diagnosis, assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.
Here, we briefly review the clinical and basic science background of FOP, the scientific basis for the use of various medications, special medical considerations, and guidelines for the symptomatic relief of symptoms of FOP based upon currently available knowledge. This report is not intended to present a specific approach for managing the symptoms of FOP, but rather is intended to present views, statements, or opinions of the authors that may be helpful to others who face similar challenges.
Further advances in therapeutics will be based on knowledge of disease mechanisms at the molecular and cellular level, the refinement of genetically based animal models for drug testing, and rigorous clinical trials to assess novel and emerging treatment and prevention strategies.

第二章. 关键实践要点的执行摘要

方法

由来自 14 个国家的 21 名国际临床委员会（ICC）成员及 5 名顾问共同协作完成了本总结报告，所有参与者均因其在 FOP 领域的临床专长而被选中。参与人员包括：麻醉师、内分泌科医生、风湿病科医生、骨科医生、临床遗传学家、分子遗传学家、新生儿科医生、儿科医生、内科医生、康复理疗师、老年病科医生、皮肤科医生、牙科医生、口腔外科医生，以及一名来自家长支持组织的非投票代表。所有参与者均完成了利益冲突声明。本次共识制定由学术资金支持，未获得制药行业的资助。
研究采用了改进的德尔菲（Delphi）共识法(Di Rocco et al., 2017)。研究人员在 PubMed 数据库中以“fibrodysplasia ossificans progressiva”为搜索词进行了全面的文献检索。在需要补充信息时，通过 PubMed 检索了其他相关的 FOP 文章。ICC 出版委员会对 2900 多篇文章进行了全面审阅，并以此作为讨论的基础。共识的准备工作历时 12 个月，包括多次筹备会议以及工作组成员之间的定期远程电话会议讨论。
此外，还采纳了Di Rocco et al., 2017和 Hsiao et al.,（2019 年）提出的具有广泛参考价值的建议。在共识会议上，与会者对各项命题和建议进行了审议，并在全体会议上进行了讨论，以便在必要时对建议进行重新调整。由于 FOP 属于极罕见疾病，循证依据的等级通常为中到低。在缺乏或不足以获得发表数据的情况下，则参考专家的临床经验和意见。最后，所有临床专家均批准了该执行摘要。所有修订工作均按照相同标准进行。

总体建议

  1. FOP可以通过临床做出诊断（骨骼畸形，包括畸形的大脚趾，软组织肿胀和进行性异位骨化（HO），但需要通过遗传学基因检测确认ACVR1基因突变）。如果疑似FOP，要推迟延期所有的外科手术，组织活检，以及免疫接种，直到做出明确的临床诊断。要为患者提供紧急的医疗护理。
  1. 每一位患者都需要一名主治医生，他要有意愿去咨询FOP专家，并且提供帮助协调当地的护理团队。
  1. 在确诊后，应告知患者和家属有关国际FOP临床委员会（ICC）、国际FOP协会（IFOPA）和当地国家或地区的支持团体。
 
身体活动：鼓励各年龄段患者进行活动，但必须严禁被动的关节活动度训练（即由他人而非患者本人操作、不借助患者肌肉力量而进行的关节运动）。鼓励进行唱歌、水上运动，以及有助于呼吸健康的活动。应避免软组织损伤、接触性运动、软组织过度拉伸、肌肉疲劳、活检、异位骨切除术以及所有非急需的外科手术。
麻醉：在所有的情况下，都务必在术前咨询对FOP患者全身麻醉方面有丰富经验的麻醉专家。如果需要全身麻醉，应该采用鼻气管光纤技术进行清醒插管，因为FOP患者颈部畸形，下颌活动受限，气道敏感，并且会有诱发阻滞性颈部恶化。所有选择性器官插管应要有具备FOP认识的超高技能的麻醉师在场。
慢性疼痛：慢性疼痛综合征在FOP中很常见，可能来自神经病变（例如：卡滞压迫、神经损伤）、肌肉骨骼（例如：背痛、肌肉筋膜疼痛）、炎症或机械性或压迫性原因（例如， 由于大面积的异位骨化，尤其是在急性发作的末期）。处置管理慢性疼痛的一般原则包括要确定疼痛的类型（神经性，还是伤痛性），可以采用由多学科疼痛专家综合制定的各类非侵入式治疗方法，也可以采用辅助的非药物治疗方式，并且要治疗缓解心理抑郁（纠正情绪失控需要提供独立于疼痛的额外治疗）
新冠感染：请参考本文“新冠“章节，以及ICC和IFOPA网站的最新更新(www.iccfop.org 和 www.ifopa.org)
牙科紧急情况：如果患者的口腔-面部区域肿胀或疼痛，我们始终建议对患者进行全面的牙科检查，因为很难区分牙源性肿胀和FOP急性发作。如果牙科X光片和或牙髓检测（牙齿神经的活力）表明肿胀没有明显的来源于牙齿，那么，谨慎的做法是假定FOP急性发作，并且根据FOP急性发作的剂量服用泼尼松。如果无法进行牙科X光片和或牙髓检测，则需要凭借经验开具适当的抗生素和泼尼龙， 直到可以做出明确的诊断。
摔倒：患者上肢的锁定可能会加剧摔倒造成的头部和颈部创伤。很常见的是硬膜外血肿（手术急症）。要考虑为上肢受累的儿童佩戴防护性头盔。所有头部和颈部损伤都应该立即进行紧急评估。
急性发作（背部和胸部）：要考虑使用非甾体类抗炎药或COX-2抑制剂（口服或局部外涂），并同步采取胃肠道管理的预防措施。根据需要使用镇痛药、肌肉松弛剂，以及在患处使用冰袋冰敷）。类固醇可用于严重病例，但是背部或胸部的急性发作似乎并不会像其他部位那样能够有效地进行控制。
急性发作（四肢、喉咙、下颌下）：患者表现为炎性急性发作，伴随明显的肿胀和炎症。这些症状可能会因患者和出发事件而异。泼尼松：2mg(毫克)/kg(公斤)，每日1次（每日最多100毫克），上午服药（每次口服），持续四天（或等效的皮质类固醇类药物）。在急性发作的体征和症状出现后要尽早开始服药。随身携带泼尼松可以作为紧急情况下的”口袋里的药“或”随身携带的药“。亦或，可以在医生的指导下进行脉冲式静脉注射类固醇类药物。如果可能，避免使用类固醇治疗脊椎部位有关的急性发作。根据需要使用口服或局部部位使用非甾体抗炎镇痛药和或肌肉松弛剂，并持续做好胃肠道的预防措施。冰袋在身体局部部位的使用也可能会有帮助。尽可能避免麻醉镇痛。所有下颌下急性发作时，应该咨询FOP专家，并要认真细致地遵循专家指导。
急性发作（预防）：FOP急性发作通常是由于过度使用和软组织损伤而引起。泼尼松：每天1次，持续3~4天， 以预防软组织严重损伤后的急性发作。请勿在轻微磕碰或瘀伤后使用。按照牙科或外科手术的指示，预防性地使用泼尼松。
骨折：骨折会发生在身体正常位置的骨骼和异位骨骼中，如果采用保守治疗，通常会正常愈合不会新生很多的异位骨。建议使用泼尼松进行短期治疗。在所有情况下，都应该咨询在骨折方面有经验的FOP专家。
胃肠道事件：许多FOP患者进场报告恶心和呕吐症状。其原因和意义尚不明确。需要调查胃肠道不适，以排除更为严重的疾病。在脊柱严重侧弯的情况下，体重会明显减轻或体重指数低于常人，这可能与肠梗阻和系膜动脉综合征有关。治疗包括：增加体重。
听力：传导性听力障碍在FOP患者群体中很常见。FOP患者应该在儿童时期通过听力测定筛查听力障碍。助听器可以改善严重的传导性听力损失。
免疫接种：建议对所有可以皮下接种的疫苗进行皮下注射免疫接种。避免所有肌肉内的免疫接种和鼻内活流感疫苗接种，因为可能会促发FOP的急性发作。尽管MMR活MMRV疫苗含有减毒病毒，但在使用MMR活MMRV疫苗进行皮下接种后，尚未报告任何急性发作病例。急性发作期间不应该进行免疫接种，避免在急性发作消退后的6~8周内进行免疫接种。所有家庭成员都应该接种百日咳和新冠疫苗。在ICC和IFOPA网站上可查阅详细的免疫接种指南和更新。 (www.iccfop.org 和 www.ifopa.org)
流感：皮下注射流感疫苗，但是切勿在FOP急性发作期接种。等到急性发作期消退后的6-8周再接种流感疫苗。避免接种活流感减毒疫苗， 因为有可能会引发流感症状，并促发FOP的急性发作。FOP患者的家庭接触者应该每年进行免疫接种。如果出现流感症状，要考虑抗病毒治疗。查阅详细的流感免疫接种指南，因为免疫接种建议每年都会发生变化。
损伤：预防急性发作和异位骨的形成牵涉许多方面和因素。其中包括识别和避免已知的急性发作成因（接触性运动，软组织损伤，钝性肌肉创伤，肌肉疲劳，肌肉拉伸，肌肉注射和免疫接种，活检，移除异位骨，以及所有非紧急外科手术和病毒性疾病）。
静脉注射：在具有丰富经验的采血师操作的场景下，可以对FOP患者进行外周血采集和静脉注射。尽可能地以温和与微创的方式进行操作，这点非常重要。尽可能缩短止血带的使用时间。务必要咨询熟悉FOP患者护理的临床医生。浅表静脉通路（注射静脉时的皮下埋针）和静脉穿刺是可以被接受的。一定要避免创伤性静脉注射。中心静脉导管、PICC导管（经外周静脉穿刺中心静脉置管）和动脉穿刺可能会导致异位骨化（HO），除非对患者的治疗至关重要，否则应该避免使用。
肾结石：FOP患者患肾结石的风险要高出常人3倍。鼓励患者每天补充摄入1.5~2升的液体（最好是水），并避免高蛋白和高盐的饮食。应保持基于年龄和性别的每日钙推荐摄入量。
四肢肿胀：淋巴水肿和短暂性神经病变可能伴随四肢的急性发作。要尽可能在睡觉和躺卧时抬高双腿。如有指征，每日1粒低剂量阿司匹林，随餐服用，可用于预防深静脉血栓（DVT）的形成。用多普勒超声（B超）来排除深静脉血栓。使用合身的支撑袜来治疗慢性淋巴水肿（但要避免创伤性压迫）。这种治疗有助于慢性淋巴水肿。
心理健康： 患有任何慢性疾病的患者都有出现心理健康并发症的风险。如果疑似患有抑郁症，建议给予心理支持。家庭治疗可能会有帮助。
神经系统问题： FOP患者报告神经系统症状的发生率较高，包括FOP急性发作期间和远端的疼痛。应仔细检查疼痛的来源。一些FOP患者报告患有慢性头痛。如果头痛持续存在，应将患者转诊至神经科医生，神经科医生可以提出治疗建议。
营养膳食：在颌骨强直的情况下，应咨询营养师，以确保足够的营养摄入。
作业治疗 （OT）：专注于加强日常生活活动的作业治疗可能有助于改善FOP患者的生活质量。随着日常生活活动的变化，对辅助设备进行定期OT评估。
口腔正畸： 目前没有收到常规口腔正畸护理会导致FOP急性发作的报告。但是，所有寻求口腔正畸护理的FOP患者都应咨询FOP牙科专家。 物理治疗 （PT）: 严禁超范围的被动活动。温水水疗可能会有所帮助。 怀孕： 虽然FOP患者可以怀孕，但是FOP会对母子构成严重的生命威胁，并且如果孩子出生时患有这种疾病，对于整个家庭未来的生活将是灾难性的。在没有认真考虑和计划生育的情况下，FOP患者绝对不应怀孕。要尽量避免意外怀孕。如果真有必要，可以进行独立的遗传学咨询。若发生妊娠，必须在高危妊娠中心进行指导和护理。 压疮： 对于活动受限的患者，建议通过适当的方法或设备预防压疮。伤口护理团队应参与护理。 呼吸系统健康： 鼓励唱歌，游泳和肺活量测量激励法来保持肺部功能。儿童四岁以后进行基线肺功能检查（PFT）、超声心动图、胸部X射线检查和血氧饱和度测定。要重复定期检查。肺部会诊和睡眠检查可能会有助于指导特定的呼吸治疗。补充吸氧不可在未受监控的情况下使用。对于呼吸功能不全的患者，应该考虑接种流感和肺炎球菌疫苗。请参阅文中的免疫指南。 头皮结节： 头皮结节是急性发作的常见迹象，尤其是在FOP患儿中。尽管结节的大小可能令人震惊，但它们通常会自发消退，临床意义较小。 学校： 让学校助理老师来保护和协助儿童。家长可以通过信函向学校提出医疗帮助。入学前的评估会有所帮助。学校的医护人员、工作人员和教师应该了解FOP患者的受限情况，拟定方案来管理患儿免受伤害，以及FOP急性发作时的特殊需求。 脊柱畸形： 脊柱畸形在FOP患者群体中很常见，畸形独立于FOP急性发作。脊柱畸形进展快速 – 尤其是在儿童时期 – 应由FOP专家进行评估。 手术： 除非紧急情况，否则要避免手术。避免手术切除异位骨。
牙齿：预防性牙科护理是必不可少的，应该从小就开始。避免含糖的甜食和饮料。避免下颌骨阻滞、下巴过度拉伸和肌肉疲劳。在进行任何手术之前，请咨询 FOP 牙科专家。

治疗用药

皮质类固醇
  1. 建议对严重的钝性肌肉创伤进行类固醇预防治疗，可作为潜在性急性发作或活跃性急性发作的治疗。通常推荐的剂量是，泼尼松，2毫克/公斤/天, 连续服用4天，最大剂量为100毫克/天。
  1. 建议将类固醇预防用于牙科和外科手术。
  1. 应该考虑在紧急情况下使用类固醇治疗来缓解四肢、下颌或下颌下部位的急性发作症状。
COX-2抑制剂和非甾体抗炎药
没有明确的证据表明COX-2抑制剂或非甾体类抗炎药的长期治疗可以预防或改善FOP的急性发作。然而，当不需要皮质类固醇类药物时，COX-2抑制剂或口服、局部部位使用非甾体类抗炎药，可能有助于FOP急性发作和慢性关节疾病的对症管理。
双磷酸盐类
没有明确的证据表明双磷酸盐可以预防或改善FOP的急性发作。然而，可以考虑静脉注射双磷酸盐来预防类固醇相关的骨质流失。牙科医生应该了解任何患者早前使用双磷酸盐的情况。根据护理标准，可以考虑使用双磷酸盐治疗身体正常骨骼的骨质疏松症。
非标签用药（伊马替尼、托法替尼、卡纳单抗、阿那白滞素等）
没有明确的证据表明这些药物可以预防或改善FOP急性发作后的异位骨化。这些药物可以考虑用于严重、难以控制的FOP急性发作患者。请参阅ICC关于非标签用药的建议。
化疗药物和放射治疗
没有证据表明这些药物有效。在FOP患者的治疗管理中禁用这些方法。
骨髓移植
这种方法无效，且禁用于FOP患者的治疗。
FOP的其他用药
长期使用抗血管生成剂、钙合成剂、秋水仙碱、氟喹诺酮类抗生素、普萘洛尔、矿化抑制剂、PPAR-γ 拮抗剂和 TNF-α 抑制剂，目前对FOP的治疗管理没有作用。
明确的FOP治疗靶点
本文汇集了FOP的大部分全球合作研究工作，有关工作和进展的详细描述可以在www.clinicaltrials.gov, 第29期 FOP合作研究项目年度报告，以及最新的文献综述中找到。应该告知FOP患者正在进行的临床试验项目。
获批的FOP治疗方法
Palovarotene是一种RAR-γ 激动剂，已经在美国、加拿大和澳大利亚获批。处方信息可以在以下网址找到：Microsoft Word - pi-mg-fda-comments-15aug2023-combined-rev 17Aug2023 (d2rkmuse97gwnh.cloudfront.net)。请参与2023年8月16日（www.iccfop.org）ICC 关于 Palovarotene 的声明。
参考文献
  1. Di Rocco M, Baujat G, Bertamino M, Brown M, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao E, Keen R, Morhart R, Pignolo RJ, Kaplan FS. International physician survey on management of FOP: a modified Delphi study. Orphanet J Rare Dis Jun 12;12(1):110, 2017 FOP管理的国际医师调研：一项修订的Delphi研究 • 10.1186/s13023-017-0659-4
  1. Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo R, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 85: 1199-1207, 2019 FOP临床试验的特殊注意事项 • 10.1111/bcp.13777 [PaperDB][fopchina]
原文
Methods:
Twenty-one ICC members and five consultants from 14 countries, chosen for their clinical expertise in FOP, collaborated to develop this summary statement. Participants included anesthesiologists, endocrinologists, rheumatologists, orthopaedic surgeons, clinical geneticists, molecular geneticists, neonatologists, pediatricians, internists, physiatrists, geriatricians, dermatologists, dentists, oral surgeons and a non-voting representative from a parent support group. All participants completed a conflict-of-interest declaration. The consensus was supported by academic funding, without pharmaceutical industry support. A modified Delphi-like consensus methodology was adopted (Di Rocco et al., 2017). A comprehensive literature search was conducted using Pub Med and the search terms “fibrodysplasia ossificans progressiva.” Additional relevant articles on FOP were also identified by Pub Med searches when supplementary information was necessary. A comprehensive review of >2900 articles formed the basis of discussion by the Publications Committee of the ICC. Preparations for the consensus took place over 12 months, including multiple preparatory meetings and regular teleconference discussions between the working group members. In addition, recommendations were incorporated for widespread consideration from Di Rocco et al., 2017 and Hsiao et al., 2019. At consensus meetings, propositions and recommendations were considered by participants and discussed in plenary session enabling reformulation of the recommendations, if necessary. As FOP is an ultra-rare condition, evidence-based statements are generally moderate to low. If published data were unavailable or insufficient, experts’ clinical experiences and opinions were considered. Finally, all clinical experts ratified the executive summary. All revisions have been conducted with the same standards.
General Recommendations:
  1. The diagnosis of FOP is clinical (skeletal malformations including malformed great toes, soft tissue swelling and progressive heterotopic ossification (HO) but requires genetic confirmation (ACVR1 gene mutation). If FOP is suspected, all elective procedures such as surgeries, biopsies, and immunizations should be deferred until a definitive diagnosis is made. Emergent medical care should be provided.
  1. Each patient should have a primary physician who is willing to consult with an FOP expert and help coordinate a local care team.
  1. Patients and their families should be informed about the International Clinical Council on FOP (ICC), the International FOP Association (IFOPA), and country-specific support groups at the time of diagnosis.
Physical Activities: Activity is encouraged at all ages, but passive range of motion (motion performed by someone other than the patient in other words, a movement of a joint carried out by an operator without aid of the patient's muscles) must be avoided. Singing, water exercises, and activities for respiratory health are encouraged. Avoid soft tissue injuries, contact sports, overstretching of soft tissues, muscle fatigue, biopsies, removal of heterotopic bone and all non-emergent surgical procedures.
Anesthesia: An expert anesthesiologist experienced in general anesthesia for FOP patients must be consulted pre-operatively in all cases. If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of the neck malformations, jaw motion limitations, sensitive airway and risk of inducing an obstructing neck flare. Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
Chronic Pain: Chronic pain syndromes are common in FOP and may be related to neuropathies (e.g., entrapment, nerve damage), musculoskeletal origin (e.g., back pain, myofascial pain), inflammation, or mechanical/compressive causes (e.g., from expanding heterotopic ossification especially late in the course of a flare-up). General principles of management include identification of the type of pain (neuropathic versus nociceptive), use of multiple non-invasive treatment modalities coordinated by multidisciplinary pain specialists, use of adjuvant non-pharmacologic modalities, and treatment of depression (which may provide pain relief independent from correction of any mood disorder).
Covid-19: Please see section on COVID as well as ICC and IFOPA websites (www.iccfop.org & www.ifopa.org) for latest updates.
Dental Emergencies: It is always advisable to obtain a complete dental examination if a patient has swelling or pain of the oral-facial region as it can be difficult to distinguish a swelling of dental origin from a flare-up of FOP. If the dental radiographs and/or pulpal testing (vitality of the nerve of the tooth) indicates no obvious dental origin to the swelling, it is prudent to assume an FOP flare-up and initiate prednisone flare-up dosing. If it is not possible to get a dental radiograph or do pulpal testing, then empirically prescribing an appropriate antibiotic together with prednisone is warranted until a definitive diagnosis can be made.
Falls: Locked upper limbs may accentuate head and neck trauma from falls. Epidural hematomas are common (surgical emergency). Consider protective headgear in children who have upper limb involvement. All head and neck injuries should be evaluated immediately on an emergent basis.
Flare-up: (Back/chest): Consider non-steroidal anti-inflammatory medications or COX-2 inhibitors (oral or topical) with gastrointestinal (GI) precautions. Use analgesics, muscle relaxants, and local applications of ice packs, as needed. Avoid narcotic analgesia. Steroids may be used in severe cases, but do not appear to be as effective for controlling back/chest flares as other types of flares.
Flare-ups: (Limbs/throat/submandibular): Patients can present with inflammatory flare-ups with significant swelling and inflammation. These symptoms can be highly variable between patients and events. Prednisone – 2 mgs/kg once daily (up to 100 mgs daily) in AM (per oral) for four days (or equivalent corticosteroid); begin as early as possible after the onset of flare-up signs and symptoms. Keep prednisone on-hand as “pill-in-pocket” approach for emergencies. Alternatively, pulse IV steroids may be used as directed. Avoid corticosteroids, if possible, for axial flares. Use oral and/or topical NSAID analgesics and/or muscle relaxants, as needed, with assiduous GI precautions. Local application of cool packs may also be helpful. Avoid narcotic analgesia whenever possible. FOP experts should be consulted with all submandibular flare-ups and the detailed guidelines should be assiduously followed.
Flare-ups (Prophylaxis): Flare-ups often result from over-use and soft tissue injuries. Prednisone - 1-2 mgs/kg (per oral) once daily for 3-4 days can be given to prevent flare-up after severe soft-tissue injury. Do not use after minor bumps or bruises. Use prednisone prophylactically as directed for dental or surgical procedures.
Fractures: Fractures can occur in both normotopic and heterotopic bone, and usually heal normally without much heterotopic bone if treated conservatively. A brief course of prednisone is suggested. An FOP expert in fracture management should be consulted in all cases.
Gastrointestinal Issues: Many patients with FOP report frequent nausea and vomiting. The cause and significance of this is unknown. Gastrointestinal complaints should be investigated to rule-out more serious conditions. Significant weight loss or very low body mass index in the setting of severe scoliosis can be associated with bowel obstruction and superior mesenteric artery (SMA) syndrome. Treatment would include weight gain.
Hearing: Conductive hearing impairment is common in FOP. FOP patients should be screened in childhood by audiometry for hearing impairment. Hearing aids may improve severe conductive hearing loss.
Immunizations: Immunization by subcutaneous administration is recommended for all vaccines that can be administered by that route. Avoid all intramuscular immunizations and intra-nasal influenza immunizations with live as they may precipitate flare-ups of FOP. There have been no reported cases of flare-ups following subcutaneous immunization with the MMR or MMRV vaccines despite the fact that they contain attenuated viruses. Immunizations should not be given during flare-ups and should be avoided until 6-8 weeks after flare-ups resolve. All household contacts should be immunized against pertussis and COVID-19. Consult detailed immunization guidelines and updates on the ICC and IFOPA websites (www.iccfop.org & www.ifopa.org).
Influenza: Administer influenza vaccines subcutaneously, but never during flare-ups. Wait until 6-8 weeks after a flare-up has resolved before administering influenza vaccine. Avoid live attenuated flu vaccine as it may cause flu-like symptoms and precipitate flare-ups of FOP. Household contacts of FOP patients should be immunized annually. Consider anti-viral therapy if flu symptoms occur. Consult detailed influenza immunization guidelines as recommendations may change annually.
Injuries: The prevention of flare-ups and heterotopic bone formation involves multimodal approaches. This includes the recognition and avoidance of known causes of flare-ups (contact sports, soft tissue injuries, blunt muscle trauma, muscle fatigue, muscle stretching, intramuscular injections and immunizations, biopsies, removal of heterotopic bone, all non-emergent surgical procedures and viral illnesses).
IVs: Patients with FOP can tolerate peripheral blood collection and IVs when performed by an experienced phlebotomist. It is critical that the procedure be performed in as gentle and minimally-invasive manner as possible. Tourniquet time should be minimized. Consultation with clinicians who are familiar with the care of FOP patients is essential. Superficial IV access and venipuncture are acceptable. Traumatic IV’s must be avoided. Central lines, PICC lines, and arterial punctures may cause HO and should be avoided unless critical for the patient’s medical management.
Kidney Stones: There is a three-fold greater risk of kidney stones in FOP. Encourage fluid intake (preferably water) of 1.5-2 liters/day, and avoidance of high protein and high salt diets. Age- and sex-based recommended daily allowances for calcium should be maintained.
Limb Swelling: Lymphedema and transient neuropathy may occur with flare-ups of limbs. Elevate legs while sleeping and recumbent, whenever possible. Take one low-dose aspirin daily with food for deep venous thrombosis (DVT) prophylaxis, if indicated. Rule-out deep vein thrombosis with Doppler ultrasound. Use fitted support stockings for chronic lymphedema (but avoid traumatic compression). Lymphedema therapy may be helpful for chronic lymphedema.
Medications:
Corticosteroids
  1. Steroid prophylaxis is recommended for significant blunt muscle trauma, as prophylaxis for a potential flare or as treatment of an active flare. The usual recommended dose is prednisone 2 mg/kg/day x 4 days, with a maximum dose of 100 mg/day.
  1. Steroid prophylaxis is recommended for dental and surgical procedures.
  1. Steroid treatment should be considered for the symptomatic relief of emergent flare-ups of the limbs, jaw or submandibular area.
COX-2 Inhibitors & NSAIDs
There is no definitive evidence that chronic treatment with COX-2 inhibitors or NSAIDS prevents or ameliorates flare-ups in FOP. However, COX-2 inhibitors or oral/topical NSAIDS may be helpful for symptomatic management of flare-ups and chronic arthropathy when corticosteroids are not indicated.
Bisphosphonates
There is no definitive evidence that bisphosphonates prevent or ameliorate flare-ups in FOP. However, intravenous bisphosphonates may be considered for the prevention of steroid-associated bone loss. Dentists should be made aware of any prior bisphosphonate use. Bisphosphonates may be considered for treating osteoporosis of the native skeleton, as guided by standard of care.
Off-Label Medications (imatinib, tofacitinib, canakinumab, anakinra, etc.)
There is no definitive evidence that these medications prevent or ameliorate heterotopic ossification after flare-ups in FOP. These medications may be considered for patients with severe, intractable FOP flare-ups. See the ICC recommendations regarding off-label medication use.
Chemotherapy Agents & Radiation Therapy
There is no evidence of efficacy with these agents. The use of these approaches is contraindicated in the management of FOP.
Bone Marrow Transplantation
This approach is ineffective and contraindicated in the treatment of FOP.
Miscellaneous Agents in FOP
The chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, propranolol, mineralization inhibitors, PPAR-γ antagonists and TNF-α inhibitors currently have no role in the management of FOP.
Definitive Therapeutic Targets in FOP
Much of the worldwide collaborative research effort in FOP is focused here, and detailed accounts of the work and progress can be found on www.clinicaltrials.gov, in the Twenty-Ninth Annual Report of the FOP Collaborative Research Project (Kaplan, Al Mukaddam, Shore et al., 2024), as well as in recent reviews. Patients should be informed about ongoing clinical trials.
Approved Therapies in FOP
Palovarotene, an RAR-γ agonist, has been approved in the US, Canada, and Australia. Prescribing information can be found at: Microsoft Word - pi-mg-fda-comments-15aug2023-combined-rev 17Aug2023 (d2rkmuse97gwnh.cloudfront.net). Please see ICC statement on Palovarotene of August 16, 2023 (www.iccfop.org).
Mental Health: Patients with any chronic illness are at risk of mental health complications. If there is suspicion of depression, psychological support is recommended. Family therapy may be helpful.
Neurological Issues: Patients with FOP have reported a higher incidence of neurological symptoms including pain both during and remote from an FOP flare-up. The sources of pain should be carefully explored. Some individuals with FOP report chronic headaches. If headaches persist, patients should be referred to a neurologist, who can make recommendations for treatment.
Nutrition: In cases of ankylosis of the jaw, a dietician should be consulted to ensure adequate nutrition.
Occupational Therapy (OT): Occupational therapy, focused on enhancing activities of daily living may be useful to improve the quality of life of FOP patients. Perform periodic OT evaluations for assistive devices as activities of daily living change.
Orthodontics: Routine orthodontic care has not been reported to cause flare-ups of FOP. However, all FOP patients seeking orthodontic care should consult with an FOP dental expert.
Physical Therapy (PT): Passive range of motion is strictly prohibited. Warm water hydrotherapy may be helpful.
Pregnancy: Although pregnancy with FOP is possible, FOP poses major life-threatening risks to mother and child as well as life altering consequences to the entire family if a child is born with this condition. Pregnancy in FOP should never be undertaken without serious consideration and family planning. Unwanted pregnancies should be assiduously avoided. Independent genetic counseling is available, if desired. Should a pregnancy occur, guidance and care at a high-risk pregnancy center are imperative.
Pressure Ulcers: In patients with limited motion, prevention of pressure sores by appropriate methods or devices is recommended. A wound care team should be involved in the care.
Respiratory Health: Singing, swimming and incentive spirometry are encouraged to maintain lung function. Perform baseline pulmonary function tests (PFTs), echocardiogram, chest x-ray and pulse oximetry after four years of age. Repeat periodically. Pulmonary consultation and sleep studies may be helpful in directing specific respiratory therapies. Supplemental oxygen should not be used in an unmonitored setting. In patients with respiratory insufficiency, immunization for influenza and pneumococcal pneumonia should be considered. Please follow immunization guidelines above.
Scalp Nodules: Scalp nodules are common signs of flare-up, especially in children with FOP. Although they can be alarming in size, they often spontaneously regress and are of minimal clinical significance.
School: Use school aides to protect and assist children. Parents can request a medical letter for assistance. Preschool evaluation is helpful. School nurses, staff, and teachers should be aware of the limitations of FOP, and protocols for managing injuries and flare-ups as well as special adaptive needs.
Spinal Deformity: Spinal deformity is common in FOP and can occur independently of flare-ups. Rapid progression of spinal deformity – especially in childhood – should be evaluated by an expert in FOP.
Surgery: Avoid surgery, except in emergencies. Always avoid surgery to remove heterotopic bone.
Teeth: Preventative dental care is essential and should begin at an early age. Avoid sugary sweets and drinks. Avoid mandibular blocks, over-stretching of the jaw, and muscle fatigue. Consult FOP dental experts before any procedure.
References
Di Rocco M, Baujat G, Bertamino M, Brown M, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao E, Keen R, Morhart R, Pignolo RJ, Kaplan FS. International physician survey on management of FOP: a modified Delphi study. Orphanet J Rare Dis Jun 12;12(1):110, 2017
Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo R, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 85: 1199-1207, 2019

第三章. FOP的临床与基础科学背景

1. 引言

本章我们简要总结了FOP的临床与科学北京，以便将随后的治疗注意事项置于临床与科学的背景中。(Kaplan et al., 2008; Shore & Kaplan, 2010; Pignolo et al., 2013; Huning & Gillessen-Kaesbach, 2014; Kaplan et al., 2019).
参考文献
  1. Huning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: Clinical course, genetic mutations and genotype-phenotype correlations. Molec Syndromology 5: 201-211, 2014 FOP：临床研究、基因突变与基因型-表型的关联性• 10.1159/000365770
  1. Kaplan FS, Pignolo RJ, Al Mukaddam M, Shore EM. Genetic disorders of heterotopic ossification: fibrodysplasia ossificans progressiva and progressive osseous heteroplasia (chapter 112, pp. 865-870). In Bilezikian J (ed). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism Ninth Edition. The American Society for Bone and Mineral Research, Washington, D.C., 2019 遗传性异位骨化疾病：FOP和POH（第112章，第865-870页）• 10.1002/9781119266594.CH112
  1. Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008 进行性骨化性纤维发育不良（2008） • 10.1016/j.berh.2007.11.007
  1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10(S-2): 437-448, 2013 FOP：诊断、管理和治疗前景 NCBI - WWW Error Blocked Diagnostic
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  1. Shore EM, Kaplan FS. Inherited human disease of heterotopic bone formation. Nat Rev Rheumatol 6: 518527, 2010 形成异位骨骼的人类遗传性疾病 • 10.1038/nrrheum.2010.122
原文
  1. Introduction
      2. Here, we provide a brief summary of the clinical and scientific background of FOP in order to place the treatment considerations that follow into a clinical and scientific context. Comprehensive clinical reviews of FOP are available (Kaplan et al., 2008; Shore & Kaplan, 2010; Pignolo et al., 2013; Huning & Gillessen-Kaesbach, 2014; Kaplan et al., 2019).
      References
      Huning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: Clinical course, genetic mutations and genotype-phenotype correlations. Molec Syndromology 5: 201-211, 2014
      Kaplan FS, Pignolo RJ, Al Mukaddam M, Shore EM. Genetic disorders of heterotopic ossification: fibrodysplasia ossificans progressiva and progressive osseous heteroplasia (chapter 112, pp. 865-870). In Bilezikian J (ed). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism Ninth Edition. The American Society for Bone and Mineral Research, Washington, D.C., 2019
      Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008
      Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10(S-2): 437-448, 2013
      Shore EM, Kaplan FS. Inherited human disease of heterotopic bone formation. Nat Rev Rheumatol 6: 518527, 2010

2. FOP的经典临床特征

Fibrodysplasia ossificans progressiva (FOP: OMIM #135100) 进行性骨化性纤维发育不良 (FOP: OMIM #135100) 是一种超罕见的结缔组织遗传性疾病，其特征是大脚趾先天畸形，以及在解剖模式下特有的进行性异位骨化 (HO)(Kaplan et al., 2005; Pignolo et al., 2019)。
FOP患者在出生时，除了所有经典型FOP患者都存在的大脚趾畸形特征，其他看起来都是正常的(Kaplan et al., 2005; Towler, Kaplan, Shore, 2020; Towler, Peck, Kaplan, Shore, 2021)。在患者生命中的第一个十年里，绝大部分的FOP儿童病情会间歇性发展，伴随疼痛的炎性软组织肿胀（称为：急性发作）(Cohen et al., 1993; Pignolo et al., 2016)。这种疾病经常会被误诊为肿瘤。普遍存在误诊和较高的医源性伤害(Kitterman et al., 2005; Zaghloul et al., 2008)。
虽然一些急性发作症状会自然消退，但大多数情况下会将软组织转化为成熟的异位骨骼，软组织如：腱膜、筋膜、韧带、肌腱和骨骼肌。带状、片状和板状结构的异位骨通过一种软骨内成骨（endochondral ossification）的过程，取代了骨骼肌和结缔组织，这导致身体像被用骨头制造的盔甲所包裹，将永远被固定住。轻微的创伤，如：肌肉注射的免疫接种，牙科操作后的下颌活动限制，肌肉疲劳，磕碰肌肉造成的钝性创伤，瘀伤，摔倒，或类似流感一样的病毒性疾病，都会触发新的痛性FOP急性发作，进而向进行性异位骨化（HO）发展。若尝试用手术移除异位骨骼，通常会激起剧烈的爆发，并伴随痛苦的新骨生长(Kaplan et al., 2005)。
在典型的解剖模式和以随着年龄增长的模式下，一般首次发生在背部，身体轴向(以脊柱为中心)，头顶，身体中央区域，后期会发生在腹部，四肢，身体尾端和趾端部位。当前，研究人员注意到FOP的异位骨化进程清晰可辨，但无法解释其空间和时间发展模式与人类身体的精确温度梯度分布相关。FOP的成因是一种激活素A受体I型 (ACVR1/ALK2)中的致病功能获得型基因突变所致，它编译一种骨形态发生蛋白（BMP）I型受体激酶。
与所有酶一样，ACVR1的活性与温度有关。研究者假设结缔组织祖细胞(CTPCs)，表达常见的杂合子ACVR1 R206H的突变与对照组的CTPC 相比表现出失调的温度反应，并且FOP的结缔组织祖细胞(CTPCs)在身体组织各处，对异位骨化的启动和维持起到了决定作用，在一定程度上，起到了FOP异位骨化的组织学分配的作用。从FOP患者和未收影响的对照组体内分离出的初代结缔组织祖细胞，在生理温度的范围下比较了骨形态发生蛋白（BMP）信号通路的信号传导。FOP患者的结缔组织祖细胞（CTPCs）中，骨形态发生蛋白（BMP）信号通路的活性，以及由此导致的软骨生成（chondrogenesis）相较于健康对照组的CTPCs明显增强，且这一结果具有统计学意义（p < 0.05）。FOP中异位骨化的解剖学分布，可能部分是由于FOP患者结缔组织祖细胞（CTPCs）对温度反应的调节异常所致，这种异常反应与身体的特定解剖位置相关。尽管温度梯度与FOP中的异位骨化的空间分布之间的关联，并不能证明其因果关系，但是这些发现为FOP中异位骨化的解剖学分布的生理学基础提供了一个范例，并揭示了一个潜在的新兴治疗靶点，可以为FOP的治疗提供新的思路(Wang et al., 2021)。
肢体的急性发作经常伴随剧烈的疼痛，通常会被归因于间室综合征（compartment syndrome）(Kaplan et al., 2020)。在FOP的急性发作期间，有一个独特的病例记录了间室综合征的发生(Kaplan et al., 2020)。
在一项关于FOP的大规模前瞻性的国籍自然历史研究中，对年龄在65岁及以下且具有经典型FOP特征的个体进行了基线评估，并且在随后的36个月内进行了追踪。在这项自然历史研究中，接受标准护理的个体在长达3年的观察结果呈现了FOP的严重影响和逐步进展的特性，而且这种进展在儿童和成年的早期尤为明显(Pignolo et al., 2022)。
在FOP中，包括膈肌、舌头在内的肌肉和眼外肌在内的几种骨骼肌，并不会受到异位骨化的影响。心肌和平滑肌在FOP中也明显不会受到异位骨化的影响(Cohen et al., 1993; Kaplan et al., 2005; Pignolo et al., 2018)。
FOP中的异位骨化是间歇性发生的，但是由此导致的残疾是累积性的。大部分FOP患者在30岁左右时会被迫使用轮椅，并且在日常生活中需要终身帮助(Cohen et al., 1993; Rocke et al., 1994; Kaplan et al., 2018a; Kaplan et al., 2018b)。下颌关节的强直可能导致体重骤降。由于肋椎关节的发育性关节病和胸壁的异位骨化，严重的限制性胸壁疾病和肺功能会在早期出现(Towler, Shore, Kaplan, 2020; Botman et al., 2021)。胸壁的刚性固定可能会导致肺炎或右侧心力衰竭等并发症。FOP的严重残疾会导致生育能力低下。全球已知可见的FOP子代遗传的多代家庭至少有十个。FOP患者中的中位死亡年龄约为40岁， 但是中位预期寿命为56岁。死亡通常是由于胸腔功能不全综合征和肺炎的并发症所致(Kaplan et al., 2010)。
一个全球范围内的患者报告登记系统已经建立，用于描述进行性骨化性纤维发育不良（FOP）的疾病过程，并追踪患者的临床结果。根据来自于54个国家的299名患者的基础表型数据，这些数据是基于国际FOP协会（IFOPA）全球登记系统（即“FOP登记系统”）的汇总信息。总体而言，FOP登记系统数据库为扩展对FOP的认识、设计临床试验以及促进基于证据的决策提供了有用的工具，以优化对受影响个体的监测和管理(Pignolo et al., 2020)。
参考文献
  1. Botman E, Smilde BJ, Hoebink M, Treurniet S, Raijmakers P, Kamp O, Teunissen BP, Bökenkamp A, Jak P, Lammertsma AA, van den Aardweg JG, Boonstra A, Eekhoff EMW. Deterioration of pulmonary function: An early complication in Fibrodysplasia Ossificans Progressiva. Bone Rep 2021 Feb 25;14:100758 肺功能恶化：FOP的早期并发症 • 10.1016/j.bonr.2021.100758
  1. Cohen RB, Hahn GV, Tabas J, Peeper J, Levitz CL, Sando A, Sando N, Zasloff M, Kaplan FS. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75: 215-219, 1993 FOP患者异位骨化的自然病程 • 10.2106/00004623-199302000-00008
  1. Kaplan FS, Glaser DL, Shore EM, Deirmengian GK, Gupta R, Delai P, Morhart P, Smith R, Le Merrer M, Rogers JG, Connor JM, Kitterman JA. The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 183-188, 2005 进行性骨化性纤维发育不良的表型 • 10.1385/BMM:3:3-4:183
  1. Kaplan FS, Zasloff MA, Kitterman JA. Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 92: 686-691, 2010 FOP患者的早期死亡率和心肺功能衰竭 • 10.2106/JBJS.I.00705
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale for fibrodysplasia ossificans progressiva (FOP). Bone 101: 123-128, 2018a FOP的累积模拟关节受累量表(CAJIS) • 10.1016/j.bone.2017.04.015
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP). Bone 109: 150-161, 2018b FOP患者纵向自我报告的运动能力评估 • 10.1016/j.bone.2017.06.005
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. Compartment syndrome of the thigh in a patient with fibrodysplasia ossificans progressiva. J Orthopaedic Case Reports 10: 103-107, 2020 FOP患者的大腿筋膜室综合征 • 10.13107/jocr.2020.v10.i03.1770
  1. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: 654-661, 2005 由误诊导致的FOP医源性损害 • 10.1542/peds.2005-0469
  1. Pignolo RJ, Baujat G, Brown MA, De Cunto C, Di Rocco M, Hsiao EC, Keen R, Al Mukaddam M, Sang KLQ, Wilson A, White B, Grogan DR, Kaplan FS. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis 2019 May 3;14(1):98 FOP的自然病程：注解版基线表型的横断面分析 • 10.1186/s13023-019-1068-7
  1. Pignolo RJ, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Al Mukaddam M, Le Quan Sang KH, Wilson A, Marino R, Strahs A, Kaplan FS. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genet Med 24:2422-2433, 2022 FOP的自然病程：一项全球前瞻性的36个月研究 • 10.1016/j.gim.2022.08.013
  1. Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016 FOP急性发作的自然病史：一项综合性全球评估 • 10.1002/jbmr.2728
  1. Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint-specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 109: 124-133, 2018 FOP中关节特异性功能受损的风险 • 10.1016/j.bone.2017.06.009
  1. Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, De Cunto C, Al Mukaddam M, Hsiao EC, Baujat G, Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z, Haga N, Keen R, Levi B, Morhart R, Scott C, Sherman A, Zhang K, Kaplan FS. Self-reported baseline phenotypes from the international fibrodysplasia ossificans progressiva (FOP) association global registry. Bone 2020 May;134:115274 来自IFOPA（国际FOP协会）全球注册系统的自我评估基线表型 • 10.1016/j.bone.2020.115274
  1. Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 301: 243-248, 1994 FOP患者早期异位骨化的年龄和关节特异性风险 • 10.1097/00003086-199404000-00038
  1. Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116 FOP患者的骨骼畸形和发育性关节病 • 10.1016/j.bone.2019.115116
  1. Towler OW, Kaplan FS, Shore EM. The developmental phenotype of the great toe in fibrodysplasia ossificans progressiva. Front Cell Dev Biol 2020 Dec 8;8:612853 FOP患者大脚趾的发育表型 • 10.3389/fcell.2020.612853
  1. Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021 由于ACVR1的BMP信号失调阻碍了FOP的趾关节发育 • 10.1016/j.ydbio.2020.11.004
  1. Wang H, De Cunto CL, Pignolo RJ, Kaplan FS. Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients. Bone 149:115978, 2021 FOP异位骨化的空间模式与组织温度梯度相关 • 10.1016/j.bone.2021.115978
  1. Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB. Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neursurg Pediatrics 1: 91-94, 2008 对一名未诊断的FOP儿童进行腰椎穿刺和外科手术 • 10.3171/PED-08/01/091
多爸笔记
软骨内成骨（endochondral ossification）：
Endochondral ossification（软骨内成骨）是骨骼发育的一种过程，在这一过程中，软骨逐渐被骨组织替代，形成成熟的骨骼结构。它是长骨（如四肢骨骼）和一些短骨的主要发育方式，尤其在胚胎发育和儿童生长期非常重要。
具体过程如下：
  1. 软骨模型形成：在胚胎阶段，先形成由透明软骨组成的“骨骼原型”或软骨模型。
  1. 软骨增生：软骨细胞（软骨细胞或软骨母细胞）在这个软骨模型中增殖，软骨增厚和延长。
  1. 软骨钙化：随着发育进行，软骨细胞开始经历钙化，即软骨基质中沉积钙盐，软骨细胞逐渐死亡，留下钙化的基质。
  1. 骨骼侵入：血管侵入钙化区域，带来骨祖细胞和破骨细胞。骨祖细胞分化为成骨细胞，开始在软骨基质上沉积新生骨组织。
  1. 骨化中心形成：在长骨中，首先在骨干（中间）形成原发性骨化中心，然后在骨骺（骨端）形成次级骨化中心。
  1. 骨骼延长和成熟：在儿童和青少年中，骨骼继续通过软骨生长区（骨骺板）的增殖和骨化来延长，直到骨骺板完全闭合，停止生长。
总之，软骨内成骨是通过软骨模型作为临时模板，逐步转化为坚硬骨组织的过程。
原文
  1. Classic Clinical Features of FOP
      2. Fibrodysplasia ossificans progressiva (FOP: OMIM #135100) is an ultra-rare heritable disorder of connective tissue characterized by congenital malformations of the great toes, and progressive heterotopic ossification (HO) in characteristic anatomic patterns (Kaplan et al., 2005; Pignolo et al., 2019).
      Individuals with FOP appear normal at birth except for characteristic malformations of the great toes that are present in all classically affected individuals (Kaplan et al., 2005; Towler, Kaplan, Shore, 2020; Towler, Peck, Kaplan, Shore, 2021). During the first decade of life, most children with FOP develop episodic, painful inflammatory soft tissue swellings (called flare-ups) (Cohen et al., 1993; Pignolo et al., 2016). These are often mistaken for tumors. Misdiagnosis is common and iatrogenic harm is high (Kitterman et al., 2005; Zaghloul et al., 2008).
      While some flare-ups regress spontaneously, most transform soft connective tissues - including aponeuroses, fascia, ligaments, tendons, and skeletal muscles - into mature heterotopic bone. Ribbons, sheets, and plates of heterotopic bone replace skeletal muscles and connective tissues through a process of endochondral ossification that leads to an armament-like encasement of bone and permanent immobility. Minor trauma such as intramuscular immunizations, mandibular blocks for dental work, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses can trigger painful new flare-ups of FOP leading to progressive HO. Attempts to surgically remove heterotopic bone often provoke explosive and painful new episodes of bone growth (Kaplan et al., 2005).
      FOP HO progresses in characteristic anatomic and temporal patterns with age, typically first occurring in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions. Recently, investigators noticed that HO in FOP progresses in well-defined but unexplained spatial and temporal patterns that correlate precisely with infrared thermographs of the human body. FOP is caused by gain-of-function pathogenic variants in Activin A receptor type I (ACVR1/ALK2), encoding a bone morphogenetic protein (BMP) type I receptor kinase.
      As with all enzymes, the activity of ACVR1 is temperature dependent. Investigators hypothesized that connective tissue progenitor cells (CTPCs) that express the common heterozygous ACVR1 R206H variant exhibit a dysregulated temperature response compared to control CTPCs and that the temperature of FOP CTPCs that initiate and sustain HO at various anatomic sites determines, in part, the anatomic distribution of HO in FOP. BMP pathway signaling was compared at a range of physiologic temperatures in primary CTPCs isolated from FOP patients and unaffected controls. BMP pathway signaling and resultant chondrogenesis were amplified in FOP CTPCs compared to control CTPCs (p < 0.05). Thus, the anatomic distribution of HO in FOP may be due, in part, to a dysregulated temperature response in FOP CTPCs that reflect anatomic location. While the association of temperature gradients with spatial patterns of HO in FOP does not demonstrate causality, the findings provide a paradigm for the physiologic basis of the anatomic distribution of HO in FOP and unveil a novel therapeutic target that might be exploited for FOP (Wang et al., 2021).
      The severe pain that commonly accompanies appendicular flare-ups is often ascribed to compartment syndrome (Kaplan et al., 2020). A unique case documented compartment syndrome during an acute flare-up of FOP (Kaplan et al., 2020).
      In a large prospective, international, natural history study on FOP, individuals aged ≤65 years with classic FOP (ACVR1 R206H variant) were assessed at baseline and over 36 months. Results from individuals receiving standard care for up to 3 years in this natural history study showed the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood (Pignolo et al., 2022).
      Several skeletal muscles including the diaphragm, intrinsic muscles of the tongue, and extra-ocular muscles are spared from HO in FOP. Cardiac muscle and smooth muscle are also notably spared from HO (Cohen et al., 1993; Kaplan et al., 2005; Pignolo et al., 2018).
      HO in FOP is episodic, but disability is cumulative. Most patients with FOP are confined to a wheelchair by the third decade of life and require lifelong assistance in performing activities of daily living (Cohen et al., 1993; Rocke et al., 1994; Kaplan et al., 2018a; Kaplan et al., 2018b). Severe weight loss may result following ankylosis of the jaw. Severe restrictive chest wall disease and decrease in pulmonary function due to developmental arthropathy of the costo-vertebral joints and heterotopic ossification of the chest wall develops early (Towler, Shore, Kaplan, 2020; Botman et al., 2021). Pneumonia or right-sided heart failure may complicate rigid fixation of the chest wall. The severe disability of FOP results in low reproductive fitness. Fewer than ten multigenerational families showing inheritance of FOP are known worldwide. The median age at death is approximately 40 years, but the median estimated life expectancy is 56 years. Death often results from complications of thoracic insufficiency syndrome or pneumonia (Kaplan et al., 2010).
      A global, patient-reported registry has been established to characterize the course of disease and track clinical outcomes in patients with FOP. Baseline phenotypes on 299 patients from 54 countries are reported based on aggregate data from the International FOP Association (IFOPA) Global Registry (the "FOP Registry"). Overall, the FOP Registry database provides a useful tool for expanding knowledge of FOP, designing clinical trials and facilitating evidence-based decisions about the optimal monitoring and management of affected individuals (Pignolo et al., 2020).
      References
      Botman E, Smilde BJ, Hoebink M, Treurniet S, Raijmakers P, Kamp O, Teunissen BP, Bökenkamp A, Jak P, Lammertsma AA, van den Aardweg JG, Boonstra A, Eekhoff EMW. Deterioration of pulmonary function: An early complication in Fibrodysplasia Ossificans Progressiva. Bone Rep 2021 Feb 25;14:100758
      Cohen RB, Hahn GV, Tabas J, Peeper J, Levitz CL, Sando A, Sando N, Zasloff M, Kaplan FS. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75: 215-219, 1993
      Kaplan FS, Glaser DL, Shore EM, Deirmengian GK, Gupta R, Delai P, Morhart P, Smith R, Le Merrer M, Rogers JG, Connor JM, Kitterman JA. The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 183-188, 2005
      Kaplan FS, Zasloff MA, Kitterman JA. Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 92: 686-691, 2010
      Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale for fibrodysplasia ossificans progressiva (FOP). Bone 101: 123-128, 2018a
      Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP). Bone 109: 150-161, 2018b
      Kaplan FS, Al Mukaddam M, Pignolo RJ. Compartment syndrome of the thigh in a patient with fibrodysplasia ossificans progressiva. J Orthopaedic Case Reports 10: 103-107, 2020
      Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: 654-661, 2005
      Pignolo RJ, Baujat G, Brown MA, De Cunto C, Di Rocco M, Hsiao EC, Keen R, Al Mukaddam M, Sang KLQ, Wilson A, White B, Grogan DR, Kaplan FS. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis 2019 May 3;14(1):98
      Pignolo RJ, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Al Mukaddam M, Le Quan Sang KH, Wilson A, Marino R, Strahs A, Kaplan FS. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genet Med 24:2422-2433, 2022
      Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016
      Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint -specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 109: 124-133, 2018
      Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, De Cunto C, Al Mukaddam M, Hsiao EC, Baujat G, Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z, Haga N, Keen R, Levi B, Morhart R, Scott C, Sherman A, Zhang K, Kaplan FS. Self-reported baseline phenotypes from the international fibrodysplasia ossificans progressiva (FOP) association global registry. Bone 2020 May;134:115274
      Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 301: 243-248, 1994
      Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116
      Towler OW, Kaplan FS, Shore EM. The developmental phenotype of the great toe in fibrodysplasia ossificans progressiva. Front Cell Dev Biol 2020 Dec 8;8:612853
      Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021
      Wang H, De Cunto CL, Pignolo RJ, Kaplan FS. Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients. Bone 149:115978, 2021
      Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB. Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neursurg Pediatrics 1: 91-94, 2008

3. FOP的其他骨骼异常

虽然大脚趾的畸形是进行性骨化性纤维发育不良（FOP）的特征，但其他发育异常也常被观察到。FOP中的致病性ACVR1受体对诱导非骨骼骨形成有明显影响。然而，这个BMP信号通路的受体在骨骼发育中广泛表达，并在轴向和附肢软骨生成中起着重要作用，这引发了对ACVR1突变者普遍存在骨骼和关节缺陷的怀疑(Towler et al., 2020)。
在所有年龄段的进行性骨化性纤维发育不良（FOP）患者中，广泛存在轴向和附肢骨骼的发育性关节病。在所有年龄段的进行性骨化性纤维发育不良（FOP）患者的正常位置骨骼的关节中，普遍存在不对称性狭窄和软骨内硬化，同时，髋关节和膝关节常见有骨刺的形成。肋椎关节、椎间面关节和近端胫腓关节在FOP患者中经常出现部分或完全的关节内强直，尤其是在13岁之后更为明显。进行性骨化性纤维发育不良（FOP）患者的髋关节常常出现畸形和发育不良，具体表现为股骨颈短而宽、骨骼生长板小，以及关节内存在滑膜骨软骨瘤。在13岁之后，尤其是在脊柱、骶髂关节和下肢，有证据表明出现了退行性关节表型(Towler et al., 2020)。
因此，ACVR1突变对进行性骨化性纤维发育不良（FOP）患者的正常位置骨骼的影响不仅限于大脚趾的畸形，还包括形态缺陷和发育性关节病。伴随的退行性关节病在多个部位出现，从青春期开始并持续进展至一生。这些表型似乎与异位骨形成无关，这表明ACVR1在退行性关节病的发展和进展中可能发挥作用(Towler et al., 2020)。
因此，进行性骨化性纤维发育不良（FOP）不仅是一种进行性异位骨化的疾病，还包括广泛而严重的发育性关节病和相关的退行性关节病。这些发现对于理解进行性骨化性纤维发育不良（FOP）的自然历史，以及设计和评估新兴治疗方法的临床试验具有重要意义(Towler et al., 2020; Kaplan et al., 2020; Pignolo et al., 2020)。
颈部的僵硬是大多数患者的早期表现，且可以在该部位的异位骨化（HO）出现之前就发生。颈椎的特征性异常包括大的后部结构、高而窄的椎体，以及C2到C7之间椎间关节的可变性融合(Schaffer et al., 2005)。尽管颈椎在生命早期通常会发生强直（融合），但即使是微小的残余运动也可能最终导致慢性头痛和疼痛的关节炎症状。
与进行性骨化性纤维发育不良（FOP）相关的其他骨骼异常包括短小且畸形的拇指，伴有指间关节融合、弯指畸形、颞下颌关节畸形、可变且常常不对称的肋椎关节和肋横关节融合、短而宽的股骨颈，以及骨软骨瘤，尤其是在胫骨和股骨的内侧近端，但在正常骨骼中也可能存在不同程度的表现(Deirmengian et al., 2008; Kaplan et al., 2009; Bauer et al., 2018; Kaplan et al., 2018; Towler et al., 2020)。常常可以观察到一种共同的面部特征(Hammond et al., 2012)。
总之，进行性骨化性纤维发育不良（FOP）患者常常会出现多种骨骼异常和关节畸形，以下平片可以帮助快速的表型筛查和临床诊断：
  • 双手的前后位（AP）
  • 双脚的前后位（AP）
  • 颈椎的侧位片
  • 胸部的前后位（AP）和侧位片
  • 骨盆的前后位（AP）
  • 双膝的前后位（AP）和侧位片
参考文献
  1. Bauer AH, Bonham J, Gutierrez L, Hsiao EC, Motamedi D. Fibrodysplasia ossificans progressiva: a current review of imaging findings. Skeletal Radiol 47: 1043-1050, 2018 FOP：影像学发现的当前综述 • 10.1007/s00256-018-2889-5
  1. Deirmengian GK, Hebela NM, O’Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 90: 366374, 2008 FOP患者的胫骨近端骨软骨瘤 • 10.2106/JBJS.G.00774
  1. Hammond P, Suttie M, Hennekam RC, Allanson J, Shore EM, Kaplan FS. The face signature of fibrodysplasia ossificans progressiva. Am J Med Genet 158A: 1368-1380, 2012 FOP患者的面部特征 • 10.1002/ajmg.a.35346
  1. Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009 经典和非典型FOP表型由BMP I型受体ACVR1的突变引起 • 10.1002/humu.20868
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva. Bone 109: 115-119, 2018 FOP患者单方面的急性髋部疼痛 • 10.1016/j.bone.2017.08.009
  1. Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM. Fibrodysplasia ossificans progressiva: a disorder of osteochondrogenesis. Bone 2020 Jul;140:115539 FOP：一种骨和软骨形成过程的障碍 • 10.1016/j.bone.2020.115539
  1. Pignolo RJ, Wang H, Kapan FS. Fibrodysplasia ossificans progressiva (FOP): A segmental progeroid syndrome. Front Endocrinol (Lausanne) 2020 Jan 10;10:908 FOP：一种局部性表现的早衰综合征 • 10.3389/fendo.2019.00908
  1. Schaffer AA, Kaplan FS, Tracy MR, O’Brien ML, Dormans JP, Shore EM, Harland RM, Kusumi K. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome. Spine 30: 1379-1385, 2005 FOP患者的颈椎发育异常与Klippel-Feil（颈椎融合）综合征患者的显著不同 • 10.1097/01.brs.0000166619.22832.2c
  1. Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116 FOP患者的骨骼畸形和发育性关节病 • 10.1016/j.bone.2019.115116
原文
  1. Other Skeletal Anomalies of FOP
      2. While malformations of the great toes are characteristic of FOP, other developmental anomalies are frequently observed. The pathogenic ACVR1 receptor in FOP has a clear effect on the induction of extraskeletal bone formation. However, this BMP pathway receptor is expressed widely throughout skeletal development and has a seminal role in axial and appendicular chondrogenesis, prompting suspicion of widespread bone and joint defects in those with ACVR1 mutations (Towler et al., 2020).
      There is widespread evidence for developmental arthropathy throughout the axial and appendicular skeleton at all ages in individuals with FOP. Asymmetric narrowing and subchondral sclerosis are present throughout the joints of the normotopic skeleton and osteophytes are common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints, and proximal tibio-fibular joints frequently show partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic with short and wide femoral necks, small growth plates and intra-articular synovial osteochondromas. There is also evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacroiliac joints, and lower limbs (Towler et al., 2020).
      Thus, the effects of the ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease (Towler et al., 2020).
      Thus, FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics (Towler et al., 2020; Kaplan et al., 2020; Pignolo et al., 2020).
      Stiffness of the neck is an early finding in most patients and can precede the appearance of HO at that site. Characteristic anomalies of the cervical spine include large posterior elements, tall narrow vertebral bodies, and variable fusion of the facet joints between C2 and C7 (Schaffer et al., 2005). Although the cervical spine often becomes ankylosed early in life, any minimal residual movement may eventually result in chronic headaches and painful arthritic symptoms.
      Other skeletal anomalies associated with FOP include short malformed thumbs with interphalangeal joint fusion, clinodactyly, malformation of the temporomandibular joints, variable and often asymmetric fusions of the costovertebral and costotransverse joints, short broad femoral necks, and osteochondromas, most notably of the proximal medial tibias and femurs, but variably present throughout the normotopic skeleton (Deirmengian et al., 2008; Kaplan et al., 2009; Bauer et al., 2018; Kaplan et al., 2018; Towler et al., 2020). A common face signature is often noted (Hammond et al., 2012).
      In summary, multiple skeletal abnormalities and joint malformations are often seen in individuals with FOP, and the following plain radiographs can aid in rapid phenotypic screening and clinical diagnosis:
      • Anterior-Posterior (AP) of hands
      • AP of both feet
      • Lateral of cervical spine
      • AP & lateral of chest
      • AP of pelvis
      • AP & lateral of both knees
      References
      Bauer AH, Bonham J, Gutierrez L, Hsiao EC, Motamedi D. Fibrodysplasia ossificans progressiva: a current review of imaging findings. Skeletal Radiol 47: 1043-1050, 2018
      Deirmengian GK, Hebela NM, O’Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 90: 366374, 2008
      Hammond P, Suttie M, Hennekam RC, Allanson J, Shore EM, Kaplan FS. The face signature of fibrodysplasia ossificans progressiva. Am J Med Genet 158A: 1368-1380, 2012
      Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009
      Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva. Bone 109: 115-119, 2018
      Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM. Fibrodysplasia ossificans progressiva: a disorder of osteochondrogenesis. Bone 2020 Jul;140:115539
      Pignolo RJ, Wang H, Kapan FS. Fibrodysplasia ossificans progressiva (FOP): A segmental progeroid syndrome. Front Endocrinol (Lausanne) 2020 Jan 10;10:908
      Schaffer AA, Kaplan FS, Tracy MR, O’Brien ML, Dormans JP, Shore EM, Harland RM, Kusumi K. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome. Spine 30: 1379-1385, 2005
      Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116
 

4. FOP的放射学特征

对进行性骨化性纤维发育不良（FOP）中异位骨的放射学评估显示正常的建模和重塑[5]。患有进行性骨化性纤维发育不良（FOP）的人由于摔倒风险增加、活动能力受限以及使用泼尼松而面临正常骨骼和异位骨骼骨折的风险增加[7]。在进行性骨化性纤维发育不良（FOP）患者中，骨折似乎能够正常愈合。在传统X光片检测到异位骨（HO）之前，骨扫描会显示异常[5, 6]。早期病变的计算机断层扫描、磁共振成像和18F-NaF正电子发射断层扫描（PET）已被描述[2, 3, 4]。虽然这些评估方法在诊断上通常是多余的，但它们可以为疾病过程提供有用的研究视角，并正在被纳入现代临床试验中的评估方案中，进行各种定量评估[8, 1, 4]。进行性骨化性纤维发育不良（FOP）的临床诊断可以通过简单的临床评估来完成，这种评估将快速出现的软组织病变与大脚趾的畸形联系起来。
参考文献
  1. Al Mukaddam M, Rajapakse CS, Pignolo RJ, Kaplan FS, Smith SE. Imaging assessment in fibrodysplasia ossificans progressiva: Qualitative, quantitative and questionable. Bone 109: 147-152, 2018 影像评估在FOP中的应用：定性、定量与疑难问题 • 10.1016/j.bone.2017.08.011
  1. Botman E, Raijmakers PGHM, Yaqub M, Teunissen B, Netelenbos C, Lubbers W, Schwarte LA, Micha D, Bravenboer N, Schoenmaker T, de Vries TJ, Pals G, Smit JM, Koolwijk P, Trotter DG, Lammertsma AA, Eekhoff EMW. Evolution of heterotopic bone in fibrodysplasia ossificans progressiva: An [(18)F]NaF PET/CT study. Bone 124: 1-6, 2019 FOP中的异位骨演变：一项[(18)F]NaF PET/CT研究 • 10.1016/j.bone.2019.03.009
  1. Botman E, Teunissen BP, Raijmakers P, de Graaf P, Yaqub M, Treurniet S, Schoenmaker T, Bravenboer N, Micha D, Pals G, Bökenkamp A, Netelenbos JC, Lammertsma AA, Eekhoff EM. Diagnostic value of magnetic resonance imaging in fibrodysplasia ossificans progressiva. JBMR Plus 2020 Apr 28;4(6):e10363 核磁共振（MRI）成像在FOP中的诊断价值 • 10.1002/jbm4.10363
  1. Eekhoff EMW, Botman E, Coen Netelenbos J, de Graaf P, Bravenboer N, Micha D, Pals G, de Vries TJ, Schoenmaker T, Hoebink M, Lammertsma AA, Raijmakers PGHM. [18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva. Bone 109: 143-146, 2018 [18F]NaF PET/CT扫描作为FOP中异位骨化的早期指标 • 10.1016/j.bone.2017.08.012
  1. Kaplan FS, Strear CM, Zasloff MA. Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva. Clin Orthop 304: 238247, 1994 FOP患者的异位骨骼中，建模和重塑的X光影像与核放射性成像的特征 • 10.1097/00003086-199407000-00037
  1. Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva. Pediatr Radiol 31: 307-314, 2001 进行性骨化性纤维发育不良（Mahboubi-2001）• 10.1007/s002470100447
  1. Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016 FOP急性发作的自然病史：一项综合性全球评估 • 10.1002/jbmr.2728
  1. Rajapakse CS, Lindborg C, Wang H, Newman BT, Kobe EA, Chang G, Shore EM, Kaplan FS, Pignolo RJ. Analog method for radiographic assessment of heterotopic bone in fibrodysplasia ossificans progressiva. Acad Radiol 24: 321-327, 2017 用于评估FOP中异位骨骼的放射学类比方法 • 10.1016/j.acra.2016.10.010
原文
  1. Radiographic Features of FOP
      2. Radiographic evaluation of heterotopic bone in FOP shows normal modeling and remodeling (Kaplan et al., 1994). Individuals with FOP are at increased risk of fractures of both the normotopic and heterotopic skeleton due to the increased risk of falls, immobility and prednisone use (Pignolo et al., 2016). Fractures appear to heal normally in FOP. Bone scans are abnormal before HO can be detected by conventional radiographs (Kaplan et al., 1994; Mahboubi et al., 2001). Computed tomography, magnetic resonance imaging, and 18 F-NaF Positron Emission Tomography (PET) scans of early lesions have been described (Eekhoff et al., 2018; Botman et al., 2019; Botman et al., 2020). While these evaluation methods are generally superfluous from a diagnostic standpoint, they can provide a useful research perspective of the disease process and are being incorporated into evaluation schemes in contemporary clinical trials with various quantitative assessments (Rajapakse et al., 2017; Al Mukaddam et al., 2018; Eekhoff et al., 2018). The clinical diagnosis of FOP can be made by simple clinical evaluation that associates rapidly appearing soft tissue lesions with malformations of the great toes.
      References
      Al Mukaddam M, Rajapakse CS, Pignolo RJ, Kaplan FS, Smith SE. Imaging assessment in fibrodysplasia ossificans progressiva: Qualitative, quantitative and questionable. Bone 109: 147-152, 2018
      Botman E, Raijmakers PGHM, Yaqub M, Teunissen B, Netelenbos C, Lubbers W, Schwarte LA, Micha D, Bravenboer N, Schoenmaker T, de Vries TJ, Pals G, Smit JM, Koolwijk P, Trotter DG, Lammertsma AA, Eekhoff EMW. Evolution of heterotopic bone in fibrodysplasia ossificans progressiva: An [(18)F]NaF PET/CT study. Bone 124: 1-6, 2019
      Botman E, Teunissen BP, Raijmakers P, de Graaf P, Yaqub M, Treurniet S, Schoenmaker T, Bravenboer N, Micha D, Pals G, Bökenkamp A, Netelenbos JC, Lammertsma AA, Eekhoff EM. Diagnostic value of magnetic resonance imaging in fibrodysplasia ossificans progressiva. JBMR Plus 2020 Apr 28;4(6):e10363
      Eekhoff EMW, Botman E, Coen Netelenbos J, de Graaf P, Bravenboer N, Micha D, Pals G, de Vries TJ, Schoenmaker T, Hoebink M, Lammertsma AA, Raijmakers PGHM. [18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva. Bone 109: 143-146, 2018
      Kaplan FS, Strear CM, Zasloff MA. Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva. Clin Orthop 304: 238247, 1994
      Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva. Pediatr Radiol 31: 307-314, 2001
      Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016
      Rajapakse CS, Lindborg C, Wang H, Newman BT, Kobe EA, Chang G, Shore EM, Kaplan FS, Pignolo RJ. Analog method for radiographic assessment of heterotopic bone in fibrodysplasia ossificans progressiva. Acad Radiol 24: 321-327, 2017

5. FOP病变的病理学

早期的非骨化性进行性骨化性纤维发育不良（FOP）病变由大量的单核炎症细胞聚集而成，这些细胞包括淋巴细胞、巨噬细胞和肥大细胞，主要集中在水肿肌肉的血管周围空间。肥大细胞、巨噬细胞和细胞缺氧在进行性骨化性纤维发育不良（FOP）病变的生成中发挥直接作用。在肌肉细胞死亡后的分解代谢阶段，接着是一个高度合成代谢的纤维增生阶段（常常被误认为是侵袭性幼年纤维瘤），这个阶段部分由Sca1+/PDGFRα+/Tie2+/CD34- 纤维脂肪前体（FAP）细胞组成，这些细胞通过内软骨化途径分化为成熟的异位骨。
参考文献
  1. Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of Mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018 减少肥大细胞和巨噬细胞对FOP（ACVR1 R206H）小鼠模型异位骨化的影响 • 10.1002/jbmr.3304
  1. Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva (FOP). Hum Pathol 32: 842-848, 2001 肥大细胞在进行性骨化性纤维发育不良（FOP）中的作用 • 10.1053/HUPA.2001.26464
  1. Gannon FH, Valentine BA, Shore EM, Zasloff MA, Kaplan FS. Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop 346: 19-25, 1998 在FOP的极早期病变中发现急性淋巴细胞浸润 • 10.1097/00003086-199801000-00005
  1. Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG, Hematopoietic stem cell contribution to ectopic skeletogenesis. J Bone Joint Surg 89: 347-357, 2007 造血干细胞对异位骨骼形成的贡献 • 10.2106/JBJS.F.00472
  1. Kaplan FS, Tabas J, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva: an endochondral process. J Bone Joint Surg Am 75-A: 220-230, 1993 FOP的组织病理学：一种内源性骨化过程 • 10.2106/00004623-199302000-00009
  1. Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun 9:471, 2018 在纤维/脂肪前体细胞中的激活素依赖性信号传导导致了FOP • 10.1038/s41467-018-02872-2
  1. Lounev VY, Ramachandran R, Wosczyna MN, Yamamoto M, Maidment AD, Shore EM, Glaser DL, Goldhamer DJ, Kaplan FS. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am 91: 652-663, 2009 识别对异位骨骼生成有贡献的前体细胞 • 10.2106/JBJS.H.01177
  1. Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016 细胞缺氧通过增强BMP信号促进异位骨化 • 10.1002/jbmr.2848
  1. Wosczyna MN, Biswas AA, Cogswell CA, Goldhamer DJ. Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification. J Bone Miner Res 27: 1004-1017, 2012 驻留在骨骼肌间质中的多能前体细胞表现出强大的BMP依赖性成骨活性，并介导异位骨化 • 10.1002/jbmr.1562
原文
  1. Pathology of FOP Lesions
      2. Early pre-osseous FOP lesions consist of an intense aggregation of mononuclear inflammatory cells including lymphocytes, macrophages, and mast cells in the perivascular spaces of edematous muscle (Gannon et al., 1998; Gannon et al., 2001). Mast cells, macrophages, and cellular hypoxia play a direct role in the generation of FOP lesions (Wang et al., 2016; Convente et al., 2018). Following the catabolic phase of muscle cell death, a highly anabolic fibroproliferative phase (often mistaken for aggressive juvenile fibromatosis) consists, in part, of Sca1+/PDGFRα+/Tie2+/CD34- fibroadipogenic progenitor (FAP) cells that differentiate through an endochondral pathway into mature heterotopic bone (Kaplan et al.,1993; Lounev et al., 2009; Wosczyna et al., 2012; Lees-Shepard et al., 2018).
      References
      Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of Mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018
      Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva (FOP). Hum Pathol 32: 842-848, 2001
      Gannon FH, Valentine BA, Shore EM, Zasloff MA, Kaplan FS. Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop 346: 19-25, 1998
      Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG, Hematopoietic stem cell contribution to ectopic skeletogenesis. J Bone Joint Surg 89: 347-357, 2007
      Kaplan FS, Tabas J, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva: an endochondral process. J Bone Joint Surg Am 75-A: 220-230, 1993
      Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun 9:471, 2018
      Lounev VY, Ramachandran R, Wosczyna MN, Yamamoto M, Maidment AD, Shore EM, Glaser DL, Goldhamer DJ, Kaplan FS. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am 91: 652-663, 2009
      Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016
      Wosczyna MN, Biswas AA, Cogswell CA, Goldhamer DJ. Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification. J Bone Miner Res 27: 1004-1017, 2012

6. FOP的实验室研究

在进行性骨化性纤维发育不良（FOP）的常规生化检查中，通常结果是正常的。然而，在炎症、纤维增生、软骨生成和骨生成的不同阶段，以下几种生物标志物的水平可能会有所升高：
  • 血清前列腺素（serum prostanoids）
  • 尿液中的基础成纤维生长因子（urinary basic fibroblast growth factor）
  • 来源于软骨的视黄酸蛋白（cartilage-derived retinoic acid protein, CD-RAP）
  • 碱性磷酸酶（alkaline phosphatase）
在进行性骨化性纤维发育不良（FOP）的早期急性发作期间，观察到循环中的成骨前体细胞数量升高。
在一项病例对照研究中，研究人员使用了一组精心收集和整理的血浆样本，该样本包括40名具有经典ACVR1 R206H突变的进行性骨化性纤维发育不良（FOP）患者和40名按年龄和性别匹配的对照组。研究人员报告通过对113种血浆可溶性分析物的多重分析，鉴定出了与FOP相关的疾病生物标志物以及与急性发作相关的生物标志物。与进行性骨化性纤维发育不良（FOP）基因型高度相关的生物标志物包括：脂联素（Adiponectin）（与缺氧、炎症和异位骨化有关）和十铃蛋白C（tenascin-C）（一种通过TLR4通路激活先天免疫信号的内源性激活物，以及肽酶-7的底物）；而肽酶-7（kallikrein-7）则与急性发作状态高度相关。尽管这些发现需要进一步的研究，但血浆溶解生物标志物为进行性骨化性纤维发育不良（FOP）提供了支持，表明该疾病活动的急性炎症阶段与基因型背景下的慢性炎症相重叠。
参考文献
  1. Kaplan FS, Sawyer J, Connors S, Keough K, Shore E, Gannon F, Glaser D, Rocke D, Zasloff M, Folkman J. Urinary basic fibroblast growth factor: a biochemical marker for preosseous fibroproliferative lesions in patients with FOP. Clin Orthop 346: 59-65, 1998 尿基成纤维生长因子：FOP患者预骨性纤维增生病变的生化标志物 • 10.1097/00003086-199801000-00010
  1. Lindborg CM, Brennan TA, Wang H, Kaplan FS, Pignolo RJ. Cartilage-derived retinoic acid-sensitive protein (CD-RAP): A stage-specific biomarker of heterotopic endochondral bone ossification (HEO) in fibrodysplasia ossification progressiva (FOP). Bone 109: 153-157, 2018 软骨来源的视黄酸敏感蛋白（CD-RAP）：FOP中异位内源骨化（HEO）的阶段特异性生物标志物 • 10.1016/j.bone.2017.09.016
  1. Pignolo RJ, McCarrick-Walmsley R, Wang H, Qiu S, Hunter J, Barr S, He K, Zhang H, Kaplan FS. Plasma‐Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States. J Bone Miner Res 37: 475-483, 2022 FOP的血溶解生物标志物反映了急性和慢性炎症的状态 • 10.1002/jbmr.4492
原文
  1. Laboratory Findings in FOP
      2. Routine biochemical studies are usually normal, although serum prostanoids, urinary basic fibroblast growth factor, cartilage-derived retinoic acid protein (CD-RAP), and alkaline phosphatase levels may be increased during the inflammatory, fibroproliferative, chondrogenic, and osteogenic phases of flare-ups, respectively (Kaplan et al., 1998; Lindborg et al., 2018). Elevated numbers of circulating osteoprogenitor cells have been noted during early flare-ups.
      In a case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1 R206H mutation and 40 age- and sex-matched controls, investigators reported the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Although these findings require further study, plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation (Pignolo, McCarrick-Walmsley et al., 2022).
      References
      Kaplan FS, Sawyer J, Connors S, Keough K, Shore E, Gannon F, Glaser D, Rocke D, Zasloff M, Folkman J. Urinary basic fibroblast growth factor: a biochemical marker for preosseous fibroproliferative lesions in patients with FOP. Clin Orthop 346: 59-65, 1998
      Lindborg CM, Brennan TA, Wang H, Kaplan FS, Pignolo RJ. Cartilage-derived retinoic acid-sensitive protein (CD-RAP): A stage-specific biomarker of heterotopic endochondral bone ossification (HEO) in fibrodysplasia ossification progressiva (FOP). Bone 109: 153-157, 2018
      Pignolo RJ, McCarrick-Walmsley R, Wang H, Qiu S, Hunter J, Barr S, He K, Zhang H, Kaplan FS. PlasmaSoluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States. J Bone Miner Res 37: 475-483, 2022

7. FOP的病因和病理

在对果蝇和脊椎动物的早期观察中，研究人员提出了一个假设：骨形态发生蛋白（BMP）信号通路在进行性骨化性纤维发育不良（FOP）中存在失调。实际上，在进行性骨化性纤维发育不良（FOP）中，BMP信号通路严重失调。FOP细胞过度表达BMP4，但在面对BMP挑战时无法上调多种BMP拮抗剂的表达，并且表现出BMP受体内化的缺陷，伴随下游靶标的激活增加，这表明改变的BMP受体信号传导在FOP的异位骨化（HO）形成中起着重要作用。
全基因组连锁分析将进行性骨化性纤维发育不良（FOP）的致病基因定位到第2号染色体的q23-24区域，该区域包含激活素A受体1型（ACVR1）基因，该基因编码一种BMP（骨形态发生蛋白）类型的1型受体。在所有具有经典特征的进行性骨化性纤维发育不良（FOP）患者中，发现了一种反复出现的杂合性错义突变（c.617G>A; p.R206H），该突变位于ACVR1基因的甘氨酸-丝氨酸（GS）激活区。这确立了该基因的突变是FOP的决定性原因，并使得分子确认成为可能。一种“基因敲入”小鼠模型被用来确认这个单核苷酸替换（突变）足以引发与进行性骨化性纤维发育不良（FOP）相关的所有特征。
蛋白质建模预测了ACVR1的GS（甘氨酸-丝氨酸）结构域的不稳定性，这与增强的ACVR1信号通路活化一致，作为进行性骨化性纤维发育不良（FOP）中异位软骨生成、成骨和关节融合的基础发病机制。GS结构域是FKBP12的特定结合位点，FKBP12是一种高度保守的抑制蛋白，能够防止在没有配体的情况下I型受体的非特异性激活。ACVR1（R206H）在没有BMP的情况下与FKBP12的相互作用较弱，表明这种FKBP12-ACVR1相互作用的损伤在一定程度上促使了BMP独立通路的信号传导。
来自进行性骨化性纤维发育不良（FOP）患者的结缔组织前体细胞在基础状态和配体刺激下，表现出BMP信号通路信号传导的失调，这种现象在体外和体内的FOP模型中也是特征性的。ACVR1 R206H突变通过调节BMP信号通路导致进行性骨化性纤维发育不良（FOP），这主要是通过以下几种机制：独立于配体的受体激活，对BMP配体的过度反应，以及对通常具有拮抗作用的配体Activin A的反应。在进行性骨化性纤维发育不良（FOP）中，ACVR1受体能够在缺乏正常所需的I型受体伴侣的情况下进行信号传导，并且对GS（甘氨酸-丝氨酸）结构域中的丝氨酸/苏氨酸磷酸化位点的要求减少，这进一步表明了ACVR1受体激活的正常调节约束的丧失。Ramachandran及其同事表示，ACVR1 R206H的致病性信号传导主要是通过依赖Activin A的受体聚集来介导的，这种聚集会诱导突变受体的自我激活。
此外，早期的进行性骨化性纤维发育不良（FOP）病变通过一种细胞内的、与配体无关的HIF-1α机制显著增强了BMP信号通路的信号传导，从而确立了细胞缺氧作为刺激和放大FOP病变的一个核心机制。最近的研究还表明，ACVR1 R206H FOP突变改变了在异位骨化过程中对机械刺激的感知和组织的硬度，并且ACVR1 R206H突变在诱导异位骨形成的同时，妨碍了异位骨化发生部位的骨骼肌再生。
哺乳动物骨骼中关节的发育依赖于多种相互作用的信号通路的精确调控，其中包括骨形态发生蛋白（BMP）通路，这是一种关节发育、数字模式形成、骨骼生长和软骨生成的关键调节因子。在小鼠FOP模型中，Towler及其同事表示，Acvr1R206H突变导致的Acvr1介导的信号增加的影响不仅限于第一指，而是改变了BMP信号通路、Gdf5+关节祖细胞的位置，以及关节的发育，从而在胚胎发育过程中以不同方式影响各个手指。Acvr1 R206H突变导致手指的关节特征和分裂的延迟和干扰，同时也改变了在关节形态发生部位的软骨和内源性骨化的发育。这些发现显示了ACVR1介导的BMP信号在关节和骨骼形成调控中的重要作用，表明在预期的关节间隙中未能限制BMP信号与关节分裂失败之间存在直接联系，并且暗示ACVR1 R206H突变与关节发育受损有关。
参考文献
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  1. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015 ACVR1(R206H)受体突变通过赋予对Activin A的响应性导致FOP • 10.1126/scitranslmed.aac4358
  1. Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1 mutations. Bone 109: 232-240, 2018 FOP的ACVR1突变信号活性可变 • 10.1016/j.bone.2017.10.027
  1. Haupt J, Stanley A, McLeod CM, Cosgrove BD, Culbert AL, Wang L, Mourkioti F, Mauck RL, Shore EM. ACVR1 R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification. Mol Biol Cell 30: 17-29, 2019 FOP的ACVR1 R206H突变在异位骨化过程中改变机械感知和组织刚度 • 10.1091/mbc.E18-05-0311
  1. Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA 112: 15438-15443, 2015 ACVR1在FOP中的新功能 • 10.1073/pnas.1510540112
  1. Kaplan FS, Pignolo RJ, Shore EM. The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling. Cytokine Growth Factor Rev 20: 399-407, 2009b FOP突变基因编码一种新型I型受体，导致BMP信号失调 • 10.1016/j.cytogfr.2009.10.006
  1. Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia ossificans progressiva: A clue from the fly? Calcif Tiss Int 47: 117-125, 1990 FOP：来自果蝇的线索？ • 10.1007/BF02555995
  1. Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009a 经典和非典型FOP表型由BMP I型受体ACVR1的突变引起 • 10.1002/humu.20868
  1. Ramachandran A, Mehić M, Wasim L, Malinova D, Gori I, Blaszczyk BK, Carvalho DM, Shore EM, Jones C, Hyvönen M, Tolar P, Hill CS. Pathogenic ACVR1 R206H activation by Activin A-induced receptor clustering and autophosphorylation. EMBO J 2021 Jul 15;40(14):e106317. 由Activin A诱导的受体聚集和自磷酸化导致致病性ACVR1 R206H的激活 • 10.15252/embj.2020106317
  1. Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embargo ventralization. J Clin Invest 119: 3462-3472, 2009 FOP R206H ACVR1突变激活了与BMP无关的软骨形成和斑马鱼的胚胎腹侧化 • 10.1172/JCI37412
  1. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38: 525-527, 2006 BMP I型受体ACVR1中的复发性突变导致遗传性和散发性的FOP • 10.1038/ng1783
  1. Stanley A, Heo SJ, Mauck RL, Mourkioti F, Shore EM. Elevated BMP and Mechanical Signaling Through YAP1/RhoA Poises FOP Mesenchymal Progenitors for Osteogenesis. J Bone Miner Res 34: 1894-1909, 2019 增强的BMP信号和机械信号通过YAP1/RhoA通路，使FOP中的间充质前体细胞更易于进行骨生成 • 10.1002/jbmr.3760
  1. Stanley, A., E.D. Tichy, J. Kocan, D.W. Roberts, E.M. Shore, F. Mourkioti. Dynamics of skeletal muscleresident stem cells during myogenesis in fibrodysplasia ossificans progressiva. npj Regenerative Medicine 7(1);5, 2022 FOP中骨骼肌驻留干细胞在肌肉生成过程中的动态变化 • 10.1038/s41536-021-00201-8
  1. Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021 由于ACVR1的BMP信号失调阻碍了FOP的趾关节发育 • 10.1016/j.ydbio.2020.11.004
  1. van Dinther M, Visser N, de Gorter DJJ, Doorn J, Goumans M-J, de Boer J, ten Dijke P. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res 25: 1208-1215, 2010 与FOP相关的ALK2 R206H突变赋予BMP I型受体的构成活性，并使间充质细胞对BMP诱导的成骨细胞分化和骨形成敏感 • 10.1359/jbmr.091110
  1. Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016 细胞缺氧通过放大BMP信号促进异位骨化 • 10.1002/jbmr.2848
  1. Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induced chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone 109: 218-224, 2018 Activin A放大失调的BMP信号并诱导进行性骨化性纤维发育不良（FOP）患者初级结缔组织祖细胞的软骨-骨分化 10.1016/j.bone.2017.11.014a
原文
  1. Etiology & Pathogenesis of FOP
      2. Early observations in flies and vertebrates led to the hypothesis that the bone morphogenetic protein (BMP) signaling pathway was dysregulated in FOP (Kaplan et al., 1990). In fact, the BMP signaling pathway is highly dysregulated in FOP. FOP cells over-express BMP4, cannot up-regulate expression of multiple BMP antagonists in response to a BMP challenge, and exhibit a defect in BMP receptor internalization with increased activation of downstream targets, suggesting that altered BMP receptor signaling participates in HO formation in FOP (reviewed in Kaplan et al., 2009b).
      Genome-wide linkage analysis localized the causative gene for FOP to chromosome 2q23-24, a locus containing the Activin A receptor, type 1 (ACVR1) gene encoding a BMP type 1 receptor. A recurrent heterozygous missense mutation (c.617G>A; p.R206H) in the glycine-serine (GS) activation domain of ACVR1 was identified in all affected individuals with classic features of either sporadic or inherited FOP, establishing mutation of this gene as the definitive cause of FOP and making molecular confirmation possible (Shore et al., 2006; Couzin, 2006; Kaplan et al., 2009a). A knock-in mouse model was used to confirm that this single nucleotide substitution is sufficient to induce all features associated with FOP (Chakkalakal et al., 2012).
      Protein modeling predicted destabilization of the GS domain, consistent with enhanced activation of ACVR1 signaling as the underlying pathogenesis of the ectopic chondrogenesis, osteogenesis, and joint fusion of FOP (Shore et al., 2006; Groppe et al., 2007; Shen et al., 2009; van Dinther et al., 2010; Chaikaud et al., 2012; Culbert et al., 2014). The GS domain is a specific binding site for FKBP12, a highly conserved inhibitory protein that prevents leaky activation of type I receptors in the absence of ligand. ACVR1 (R206H) interacts less with FKBP12 in the absence of BMP, suggesting this impaired FKBP12-ACVR1 interaction contributes in part to BMP-independent pathway signaling (Shen et al., 2009; Groppe et al., 2011).
      Basal and ligand-stimulated dysregulation of BMP pathway signaling are characteristic of connective tissue progenitor cells from FOP patients, and in vitro and in vivo FOP models. ACVR1 R206H causes FOP through dysregulation of the BMP signaling pathway, in part, by receptor activation independently of ligands, but also by being hyper-responsive to BMP ligands, and by responding to the normally antagonistic ligand Activin A (Billings et al., 2008; Shen et al., 2009; Culbert et al., 2014; Hatsell et al., 2015; Hino et al., 2015; Haupt et al., 2018; Wang et al., 2018; Allen et al., 2020). In addition, FOP ACVR1 signals in the absence of a normally required type I receptor partner and has reduced GS domain serine/threonine phosphorylation site requirements, further demonstrating the loss of normal regulatory constraints on ACVR1 receptor activation (Allen et al., 2020; Allen et al., 2023). Ramachandran and colleagues showed that pathogenic signaling of ACVR1 R206H is mediated predominantly by Activin A-dependent receptor clustering, which induces auto-activation of the mutant receptor (Ramachandran et al., 2021).
      Additionally, early FOP lesions dramatically amplify BMP pathway signaling through an intracellular ligand-independent HIF-1α mechanism thus establishing cellular hypoxia as a central mechanism for the stimulation and amplification of FOP lesions (Wang et al., 2016). Recent studies also show that the ACVR1 R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification (Haupt et al., 2019; Stanley et al., 2019), and that in parallel with inducing ectopic bone formation, ACVR1 R206H impairs regeneration of the skeletal muscle where HO forms (Barruet et al., 2021; Stanley et al., 2022).
      The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. In murine models of FOP, Towler and colleagues showed that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, localization of Growth Differentiation Factor-5 (Gdf5+) joint progenitor cells, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1 R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and also alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate ACVR1 R206H in impaired joint development (Towler, Peck, Kaplan, Shore, 2021).
      References
      Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020
      Allen, RS, Jones WD, Hale M, Warder BN Shore EM, and Mullins MC. Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish. J Bone Miner Res 38: 1364-1385, 2023
      Barruet E, Garcia SM, Wu J, Morales BM, Tamaki S, Moody T, Pomerantz JH, Hsiao EC. Modeling the ACVR1 R206H mutation in human skeletal muscle stem cells. eLife 2021 Nov 10;10:e66107
      Billings PC, Fiori JL, Bentwood JL, O'Connell MP, Jiao X, Nussbaum B, Caron RJ, Shore EM, Kaplan FS. Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res 23: 305-313, 2008
      Chaikuad A, Alfano I, Kerr G, Santivale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem 287: 36990-36998, 2012
      Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 Knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res 27: 1746-1756, 2012
      Couzin J. Bone disease gene finally found. Science 312: 514-515, 2006
      Culbert AL, Chakkalakal SA, Theosmy EG, Brennan TA, Kaplan FS, Shore EM. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells 32: 1289-1300, 2014
      Groppe JC, Shore EM, Kaplan FS. Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin Orthop Relat Res 462: 87-92, 2007
      Groppe JC, Wu J, Shore EM, Kaplan FS. In vitro analysis of dysregulated R206H ALK2 kinase-FKBP12 interaction associated with heterotopic ossification in FOP. Cells Tissues Organs 194: 291-295, 2011
      Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015
      Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1 mutations. Bone 109: 232-240, 2018
      Haupt J, Stanley A, McLeod CM, Cosgrove BD, Culbert AL, Wang L, Mourkioti F, Mauck RL, Shore EM. ACVR1 R206H FOP mutation alters mechanosensing and tissue stiffness during heterotopic ossification. Mol Biol Cell 30: 17-29, 2019
      Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA 112: 15438-15443, 2015
      Kaplan FS, Pignolo RJ, Shore EM. The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling. Cytokine Growth Factor Rev 20: 399-407, 2009b
      Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia ossificans progressiva: A clue from the fly? Calcif Tiss Int 47: 117-125, 1990
      Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009a
      Ramachandran A, Mehić M, Wasim L, Malinova D, Gori I, Blaszczyk BK, Carvalho DM, Shore EM, Jones C, Hyvönen M, Tolar P, Hill CS. Pathogenic ACVR1 R206H activation by Activin A-induced receptor clustering and autophosphorylation. EMBO J 2021 Jul 15;40(14):e106317.
      Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embargo ventralization. J Clin Invest 119: 3462-3472, 2009
      Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38: 525-527, 2006
      Stanley A, Heo SJ, Mauck RL, Mourkioti F, Shore EM. Elevated BMP and Mechanical Signaling Through YAP1/RhoA Poises FOP Mesenchymal Progenitors for Osteogenesis. J Bone Miner Res 34: 1894-1909, 2019
      Stanley, A., E.D. Tichy, J. Kocan, D.W. Roberts, E.M. Shore, F. Mourkioti. Dynamics of skeletal muscleresident stem cells during myogenesis in fibrodysplasia ossificans progressiva. npj Regenerative Medicine 7(1);5, 2022
      Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021
      van Dinther M, Visser N, de Gorter DJJ, Doorn J, Goumans M-J, de Boer J, ten Dijke P. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res 25: 1208-1215, 2010
      Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016
      Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induced chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone 109: 218-224, 2018

8. FOP中大脚趾畸形的发育分子生物学

患有进行性骨化性纤维发育不良（FOP）的儿童在出生时通常表现出大脚趾的畸形，这表明ACVR1基因突变在胚胎发育过程中发挥作用，导致骨骼形成的改变。大脚趾通常伴有关节活动受限、趾骨缩短，以及缺失、融合或畸形的指骨。尽管在FOP人群中大脚趾畸形的发生率很高，但由于它在临床上并不严重，因而相对较少受到关注。
通过对一组年龄从2个月到48岁的41名FOP患者的X光片进行检查，提供了有关FOP大脚趾畸形的详细分析，涵盖其发育特征、进展及变异性。具体表现包括骨结构缺失、骺（骨端）的畸形、异位骨化中心、第一跖骨（脚掌骨）的畸形及指骨融合。
在研究ACVR1介导的BMP（骨形态发生蛋白）信号在指骨发育中的作用时，使用了一种模仿人类FOP（进行性骨化性纤维发育不良）第一指（大拇指）表型的小鼠模型。研究者通过这个模型发现，由Acvr1 R206H突变引起的信号增强作用并不仅仅局限于第一指，还影响其他手指或脚趾的发育。在胚胎发育过程中，改变的BMP信号、Gdf5（生长分化因子5）关节前体细胞的定位以及关节发育，以影响单个手指的方式发生变化。Acvr1 R206H突变对指关节发育的影响，具体描述了该突变如何导致关节的形成和分化过程出现延迟和紊乱，并进一步影响软骨和内软骨化的发育。
这些发现表明ACVR1介导的BMP信号在关节和骨骼形成的调控中发挥着重要作用，展示了未能限制指关节间区中BMP信号与在预期间区中关节分裂失败之间的直接联系，并暗示受损的特异于指骨的关节发育是FOP（进行性骨化性纤维发育不良）中指畸形的近因。
参考文献
  1. Towler OW, Kaplan FS, Shore EM. The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva. Front Cell Dev Biol. 2020;8:612853, 2020 进行性骨化性纤维发育不良中大脚趾的发育表型
  1. Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021 通过ACVR1失调的BMP信号影响进行性骨化性纤维发育不良（FOP）中的指关节发育
  1. Towler OW, Shore EM. BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP). Dev Dyn 251: 164-177, 2022 进行性骨化性纤维发育不良（FOP）中的BMP信号与骨骼发育
原文
  1. The Developmental Molecular Biology of the Great Toe Malformation in FOP
Children with FOP characteristically exhibit malformation of their great toes at birth, indicating that the ACVR1 mutation acts during embryonic development to alter skeletal formation. The great toes are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. Despite the high prevalence of the great toe malformation in the FOP population, it has received relatively little attention due to its clinically benign nature.
Towler et al. (2020) examined radiographs from a cohort of 41 FOP patients ranging from 2 months to 48 years of age to provide a detailed analysis of the developmental features, progression, and variability of the great toe malformation of FOP, which include absent skeletal structures, malformed epiphyses, ectopic ossification centers, malformed first metatarsals and phalangeal fusion.
In order to elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, Towler et al. (2021) used an FOP knock-in mouse model that mimics the first digit phenotype of human FOP and determined that the effects of increased Acvr1-mediated signaling by the Acvr1 R206H mutation are not limited to the first digit. Altered BMP signaling, Growth Differentiation Factor-5 (Gdf5) joint progenitor cell localization, and joint development occur in a manner that affects individual digits during embryogenesis. The Acvr1 R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis.
These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP (Towler et al., 2021; Towler & Shore, 2022).
References
Towler OW, Kaplan FS, Shore EM. The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva. Front Cell Dev Biol. 2020;8:612853, 2020
Towler OW, Peck SH, Kaplan FS, Shore EM. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol 470: 136-146, 2021
Towler OW, Shore EM. BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP). Dev Dyn 251: 164-177, 2022

9. 变异型FOP

所有具有典型FOP临床特征的患者（如大脚趾畸形和进行性骨化）在ACVR1的甘氨酸-丝氨酸激活区都有相同的杂合突变（c.617G>A; p.R206H），全球约97%的FOP患者都携带该突变。大约3%的FOP患者被发现具有与典型FOP相比不寻常的临床特征，最显著的是大脚趾畸形的严重程度有所增加或减少。这些具有“变异”临床表现的FOP患者在ACVR1基因中有新型的非R206H激活突变。已观察到某些ACVR1致病变异与进行性骨化（HO）发作年龄或胚胎骨骼发育之间存在基因型-表型的相关性。
参考文献
  1. Haupt, J., M. Xu, and E.M. Shore. Variable signaling activity by FOP ACVR1 mutations. Bone 109: 232240, 2018 FOP ACVR1突变的信号活性变异
  1. Huning I, Gillessen-Kaesbach G. Fibrodysplasia Ossificans Progressiva: Clinical Course, Genetic Mutations and Genotype-Phenotype Correlations. Molec Syndromology 5: 201-211, 2014 进行性骨化性纤维发育不良：临床过程、遗传突变和基因型-表型相关性
  1. Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167: 2265-2271, 2015 在一种严重变异型进行性骨化性纤维发育不良（ACVR1 c.772G>A; R258G）中涉及多系统：两例患者的报告
  1. Kaplan FS, Groppe JC, Xu M, Towler OW, Grunvald E, Kalunian K, Kallish S, Al Mukaddam M, Pignolo RJ, Shore EM. An ACVR1 R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva. Am J Med Genet A 188: 806-817, 2022 在两例轻度进行性骨化性纤维发育不良的家庭中发现ACVR1 R375P致病变异。
  1. Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009 典型和非典型FOP表型是由BMP I型受体ACVR1的突变引起的。
原文
  1. FOP Variants
All patients with classic clinical features of FOP (great toe malformations and progressive HO) have the same heterozygous mutation (c.617G>A; p.R206H) in the glycine-serine activation domain of ACVR1 (~97% of all FOP patients worldwide). Approximately 3% of FOP patients have been identified with clinical features unusual compared to classical FOP, most notably greater or lesser severity of the great toe malformations. These patients with “variant” clinical presentation of FOP have novel non-R206H activating mutations in the ACVR1 gene. Genotype-phenotype correlations have been observed between some ACVR1 pathogenic variants and the age of onset of HO or on embryonic skeletal development (Kaplan et al., 2009; Kaplan et al., 2015; Haupt et al., 2018; Kaplan et al., 2022; reviewed in Huning & Gillessen-Kaesbach, 2014). A more detailed discussion of FOP variants is found in Section V.
References
Haupt, J., M. Xu, and E.M. Shore. Variable signaling activity by FOP ACVR1 mutations. Bone 109: 232240, 2018
Huning I, Gillessen-Kaesbach G. Fibrodysplasia Ossificans Progressiva: Clinical Course, Genetic Mutations and Genotype-Phenotype Correlations. Molec Syndromology 5: 201-211, 2014
Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167: 2265-2271, 2015
Kaplan FS, Groppe JC, Xu M, Towler OW, Grunvald E, Kalunian K, Kallish S, Al Mukaddam M, Pignolo RJ, Shore EM. An ACVR1 R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva. Am J Med Genet A 188: 806-817, 2022
Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009

10. 免疫系统与FOP

在所有受影响个体中，进行性骨化性纤维发育不良（FOP）是由ACVR1中的一种杂合错义功能获得性变异引起的。突变受体的自抑制功能丧失导致BMP信号通路信号失调，这对FOP的多种发育特征是必要的，但可能不足以诱发导致残疾的产后进行性骨化（HO）及该病的标志性症状的发作。来自人类和动物模型各个研究层面的证据强烈支持先天免疫系统在诱发HO发作中发挥关键作用。
产后进行性骨化性纤维发育不良（FOP）的发作强烈暗示存在一个潜在的免疫触发因素，涉及炎症和先天免疫系统。近期研究表明，肥大细胞、巨噬细胞、缺氧，以及经典和非经典TGFβ/BMP家族配体在放大突变ACVR1信号通路中发挥作用，从而导致FOP病变的形成和随后的骨化。刺激突变ACVR1信号的BMP和Activin配体在免疫系统中也具有重要的调控功能。来自FOP患者的巨噬细胞在M1样极化后显示出延长的炎性细胞因子产生和更高的Activin A产生，导致对额外的LPS刺激反应减弱，确认巨噬细胞是Activin A的来源，可能促使FOP中的异位骨化。
一项病例对照研究使用了一组经过仔细收集和整理的血浆样本，包括40名具有典型ACVR1 R206H突变的FOP患者和40名按年龄和性别匹配的对照组，报告了使用113种血浆可溶性分析物的多重分析识别FOP相关疾病和发作相关生物标志物。与FOP基因型高度相关的生物标志物包括脂联素（与缺氧、炎症和异位骨化有关）和tenascin-C（通过TLR4通路作为先天免疫信号的内源性激活剂以及kallikrein-7的底物），而kallikrein-7则与急性发作状态高度相关。FOP的血浆可溶性生物标志物支持疾病活动的急性炎症阶段与慢性炎症的基因型背景重叠。调节组织维持和修复的形态发生和免疫通路之间的相互作用确定了FOP潜在的有效治疗靶点。
Lounev等人最近报告了一名35岁健康男性（患者R），他有典型的先天性FOP大脚趾畸形以及经典的致病性ACVR1 R206H突变，但产后几乎没有异位骨化，并且运动能力几乎正常。作者提出假设，认为患者R缺乏足够的产后炎症刺激来引发异位骨化。对该患者及多种FOP小鼠模型的深入研究显示，MMP-9的缺乏使得FOP患者更具韧性，MMP-9在FOP的发病机制中起着重要作用，将炎症与异位骨化联系在一起。更重要的是，这些发现表明，单个患者的临床表型可能揭示出新的治疗策略。
参考文献
  1. Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight 2018 Nov 15;3(22). pii: 122958 NF-κB/MAPK激活是人类异位骨化中ACVR1介导的炎症基础
  1. Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018 去除肥大细胞和巨噬细胞会损害ACVR1 (R206H)小鼠模型中进行性骨化性纤维发育不良的异位骨化
  1. Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016 赋予FOP免疫并捕捉异位骨化的发生
  1. Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J Bone Miner Res 39: 382-398, 2024 基质金属蛋白酶-9缺乏使得一名患者和小鼠在进行性骨化性纤维发育不良中表现出韧性
  1. Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 17: 387-394, 2019 进行性骨化性纤维发育不良及其他形式的异位骨化中的炎症
  1. Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC. ACVR1 R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone 2021 Dec;153:116129 ACVR1 R206H延长了人源诱导多能干细胞衍生巨噬细胞的炎症反应
  1. Pignolo RJ, McCarrick-Walmsley R, Wang H, Qiu S, Hunter J, Barr S, He K, Zhang H, Kaplan FS. Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States. J Bone Miner Res 37: 475-483, 2022 进行性骨化性纤维发育不良（FOP）的血浆可溶性生物标志物反映了急性和慢性炎症状态
  1. Wang H, Behrens EM, Pignolo RJ, Kaplan FS. ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. Bone 109: 201-209, 2018 进行性骨化性纤维发育不良（FOP）的血浆可溶性生物标志物反映了急性和慢性炎症状态
  1. Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016 细胞缺氧通过增强BMP信号促进异位骨化
  1. Wein MN, Yang Y. Actionable disease insights from bedside-to-bench investigation in fibrodysplasia ossificans progressiva. J Bone Miner Res 39: 375-376, 2024 从床边到实验室研究中获得的可操作性疾病见解，针对进行性骨化性纤维发育不良
原文
  1. The Immune System & FOP
      2. In all affected individuals, FOP is caused by a heterozygous missense gain-of-function variant in ACVR1. Loss of autoinhibition of the mutant receptor results in dysregulated BMP pathway signaling and is necessary for the myriad developmental features of FOP but may not be sufficient to induce the episodic flare-ups that lead to disabling post-natal HO and that are a hallmark of the disease. Evidence from all levels of investigation in humans and animal models strongly support that the innate immune system plays a key role in inducing episodes of HO.
      Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system (reviewed in Kaplan et al., 2016; Matsuo et al., 2019). Recent studies implicate mast cells, macrophages and hypoxia as well as canonical and non-canonical TGFβ/BMP family ligands in the amplification of mutant ACVR1 signaling leading to the formation of FOP lesions and resultant HO (Kaplan et al., 2016; Wang et al., 2016; Convente et al., 2018). BMP and Activin ligands that stimulate mutant ACVR1 signaling also have critical regulatory functions in the immune system (reviewed in Kaplan et al., 2016; Barruet et al., 2018). Macrophages derived from patients with FOP show prolonged inflammatory cytokine production and higher Activin A production after M1-like polarization, resulting in dampened responses to additional LPS stimulation, identifying macrophages as a source of Activin A that may drive heterotopic ossification in FOP (Matsuo et al., 2021).
      A case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1 R206H mutation and 40 age- and sex-matched controls, reported the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation (Pignolo et al., 2022). Crosstalk between the morphogenetic and immunological pathways that regulate tissue maintenance and repair identifies potential robust therapeutic targets for FOP (Wang et al., 2018).
      Lounev et al. recently reported that an otherwise healthy 35-year-old man (patient-R) with the classic congenital great toe malformation of FOP and the canonical pathogenic ACVR1 R206H mutation had extreme paucity of post-natal heterotopic ossification and nearly normal mobility. The authors hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for heterotopic ossification. Extensive studies in the patient and in multiple mouse models of FOP revealed that deficiency of MMP-9 confers resilience in FOP, that MMP-9 orchestrates a critical role in the pathogenesis of FOP by linking inflammation to heterotopic ossification, and importantly illustrates that a single patient's clinical phenotype can unveil novel treatment strategies (Lounev et al., 2024; Wein & Yang, 2024).
      References
      Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight 2018 Nov 15;3(22). pii: 122958
      Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018
      Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016
      Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J Bone Miner Res 39: 382-398, 2024
      Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 17: 387-394, 2019
      Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC. ACVR1 R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone 2021 Dec;153:116129
      Pignolo RJ, McCarrick-Walmsley R, Wang H, Qiu S, Hunter J, Barr S, He K, Zhang H, Kaplan FS. Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States. J Bone Miner Res 37: 475-483, 2022
      Wang H, Behrens EM, Pignolo RJ, Kaplan FS. ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. Bone 109: 201-209, 2018
      Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016
      Wein MN, Yang Y. Actionable disease insights from bedside-to-bench investigation in fibrodysplasia ossificans progressiva. J Bone Miner Res 39: 375-376, 2024

11. FOP的流行病学、遗传学和环境因素

进行性骨化性纤维发育不良（FOP）是人类最罕见的疾病之一。由于该病罕见且临床表现异质性，FOP的患病率估计受到了一定限制。美国进行了一项关于FOP患病率的研究，研究基于与三大FOP治疗中心（宾夕法尼亚大学、梅奥诊所或加州大学旧金山分校）的接触、国际进行性骨化性纤维发育不良协会（IFOPA）的会员名单，或IFOPA FOP登记处截至2020年7月22日的数据。研究结果表明，FOP的患病率高于通常引用的每百万0.5的数值。
所有种族均可受到FOP的影响。该病没有种族、民族、性别或地理倾向。FOP的遗传方式为常染色体显性遗传，具有完全的致病率但表现形式可变。遗传可来自母亲或父亲。大多数病例是由于自发新突变所致。有研究报告了父亲年龄效应。母体嵌合现象也可能存在。全球已知的多代FOP小家庭不超过十个。该病表现出表型异质性。
遗传和环境因素都对FOP的表型有影响。一项对三对FOP单卵双胞胎的研究发现，在每对双胞胎中，先天性脚趾畸形是相同的。然而，产后异位骨化则因生活经历和环境因素（如病毒感染和软组织创伤）而存在较大差异。遗传因素似乎在产前发育过程中起着关键作用，而环境因素则对产后异位骨化的发展有着强烈影响。
参考文献
  1. Baujat G, Choquet R, Bouée S, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis 12:123, 2017 法国进行性骨化性纤维发育不良（FOP）的患病率：基于两个国家数据库的记录链接的估计
  1. Connor JM, Evans DA. Genetic aspects of fibrodysplasia ossificans progressiva. J Med Genet 19: 35-39, 1982 进行性骨化性纤维发育不良的遗传学方面
  1. Hebela N, Shore EM, Kaplan FS. Three pairs of monozygotic twins with fibrodysplasia ossificans progressiva: the role of environment in the progression of heterotopic ossification. Clin Rev Bone Miner Metab 3: 205-208, 2005 三对单卵双胞胎患有进行性骨化性纤维发育不良：环境在异位骨化进展中的作用
  1. Kaplan FS, McCluskey W, Hahn G, Tabas J, Muenke M, Zasloff MA. Genetic transmission of fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75: 1214-1220, 1993 进行性骨化性纤维发育不良的遗传传递
  1. Morales Piga A, Bachiller-Corral J, Trujillo-Tiebas MJ, Villaverde-Hueso A, Gamir-Gamir ML, AlonsoFerreira V, et al. Fibrodysplasia ossificans progressiva in Spain: epidemiological, clinical, and genetic aspects. Bone 51:748–755, 2012 西班牙的进行性骨化性纤维发育不良：流行病学、临床和遗传学方面
  1. Pignolo RJ, Hsiao EC, Baujat G, Lapidus D, Sherman A, Kaplan FS. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis 16:350, 2021 美国进行性骨化性纤维发育不良（FOP）的患病率：来自三个治疗中心和一个患者组织的估计
  1. Rogers JG, Chase GA. Paternal age effect in fibrodysplasia ossificans progressiva. J Med Genet 16: 147148, 1979 进行性骨化性纤维发育不良中的父亲年龄效应
  1. Shore EM, Feldman GJ, Xu M, Kaplan FS. The genetics of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 201-204, 2005 进行性骨化性纤维发育不良的遗传学
原文
  1. Epidemiologic, Genetic, & Environmental Factors in FOP
      2. FOP is among the rarest of human afflictions (Connor & Evans, 1982; Morales Piga et al., 2012; Baujat et al., 2017). Prevalence estimates for FOP have been hindered by the rarity of the condition and the heterogeneity of disease presentation. A study of disease prevalence was conducted in the United States, based on contact with one of 3 major treatment centers for FOP (University of Pennsylvania, Mayo Clinic, or University of California San Francisco), the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) membership list, or the IFOPA FOP Registry through July 22, 2020. The results of the study suggested that the prevalence of FOP is higher than the often-cited value of 0.5 per million (Pignolo, Hsiao et al., 2021).
      All races are affected with FOP. There is no ethnic, racial, gender, or geographic predisposition. Autosomal dominant transmission with complete penetrance but variable expression is established. Inheritance can be from either mothers or fathers (Kaplan et al., 1993; Shore et al., 2005). Most cases arise as a result of a spontaneous new mutation (reviewed in Shore et al., 2005). A paternal age effect has been reported (Rogers & Chase, 1979). Maternal mosaicism may exist. Fewer than ten small families with multigenerational members with FOP are known worldwide. Phenotypic heterogeneity is observed (Shore et al., 2005).
      Both genetic and environmental factors affect the phenotype of FOP. A study of three pairs of monozygotic twins with FOP found that within each pair, congenital toe malformations were identical. However, postnatal HO varied greatly depending on life history and environmental exposure to viral illnesses and to soft tissue trauma. Genetic factors appear to be the key determinants during prenatal development while environmental factors strongly influence postnatal progression of HO (Hebela et al., 2005).
      References
      Baujat G, Choquet R, Bouée S, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis 12:123, 2017
      Connor JM, Evans DA. Genetic aspects of fibrodysplasia ossificans progressiva. J Med Genet 19: 35-39, 1982
      Hebela N, Shore EM, Kaplan FS. Three pairs of monozygotic twins with fibrodysplasia ossificans progressiva: the role of environment in the progression of heterotopic ossification. Clin Rev Bone Miner Metab 3: 205-208, 2005
      Kaplan FS, McCluskey W, Hahn G, Tabas J, Muenke M, Zasloff MA. Genetic transmission of fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75: 1214-1220, 1993
      Morales Piga A, Bachiller-Corral J, Trujillo-Tiebas MJ, Villaverde-Hueso A, Gamir-Gamir ML, AlonsoFerreira V, et al. Fibrodysplasia ossificans progressiva in Spain: epidemiological, clinical, and genetic aspects. Bone 51:748–755, 2012
      Pignolo RJ, Hsiao EC, Baujat G, Lapidus D, Sherman A, Kaplan FS. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis 16:350, 2021
      Rogers JG, Chase GA. Paternal age effect in fibrodysplasia ossificans progressiva. J Med Genet 16: 147148, 1979
      Shore EM, Feldman GJ, Xu M, Kaplan FS. The genetics of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 201-204, 2005

12. 基因检测与FOP

进行性骨化性纤维发育不良（FOP）的确诊性基因检测可以通过对ACVR1基因座的DNA序列分析在异位骨化（HO）出现之前确认FOP的诊断（Kaplan等，2008）。基于大脚趾畸形，早期对FOP的临床怀疑可以导致早期临床诊断、确认性基因检测（如适用）以及避免有害的诊断和治疗程序。临床医生应当注意FOP的早期诊断迹象——先天性大脚趾畸形和间歇性软组织肿胀，即使在异位骨化出现之前。这种意识应促使进行基因咨询和检测，并采取积极的预防措施以防止伤害和医源性损害。
参考文献
  1. Kaplan FS, Xu M, Glaser DL, Collins F, Connor M, Kitterman J, Sillence D, Zackai E, Ravitsky V, Zasloff M, Ganguly A, Shore EM. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 121: e1295e1300, 2008 进行性骨化性纤维发育不良的早期诊断
原文
  1. Genetic Testing & FOP
      2. Definitive genetic testing of FOP by DNA sequence analysis of the ACVR1 locus can confirm a diagnosis of FOP prior to the appearance of HO (Kaplan et al., 2008). Clinical suspicion of FOP early in life on the basis of malformed great toes can lead to early clinical diagnosis, confirmatory diagnostic genetic testing (if appropriate), and the avoidance of harmful diagnostic and treatment procedures. Clinicians should be aware of the early diagnostic signs of FOP - congenital malformation of the great toes and episodic soft tissue swelling even before the appearance of HO. This awareness should prompt genetic consultation and testing and the institution of assiduous precautions to prevent injury and iatrogenic harm.
      References
      Kaplan FS, Xu M, Glaser DL, Collins F, Connor M, Kitterman J, Sillence D, Zackai E, Ravitsky V, Zasloff M, Ganguly A, Shore EM. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 121: e1295e1300, 2008
 

13. FOP的动物模型

FOP的动物模型对于解析FOP的病理生理机制以及测试潜在疗法至关重要。实验室生成的果蝇、斑马鱼和小鼠等动物模型具有FOP特征，这为我们更好地理解与BMP信号通路相关的异位骨化的生物学提供了机会，并研究目前可用和新兴疗法的有效性和安全性。已开发出经典FOP突变的小鼠条件性插入模型，这对于确立FOP的特异性治疗和探究许多之前未被研究的疾病方面至关重要。在两只短毛家猫中也确认了FOP的临床和基因特征。
参考文献
  1. Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020 进行性骨化性纤维发育不良突变的ACVR1在发育中的斑马鱼中通过多种方式进行信号传导
  1. Allen, RS, Jones WD, Hale M, Warder BN Shore EM, and Mullins MC. Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish. J Bone Miner Res 38: 1364-1385, 2023 进行性骨化性纤维发育不良突变的I型BMP受体ACVR1在斑马鱼中减少了GS结构域的丝氨酸/苏氨酸需求
  1. Casal ML, Engiles JB, Zakošek Pipan M, Berkowitz A, Porat-Mosenco Y, Mai W, Wurzburg K, Xu MQ, Allen R, ODonnell PA, Henthorn PS, Thompson K, Shore EM. Identification of the identical human mutation in ACVR1 in two cats with fibrodysplasia ossificans progressiva. Vet Pathol 56: 614-618, 2019 在两只患有进行性骨化性纤维发育不良的猫中发现ACVR1的相同人类突变
  1. Chakkalakal SA, Shore EM. Heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 247-255, 2019 小鼠模型中的异位骨化与进行性骨化性纤维发育不良相关
  1. Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016 Palovarotene抑制异位骨化，维持携带人类ACVR1（R206H）进行性骨化性纤维发育不良（FOP）突变的小鼠的肢体活动和生长
  1. Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 Knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res 27: 1746-1756, 2012 一个Acvr1插入小鼠具有进行性骨化性纤维发育不良
  1. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015 ACVR1(R206H)受体突变通过对activin A的反应性引起进行性骨化性纤维发育不良
  1. Kaplan FS, Chakkalakal SA, Shore EM. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech 5: 756-762, 2012 进行性骨化性纤维发育不良：骨骼蜕变的机制和模型
  1. Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia ossificans progressiva: A clue from the fly? Calcif Tiss Int 47: 117-125, 1990 进行性骨化性纤维发育不良：来自果蝇的线索？
  1. LaBonty M, Yelick PC. Animal models of fibrodysplasia ossificans progressiva. Dev Dyn 247: 279-288, 2018 进行性骨化性纤维发育不良的动物模型
  1. LaBonty M, Yelick PC. An adult zebrafish model of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 155-163, 2019 一个成年斑马鱼模型的进行性骨化性纤维发育不良
  1. Le VQ, Anderson E, Akiyama T, Wharton KA. Drosophila models of FOP provide mechanistic insight. Bone 109: 192-200, 2018 果蝇模型为FOP提供了机制上的见解
  1. Le VQ, Wharton KA. Hyperactive BMP signaling induced by ALK2 (R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva. Dev Dyn 241: 200-214, 2012 由ALK2（R206H）诱导的超活跃BMP信号在经典进行性骨化性纤维发育不良的果蝇模型中需要II型受体的功能
  1. Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun 9(1):471. doi: 10.1038/s41467-018-02872-2, 2018 依赖activin的信号在纤维/脂肪前体中引起进行性骨化性纤维发育不良
  1. Mucha BE, Hashiguchi M, Zinski J, Shore EM, Mullins MC. Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone 109: 225-231, 2018 导致人类进行性骨化性纤维发育不良（FOP）的变异BMP受体突变在斑马鱼中显示出BMP配体独立的受体激活
  1. Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embargo ventralization. J Clin Invest 119: 3462-3472, 2009 进行性骨化性纤维发育不良的R206H ACVR1突变激活了BMP独立的软骨发生和斑马鱼的腹侧化
原文
  1. Animal Models of FOP
      2. Animal models of FOP are important in deciphering the pathophysiology of FOP and in testing possible therapies. Laboratory-generated animal models of FOP in Drosophila, zebrafish and mice with features of FOP have provided the opportunity to better understand the biology of BMP pathway-associated HO and to study the effectiveness and safety of currently available and emerging therapies (Kaplan et al., 1990; Shen et al., 2009; Chakkalakal et al., 2012; Kaplan et al., 2012; Le et al., 2012; LaBonty & Yelick, 2018; Le & Wharton, 2018; Mucha et al., 2018; LaBonty & Yelick, 2019; Allen et al., 2020; Allen et al., 2023). Mouse conditional knock-in models of the classic FOP mutation have been developed and are critical in establishing specificity of treatment for FOP as well as investigating many previously unexplored aspects of the condition (Hatsell et al., 2015; Chakkalakal et al, 2016; Lees-Shepard et al., 2018; Chakkalakal & Shore, 2019). FOP was confirmed clinically and genetically in two domestic shorthaired cats (Casal et al., 2019).
      References
      Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020
      Allen, RS, Jones WD, Hale M, Warder BN Shore EM, and Mullins MC. Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish. J Bone Miner Res 38: 1364-1385, 2023
      Casal ML, Engiles JB, Zakošek Pipan M, Berkowitz A, Porat-Mosenco Y, Mai W, Wurzburg K, Xu MQ, Allen R, ODonnell PA, Henthorn PS, Thompson K, Shore EM. Identification of the identical human mutation in ACVR1 in two cats with fibrodysplasia ossificans progressiva. Vet Pathol 56: 614-618, 2019
      Chakkalakal SA, Shore EM. Heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 247-255, 2019
      Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016
      Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 Knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res 27: 1746-1756, 2012
      Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015
      Kaplan FS, Chakkalakal SA, Shore EM. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech 5: 756-762, 2012
      Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia ossificans progressiva: A clue from the fly? Calcif Tiss Int 47: 117-125, 1990
      LaBonty M, Yelick PC. Animal models of fibrodysplasia ossificans progressiva. Dev Dyn 247: 279-288, 2018
      LaBonty M, Yelick PC. An adult zebrafish model of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 155-163, 2019
      Le VQ, Anderson E, Akiyama T, Wharton KA. Drosophila models of FOP provide mechanistic insight. Bone 109: 192-200, 2018
      Le VQ, Wharton KA. Hyperactive BMP signaling induced by ALK2 (R206H) requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva. Dev Dyn 241: 200-214, 2012
      Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun 9(1):471. doi: 10.1038/s41467-018-02872-2, 2018
      Mucha BE, Hashiguchi M, Zinski J, Shore EM, Mullins MC. Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone 109: 225-231, 2018
      Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embargo ventralization. J Clin Invest 119: 3462-3472, 2009

14. FOP的预后

尽管广泛的异位骨化（HO）和严重的残疾，一些患者仍能在七十岁时过上有生产力的生活。然而，大多数患者则因严重的胸壁受限而导致心肺并发症而早逝。
为构建进行性骨化性纤维发育不良（FOP）临床分期的概念框架，已经提出了一些工具。这些FOP的分期措施评估了异位骨化和加速关节功能障碍（由于先天性异常）对进行日常功能活动能力的影响，因此，从一个阶段到下一个阶段功能丧失的延迟或缺乏进展，代表了药物试验疗效的最终检验。这一框架将作为FOP进展的预测工具，同时为验证治疗干预提供关键机会。最终，这一临床分期将有助于推动该领域向更早的干预迈进，尤其是在疾病修改疗法可能最有效的阶段。
在过去十年中，FOP研究已确定了强有力的基因、分子和细胞治疗靶点。临床试验正在进行中，更多试验即将展开。未来充满希望。
参考文献
  1. Kaplan FS. The key to the closet is the key to the kingdom: a common lesson of rare diseases. Orphan Disease Update 24(3): 1-9, 2006 橱柜的钥匙就是王国的钥匙：一种关于罕见疾病的共同教训
  1. Kaplan FS. The skeleton in the closet. Gene 528: 7-11, 2013 不为人知的骨架
  1. Pignolo RJ, Kaplan FS. Clinical staging of fibrodysplasia ossificans progressiva. Bone 109: 111-114, 2018 进行性骨化性纤维发育不良的临床分期
原文
  1. Prognosis of FOP
      2. Despite widespread HO and severe disability, some patients live productive lives into their seventh decade. Most, however, succumb earlier from cardiopulmonary complications of severe restrictive chest wall involvement (Kaplan, 2006; Kaplan, 2013).
      Tools to construct a conceptual framework for the clinical staging of FOP have been proposed. These staging measures for FOP assess the influence of HO and accelerated joint dysfunction (due to congenital abnormalities) on the ability to perform common functional activities, and thus a delay or lack of progression of functional loss from one stage to the next represents the ultimate test of efficacy for drug trials. This framework will serve both as a prediction tool for FOP progression as well as a critical opportunity to substantiate therapeutic interventions. Ultimately, this clinical staging will aid the field in moving toward earlier intervention at a stage when disease-modifying therapies may be most efficacious (reviewed in Pignolo & Kaplan, 2018).
      Over the past decade, FOP research has identified robust genetic, molecular and cellular targets for therapy. Clinical trials are underway, and more are set to occur. There is hope for the future.
      References
      Kaplan FS. The key to the closet is the key to the kingdom: a common lesson of rare diseases. Orphan Disease Update 24(3): 1-9, 2006
      Kaplan FS. The skeleton in the closet. Gene 528: 7-11, 2013
      Pignolo RJ, Kaplan FS. Clinical staging of fibrodysplasia ossificans progressiva. Bone 109: 111-114, 2018

15. FOP治疗评估的挑战

进行性骨化性纤维发育不良（FOP）的急性发作是偶发的，且不可预测，患者在疾病进展速度上存在很大的个体差异。几项关于FOP自然历史的大型研究证实，尽管描述了特征性的组织学发展模式，但仍然无法预测FOP急性发作的发生、持续时间或严重程度。FOP的稀有性和该病不可预测的特质使得评估任何的治疗干预变得极其困难，这一点早在1918年就被朱利叶斯·罗森斯廷所确认：
“该疾病使用各种疗法和替代疗法进行治疗，以应对其代谢障碍；这些疗法的效果各有差异，通常只有最初的医生会观察到显著的成功，但在其他人看来则完全失败。在许多情况下，疾病症状常常会自发消失，因此（任何治疗）的疗效不应被完全认可。”
这些话在今天仍然与一个世纪前的表述一样真实。随着FOP基因的发现以及对FOP病理和分子遗传学的理解加深，新的药物策略正在出现，以期能有效治疗FOP。目前，医生面临着越来越多的潜在医疗干预选择。然而，目前使用这些药物治疗FOP的临床经验大多还是个案报告。
在本报告的下一部分，我们将回顾用于管理FOP患者症状的主要药物类别，并提供对这些药物使用的适应症和禁忌症的看法。
参考文献
  1. Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017 针对第二骨架的艰巨目标：进行性骨化性纤维发育不良（FOP）的治疗前景
  1. Rosenstirn J. A contribution to the study of myositis ossificans progressiva. Ann Surg 68: 485-520, 591637, 1918 对进行性骨化性肌炎研究的贡献
原文
  1. Challenges of Therapeutic Assessment in FOP
      2. Flare-ups of FOP are sporadic and unpredictable, and there is great individual variability in the rate of disease progression. Several large studies on the natural history of FOP have confirmed that it is impossible to predict the occurrence, duration or severity of an FOP flare-up, although characteristic anatomic patterning has been described. The rarity of FOP and the unpredictable nature of the condition make it extremely difficult to assess any therapeutic intervention, a fact recognized as early as 1918 by Julius Rosenstirn (Rosenstirn, 1918):
      “The disease was attacked with all sorts of remedies and alternatives for faulty metabolism; every one of them with more or less marked success observed solely by its original author but pronounced a complete failure by every other follower. In many cases, the symptoms of the disease disappear often spontaneously, so the therapeutic effect (of any treatment) should not be unreservedly endorsed.”
      These words ring true today as they did when they were written a century ago. With the discovery of the FOP gene and emerging understanding of the pathology and molecular genetics of FOP, new pharmacologic strategies are emerging to definitively treat FOP. Presently, physicians are faced with an increasing number of potential medical interventions. At present, clinical experience using these medications for FOP is mostly anecdotal (Kaplan et al., 2017).
      In the next section of this report, we will review the major classes of medications that are being used to manage symptoms in patients who have FOP. We will provide a perspective on indications and contraindications for the use of such medications.
      References
      Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017
      Rosenstirn J. A contribution to the study of myositis ossificans progressiva. Ann Surg 68: 485-520, 591637, 1918

第四章. 基于病理学与病理生理学的FOP治疗

我们强调，本报告反映了作者对各种症状调节药物类别的经验和观点，仅作为该争议性治疗领域的指导。尽管每个患有进行性骨化性纤维发育不良（FOP）的人在身体特征上有共同点，但个体之间的差异可能会影响任何药物或药物类别的潜在益处或风险。是否使用或停用特定药物，最终应由患者本人及其医生共同做出决定。
原文
We emphasize that this report reflects the authors’ experience and opinions on the various classes of symptom-modifying medications, and is meant only as a guide to this controversial area of therapeutics. Although there are common physical features shared by every person who has FOP, there are differences among individuals that may alter the potential benefits or risks of any medication or class of medications discussed here. The decision to use or withhold a particular medication must ultimately rest with an individual patient and his or her physician.

1. 简介

FOP（进行性骨化性纤维发育不良）的最终治疗可能将基于对该疾病的细胞和分子病理生理学的综合认识。我们当前知识的简要概述见图1。多篇关于FOP治疗的综述提供了背景参考资料，但感兴趣的临床医生可以参考这些指南以获取关于症状治疗的最新综述。
参考文献
  1. Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008 进行性骨化性纤维发育不良
  1. Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017 为“第二副骨架”设定难以攻克的目标：进行性骨化性纤维发育不良 (FOP) 的治疗前景
  1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10 (S-2): 437-448, 2013 进行性骨化性纤维发育不良 (FOP)：诊断、管理与治疗前景
原文
1. Introduction
The ultimate treatment of FOP will likely be based on integrated knowledge of the cellular and molecular pathophysiology of the condition. An abbreviated outline of our current knowledge is presented in Figure 1. Several reviews of treatment in FOP provide general background references (Kaplan et al., 2008; Pignolo et al., 2013; Kaplan et al., 2017) but interested clinicians are guided to these guidelines for the most recent review of symptomatic treatment.
References
Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008
Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017
Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10 (S-2): 437-448, 2013

2. 皮质类固醇

基于类固醇强效抗炎作用的合理使用，尤其是在 FOP（进行性骨化性纤维发育不良）爆发的早期阶段，是根据其已知的抗炎效果，以及有关炎症诱发 FOP 发作的重要性的最新研究发现。
FOP 社区广泛的临床观察报告显示，在爆发的前 24 小时内开始为期 4 天的高剂量类固醇治疗，可能有助于减轻疾病早期阶段的剧烈炎症和组织水肿。在针对全球超过 500 名患者的 FOP 爆发评估中，记录了 198 次治疗，其中抗炎药物是最常使用的治疗方式。75% 的患者在肢体部位的爆发中使用了短期糖皮质激素进行症状治疗。55% 的患者报告糖皮质激素偶尔能改善症状，31% 表示它总能产生效果。然而，只有 12% 的患者报告在使用糖皮质激素后爆发完全缓解。43% 的患者在完成糖皮质激素疗程后的 1 至 7 天内出现了症状反弹。
FOP 中的异位骨化（HO）过程是分阶段发展的。在非常早期阶段，表现为强烈的炎症浸润。类固醇通过多种机制抑制炎症反应。然而，这一阶段持续的时间以及类固醇的使用期限尚需进一步研究。
类固醇的使用应限制在以下情况：
  1. 非常早期症状治疗适用于爆发影响到以下部位的情况：
      • 主要关节（如髋关节）
      • 下颌
      • 下颌下区域
  1. 预防在严重软组织损伤（如严重创伤）后发生的爆发。
  1. 预防在紧急、择期、重大或小型手术（如牙科手术、尿道下裂修复术、阑尾切除术等）中的爆发（围手术期使用），因为这可能减少异位骨化（HO）发生的可能性。
不建议使用糖皮质激素来对颈部或躯干的爆发进行症状治疗，因为这些爆发往往持续时间长、容易复发，并且很难确定其真正的发作时间。虽然在某些罕见情况下，可以短期使用糖皮质激素来打破儿童早期经常出现的反复爆发循环，或缓解难以控制的疼痛，但这种方法的效用尚未广泛认可，因为在停止激素治疗后，爆发往往会迅速复发。
糖皮质激素在爆发早期、特别是在影响到大关节活动时的前24小时内使用效果最好，也可在严重软组织创伤后预防性使用，或者在围手术期使用。激素的剂量取决于体重。
对于急性爆发，常用的泼尼松剂量为每天2毫克/公斤（最多不超过100毫克），每天服用一次，持续不超过4天。为了尽量减少对下丘脑-垂体-肾上腺轴的抑制，药物应在早晨服用。然而，有些患者可能更适合将剂量分为每天两次服用。也可使用等效剂量的其他类固醇药物。如果症状顽固，可能需要重复使用激素，且根据情况可以采用10天至2周的逐渐减量方案。
对于手术预防性用药，手术时应使用1.6毫克/公斤（最高80毫克）的注射用美卓乐。如果患者可以口服药物，则手术当天和手术后连续3天每天服用2毫克/公斤的泼尼松。总共应服用四天的剂量。
根据一项国际前瞻性自然史研究的数据，36个月内，79.8%的患者启动了新的药物治疗，其中32.5%使用了糖皮质激素。
另外，高剂量的静脉注射激素冲击疗法也可以考虑，但必须在住院期间进行，监测可能的副作用如高血压。
在停用泼尼松后，可以使用非甾体抗炎药（NSAIDs）或COX-2抑制剂（联合使用白三烯抑制剂）来缓解爆发期间的症状。长期使用糖皮质激素治疗FOP并不可取，因为长期使用可能导致肾上腺抑制以及其他副作用，如骨质疏松症和医源性库欣综合征。
糖皮质激素是处理FOP下颌下爆发的重要组成部分。FOP患者的下颌下肿胀可能是医疗急症，需要采取严密的预防措施，以避免严重的临床恶化。这些措施包括早期识别下颌下爆发，避免损伤部位的操作，监控呼吸道、预防吸入、提供营养支持（因为吞咽困难），并使用糖皮质激素。下颌下区域和下颌的爆发可能会更加危险，可能需要较长时间使用糖皮质激素，并逐渐减量，直至急性肿胀消退。
FOP爆发通常由过度使用或软组织损伤引起。泼尼松——1-2毫克/公斤，每天一次，连续3-4天，通常用于预防严重软组织损伤后的爆发。对于轻微碰撞或擦伤不应使用泼尼松，按照指示在牙科或手术过程中预防性使用。
尽管建议患者在爆发的早期或重大创伤后立即联系医生，但很多患者会觉得家中备有紧急泼尼松药物更为安心。实践表明，“口袋里的药”方案是可行且安全的，并且减少了急诊和住院的次数。
参考文献
  1. Cruz-Topete D, Cidlowski JA. One hormone two actions: anti and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22: 20-32, 2015 一种激素，两种作用：糖皮质激素的抗炎与促炎作用
  1. Hapgood JP, Avenat C, Moliki JM. Glucocorticoid-independent modulation of GF activity: Implications for immunotherapy. Pharmacol Ther 165: 93-113, 2016 糖皮质激素非依赖性调节生长因子活性：对免疫治疗的启示
  1. Janoff HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996 纤维发育不良性骨化石化症患者的下颌下肿胀
  1. Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89: 347-357, 2007 造血干细胞对异位骨生成的贡献
  1. Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016 为FOP提供免疫力并捕捉异位骨化
  1. Kaplan FS, Shore EM, Gupta R, Billings PC, Glaser DL, Pignolo RJ, Graf D, Kamoun M. Immunological features of fibrodysplasia ossificans progressiva and the dysregulated BMP4 Pathway. Clin Rev Bone & Miner Metab 3: 189-193, 2005 纤维发育不良性骨化石化症的免疫学特征及BMP4通路失调
  1. Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31:650-656, 2016 纤维发育不良性骨化石化症爆发的自然历史：全球综合评估
  1. Pignolo RJ, Baujat G, Brown M, De Cunto C, Hsiao E, Keen R, Al Mukaddam M, Le Quan Sang K, Wilson A, Marino R, Strahs A, Kaplan F. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genetics in Medicine 24: 2422-2433, 2022 FOP的自然历史：一项全球性36个月的前瞻性研究
  1. Rhen T & Cidlowski JA. Anti-inflammatory action of glucocorticoids – new mechanisms for old drugs. N Engl J Med 353: 1711-1723, 2005 糖皮质激素的抗炎作用——老药新机制
  1. Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6: 518-527, 2010 异位骨形成的遗传性人类疾病
  1. Sinha A, Bagga A. Pulse steroid therapy. Indian J Pediatrics 75: 1057-1066, 2008 激素冲击治疗
  1. van Staa TP, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18: 913-918, 2003 儿童口服糖皮质激素引发骨折的风险
  1. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, Nobuhiro K, Fukuda T, Mishina Y, Peterson RT, Bloch KD. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med 14: 1363-1369, 2008 抑制BMP I型受体减少异位骨化
原文
  1. Corticosteroids in FOP
      2. The rational use of corticosteroids early in the course of an FOP flare-up is based primarily on its potent anti-inflammatory effects (Rhen & Cidlowski, 2005; Hapgood et al., 2016) and on emerging knowledge of the importance of inflammatory triggers in FOP flare-ups (Kaplan et al., 2005; Kaplan et al., 2007; Yu et al., 2008; Kaplan et al., 2016).
      Widespread favorable anecdotal reports from the FOP community suggest that a brief 4-day course of highdose corticosteroids, begun within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. In a global assessment of FOP flare-ups involving more than 500 individuals, 198 treatments were reported. Anti-inflammatory agents were the most common. Seventy-five percent used short-term glucocorticoids as a symptomatic treatment for flare-ups at appendicular sites. Fifty-five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare-up with glucocorticoids. Forty-three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids (Pignolo et al., 2016). The process of heterotopic ossification (HO) in FOP develops in stages. The very early stage is characterized by intense inflammatory infiltrates (Shore & Kaplan, 2010). Corticosteroids suppress inflammation by multiple mechanisms (Cruz-Topete & Cidlowski, 2015). How long this stage lasts, and the duration of corticosteroid use still needs to be elucidated.
      The use of corticosteroids should be restricted to:
      1. The extremely early symptomatic treatment of flare-ups that affect:
          • Major joints (e.g., hip)
          • The jaw
          • The submandibular area
      1. The prevention of flare-ups following major soft tissue injury (severe trauma)
      1. The prevention of flare-ups in emergent, elective, major or minor surgeries such as dental surgery, hypospadias repair, appendectomies, etc. (peri-operative use) as they may decrease the likelihood of HO.
      Corticosteroids should not generally be used for the symptomatic treatment of flare-ups involving the neck or trunk due to the long duration and recurring nature of these flare-ups, and the difficulty in assessing the true onset of such flare-ups. On rare occasions, a brief course of corticosteroids may be used to break the cycle of recurrent flare-ups often seen in early childhood or to mitigate intractable pain. However, the utility of this approach is not widely accepted, as flare-ups tend to recur rapidly following cessation of corticosteroid therapy.
      Corticosteroids are most effective if used within the first 24 hours of a new flare-up that affects the movement of a major joint, prophylactically following major soft tissue trauma, or peri-operatively as noted above. The dose of corticosteroids is dependent upon body weight.
      A typical dose of prednisone for acute flare-ups is 2 mg/kg/day (up to 100 mg), administered as a single daily dose for no more than 4 days (Table 1). In order to have the least suppressive effect on the hypothalamic-pituitary-adrenal axis, the medication should be taken in the morning. However, some patients may tolerate the medication better if divided into twice per day dosing. Equivalent doses of other steroids can also be used. A repeat course may be needed for refractory symptoms and a tapering course may be prescribed over 10 days to 2 weeks maximum if symptoms warrant.
      For surgical prophylaxis, solumedrol (1.6 mg/kg; up to 80 mg) should be administered at the time of surgery. If the patient can take oral meds, then prednisone 2mg/kg should be administered once daily on the day of surgery and for 3 days after surgery. In summary, steroids should be administered for a total of four daily doses.
      Data from an international prospective, natural history study showed that throughout the 36-month study period, 79.8% of individuals initiated a new medication, of which glucocorticoids represented 32.5% (Pignolo, et al., 2022).
      Alternatively, high dose intravenous corticosteroid pulse therapy may be considered, but must be performed with an inpatient hospitalization to monitor for potentially dangerous side-effects of hypertension (Sinha & Bagga, 2008; Table 1).
      When prednisone is discontinued, a non-steroidal anti-inflammatory medication or COX-2 inhibitor (in conjunction with a leukotriene inhibitor) may be used symptomatically for the duration of the flareup (Table 1). Corticosteroids should not be used for the long-term chronic treatment of FOP as chronic dependence due to adrenal suppression and other steroid-associated side-effects such as osteoporosis and iatrogenic Cushing’s disease will likely result.
      Corticosteroids are an important component in the management of a submandibular flare-up of FOP. Submandibular swelling in patients who have FOP can be a medical emergency and requires intensive precautionary measures to avoid catastrophic clinical deterioration. These measures include early identification of the submandibular flare-up, avoidance of lesional manipulation, airway monitoring, aspiration precautions, nutritional support due to the difficulty in swallowing, and the use of corticosteroids. The potentially dangerous nature of flare-ups in the submandibular region and jaw may dictate a slightly longer use of corticosteroids with an appropriate taper for the duration of the flare-up or until the acute swelling subsides (Janoff et al., 1996).
      Flare-ups often result from over-use and soft tissue injuries. Prednisone – 1-2 mgs/kg, (per oral) once daily for 3-4 days is often used in attempt to prevent flare-up after severe soft-tissue injury. Do not use after minor bumps or bruises. Use prednisone prophylactically as directed for dental or surgical procedures.
      While patients are encouraged to contact their physician at the earliest sign of a flare-up or following major trauma, many find it comforting to have a supply of prednisone on hand at home in case of an emergency. This “pill in the pocket” approach has been feasible and safe with a monitored reduction in emergency room and hospital visits.
      References
      Cruz-Topete D, Cidlowski JA. One hormone two actions: anti and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22: 20-32, 2015
      Hapgood JP, Avenat C, Moliki JM. Glucocorticoid-independent modulation of GF activity: Implications for immunotherapy. Pharmacol Ther 165: 93-113, 2016
      Janoff HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996
      Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89: 347-357, 2007
      Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016
      Kaplan FS, Shore EM, Gupta R, Billings PC, Glaser DL, Pignolo RJ, Graf D, Kamoun M. Immunological features of fibrodysplasia ossificans progressiva and the dysregulated BMP4 Pathway. Clin Rev Bone & Miner Metab 3: 189-193, 2005
      Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31:650-656, 2016
      Pignolo RJ, Baujat G, Brown M, De Cunto C, Hsiao E, Keen R, Al Mukaddam M, Le Quan Sang K, Wilson A, Marino R, Strahs A, Kaplan F. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genetics in Medicine 24: 2422-2433, 2022
      Rhen T & Cidlowski JA. Anti-inflammatory action of glucocorticoids – new mechanisms for old drugs. N Engl J Med 353: 1711-1723, 2005
      Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6: 518-527, 2010
      Sinha A, Bagga A. Pulse steroid therapy. Indian J Pediatrics 75: 1057-1066, 2008
      van Staa TP, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18: 913-918, 2003
      Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, Nobuhiro K, Fukuda T, Mishina Y, Peterson RT, Bloch KD. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med 14: 1363-1369, 2008

3. 环氧合酶-2（COX-2）抑制剂和非甾体抗炎药（NSAIDs）

选择性环氧合酶-2（COX-2）抑制剂、非甾体类抗炎药（NSAIDs）和白三烯受体拮抗剂（如孟鲁司特）可能在管理FOP（进行性骨化性纤维发育不良）症状中发挥作用。
人体产生两类前列腺素：“生理性”前列腺素和“炎症性”前列腺素。生理性前列腺素在许多组织中正常产生，保护器官，如胃，免受代谢性损伤。而炎症性前列腺素在组织受损时产生，在炎症反应和组织修复中起关键作用。传统的NSAIDs，如阿司匹林、布洛芬和吲哚美辛，抑制这两类前列腺素的生成。选择性COX-2抑制剂则主要抑制炎症性前列腺素，较大程度上保留了生理性前列腺素的功能。
炎症性前列腺素是骨形态发生蛋白（BMP）在正常和异位骨形成中的协同刺激分子。在FOP患者中，尤其在疾病爆发期间，这些前列腺素在尿液中的含量升。这表明降低FOP患者中炎症性前列腺素的基础水平可能提高异位骨化（HO）发生的阈值，即使ACVR1基因异常活跃。
正如骨科文献所示，在实验动物中降低炎症性前列腺素的水平大大提高了外伤诱导HO的阈值，使异位骨的形成变得更加困难。在髋关节置换术中，术前和术后使用NSAIDs可预防HO的发生。
相比传统的NSAIDs，选择性COX-2抑制剂的胃肠道风险较低。其较长的半衰期也使其能够每天服用一到两次，从而有助于提高患者的依从性。
然而，选择性COX-2抑制剂在心血管和脑血管疾病高危患者中存在安全性问题。虽然COX-2对炎症性前列腺素的合成至关重要，但它也控制了前列腺环素的合成，而前列腺环素对于心脏和大脑血管的健康非常重要。
尽管存在这些担忧，对于心血管风险较低、胃肠道风险较高的患者，选择性COX-2抑制剂依然是一个合理选择，尤其是在需要间歇使用糖皮质激素治疗急性爆发的FOP患者中。目前，COX-2抑制剂塞来昔布（Celebrex）和依托考昔（Arcoxia）在许多国家可用，且显示出较低的胃肠道风险。塞来昔布的安全性和药代动力学数据也适用于儿科人群，目前正用于治疗幼年特发性关节炎患者。
关于NSAIDs和选择性COX-2抑制剂的研究结合了FOP实验室的重要发现，包括前列腺素的生成、肥大细胞的募集以及血管生成因子的释放。
尽管围绕选择性COX-2抑制剂存在争议，但非选择性抑制COX-1和COX-2的传统NSAIDs仍是FOP儿童和成人症状管理的备选方案。然而，长期使用NSAIDs可能增加严重胃肠道副作用的风险，特别是胃肠道出血。
数据表明，在国际前瞻性自然病程研究中，基线时最常使用的药物为非甾体类抗炎药，使用率为28.9%。
虽然尚无证据表明COX-2抑制剂或NSAIDs的长期使用能预防FOP的爆发，但它们可能在不能使用糖皮质激素时，对症管理爆发和慢性关节病有帮助。下一部分将讨论外用NSAIDs。
参考文献
  1. Brunnekreef J, Hoogervorst P, Ploegmakers MJ, Rijnen WH, Schreurs BW. Is etoricoxib effective in preventing heterotopic ossification after primary total hip arthroplasty? International Orthopaedics (SICOT) 37: 583-587, 2013 依托考昔在预防初次全髋关节置换术后异位骨化中的有效性？
  1. Convente MR, Wang H, Pignolo RJ, Kaplan FS, Shore EM. The immunological contribution to heterotopic ossification disorders. Curr Osteoporos Rep 13:116-124, 2015 免疫系统对异位骨化疾病的贡献
  1. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomized controlled trials. British Med J (Review) 325(7365): 619, 2002 塞来昔布治疗骨关节炎和类风湿性关节炎的疗效、耐受性及上消化道安全性：随机对照试验的系统性回顾
  1. DiCesare PE, Nimni ME, Pen L, Yazdi M, Cheung DT. Effects of indomethacin on demineralized boneinduced heterotopic ossification in the rat. J Orthop Res 9: 855-861, 1999 吲哚美辛对大鼠去矿化骨诱导的异位骨化的影响
  1. Feng X, Tian M, Zhang W, Mei H. Gastrointestinal safety of etoricoxib in osteoarthritis and rheumatoid arthritis: A meta-analysis. PLoS ONE 2018; 13(1): e0190798 依托考昔在骨关节炎和类风湿性关节炎中的胃肠道安全性：一项荟萃分析
  1. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 351: 1709-1711, 2004 Coxibs类药物与心血管疾病的关系
  1. Grosser T, Ricciotti E, Fitzgerald GA. The cardiovascular pharmacology of non-steroidal anti-inflammatory drugs. Trends Pharmacol Sci 38: 733-748, 2017 非甾体类抗炎药的心血管药理学
  1. Hochberg Mc. COX-2: where are we in 2003? Be strong and resolute: continue to use COX-2 selective inhibitors at recommended dosages in appropriate patients. Arthritis Res Ther 5: 28-31, 2003 COX-2：2003年的研究现状？保持坚强和决心：继续在适合患者中按照推荐剂量使用COX-2选择性抑制剂
  1. Joice M, Vasileiadis GI, Amanatullah DF. Non-steroidal anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty. Bone Joint J 100-B: 915-922, 2018 非甾体类抗炎药在全髋关节置换术后预防异位骨化中的应用
  1. Jones, MK, Wang H, Peskar BM, Levin E, Itani RM Sarfeh IJ, Tarnawski AS. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nature Med 5: 1418-1423, 1999 非甾体类抗炎药通过抑制血管生成的机制及其对癌症生长和溃疡愈合的影响
  1. Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflammation Res 49: 367-392, 2000 环氧合酶-2的多样化作用及其选择性抑制剂的可能应用
  1. Levitz CL, Cohen RB, Zasloff MA, Kaplan FS. The role of prostaglandins in bone formation. Abstracts from The First International Symposium on Fibrodysplasia Ossificans Progressiva, September 25-26, 1991, Philadelphia, Pennsylvania. Calcif Tissue Int 50: 385-388, 1992 前列腺素在骨形成中的作用
  1. Pignolo RJ, Baujat G, Brown M, De Cunto C, Hsiao E, Keen R, Al Mukaddam M, Le Quan Sang K, Wilson A, Marino R, Strahs A, Kaplan F. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genetics in Medicine 24: 2422-2433, 2022 进行性骨化性纤维发育不良的自然病程：一项为期36个月的全球前瞻性研究
  1. Sobel RE, Lovell DJ, Brunner HI, Weiss JE, Morris PW, et al. for the Pediatric Rheumatology Collaborative Study Group. Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the phase 4 registry. Pediatric Rheumatol Online J 12: 29, 2014 儿科风湿病协作研究小组：塞来昔布和非选择性非甾体类抗炎药在幼年特发性关节炎中的安全性：第四阶段注册研究结果
  1. Stempak D, Gammon J, Klein J, Koren G, Baruchel S. Single-dose and steady-state pharmacokinetics of celecoxib in children. Clin Pharmacol Ther 72: 490-497, 2002 塞来昔布在儿童中的单剂量和稳态药代动力学
  1. Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 351: 1707-1709, 2004 公共卫生的失败——罗非昔布、默克公司与FDA
  1. Van Ryn J, Pairet M. Clinical experience with cyclooxygenase-2 inhibitors. Inflammation Res 48: 247254, 1999 COX-2抑制剂的临床经验
  1. Weinreb M, Suponitsky I, Keila S. Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow. Bone 120: 521-526, 1997 全身给予PGE2的促骨生成剂量可增加年轻大鼠骨髓的成骨能力
  1. White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 92: 411-418, 2003 塞来昔布用于关节炎试验中的心血管血栓事件
  1. White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 89: 425-430, 2002 使用COX-2特异性抑制剂塞来昔布与使用布洛芬或双氯芬酸的患者的血栓事件对比
原文
  1. Cyclo-Oxygenase-2 (COX-2) Inhibitors & NSAIDs in FOP
      2. Selective cyclo-oxygenase-2 (COX-2) inhibitors, non-steroidal anti-inflammatory medications (NSAIDs) and leukotriene receptor antagonists (montelukast) may have a role in the management of FOP symptoms.
      The body produces two types of prostaglandins: “physiological” prostaglandins and “inflammatory” prostaglandins. Physiological prostaglandins are normally produced in many of the body’s tissues and serve to protect organs, such as the stomach, from metabolic injury. Inflammatory prostaglandins are produced in response to injury and play a major role in the inflammatory response to tissue injury and repair. Traditional NSAIDs such as aspirin, ibuprofen, and indomethacin inhibit the formation of both physiological and inflammatory prostaglandins. The selective cyclo-oxygenase-2 (COX-2) inhibitors primarily inhibit inflammatory prostaglandins and leave most, but not all, of the physiological prostaglandins relatively intact (Katori & Majima, 2000; Van Ryn & Pairet, 2000).
      Inflammatory prostaglandins are potent co-stimulatory molecules along with BMPs in the induction of normotopic and heterotopic bone (Weinreb et al. 1997; Jones et al. 1999; Convente et al., 2015) and are elevated in the urine of patients who have FOP, especially during times of disease flare-up (Levitz et al., 1992). These observations suggest that lowering baseline levels of inflammatory prostaglandins in patients with FOP may raise the threshold for HO even in the presence of promiscuously active ACVR1.
      Studies in the orthopaedic literature have shown that lowering inflammatory prostaglandin levels in experimental animals dramatically raise the threshold for trauma-induced HO, thus, making it more difficult for heterotopic bone to form (DiCesare et al. 1991). Preoperative and postoperative treatment with NSAIDs in patients undergoing hip arthroplasty prevents HO (Brunnerkreef et al., 2013; Joice et al., 2018).
      Compared to the parent class of NSAIDs, the selective COX-2 inhibitors offer the possibility of a lower gastrointestinal risk profile. Also, the half-life of most COX-2 inhibitors is conducive to a once or twice daily dosage regimen, a factor which may help promote patient compliance (Deeks et al. 2002).
      However, substantial concerns have been raised about the safety of the COX-2 inhibitors in patients at high risk of cardiovascular and cerebrovascular disease (White et al. 2002; White et al. 2003; Grosser et al. 2017). Although COX-2 activity is necessary for the synthesis of inflammatory prostaglandins, it also controls the synthesis of prostacyclin, a prostaglandin that is essential for the health and patency of blood vessels, especially in the heart and brain.
      While concerns have been raised about all COX-2 inhibitors (Fitzgerald, 2004; Topol, 2004), selective COX-2 inhibitors remain a rational choice for patients at low cardiovascular risk who have had serious gastrointestinal events or in patients who are at high risk of serious gastrointestinal events, such as those with FOP who may need to use glucocorticoids intermittently for the treatment of acute flareups.
      At the present time, the COX-2 inhibitor celecoxib (Celebrex), as well as etoricoxib (Arcoxia) is available in many countries and exhibits reduced gastrointestinal risk compared with other NSAIDs (Feng et al. 2018). Presently, safety and pharmacokinetic data are available for celecoxib in the pediatric population (Stempak et al., 2002). This medication is being used in patients with juvenile idiopathic arthritis. The results of a multicenter pharmacovigilance study in the US, showed a good safety profile of celecoxib compared to nonselective NSAIDs at a minimum 12-month follow-up (Sobel et al. 2014).
      Studies on the NSAIDs and selective COX-2 inhibitors integrate important findings from the FOP laboratory on prostaglandin production, mast cell recruitment, and angiogenic factor release with the pathologic findings of severe inflammatory pre-osseous lesions of FOP. As with any condition, the relative risks and benefits of potential therapies must be weighed against the potential risks of the underlying condition being treated (Hochberg, 2003).
      With all of the controversy swirling around the selective cox-2 inhibitors, the standard NSAIDs, which inhibit both COX-1 and COX-2 non-selectively, remain an option to consider in the symptomatic management of children and adults with FOP (Table 1). As with the chronic use of all NSAIDs, the risks of serious gastrointestinal side-effects, especially gastrointestinal bleeding, are possible, and special precautions may be warranted in susceptible individuals.
      Data from an international prospective natural history study showed that at baseline the most common ongoing medications were non-steroidal anti-inflammatory drugs, used by 28.9 % of individuals (Pignolo et al., 2022).
      Finally, although there is no evidence that chronic treatment with COX-2 inhibitors or NSAIDs prevent flare-ups in FOP, COX-2 inhibitors or oral/topical NSAIDS may be helpful for symptomatic management of flare-ups and chronic arthropathy when corticosteroids are not indicated. Topical NSAIDs are discussed in the next section.
      References
      Brunnekreef J, Hoogervorst P, Ploegmakers MJ, Rijnen WH, Schreurs BW. Is etoricoxib effective in preventing heterotopic ossification after primary total hip arthroplasty? International Orthopaedics (SICOT) 37: 583-587, 2013
      Convente MR, Wang H, Pignolo RJ, Kaplan FS, Shore EM. The immunological contribution to heterotopic ossification disorders. Curr Osteoporos Rep 13:116-124, 2015
      Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomized controlled trials. British Med J (Review) 325(7365): 619, 2002
      DiCesare PE, Nimni ME, Pen L, Yazdi M, Cheung DT. Effects of indomethacin on demineralized boneinduced heterotopic ossification in the rat. J Orthop Res 9: 855-861, 1999
      Feng X, Tian M, Zhang W, Mei H. Gastrointestinal safety of etoricoxib in osteoarthritis and rheumatoid arthritis: A meta-analysis. PLoS ONE 2018; 13(1): e0190798
      Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 351: 1709-1711, 2004
      Grosser T, Ricciotti E, Fitzgerald GA. The cardiovascular pharmacology of non-steroidal anti-inflammatory drugs. Trends Pharmacol Sci 38: 733-748, 2017
      Hochberg Mc. COX-2: where are we in 2003? Be strong and resolute: continue to use COX-2 selective inhibitors at recommended dosages in appropriate patients. Arthritis Res Ther 5: 28-31, 2003
      Joice M, Vasileiadis GI, Amanatullah DF. Non-steroidal anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty. Bone Joint J 100-B: 915-922, 2018
      Jones, MK, Wang H, Peskar BM, Levin E, Itani RM Sarfeh IJ, Tarnawski AS. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nature Med 5: 1418-1423, 1999
      Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflammation Res 49: 367-392, 2000
      Levitz CL, Cohen RB, Zasloff MA, Kaplan FS. The role of prostaglandins in bone formation. Abstracts from The First International Symposium on Fibrodysplasia Ossificans Progressiva, September 25-26, 1991, Philadelphia, Pennsylvania. Calcif Tissue Int 50: 385-388, 1992
      Pignolo RJ, Baujat G, Brown M, De Cunto C, Hsiao E, Keen R, Al Mukaddam M, Le Quan Sang K, Wilson A, Marino R, Strahs A, Kaplan F. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genetics in Medicine 24: 2422-2433, 2022
      Sobel RE, Lovell DJ, Brunner HI, Weiss JE, Morris PW, et al. for the Pediatric Rheumatology Collaborative Study Group. Safety of celecoxib and nonselective nonsteroidal anti-inflammatory drugs in juvenile idiopathic arthritis: results of the phase 4 registry. Pediatric Rheumatol Online J 12: 29, 2014
      Stempak D, Gammon J, Klein J, Koren G, Baruchel S. Single-dose and steady-state pharmacokinetics of celecoxib in children. Clin Pharmacol Ther 72: 490-497, 2002
      Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 351: 1707-1709, 2004
      Van Ryn J, Pairet M. Clinical experience with cyclooxygenase-2 inhibitors. Inflammation Res 48: 247254, 1999
      Weinreb M, Suponitsky I, Keila S. Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow. Bone 120: 521-526, 1997
      White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 92: 411-418, 2003
      White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM, Geis GS, Lefkowith JB. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 89: 425-430, 2002

4. 局部镇痛药

局部非甾体类抗炎药物 (NSAIDs) 的潜在优势包括较低的全身吸收率、减少全身不良反应（如胃肠道毒性），并且可以直接应用于疼痛部位。有几种局部药物可用于治疗肌肉骨骼疼痛，如凝胶、喷雾或乳膏。一个研究比较了三种局部药物的效果，发现酮洛芬凝胶（2.5% w/w）在治疗急性软组织损伤时，比吡罗昔康凝胶（0.5% w/w）效果更好，且略好于双氯芬酸凝胶（1% w/w）。该研究通过评估治疗反应、改善僵硬、活动受限以及压力和运动时的疼痛来进行评估。此外，酮洛芬凝胶还具有“清凉效果”。在头对头的比较研究中，这些药物均每日使用三次。临床研究显示，局部NSAIDs通常用于急性疼痛时每日涂抹三次。
在进行性骨化性纤维发育不良（FOP）中，局部NSAIDs在临床经验中用于缓解急性和慢性疼痛，通常每天涂抹3-4次。在FOP相关的肌肉骨骼问题中，酮洛芬凝胶的起始剂量通常为5%的配制凝胶，并可能逐步提高到15%-20%。对于儿童，通常不超过10%的浓度，以避免全身吸收的风险。
其他局部药物包括利多卡因贴剂、凝胶、乳膏或喷雾（市场上有高达5%的配方）。局部利多卡因适用于局部神经性疼痛的患者。辣椒碱乳膏是从辣椒中提取的一种生物碱，认为其可以耗竭初级传入（感觉）神经元中的P物质，因此可能在FOP的疼痛控制中具有理论上的优势；然而，临床经验极其有限，而且由于对其可能的反作用效果的担忧，需非常谨慎使用。
参考文献
  1. Asbill S, Sweitzer SM, Spigener S, Romero-Sandoval A. Compounded pain formulations: what is the evidence? Intl J Pharmaceutical Compounding 18: 278-286, 2014 复合疼痛配方：证据是什么？
  1. Branvold A & Carvalho M. Pain management therapy: the benefits of compounded transdermal pain medication. J Gen Practice 2: 1-8, 2014 疼痛管理治疗：复合透皮镇痛药的益处
  1. Patel RK, Leswell PF. Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group. Clin Ther 18:497-507, 1996 酮洛芬、吡罗昔康和双氯芬酸凝胶在普通科急性软组织损伤治疗中的比较
原文
  1. Topical Analgesics in FOP
      2. Potential advantages of topical Non-steroidal Anti-inflammatory Agents (NSAIDs) include lower initial rates of systemic absorption, reduced systemic adverse effects (including gastrointestinal toxicity) and directed application to area(s) of pain (Asbill et al., 2014; Branvold & Carvalho, 2014). Several topical agents, available as a gel, spray, or cream, are available for the treatment of musculoskeletal pain. In one study comparing three available topical applications, ketoprofen gel (2.5% w/w), was better than piroxicam gel (0.5% w/w), and slightly better than diclofenac gel (1% w/w) in the treatment of acute soft tissue injury that included a global assessment of treatment response, improvements in stiffness, restriction of mobility, and pain on pressure and movement (Patel and Leswell, 1996). Ketoprofen gel also has a reported "cooling effect". In a head-to-head comparison study, they were each applied three times daily. In clinical studies, topical NSAIDS are typically applied three times daily for acute pain.
      In FOP, topical NSAIDs have anecdotally been used for both acute and chronic pain and applied 3-4 times daily. In the use of ketoprofen gel for FOP musculoskeletal complaints, a compounded formulation of 5% gel is commonly the initial dose, with the potential for upward titration to 15-20%. Pediatric use typically does not exceed 10% gel due to the potential for systemic absorption.
      Other topical agents include lidocaine patch, gel, cream or spray (available over-the-counter in up to 5% formulations). Topical lidocaine is most appropriate for patients with well localized neuropathic pain. Capsaicin cream, an alkaloid derived from chili peppers and thought to deplete substance P from primary afferent (sensory) neurons may have a theoretical advantage for pain control in FOP; however, clinical experience is very limited and concern over paradoxical effects mandates its very cautious use.
      References
      Asbill S, Sweitzer SM, Spigener S, Romero-Sandoval A. Compounded pain formulations: what is the evidence? Intl J Pharmaceutical Compounding 18: 278-286, 2014
      Branvold A & Carvalho M. Pain management therapy: the benefits of compounded transdermal pain medication. J Gen Practice 2: 1-8, 2014
      Patel RK, Leswell PF. Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group. Clin Ther 18:497-507, 1996

5. 肥大细胞抑制剂

进行性骨化性纤维发育不良（FOP）急性发作的最典型特征之一是剧烈的肌肉水肿、纤维增生和早期前骨性FOP病变特有的血管生成，以及病变迅速扩散至邻近组织。一种病变可能在数小时内出现，并在一夜之间迅速增大到令人担忧的规模。FOP病变的突然出现和快速扩散表明，涉及多种炎症介质以及异常的结缔组织伤口反应，并暗示炎症肥大细胞及其介质在疾病过程扩展中可能发挥作用。
肥大细胞是身体结缔组织中的固有细胞，来源于骨髓。它们作为承诺但未终末分化的细胞在血液中循环，迁移到包括骨骼肌在内的多个组织中，在那里成熟并作为无害的旁观者存在，直到受到创伤或炎症刺激的诱发。肥大细胞与血管和神经密切相邻。在正常骨骼肌中，肥大细胞在肌肉束之间的结缔组织中分布稀疏。肥大细胞含有强效的存储化学颗粒，当释放到周围组织中时，可诱导水肿、纤维增生和血管生成。多年来，肥大细胞的作用并不明确，但现在看来，它们在组织修复和伤口愈合中发挥着重要作用。
当肥大细胞的招募和激活出现问题时，会导致严重的炎症反应。这种现象在皮肤和肺部的肥大细胞激活中早已被认识，分别引发荨麻疹和哮喘的症状。然而，对于深层组织（如骨骼肌）中的肥大细胞知之甚少。除非使用特殊染色方法，否则肥大细胞在显微镜下不易被观察到。肥大细胞受到多种外部和内部刺激的刺激，如内部免疫反应和外部组织损伤。
肥大细胞的颗粒中包含的物质包括组胺、肝素、促血管生成蛋白和基质降解酶，允许受损组织自我修复。肥大细胞释放的强效促血管生成蛋白包括碱性成纤维细胞生长因子、血管内皮生长因子和转化生长因子β。肥大细胞还释放多种导致炎症的分子，包括肿瘤坏死因子α、前列腺素和白三烯。这些物质在从肥大细胞释放后，影响着包括炎症、免疫功能、血管生成、纤维组织形成、细胞外组织重塑和组织修复等众多生物过程。
早期前骨性FOP病变特有的强烈炎症肌肉水肿、纤维增生和血管生成，以及这些病变沿着肌肉平面迅速扩散到邻近组织，提示肥大细胞在FOP过程中可能发挥作用。由于对骨骼肌中常驻肥大细胞的了解甚少，因此对正常骨骼肌、未受累的FOP肌肉、FOP病变、炎症性和遗传性肌肉疾病，以及实验性诱导的异位骨化动物模型中的肥大细胞分布进行了全面分析。
Gannon等（2001）的发现令人震惊且出乎意料。在FOP病变发展各个阶段都发现了炎症肥大细胞的动员和激活。这些数据证明了肥大细胞在FOP病变病理中的重要作用：
在进行性骨化性纤维发育不良（FOP）患者中，组织损伤导致巨噬细胞、肥大细胞和淋巴细胞迁移到外观正常的骨骼肌中。肥大细胞释放的介质刺激炎症水肿、纤维化和血管生成的循环，这一过程在不断扩展的FOP病变的前缘上被增强。肌肉组织内的反应性成纤维细胞产生蛋白质，导致肥大细胞的进一步增殖，形成自我维持的疾病过程升级，称为急性发作（flare-up）。最终，肥大细胞和结缔组织祖细胞释放的转化生长因子β限制了淋巴细胞的招募和迁移，从而限制了扩展病变的大小和范围，而在纤维增生病变核心的内源性ACVR1/ALK2过度活跃则通过内软骨化途径推动病变向骨化发展。
在进行性骨化性纤维发育不良（FOP）病变中观察到肥大细胞的动员，为评估抗肥大细胞疗法在限制FOP病变扩散方面提供了新的、之前未被认识的机会。在FOP小鼠模型中，评估了创伤后FOP病变，发现促炎细胞因子TNFα、IL-1β和IL-6在小鼠FOP病变和小鼠FOP肥大细胞中均显著升高且持续时间延长。重要的是，去除肥大细胞和巨噬细胞显著损害了FOP小鼠中由损伤引起的异位骨化。
肥大细胞、巨噬细胞、淋巴细胞及其相关的炎症介质也可能通过使用肥大细胞稳定剂、长效非镇静抗组胺药、白三烯抑制剂、非甾体抗炎药、c-kit酪氨酸激酶抑制剂和COX-2抑制剂来减少。肥大细胞膜稳定剂可能减少血管生成和趋化因子的释放，而抗组胺药和白三烯抑制剂可能减少释放介质的下游效应。在使用损伤诱导的构建性活跃转基因小鼠模型中，通过色洛芬（cromolyn）抑制肥大细胞导致异位骨化显著减少。色洛芬显著降低了肥大细胞的总数，并特别减少了在前骨化FOP病变中去颗粒化和休眠去颗粒化的肥大细胞数量。
c-kit酪氨酸激酶抑制剂伊马替尼（imatinib）已被证明可以诱导肥大细胞凋亡，并减少在跟腱损伤模型中的异位骨化，以及在损伤诱导的构建性活跃转基因小鼠模型中的FOP。伊马替尼已成功用于减轻严重哮喘中的气道高反应性和肥大细胞数量，并减轻FOP中的严重且持续的发作。孟鲁司特（montelukast）在FOP中也有偶然使用的报道，但作为肥大细胞抑制剂在FOP中的系统效力尚不明确。目前尚不清楚这些药物的最佳使用方法及其在FOP中的潜在长期疗效。
参考文献
  1. Brennan TA, Lindborg CM, Bergbauer CR, Wang H, Kaplan FS, Pignolo RJ. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone 109: 259-266, 2017 肥大细胞抑制作为进行性骨化性纤维发育不良（FOP）的治疗方法
  1. Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376: 19111920, 2017 伊马替尼对重度难治性哮喘患者的KIT抑制作用
  1. Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1 R206H mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018 去除肥大细胞和巨噬细胞损害Acvr1 R206H小鼠模型中进行性骨化性纤维发育不良的异位骨化
  1. Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva. Hum Pathol 32: 842-848, 2001 肥大细胞在进行性骨化性纤维发育不良中的作用
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原文
  1. Mast Cell Inhibitors in FOP
      2. Among the most typical features of FOP flare-ups are the intense muscle edema, fibroproliferation, and angiogenesis characteristic of early pre-osseous FOP lesions, and the rapid spread of the lesions into adjacent tissue. A lesion may appear within hours and can reach an alarming size literally overnight. The sudden appearance and rapid spread of an FOP lesion suggests involvement of a repertoire of inflammatory mediators along with an abnormal connective tissue wound response, and points to a potential role for inflammatory mast cells and their mediators in the extension of the disease process.
      Mast cells are indigenous cells in the body’s connective tissues and arise from the bone marrow. They circulate in the blood as committed, but not terminally differentiated cells, and migrate into numerous tissues including skeletal muscle where they mature and reside as harmless bystanders until provoked by a traumatic or inflammatory stimulus. Mast cells are found in close proximity to blood vessels and nerves. In normal skeletal muscle, mast cells are sparsely distributed in the connective tissues between the muscle bundles. Mast cells contain granules of potent stored chemicals that induce edema, fibroproliferation and angiogenesis when released into the surrounding tissue. For many years, the role of mast cells was unknown, but it now appears that they play an important role in tissue repair and wound healing (Kaplan, 2002).
      When mast cell recruitment and activation go awry, the process can lead to severe inflammatory reactions. This has long been recognized with mast cell activation in the skin and lungs, resulting in the symptoms of hives and asthma, respectively. However, very little is known about mast cells in the deeper tissues of the body such as the skeletal muscles. Mast cells are not easily visible microscopically unless special stains are used to detect them. Mast cells are stimulated by a myriad of external and internal stimuli such as internal immune responses and external tissue injury.
      Mast cells contain granules whose sequestered contents include histamine, heparin, angiogenic proteins, and matrix degrading enzymes that allow injured tissue to repair itself. Potent angiogenic proteins released by mast cells include basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta. Mast cells also release a litany of inflammation-causing molecules including tumor necrosis factor alpha, prostaglandins, and leukotrienes. Upon release from the mast cells, these substances influence a vast array of biological processes including inflammation, immune function, angiogenesis, fibrous tissue formation, extracellular tissue remodeling, and tissue repair (Kaplan, 2002).
      The intense inflammatory muscle edema, fibroproliferation, and angiogenesis characteristic of early pre-osseous FOP lesions and the rapid spread of these lesions along muscle planes into adjacent tissue suggested a potential role for mast cells in the FOP process. As little is known about the resident mast cells in skeletal muscle, a comprehensive analysis was undertaken of mast cell distribution in normal skeletal muscle, in uninvolved FOP muscle, in FOP lesions, in inflammatory and genetic muscle diseases, and in experimentally induced animal models of HO (Gannon et al., 2001; Brennan et al., 2017; Convente et al., 2018).
      The findings by Gannon et al. (2001) were startling and unexpected. Mobilization and activation of inflammatory mast cells was found at all stages of FOP lesional development. These data documented an important role for mast cells in the pathology of FOP lesions (Gannon et al., 2001):
      Tissue injury in FOP patients leads to macrophage, mast cell, and lymphocyte migration into normally appearing skeletal muscle. Mediators released by mast cells stimulate a cycle of inflammatory edema, fibrosis, and angiogenesis which is potentiated at the leading edge of an advancing FOP lesion. Reactive fibroblasts within the muscle tissue produce proteins which lead to further proliferation of mast cells and a self-sustaining escalation of the disease process known as a flare-up. Eventually, transforming growth factor beta, released by mast cells and connective tissue progenitor cells, limits the lymphocytic recruitment and migration and thus the size and extent of the expanding lesion, while endogenous over-activity of ACVR1/ALK2 in the core of the fibroproliferative lesion drives the lesion towards ossification through an endochondral pathway.
      The observation of mast cell mobilization in FOP lesions provided a novel and previously unrecognized opportunity to evaluate anti-mast cell therapies in limiting the spread of FOP lesions. In a mouse model of FOP, posttraumatic FOP lesions were evaluated and the proinflammatory cytokine response of TNFα, IL‐1β, and IL‐6 was found to be elevated and prolonged in murine FOP lesions and in murine FOP mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury‐induced HO in FOP mice (Brennan et al., 2017; Convente et al., 2018).
      Mast cells, macrophages, lymphocytes, and their associated inflammatory-mediators may also be reduced with the use of mast cell stabilizers, long-acting non-sedating antihistamines, leukotriene inhibitors, non-steroidal anti-inflammatory medications, c-kit tyrosine kinase inhibitors, and cox-2 inhibitors. Mast cell membrane stabilizers may reduce the release of angiogenic and chemotactic factors, while antihistamines and leukotriene inhibitors may reduce the downstream effects of released mediators (Simmons, 2004). Using an injury-induced, constitutively active transgenic mouse model of FOP mast cell inhibition by cromolyn resulted in a dramatic reduction of HO (Brennan et al., 2017). Cromolyn significantly decreases the total number of mast cells and specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous FOP lesions.
      The c-kit tyrosine kinase inhibitor imatinib has been shown to induce mast cell apoptosis and decrease HO in an Achilles tendon injury model of HO (Werner et al., 2013) as well as in an injury-induced, constitutively active transgenic mouse model of FOP (Wang et al., 2016). Imatinib has been successfully used to reduce airway hyper-responsiveness and mast cell number in severe asthma (Cahill et al., 2017) and to mitigate severe and unrelenting flare-ups in FOP (Kaplan et al., 2018; Kaplan et al., 2021). Montelukast has also been used anecdotally in FOP, but its systemic efficacy as a mast cell inhibitor in FOP is unknown. The optimal use of these medications and their potential longterm efficacy in FOP is presently unknown.
      References
      Brennan TA, Lindborg CM, Bergbauer CR, Wang H, Kaplan FS, Pignolo RJ. Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). Bone 109: 259-266, 2017
      Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376: 19111920, 2017
      Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1 R206H mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018
      Gannon FH, Glaser D, Caron R, Thompson LDR, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva. Hum Pathol 32: 842-848, 2001
      Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 346: 175-179, 2002
      Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E, Pignolo RJ. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 109: 276-280, 2018
      Kaplan FS, Teachey DT, Andolina JR, Siegel DM, Mancilla EE, Hsiao EC, Al Mukaddam M, Rocke DM, Pignolo RJ. Off-on-off-on use of imatinib in three children with fibrodysplasia ossificans progressiva. Bone 2021 Sep;150:116016
      Simmons FER. Advances in H 1 antihistamines. N Engl J Med 351: 2203-2217, 2004
      Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangiavini L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-65, 2016
      Werner CM, Zimmermann SM, Wurgler-Hauri CC, et al. Use of imatinib in the prevention of heterotopic ossification. HSSJ 9: 166–170, 2013

6. 双磷酸盐

双膦酸盐是一类强效药物，对骨重塑具有深远影响，其主要作用是缩短破骨细胞的寿命。因此，双膦酸盐被广泛用于治疗多种骨病，这些疾病中骨吸收超过骨形成，包括类固醇诱导的骨质疏松症、特发性骨质疏松症、成骨不全、佩吉特病、纤维发育不良和骨癌。
此外，双膦酸盐也被实验性和偶然地用于进行性骨化性纤维发育不良（FOP）患者的发作症状管理。第一种临床使用的双膦酸盐是依替膦酸，使用高剂量时可以强效抑制新形成的软骨和骨蛋白的矿化，已被提议作为FOP及其他异位骨化疾病的可能治疗方案。由于依替膦酸对骨矿化的抑制作用及其在高剂量下可能抑制骨化，研究人员对其在FOP中的应用进行了探讨。不幸的是，在高剂量和长时间使用时，依替膦酸导致骨软化症（骨骼变软），并影响整个骨骼系统的骨化，而不仅仅是“第二骨骼”的异位骨化。因此，其应用受到限制。此外，依替膦酸在美国也已被停用。
与依替膦酸不同，新的氨基双膦酸盐对抑制矿化或引起骨软化症没有显著影响。2005年，Schuetz及其同事报道了在高风险且已有异位骨化的患者中使用高剂量氨基双膦酸盐预防异位骨化复发的一般有益但偶然的效果，这些患者正在接受手术切除异位骨。五名患者中有一名被诊断为FOP。
新的氨基双膦酸盐在FOP的难治性发作症状治疗中被偶然使用了多年。在过去的15年中，FOP患者群体中的许多人曾经经验性地使用帕米膦酸来缓解难治性发作的症状，特别是对于那些持续时间较长或对类固醇无反应的发作。大约四分之三的患者报告发作的症状和体征迅速改善，而四分之一的患者报告没有症状或体征的改善。
重要的是，接受静脉氨基双膦酸盐治疗的患者似乎对后续发作的发生没有保护作用。尽管这些患者的偶然报告在科学上并不具备有效性，但它们构成了一组重要的偶然观察，促使在受控临床研究中进行进一步严格的科学研究。
在FOP发作的辅助症状治疗中使用的双膦酸盐方案在不同患者之间略有不同（取决于年龄、体重和受累部位），但总体上是相似的。最常用的方案在第五部分——药物类别（表1）中进行了总结。
在所有患者中，在治疗前监测血清钙，以确保其在正常范围内，因为低钙血症是使用静脉帕米膦酸或任何氨基双膦酸盐的禁忌。所有患者在治疗期间及之后都进行了足够的日常口服钙和维生素D补充。基线应同时检测血清钙、磷、白蛋白、碱性磷酸酶、25-羟基维生素D、尿素氮（BUN）、肌酐和完整的血细胞计数（CBC）。
治疗方案基于对儿童和青少年成骨不全的发布指南，因为该群体是已知接受静脉氨基双膦酸盐治疗的儿童和青少年中数量最大的。对这些儿童的治疗使我们能够推断FOP的方案和安全性数据。唑来膦酸在成人和儿童中的使用较为广泛，并提供了更短的治疗方案的机会。然而，年轻儿童的副作用尚不完全清楚，尤其在急性发作期间，更倾向于使用帕米膦酸。
两到三岁之间的患者以0.75 mg/kg/天的剂量接受帕米膦酸治疗，连续三天通过每次慢速静脉输注4-5小时。三岁以上的患者以1.0 mg/kg/天的剂量接受帕米膦酸治疗，连续三天，每日慢速静脉输注4-5小时，最大剂量为60毫克。第一轮治疗的第一天，患者接受半剂量。偶然报告较低总剂量的帕米膦酸（第2天和第3天的剂量为1/2）和显著更长的输注时间（8-10小时）良好耐受。三天的治疗周期仅应在难治性发作期间重复，每年不超过4次。
另一种方法是每隔大约一周给予静脉帕米膦酸，并评估患者在此期间是否有医疗反应。在许多情况下，发现两个剂量是足够的。帕米膦酸不应常规用于治疗发作。它主要应用于辅助治疗发作，而其他症状治疗方法未能有效时。
帕米膦酸应根据以下表格用生理盐水稀释（指南由F.H. Glorieux提供：蒙特利尔儿童施赖纳医院）：
帕米膦酸的毫克数
生理盐水的毫升数
毫升/小时
0-5 5.1-10 10.1-15 15.1-25 25.1-50 50.1-60
50 100 150 250 500 600
15 30 45 75 150 180
帕米膦酸盐的最大浓度应为0.1 mg/ml。输液结束时应冲洗静脉输液管，以确保完整剂量的输送。
在进行性骨化性纤维发育不良（FOP）患者中，静脉注射帕米膦酸盐的副作用包括流感样症状，如发热、寒战和肌肉酸痛。这些症状通常可以通过预先给予对乙酰氨基酚来减轻。一名患者因在接受帕米膦酸盐治疗之前血液中维生素D水平过低而出现抽搐（肌肉不自主收缩），另一名患者在静脉注射部位出现外周静脉炎（静脉炎），需要住院静脉抗生素治疗。
一份已发表的病例报告记录了一名儿童在接受每三周60毫克静脉注射帕米膦酸盐治疗两年后出现医源性骨质过度密度增生（骨硬化症）。该儿童并未患有FOP，其累积剂量远远超过了任何已发表的关于帕米膦酸盐在骨骼疾病中使用的建议剂量。
有几个重要且罕见但严重的并发症需要注意，包括下颌骨坏死（ONJ）和低能量的非典型股骨骨折。以下参考文献详细回顾了这些罕见但严重的并发症。在开始使用双膦酸盐之前，患者应尽可能进行牙科检查。
双膦酸盐具有较长的半衰期，可以在输注后多年驻留在骨骼中。在有生育潜力的女性中，双膦酸盐对未来妊娠中胎儿的影响尚不清楚。
最近的一项研究显示，抑制破骨细胞不会影响FOP相关突变增强的异位骨化，因此，氨基双膦酸盐对异位骨化的影响（如果有的话）并非由于抗破骨细胞活性，而是通过其他尚未深入研究的机制。显然，如果氨基双膦酸盐在治疗FOP发作中确实有效，则必须存在一种作用机制与破骨细胞抑制有显著不同，并且相对短暂的机制，这种机制才使药物在正常骨骼中产生有益效果。
一个引人入胜的研究方向涉及炎症细胞在触发异位骨化中的作用。Kan及其同事表明，系统性施用双膦酸盐强烈且特异性地抑制单核细胞，并导致在BMP4转基因小鼠模型中显著抑制创伤诱导的异位骨化。
静脉注射氨基双膦酸盐还被发现能够调节循环中的巨噬细胞和多种淋巴细胞亚群，并可能是其导致流感样症状等剂量相关副作用的原因。我们尚未排除氨基双膦酸盐可能影响FOP病变中早期淋巴细胞和单核细胞渗透的可能性。此外，氨基双膦酸盐可能直接抑制在FOP中具有关键作用的巨噬细胞和单核细胞的代谢活性。
几项研究提供了一些额外的线索。这些研究记录了氨基双膦酸盐通过降低癌症患者骨转移的血清血管内皮生长因子（VEGF）和基础成纤维细胞生长因子（bFGF）水平所表现出的强大抗血管生成效果。有力的证据表明，氨基双膦酸盐通过抑制多种依赖于异戊烯基化的信号通路来抑制内皮细胞的粘附、迁移和生存。其他独立研究显示，氨基双膦酸盐通过抑制内皮细胞分化具有强大的抗血管生成特性。综合来看，这些数据强烈暗示氨基双膦酸盐可能是强效的抗血管生成剂。
氨基双膦酸盐可能影响FOP病变的其他机制包括对快速分裂细胞群体的直接抑制。此类效果在研究氨基双膦酸盐对癌细胞的体外影响时已被注意到。帕米膦酸盐和佐膦酸盐可能会影响FOP早期病变中的一种或多种细胞类型。另一项研究表明，氨基双膦酸盐在体外导致成骨细胞凋亡并抑制骨小结的形成，这表明氨基双膦酸盐可能对抑制成骨细胞的能力产生直接影响，尤其是在FOP中的早期骨小结。
目前尚不清楚双膦酸盐是否对发作有影响，尽管根据经验，它们似乎在一些患者中减少了发作症状。与所有药物一样，需要仔细评估风险和收益。只有在体外和体内进行严格的对照研究，以及安慰剂对照临床试验，才能明确解读这些可能性，并为确定氨基双膦酸盐是否在FOP治疗中具有有益作用提供坚实的理论基础。
最重要的是，静脉注射氨基双膦酸盐用于预防和治疗与类固醇相关的骨质流失或原发性骨质疏松症，这是FOP患者常见的问题。牙医在进行任何双膦酸盐使用时应知晓。
值得注意的是，地诺单抗（Denosumab）是一种针对RANK配体的单克隆抗体，是一种用于治疗骨质疏松症和某些癌症的强效抗吸收药物。根据我们的了解，地诺单抗尚未在FOP患者中使用。最近关于地诺单抗停用后脊柱压缩骨折风险增加的报告，以及在肾功能受损患者中低钙血症风险增加的报告，导致目前不建议在FOP中使用地诺单抗。
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  1. Rosen CJ, Brown S. Severe hypocalcemia after intravenous bisphosphonate therapy in occult vitamin D deficiency. N Engl J Med 348: 1503-1504, 2003 在隐匿性维生素D缺乏症患者中，静脉注射双膦酸盐治疗后严重低钙血症
  1. Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, Salerno A, Denaro V, Tonini G. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8: 1080-1084, 2002 帕米膦酸盐在癌症患者中诱导循环血管生成因子的改变
  1. Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H. Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal Cord 43: 604-610, 2005 氨基双膦酸盐在异位骨化中的应用：五例连续病例的首次经验
  1. Shane E. Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med 362: 18251827, 2010 关于转子下骨折和双膦酸盐的不断更新的数据
  1. Staa TPV, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18: 913-918, 2003 儿童与口服类固醇引起的骨折风险
  1. Tassone P, Forciniti, S, Galea E, Morrone G, Turco MC, Martinelli V, Tagliaferri P, Venuta S. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 14: 841-844, 2000 唑来膦酸和地塞米松在人体骨髓瘤细胞系中对生长的抑制和凋亡的协同诱导
  1. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med 349: 457-463, 2003 双膦酸盐诱导的骨质过度密度增生（骨硬化症）
  1. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Therap 302: 1055-1061, 2002 唑来膦酸这一双膦酸盐化合物的新型抗血管生成作用
  1. Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation. J Surg Res 151: 115-120, 2009 唑来膦酸通过抑制内皮祖细胞分化表现出的抗血管生成特性
  1. Vargas-Franco JW, Castaneda B, Rédiní F, Gómez DF, Heymann D, Lézot F. Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do? J Cell Physiol 233: 5696-5715, 2018 双膦酸盐对骨骼的悖论性副作用：我们知道什么，以及我们能做什么？
原文
  1. Bisphosphonates in FOP
      2. Bisphosphonates are a potent class of medications that have profound effects on bone remodeling and exert their primary effect by decreasing the life span of osteoclasts. Bisphosphonates are thus widely used in adults and children for the treatment of numerous bone diseases where bone resorption exceeds bone formation - disorders such as steroid-induced osteoporosis, idiopathic osteoporosis, osteogenesis imperfecta, Paget’s disease, fibrous dysplasia, and bone cancer (Orcel & Beaudreuil, 2002; Nogginuera et al., 2003; Chen & Sambrook, 2012; Baroncelli & Bertelloni, 2014).
      In addition, bisphosphonates have been used experimentally and anecdotally in the symptomatic management of flare-ups in FOP. The first clinically used bisphosphonate, etidronate, when administered at high doses, potently inhibited mineralization of newly formed cartilage and bone protein and had been proposed as a possible treatment for FOP and other disorders of HO. Etidronate had been studied in FOP because of its inhibitory effect on bone mineralization and its potential to impair ossification at high dosages (Brantus & Meunier, 1998). Unfortunately, at high doses for long durations, etidronate caused osteomalacia (soft bones) and impaired ossification of the entire skeletal system, not just the heterotopic bone of the “second skeleton.” Its utility is therefore limited. Etidronate has also been discontinued in the USA.
      Unlike etidronate, the newer aminobisphosphonates have no appreciable effect on inhibiting mineralization or causing osteomalacia. In 2005, Schuetz and colleagues reported generally beneficial but anecdotal effects of high dose aminobisphosphonates in preventing recurrence of HO in high-risk patients with established HO who were undergoing surgery to excise heterotopic bone. One of the five patients reported had FOP (Schuetz et al., 2005).
      The newer aminobisphosphonates have been used anecdotally for many years as an adjunctive symptomatic treatment for refractory flare-ups in FOP. Over the past 15 years, many patients in the FOP community have used pamidronate empirically for the symptomatic relief of refractory flare-ups, especially those that are prolonged or fail to respond to corticosteroids. Approximately three-quarters anecdotally report rapid improvement in the symptoms and signs of a flare-up while one-quarter report no improvement in the symptoms or signs of the flare-up (F. Kaplan, personal observation).
      Importantly, there seems to be no protective effect on the occurrence of subsequent flare-ups in any of the patients treated with intravenous aminobisphosphonates. While these anecdotal patient reports are not scientifically valid; they constitute an important set of anecdotal observations that compel further stringent scientific inquiry in controlled clinical studies.
      The bisphosphonate protocols used in the adjunctive, symptomatic treatment of FOP flare-ups have varied slightly between the patients (depending on age, body weight, and site of involvement) but in general were similar. The most commonly used protocol is summarized in Section V - Classes of Medications (Table 1).
      In all patients, serum calcium was monitored prior to treatment to assure that it was in the normal range, as hypocalcemia is a contraindication to the use of intravenous pamidronate or any of the aminobisphosphonates (Rosen & Brown, 2003). All patients had adequate daily oral calcium and vitamin D supplementation during and following treatment. A serum calcium, phosphate, albumin, alkaline phosphatase, 25-Hydroxy vitamin D, BUN, creatinine and complete blood count (CBC) should also be obtained at baseline.
      Treatment schedules were based upon published guidelines for children and adolescents with osteogenesis imperfecta as that group constitutes the largest known group of children and adolescents in whom intravenous aminobisphosphonates have been used (Rauch et al., 2002; Falk et al., 2003; Rauch et al., 2003; DiMeglio & Peacock 2006). The treatment of these children has allowed us to extrapolate protocols and safety data for FOP. Zoledronate has been used more recently in adults and children and offers the opportunity for shorter treatment regimens. However, the side-effects in young children are not fully known and the more prolonged exposure to pamidronate is preferred in FOP especially if administered during an acute flare-up (George et al., 2015).
      Patients between two and three years of age received pamidronate at a dose of 0.75 mg/kg/day for three consecutive days by slow intravenous infusion over 4-5 hours each day. Patients over the age of three years received Pamidronate at a dose of 1.0 mg/kg/day for three days by slow intravenous infusion over 4-5 hours each day, with a maximal dose of 60 mgs daily. On the first day of the first cycle of treatment, the patient receives half the dose. Lower total doses of pamidronate (½ listed dose on days 2 and 3) and substantially longer durations of infusions (8-10 hours) have been reported anecdotally and have been well-tolerated. The three-day cycle of treatment should be repeated only during refractory flare-ups and no more than 4 times annually.
      An alternate approach is to administer intravenous pamidronate about one week apart and assess the patient to see if there is a medical response in between. In many cases, it has been found that two doses are sufficient. Pamidronate should not be used routinely to treat flare-ups. It should be used primarily for the adjunctive treatment of flare-ups where other modes of symptomatic treatment have failed.
      Pamidronate should be diluted in normal saline according to the following table (Guidelines courtesy of F.H. Glorieux: Shriner’s Hospital for Children, Montreal):
      notion image
      The maximal concentration of pamidronate should be 0.1 mg/ml. The IV tubing should be flushed at the end of the infusion to ensure full dose delivery.
      Side-effects of intravenous pamidronate infusions in FOP patients included flu-like symptoms of fever, chills, and muscle aches. These symptoms can often be lessened by pre-treatment with acetaminophen. One patient developed tetany (uncontrolled muscle contractions due to a low vitamin D level in the blood prior to ameliorative therapy with pamidronate), and one patient developed peripheral phlebitis (inflammation of the vein) at the intravenous infusion site, which required inpatient intravenous antibiotic treatment.
      A published case report documents the development of iatrogenic osteopetrosis in a child treated with 60 mgs of intravenous pamidronate every three weeks for two years. The child did not have FOP and the cumulative doses reported far exceeded any published recommendations for the use of pamidronate in skeletal diseases (Whyte et al., 2003).
      Several important rare but serious complications the bisphosphonates are necessary to note osteonecrosis of the jaw (ONJ) and low-energy atypical femoral fractures. The following references contain detailed reviews of these rare but serious complications (Bilezikian, 2006; Black et al., 2010; Khosla et al., 2007; Shane et al., 2010; Vargas-Franco et al., 2018). Patients considering bisphosphonates should have a dental exam prior to initiation whenever possible.
      Bisphosphonates have a long half-life and can reside in the skeleton for many years after the infusion. In women of child-bearing potential, the risk of bisphosphonate exposure on the fetus with future pregnancies is unknown.
      A recent study showed that osteoclast inhibition does not affect HO enhanced by the FOP-related mutation (Kawao et al., 2016), so any effect of aminobisphosphonates on HO, if any, are not due to anti-osteoclastic activity, but through other less-explored mechanisms. Clearly, if the aminobisphosphonates are truly beneficial in the treatment of FOP flare-ups, there must be a mechanism of action that is very brief and substantially different from that of osteoclast inhibition from which the medication derives its beneficial effects in the normotopic skeleton.
      One intriguing line of investigation concerns the role of inflammatory cells in triggering HO. Kan and colleagues showed that systemically delivered bisphosphonates powerfully and specifically inhibited monocytes and led to substantial inhibition of trauma-induced HO in a BMP4-transgenic mouse model of HO (Kan et al., 2009).
      Intravenous aminobisphosphonates have also been shown to modulate macrophages and various lymphocyte subpopulations in the circulation and may be responsible for its dose-related side-effects of causing flu-like symptoms. We cannot yet rule-out the possibility that aminobisphosphonates may affect early lymphocytic and monocytic infiltration into skeletal muscle seen in FOP lesions. It is also likely that the aminobisphosphonates directly inhibit the metabolic activity of monocytes and macrophages that play such key roles in the response of the innate immune system in FOP (Convente et al., 2018).
      Several studies provide some additional clues. These studies document the potent antiangiogenic effects of the aminobisphosphonates by decreasing serum vascular endothelial growth factor (VEGF) levels and basic fibroblast growth factor (bFGF) levels in cancer patients with bone metastasis (Santini et al., 2002; Wood et al., 2002). Compelling evidence has emerged that aminobisphosphonates inhibit endothelial cell adhesion, migration and survival through suppression of multiple prenylationdependent signaling pathways (Hasmim et al., 2007). Other independent studies have shown that aminobisphosphonates have potent anti-angiogenic properties by inhibiting endothelial cell differentiation (Yamada et al., 2009). Taken together, these data strongly suggest that the aminobisphosphonates may be potent anti-angiogenic agents.
      Other possible mechanisms by which the aminobisphosphonates might affect FOP lesions include a direct inhibition on the proliferation of a rapidly dividing population of cells. Such an effect was noted in studies investigating the effects of aminobisphosphonates on cancer cells in vitro (Tassone et al., 2000; Green, 2003). It is possible that pamidronate and zoledronate may affect one or more cell types in an early FOP lesion. Another study showed (Idris et al., 2008) that aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro, thus suggesting that aminobisphosphonates may have a direct effect on inhibiting osteoblastic ability, especially in early bone nodules, as in FOP.
      It remains unclear whether bisphosphonates have effects on flare-ups, though anecdotally they seem to decrease the flare symptoms in some patients. As with all medications, the risks and benefits need to be assessed carefully. Only rigorous controlled investigations in vitro and in vivo, as well as placebocontrolled clinical trials will be able to definitively decipher these possibilities and provide a solid rational basis for determining whether or not one or more of the aminobisphosphonates may have a beneficial role in the treatment of FOP.
      Most importantly, intravenous aminobisphosphonates are indicated for the prevention and treatment of steroid-associated bone loss, or osteoporosis of the native skeleton, both of which are common problem in FOP patients (Nogginuera et al., 2003; Staa et al., 2003; Chen & Sambrook, 2012; Baroncelli & Bertelloni, 2014; Buckley & Humphrey, 2018). Dentists should be made aware of any prior bisphosphonate use.
      Of note, denosumab, a monoclonal antibody to RANK ligand, is a potent anti-resorptive drug approved for the treatment of osteoporosis and certain cancers. As far as we are aware, denosumab has not been used in patients with FOP. Recent reports of increased risks of spinal compression fractures with discontinuation of denosumab, as well as increased risk of hypocalcemia in patients with impaired renal function, lead to the recommendation not to use denosumab in FOP at this time.
      References
      Baroncelli GI, Bertelloni S. The use of bisphosphonates in pediatrics. Horm Res Paediatr 82: 290-302, 2014
      Bilezikian JP. Osteonecrosis of the jaw – do bisphosphonates pose a risk? N Engl J Med 355: 2278-2281, 2006
      Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg, Cauley J, Leung PC, Boonen S, Santora A, de Papp A, Bauer DC. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362: 1761-1771, 2010
      Brantus JF, Meunier PJ. Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin Orthop 346: 117-120, 1998
      Buckley L, Humphrey MB. Glucocorticoid-Induced Osteoporosis. New Engl J Med 379: 2547-2556, 2018
      Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol 8: 81–91, 2012
      Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of Mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res 33: 269-282, 2018
      DiMeglio LA, Peacock M. Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta. J Bone Miner Res 21: 132-140, 2006
      Falk MJ, Heeger S, Lynch KA, DeCaro KR, Bohach D, Gibson KS, Warman ML. Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics 111: 573-578, 2003
      George S, Weber DR, Kaplan P, Hummel K, Monk HM, Levine MA. Short-term safety of zoledronic acid in young patients with bone disorders: an extensive institutional experience. J Clin Endocrinol Metab 100: 4163-4171, 2015
      Green JR. Antitumor effects of bisphosphonates. Cancer 97 (supplement): 840-847, 2003
      Hasmim M, Bieler G, Rüegg C. Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways. J Throm Haemost 5: 166173, 2007
      Idris AI, Rojas J, Greig IR, Van’t Hof RJ, Ralston SH. Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int 82: 191-201, 2008
      Kan L, Liu Y, McGuire TL, Berger DM, Awatramani RB, Dymecki SM Kessler JA. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem Cells 27: 150156, 2009
      Kawao N, Yano M, Tamura Y, Okumoto K, Okada K, Kaji H. Role of osteoclasts in heterotopic ossification enhanced by fibrodysplasia ossificans progressiva-related activin-like kinase 2 mutation in mice. J Bone Miner Metab 34: 517-525, 2016
      Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of The American Society for Bone and Mineral Research. J Bone Miner Res 22: 1479-1491, 2007
      Nogginuera A, Ros JB, Pavia C, Alcover E, Valls C, Villaronga M, Gonzalez E. Bisphosphonates, a new treatment for glucocorticoid-induced osteoporosis in children. J Pediatr Endocrinol Metab 16: 529-536, 2003
      Orcel P, Beaudreuil J. Bisphosphonates in bone disease other than osteoporosis. Joint Bone Spine 69: 1927, 2002
      Rauch F, Plotkin H, Zeitlin L, Glorieux FH. Bone mass, size, and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy. J Bone Miner Res 18: 610-614, 2003
      Rauch F, Travers R, Plotkin H, Glorieux FH. The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 110: 1293-1299, 2002
      Rosen CJ, Brown S. Severe hypocalcemia after intravenous bisphosphonate therapy in occult vitamin D deficiency. N Engl J Med 348: 1503-1504, 2003
      Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, Salerno A, Denaro V, Tonini G. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8: 1080-1084, 2002
      Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H. Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal Cord 43: 604-610, 2005
      Shane E. Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med 362: 18251827, 2010
      Staa TPV, Cooper C, Leufkens HGM, Bishop N. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 18: 913-918, 2003
      Tassone P, Forciniti, S, Galea E, Morrone G, Turco MC, Martinelli V, Tagliaferri P, Venuta S. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 14: 841-844, 2000
      Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med 349: 457-463, 2003
      Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Therap 302: 1055-1061, 2002
      Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation. J Surg Res 151: 115-120, 2009
      Vargas-Franco JW, Castaneda B, Rédiní F, Gómez DF, Heymann D, Lézot F. Paradoxical side effects of bisphosphonates on the skeleton: What do we know and what can we do? J Cell Physiol 233: 5696-5715, 2018

7. 管理FOP炎症的非标签强效药物

针对罕见疾病的临床试验通常集中于一次一个靶点和一个潜在治疗。然而，现实环境中临床护理的紧迫性要求在管理症状性疾病时保持灵活性，尤其是在没有其他选择的情况下。针对某种疾病获得批准的药物可能对另一种疾病具有潜在的非靶向效应，因此可能适合基于同情理由的非标签使用。对这类药物的早期经验可能为未来临床试验中监测有意义的终点提供有用的参数。
最近，越来越多的关注集中在一些可能对管理进展性骨化纤维发育不良（FOP）有益的非标签药物上。这些药物中的许多调节免疫系统。目前，这些药物对于阻止异位骨化的具体疗效结果尚无详细数据。目前，仅建议在那些未对标准护理治疗产生反应且没有其他禁忌症或药物相互作用的患者中使用非标签药物，尤其是在难治性、严重发作的情况下。
国际进展性骨化纤维发育不良协作组（ICC）已就使用非标签药物管理FOP发布了声明。这些声明可以在ICC网站上找到 (ICCFOP.org)。
伊马替尼用于进展性骨化纤维发育不良（FOP）：
在FOP患者中，常常发生难以控制的发作、持续的不适以及儿童早期轴向运动能力的逐渐丧失，这为FOP的症状管理带来了特别的挑战。目前尚未有足够的解决方案来应对这个问题。研究表明，FOP的多种潜在治疗靶点正在被识别，同时也有新药候选物正在开发中以供临床试验测试。另一种补充方法是寻找可以针对FOP特定靶点重新利用的批准药物。
其中一种药物是伊马替尼美克沙，即一种最初用于治疗慢性髓性白血病（CML）的酪氨酸激酶抑制剂。伊马替尼具有攻击多个靶点的理想效果，这些靶点参与FOP发作的早期缺氧和炎症阶段，包括HIF1-α、PDGFRα、c-KIT以及多种MAP激酶。值得注意的是，伊马替尼在治疗系统性肥大细胞疾病中有效，并抑制多种与异位骨化（HO）形成相关的炎症蛋白。因此，伊马替尼可能对FOP的主要治疗靶点产生影响。
基于强有力的生物学原理、可靠的前临床数据和良好的安全性，伊马替尼在非试验环境中被作为非标签药物处方给七名持续FOP发作的儿童，主要集中在未对标准护理方案作出反应的轴向区域。这七名儿童对管理FOP症状的标准药物（如类固醇、非甾体抗炎药、色氨酸或静脉用双膦酸盐）未能表现出任何持久的症状反应。
这七名儿童在与父母详细讨论了伊马替尼非标签使用的相对风险和益处后，被转诊给儿科血液肿瘤学家或儿科风湿病学家以考虑伊马替尼治疗。父母被告知伊马替尼的使用是非标签性质，并且不属于临床研究的范围。父母还被告知，临床进展将会被监测，放射线检查不会定期进行。
在这些案例中的轶事报告记录了药物的耐受性良好，并且在服用药物的六名儿童中，发作的强度总体上有所降低。此外，所有六名能够每天服用伊马替尼的儿童的父母在几周使用后注意到发作强度的主观减轻。
间歇性治疗（Off-on-off-on, O4）方法提供了一个机会，可以快速评估药物的潜在症状疗效和耐受性，且患者数量有限，可能有助于设计更集中、适合入组的临床试验。报道了三名经典FOP患者，他们有顽固的背部发作，并接受了伊马替尼的O4方案治疗。所有三名儿童在“服用”伊马替尼时，父母和治疗医生报告的发作频率较少、肿胀减轻以及日常生活活动的功能改善，而在“停用”伊马替尼时则相反。服用伊马替尼后的中位改善时间为2-3周。对于三名有顽固背部发作的FOP儿童的伊马替尼的轶事O4经验支持设计一个简短的安慰剂对照试验，以评估伊马替尼在减轻FOP难治性发作症状中的潜在疗效。
目前没有确凿的证据表明伊马替尼能够预防或改善FOP的发作。然而，早期临床观察支持在控制不良的FOP发作儿童中实施伊马替尼的临床试验。
托法替尼用于FOP：
由于FOP的发作与炎症相关，因此假设JAK抑制剂可以通过阻断多条炎症信号通路来控制活动性FOP。作者报道了他们在13名对标准治疗无反应的FOP患者中观察到的托法替尼的安全性和有效性。十三名经过基因确认的FOP患者（七名男孩和六名女孩，年龄在2到20岁之间）接受了托法替尼5毫克每天两次的治疗。所有患者最初均未能对NSAIDs、类固醇和双膦酸盐治疗产生效果。患者在开始托法替尼治疗前评估了12个月，并在托法替尼治疗期间继续评估至少12个月。在试验期间，发作的中位频率从基线前12个月的10次减少到随后的12个月和24个月治疗期间的0次。研究中有12名患者的CAJIS指数没有恶化；1名患者的CAJIS指数恶化了1分。在31%的患者中观察到大关节活动范围的改善。NSAID、口服和静脉类固醇的使用比例从100%、61.5%和15.4%（基线）成功减少到12个月的46.2%、7.7%和0%以及24个月的22.2%、0%和0%。患者对药物的耐受性良好，没有注册严重不良事件。作者得出结论，托法替尼是一种耐受性良好的选择，可能减少FOP的发作，并且需要进一步研究JAK激酶抑制剂在FOP患者中的治疗潜力。
值得注意的是，JAK激酶抑制剂可能导致肾脏和肝脏毒性。人们担心托法替尼会增加深静脉血栓或肺栓塞、某些类型癌症、心脏相关事件及死亡的风险。美国FDA已于2021年9月1日发布黑框警告，详细说明了这些担忧。
www.fda.gov
www.fda.gov

www.fda.gov

抗IL-1疗法用于FOP（阿那白滞素、卡那白滞素）：
多项研究表明IL-1是炎症的主要调节因子。这种兴趣导致了针对FOP炎症成分的抗IL-1疗法的非标签试验，如阿那白滞素（靶向IL1受体）和卡那白滞素（阻断IL-1beta）。以色列一位患者的初步报告显示，控制发作的结果令人鼓舞。最近发布的四名接受长期抗IL-1药物治疗的患者的病例系列显示，发作活动显著减少。当其中一名患者的治疗短暂停止时，FOP发作复发；随后，通过重新开始抗IL-1治疗得以抑制。
卡那白滞素尤其引人关注，因为它每4到8周给药一次。而阿那白滞素则是每天用药，且在FOP和非FOP患者中均与注射部位疼痛相关。这两种药物都是免疫抑制剂，因此可能增加严重感染的风险。在与冷冻脓毒症相关的周期性综合症（CAPS）和其他炎症性疾病中，长达6年的长期使用显示出良好的安全性和耐受性。然而，减少FOP中新异位骨化（HO）形成的疗效及其长期安全性仍不明确。
其他抗炎药物：
没有令人信服的轶事数据支持其他抗炎药物的使用，包括甲氨蝶呤、利妥昔单抗、TNF-α抑制剂或雷帕霉素。因此，这些药物在FOP的主要管理中并不适用。
国际FOP临床委员会（ICC；2024年5月）关于FOP管理的非标签药物的声明
国际FOP临床委员会（ICC）了解到最近几篇文献描述了在FOP炎症管理中非标签使用有效药物的情况。这些潜在治疗方法包括阿那白滞素、卡那白滞素、托法替尼和伊马替尼。这些报告似乎显示出一些好处，特别是在管理FOP发作和发作疼痛方面。
此外，最近还报告了一些药物，如米诺环素、莫美莫尼和帕克利尼，在FOP动物模型中表现出活性，或者可能直接靶向ACVR1活性。目前尚无临床数据关于这些疗法在管理FOP患者中的风险或益处。
这些非标签和研究性药物的数据非常有限。我们对以下方面几乎没有或只有有限的数据：
  1. 是否仅有减少发作的益处（这已是所有这些药物报告的内容）；
  1. 是否对功能或减少FOP中的异位骨化有任何益处；
  1. 这些药物在FOP患者中的长期安全性；以及
  1. 患者停止用药后会发生什么。
尽管许多这些药物已在非FOP条件下的儿童中使用，但我们对这些药物在FOP儿童中的安全性几乎没有或很少有系统数据。
这些初步研究支持进行更大规模、严格对照的人体临床试验，以确定这些药物在FOP中的安全性和有效性。
在这些研究完成之前，ICC建议仅在满足所有三项最低关键标准的情况下考虑使用这些药物：
  1. FOP发作被认为是严重和难治的，或者疾病有异常严重或迅速的进展；
  1. 一旦标准护理疗法（ICCFOP.org）已耗尽；以及
  1. 临床团队认为这些药物可以安全使用（即没有其他禁忌症，没有感染的潜在问题，没有免疫缺陷的情况，没有药物相互作用等），并根据这些药物可能已被批准的年龄进行使用。
ICC特别提醒有已知与帕洛伐利（palovarotene）严重相互作用的药物。 这包括所有四环素类药物，如米诺环素或多西环素。与帕洛伐利或其他类视黄醇类药物一起使用这些药物可能导致伪肿瘤性脑膜炎，这是一种危险的高颅内压症状，可能损害大脑和神经系统。
由于所有这些药物的风险概况，ICC不建议将非标签药物用作预防。
如果您希望为自己或孩子考虑这些药物，请与您的医生和FOP临床医生详细讨论其利弊。药物相互作用和个体风险因人而异，可能非常严重。 这些风险必须在个体患者层面上进行讨论。
社交媒体上关于安全性或有效性的声明并不等同于对潜在风险和益处的开放医学讨论。 ICC相信个体选择。无论某人是否采用潜在疗法，或认为某种疗法有效，都是必须在明确呈现所有可用风险和益处的情况下进行的个人判断。
ICC还建议在做出关于这些药物的非标签使用的决定之前，审查活跃的临床试验。服用任何这些非标签或研究性药物可能使您或您的孩子失去参与正式临床试验的资格。此外，临床试验会密切监测安全性和有效性，并且来自这些临床试验的信息可以帮助FOP社区推进不同的治疗选项并支持未来的药物批准。药物在临床研究之外的非标签使用信息不足以支持药物批准。
如果您选择使用这些药物，或任何其他不被认为是FOP患者标准护理的药物，应该在您的FOP临床团队的密切监测下进行。如果您正在参加临床试验，必须在开始新药物之前讨论对您治疗的任何潜在更改。在参加临床试验期间，通常不允许使用非标签药物。
参考文献
  1. Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight 2018 Nov 15;3(22). pii: 122958 NF-κB/MAPK激活是人类异位骨化中ACVR1介导炎症的基础
  1. Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376: 19111920, 2017 伊马替尼对重度难治性哮喘患者的KIT抑制作用
  1. Galli SJ. Mast Cells and KIT as Potential Therapeutic Targets in Severe Asthma. N Engl J Med 376: 19831984, 2017 嗜碱性粒细胞和KIT作为重度哮喘的潜在治疗靶点
  1. Haviv R, Moshe V, De Benedetti F, Prencipe G, Rabinowicz N, Uziel Y. Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol Online J 2019 Dec 21:17 (1):84 纤维发育不良骨化进展症是否是一种由白细胞介素-1驱动的自身炎症综合症？
  1. Haviv R, Zeitlin L, Moshe V, Ziv A, Rabinowicz N, De Benedetti F, Prencipe G, Matteo V, De Cunto CL, Hsiao EC, Uziel Y. Long term use of interleukin-1 inhibitors reduce flare activity in patients with fibrodysplasia ossificans progressiva. Rheumatology (Oxford). 2024 May 11:keae255 白细胞介素-1抑制剂的长期使用减少了纤维发育不良骨化进展症患者的发作活动
  1. Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E, Pignolo RJ. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 109: 276-280, 2018 伊马替尼美克酸在FOP中的早期临床观察：七例报告
  1. Kaplan FS, Teachey DT, Andolina JR, Siegel DM, Mancilla EE, Hsiao EC, Al Mukaddam M, Rocke DM, Pignolo RJ. Off-on-off-on use of imatinib in three children with fibrodysplasia ossificans progressiva. Bone 150:116016, 2021 在三名纤维发育不良骨化进展症儿童中的伊马替尼交替用药
  1. Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J Bone Miner Res 39: 382-398, 2024 基质金属蛋白酶-9缺乏使得一名患者和小鼠在纤维发育不良骨化进展症中具备抵抗力
  1. Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 17: 387-394, 2019 纤维发育不良骨化进展症和其他异位骨化形式中的炎症
  1. Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC. ACVR1 R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone 2021 Dec;153:116129 ACVR1 R206H延长人类诱导多能干细胞来源巨噬细胞中的炎症反应
  1. Nikishina IP, Arsenyeva SV, Matkava VG, Arefieva AN, Kaleda MI, Smirnov AV, Blank LM, Kostik MM. Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva. Pediatr Rheumatol Online J 2023 Aug 29;21(1):92 托法替尼治疗纤维发育不良骨化进展症患者的成功经验
  1. Oh ST, Mesa RA, Harrison CN, Bose P, Gerds AT, Gupta V, Scott BL, Kiladjian JJ, Lucchesi A, Kong T, Buckley SA, Tyavanagimatt S, Harder BG, Roman-Torres K, Smith J, Craig AR, Mascarenhas J, Verstovsek S. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv 7: 5835-5842, 2023 帕克利尼是强效的ACVR1抑制剂，对骨髓纤维化患者具有显著的贫血益处
  1. Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, Miller CB, Rivera CE, Fleischman AG, Goel S, Heaney ML, O'Connell C, Arcasoy MO, Zhang Y, Kawashima J, Ganz T, Kowalski M, Brachmann CB. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv 4: 4282-4291, 2020 ACVR1/JAK1/JAK2抑制剂莫美莫尼在骨髓纤维化第二阶段试验中逆转输血依赖性并抑制肝细胞素
  1. Walker UA, Tilson HH, Hawkins PN, Poll TV, Noviello S, Levy J, Vritzali E, Hoffman HM, KuemmerleDeschner JB; CACZ885D2401 Study Investigators. Long-term safety and effectiveness of canakinumab therapy in patients with cryopyrin-associated periodic syndrome: results from the β-Confident Registry. RMD Open 2021 May;7(2):e001663 卡那白滞素治疗冷冻脓毒症相关周期性综合症患者的长期安全性和有效性：来自β-Confident登记的结果
  1. Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016 细胞缺氧通过增强BMP信号传导促进异位骨化
原文
  1. Off-Label Use of Potent Medications for Managing Inflammation in FOP
      2. Clinical trials for rare diseases commonly focus on one target and one potential therapeutic at a time. However, the exigencies of clinical care in a real-world setting require flexibility in managing symptomatic disease, especially when no other alternatives are available. Approved medicines for one condition may have potential off-target effects for another and thereby be suitable for off-label use on a compassionate basis. Early anecdotal experience with such medications may suggest useful parameters for monitoring meaningful endpoints in future clinical trials.
      Recently, there has been growing interest in a number of off-label medications that may have benefits for managing FOP. Many of these medications modulate the immune system. These medications do not have detailed outcome results for blocking of heterotopic ossification. At this time, the use of off-label medications is recommended only for patients with refractory, severe flares that have not responded to standard-of-care therapies, and in which there are no additional contraindications or medication interactions.
      The ICC has published statement on the use of off-label medications for the management of FOP. These can be found on the ICC website (ICCFOP.org).
      Imatinib for FOP:
      In FOP often relentless flare-ups, ongoing discomfort and progressive loss of axial mobility of early childhood pose a special challenge in the symptomatic management of FOP. Presently, there are no adequate solutions for this problem. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed against defined targets in FOP.
      One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases (Cahill et al., 2017; Galli, 2017). Notably, imatinib is effective in the treatment of systemic mast cell disease and inhibits multiple inflammatory proteins implicated in the formation of HO. Thus, imatinib has potential impact on major therapeutic targets of FOP.
      Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions which were not responsive to standard-of-care regimens (Wang et al., 2016; Kaplan et al., 2018). All seven children failed to demonstrate any durable symptomatic response to the standard medications used to manage symptoms of FOP such as corticosteroids, non-steroidal antiinflammatory agents, cromolyn or intravenous bisphosphonates.
      All seven children were referred to a pediatric hematologist-oncologist or a pediatric rheumatologist for consideration of imatinib therapy after detailed consultation with the parents on the relative risks and benefits of off-label use of imatinib for FOP. Parents were informed that imatinib use was on an off-label
      basis and was not part of a clinical research study. The parents were also informed that progress would be monitored clinically, and that radiographs would not be performed routinely.
      Anecdotal reports in these cases document that the medication was well-tolerated with an overall reported decrease in the intensity of flare-ups in the six children who took the medication. Moreover, the parents of all six children who were able to take imatinib on a daily basis noted subjective decreases in flare-up intensity after several weeks of use (Kaplan et al., 2018).
      Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Kaplan et al. (2021) reported three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were "on" imatinib than when they were "off" imatinib. The median time to improvement on imatinib was 2-3 weeks. The anecdotal O4 experience with imatinib reported in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo-controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP (Kaplan et al., 2021).
      Presently, there is no definitive evidence that imatinib prevents or ameliorates flare-ups in FOP. However, early clinical observations support the implementation of clinical trials of imatinib in children with uncontrolled FOP flare-ups (Kaplan et al., 2018; Kaplan et al., 2021).
      Tofacitinib for FOP:
      Since flares of FOP are associated with inflammation, it was hypothesized that JAK inhibitors can control active FOP due to blocking multiple inflammatory signaling pathways (Nikishina et al., 2023). The authors reported their observations on the safety and efficacy of tofacitinib in 13 patients with FOP refractory to standard of care treatment. Thirteen genetically confirmed FOP patients (seven boys and six girls from 2-20 years) were treated with tofacitinib 5 mg twice a day. All patients initially failed treatment with NSAIDs, corticosteroids, and bisphosphonates. Patients were evaluated for 12 months before the beginning of their treatment with tofacitinib and continued for at least12 months during their tofacitinib treatment period. During the trial, the median frequency of flares decreased from 10 during 12 months before the baseline to 0 in the following 12 months and 0 in 24 months of treatment. Twelve patients had no deteriorations of the CAJIS index during the study; in one patient the CAJIS index deteriorated by 1 point. Improvement in the range of motion in the large joints was noted in 31% of patients. NSAID, oral and intravenous corticosteroids were successfully decreased from 100%; 61.5%, and 15.4% (baseline) to 46.2%, 7.7%, and 0% (12 months) and 22.2%, 0%, and 0% (24 months). Patients tolerated the drug well. No severe adverse events were registered. The authors concluded that Tofacitinib was a well-tolerated option that may decrease FOP flares and that further studies of the therapeutic potential of JAK-kinase inhibitors in FOP patients are needed (Nikishina et al., 2023).
      Of note, JAK-kinase inhibitors can lead to renal and hepatic toxicity. There is concern about tofacitinib leading to an increased risk of deep vein thromboses or pulmonary emboli, as well as certain types of cancer, heart-related events, and death. The FDA has issued a black box warning detailing these concerns (Sept 1, 2021)
      www.fda.gov
      www.fda.gov

      www.fda.gov

      Anti-IL1 therapies for FOP (anakinra, canakinumab):
      Multiple studies suggest that IL-1 is a major regulator of inflammation (Barruet et al., 2018; Matsuo et al., 2019; Matsuo et al., 2021; Lounev et al., 2024). This interest has led to the off-label trials of anti-IL1 therapies such as anakinra (which targets the IL1 receptor) and canakinumab (which blocks IL-1beta) for treating the inflammatory components of FOP. Initial reports of a patient in Israel showed promising results with controlling flares. A subsequent case series of four patients receiving longer-term anti-IL1 drugs was recently published, showing a significant decrease in flare activity (Haviv et al., 2024). When therapy was discontinued briefly in one patient, the FOP flares returned; this was subsequently suppressed by restarting anti-IL1 therapy.
      Canakinumab is of particular interest because it is given every 4-8 weeks. Anakinra, which is a daily medication, has been associated with injection site pain in both FOP and non-FOP patients. Both of these medications are immune suppressants, and so may increase the risk of serious infections. Long term use of up to 6 years in cryopyrin associated periodic syndrome (CAPS) and other inflammatory conditions have shown good safety and tolerability (Walker et al., 2021). However, the efficacy of reducing new HO formation in FOP and long term safety for use in FOP remains unclear.
      Other anti-inflammatory medications:
      There has been no compelling anecdotal data to support the use of other anti-inflammatory medications, including methotrexate, rituximab, TNF-α inhibitors, or rapamycin. Therefore, the use of these medications for the primary management of FOP is not indicated.
      Statement Regarding Off Label Medications for the Management of FOP from the International Clinical Council on FOP (ICC; May 2024)
      The International Clinical Council (ICC) on FOP is aware of several recent publications describing the offlabel use of potent medications for managing inflammation in FOP. These potential treatments include the use of anakinra (Haviv et al., 2019), canakinumab (Haviv et al., 2019; 2024), tofacitinib (Nikishina et al., 2023), and imatinib (Kaplan et al., 2018; Kaplan et al., 2021). These reports appear to show some benefits, particularly with managing FOP flares and flare pain.
      In addition, there are recent reports of medications such as minocycline (Lounev et al., 2024), momelotinib (Oh et al., 2020), and pacritinib (Oh et al., 2023) that have activity in animal models of FOP or that may directly target ACVR1 activity. There are no clinical data regarding the risks or benefits of these therapies for managing patients with FOP.
      These off-label and investigational medications have very limited data. We have no or limited data on:
      1. whether the benefit is only for reducing flares (which is what has been reported for all of these medications);
      1. whether there is any benefit for function or reducing heterotopic ossification in FOP;
      1. the long-term safety of these medications in patients with FOP; and
      1. what happens when a patient stops the medication.
      We also have very little or no systematic data for the safety of these medications in children with FOP, even though many of these medications have been used in children with non-FOP conditions.
      These preliminary studies support the need for larger, well controlled, human clinical trials to determine the safety and efficacy of these medications in FOP.
      Until those studies are completed, the ICC recommends considering these medications only for situations where all three minimal key criteria are met:
      1. FOP flares are considered severe and intractable, or where there is unusually severe or rapid progression of the disease, and
      1. Once standard of care therapies (ICCFOP.org) have been exhausted, and
      1. The clinical team feels that the medications could be used safely (i.e. no other contra-indications, no underlying problems with infection, no immunocompromised situations, no medication interactions, etc.) and according to the age at which these drugs may have been authorized.
      The ICC brings particular attention to medications that have known severe interactions with palovarotene. This includes all tetracycline-like drugs such as minocycline or doxycycline. Taking these medications with palovarotene or other retinoids can cause pseudotumor cerebri, a dangerous condition of high pressure inside the skull that can damage the brain and nervous system.
      Due to the risk profiles of all these medications, the ICC does NOT recommend the use of off-label medications as a preventive.
      If you wish to consider these medications for you or your child, please discuss the pros and cons in detail with your doctors and FOP clinicians. Medication interactions and individual risks vary and can be severe. These risks must be discussed at the individual patient level.
      Social media claims of safety or efficacy are not the same as an open medical discussion of potential risks and benefits. The ICC believes in individual choice. Whether someone takes a potential therapy, or feels that a therapy works, is an individual judgment that must be made with all available risks and benefits clearly presented.
      The ICC also recommends review of active clinical trials before making decisions regarding off-label use of these medications. Taking any of these off-label or investigational medications may disqualify you or your child from participation in formal clinical trials. In addition, clinical trials are monitored closely for safety and efficacy, and information from those clinical trials can help the FOP community advance different therapeutic options and support future drug approvals. Information from off-label use of a medication outside of a clinical study is not sufficient for drug approval.
      If you choose to use these medications, or any other medications that are not considered standard-of-care for patients with FOP, it should be done with close monitoring in collaboration with your FOP clinical team. If you are in a clinical trial, you must discuss any potential changes to your therapy before starting a new medication. Off-label medications are often not allowed during your participation in a clinical trial.
      References
      Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC. NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. JCI Insight 2018 Nov 15;3(22). pii: 122958
      Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofalo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376: 19111920, 2017
      Galli SJ. Mast Cells and KIT as Potential Therapeutic Targets in Severe Asthma. N Engl J Med 376: 19831984, 2017
      Haviv R, Moshe V, De Benedetti F, Prencipe G, Rabinowicz N, Uziel Y. Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol Online J 2019 Dec 21:17 (1):84
      Haviv R, Zeitlin L, Moshe V, Ziv A, Rabinowicz N, De Benedetti F, Prencipe G, Matteo V, De Cunto CL, Hsiao EC, Uziel Y. Long term use of interleukin-1 inhibitors reduce flare activity in patients with fibrodysplasia ossificans progressiva. Rheumatology (Oxford). 2024 May 11:keae255
      Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E, Pignolo RJ. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 109: 276-280, 2018
      Kaplan FS, Teachey DT, Andolina JR, Siegel DM, Mancilla EE, Hsiao EC, Al Mukaddam M, Rocke DM, Pignolo RJ. Off-on-off-on use of imatinib in three children with fibrodysplasia ossificans progressiva. Bone 150:116016, 2021
      Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice. J Bone Miner Res 39: 382-398, 2024
      Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in fibrodysplasia ossificans progressiva and other forms of heterotopic ossification. Curr Osteoporos Rep 17: 387-394, 2019
      Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC. ACVR1 R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages. Bone 2021 Dec;153:116129
      Nikishina IP, Arsenyeva SV, Matkava VG, Arefieva AN, Kaleda MI, Smirnov AV, Blank LM, Kostik MM. Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva. Pediatr Rheumatol Online J 2023 Aug 29;21(1):92
      Oh ST, Mesa RA, Harrison CN, Bose P, Gerds AT, Gupta V, Scott BL, Kiladjian JJ, Lucchesi A, Kong T, Buckley SA, Tyavanagimatt S, Harder BG, Roman-Torres K, Smith J, Craig AR, Mascarenhas J, Verstovsek S. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv 7: 5835-5842, 2023
      Oh ST, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, Miller CB, Rivera CE, Fleischman AG, Goel S, Heaney ML, O'Connell C, Arcasoy MO, Zhang Y, Kawashima J, Ganz T, Kowalski M, Brachmann CB. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv 4: 4282-4291, 2020
      Walker UA, Tilson HH, Hawkins PN, Poll TV, Noviello S, Levy J, Vritzali E, Hoffman HM, KuemmerleDeschner JB; CACZ885D2401 Study Investigators. Long-term safety and effectiveness of canakinumab therapy in patients with cryopyrin-associated periodic syndrome: results from the β-Confident Registry. RMD Open 2021 May;7(2):e001663
      Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31: 1652-1665, 2016
       

8. 肌肉松弛剂

早期的FOP发作与大量嗜碱性粒细胞、巨噬细胞和淋巴细胞浸润骨骼肌相关，通常伴随局部损伤或坏死骨骼肌区域的剧烈炎症变化。因此，靠近病灶的相对健康的骨骼肌会受到代谢变化的影响，导致肌肉痉挛和纤维缩短。短期谨慎使用肌肉松弛剂，如环戊胺（Flexeril）、美克沙隆（Skelaxin）或巴氯芬（Liorisal），可以帮助减少肌肉痉挛并维持更功能性的活动，即使在FOP病变发展的情况下也是如此。这对于涉及肢体的疼痛发作尤为重要。由于多重药物相互作用和中枢神经系统（抑制剂）效应，不建议在发作间期长期使用肌肉松弛剂。注意剂量安排很重要，因为某些肌肉松弛剂（如巴氯芬）需要逐渐减少以避免副作用，而其他药物（如环戊胺）则只能使用短期，最长2-3周。
参考文献
  1. Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 243-250, 2005 进行性骨化性纤维发育不良的治疗考虑
原文
  1. Muscle Relaxants in FOP
      2. Early FOP flare-ups are associated with intense mast cell, macrophage, and lymphocytic infiltration into skeletal muscle and are often accompanied by intense inflammatory changes within regions of locally damaged or necrotic skeletal muscle. Areas of relatively healthy skeletal muscle bordering the lesion are thus subject to metabolic changes that would lead to muscle spasm and fiber shortening. The judicious short-term use of muscle relaxants such as cyclobenzaprine (Flexeril), metaxalone (Skelaxin), or baclofen (Liorisal) may help to decrease muscle spasm and maintain more functional activity even in the setting of an evolving FOP lesion (Glaser & Kaplan, 2005). This is especially true for painful flare-ups involving the limbs. The chronic use of muscle relaxants between episodes of flare-ups is not advised due to multiple drug interactions and central nervous system (depressant) effects. Careful attention to dosing schedules is important, as certain muscle relaxants (such as baclofen) need to be tapered slowly to avoid side-effects and others (such as cyclobenzaprine) can only be used for short periods of time up to 2-3 weeks.
      References
      Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 243-250, 2005

9. 化疗药物与放疗

由于进行性骨化性纤维发育不良（FOP）是一种罕见疾病，且未能将肿瘤样软组织肿胀与大脚趾的先天畸形联系起来，FOP的确诊往往会延迟。因此，许多FOP儿童被误诊为多种良性或恶性疾病。因此，不难理解，在确诊为FOP之前，许多FOP儿童接受了不必要的化疗、危险的外科切除和有害的放疗。回顾性地确认放疗或任何化疗药物是否有助于改变疾病的自然历史是非常重要的。
目前没有令人信服的案例证据表明，放疗或任何标准化疗药物（如放线菌素、阿霉素、环磷酰胺、多柔比星、异环磷酰胺、维克斯汀、长春新碱等）对FOP患者有帮助。实际上，许多这些药物会导致有害的长期副作用。因此，这些治疗方法在进行性骨化性纤维发育不良的治疗中是禁忌的。
参考文献
  1. Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 243-250. 2005 进行性骨化性纤维发育不良的治疗考虑
  1. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva (FOP). Best Practice & Research – Clinical Rheumatology 22: 191-205, 2008 进行性骨化性纤维发育不良（FOP）
原文
  1. Chemotherapy Agents & Radiation Therapy in FOP
      2. The definitive diagnosis of FOP is often delayed due to the rarity of the condition and the failure to associate the tumor-like soft tissue swellings with the congenital malformations of the great toes. As a result, many children with FOP are misdiagnosed as having a wide range of benign or malignant conditions. It is not surprising, therefore, that many children with FOP have been treated with unnecessary chemotherapy, dangerous surgical excisions, and damaging radiotherapy before the definitive diagnosis of FOP has been made. It would be important to note retrospectively if radiation therapy or any of the chemotherapy agents had been helpful in altering the natural history of the condition.
      There has been no convincing anecdotal evidence that either radiation therapy or any of the standard chemotherapy agents such as actinomycin, adriamycin, cyclosphosphamide, doxorubicin, ifosfamide, vinblastine, vincristine or any others were helpful for patients with FOP. In fact, many of these medications caused harmful long-term side-effects. The use of these approaches is, therefore, contraindicated in the treatment of FOP (Glaser & Kaplan, 2005; Kaplan et al., 2008).
      References
      Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 243-250. 2005
      Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva (FOP). Best Practice & Research – Clinical Rheumatology 22: 191-205, 2008

10. 骨髓移植

骨髓来源的干细胞在进行性骨化性纤维发育不良（FOP）的异位骨形成中被认为有重要作用。有建议通过骨髓移植替代这些干细胞，作为FOP的一种可能治疗方法。然而，骨髓来源干细胞对异位骨形成的具体贡献仍不清楚。对一名FOP患者进行了仔细的临床观察，该患者在25年前因治疗并发的再生障碍性贫血而接受了骨髓移植。用正常供体的骨髓替代FOP患者的骨髓治愈了其致命的骨髓疾病，但并不足以阻止进一步的异位骨形成和FOP的进展。然而，急性免疫消融和慢性免疫抑制则抑制了其FOP的活动。
在小鼠的补充移植研究中，来自骨髓的血细胞参与了BMP4诱导骨形成的早期炎症阶段和后期骨髓再生阶段，但未出现在FOP样病变的纤维增生、软骨生成或成骨阶。
综合这些发现表明，骨髓移植并未治愈这名患者的FOP，最可能的原因是骨髓中的造血细胞并不是形成FOP病变的细胞来源。然而，必须指出，正常的骨髓来源细胞能够在遗传易感个体中刺激异位骨形成。最近在FOP小鼠模型中进行的遗传实验和骨髓移植研究证实了这一发现，尽管一种非造血来源的常驻组织巨噬细胞群体仍然可能是触发因素。
这些发现具有巨大的研究价值和重要的临床意义，强有力地表明通过对个体患者的仔细观察可以学到很多东西。它们还说明了免疫系统在触发FOP发作中的重要性。然而，目前并不倡导在FOP的常规管理中广泛使用强效免疫抑制药物，这样的应用可能极其危险，甚至可能危及生命。在此之前（并在适当的动物模型中进行进一步研究之前），该国际联盟建议在FOP管理中不要使用慢性免疫抑制药物。
参考文献
  1. Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016 Palovarotene抑制异位骨化，并维持携带人类ACVR1 (R206H)进行性骨化性纤维发育不良（FOP）突变的小鼠的肢体活动能力和生长
  1. Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, Vonner AJ, Shen Y, Mohedas AH, Lee A, Eekhoff EM, van Schie A, Demay MB, Keller C, Wagers AJ, Economides AN, Yu PB. Two tissueresident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med 2016 Nov 23;8(366):366ra163 两种组织驻留祖细胞谱系驱动异位骨化的不同表型
  1. Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89: 347-357, 2007 造血干细胞对异位骨生成的贡献
原文
  1. Bone Marrow Transplantation in FOP
      2. Bone marrow derived stem cells have been implicated in the ectopic bone formation of FOP (reviewed in Kaplan et al., 2007). The replacement of these stem cells by bone marrow transplantation has been suggested as a possible cure for FOP. However, the definitive contribution of bone marrow derived stem cells to the formation of heterotopic bone has remained obscure. Careful clinical observations were made of an FOP patient who underwent bone marrow transplantation twenty-five years earlier for the treatment of intercurrent aplastic anemia. Replacement of the FOP patient’s bone marrow with normal donor bone marrow cured his fatal bone marrow condition but was not sufficient to prevent further HO and progression of his FOP. However, acute immunoablation and chronic immunosuppression quenched the activity of his FOP (Kaplan et al., 2007).
      In complementary transplantation studies in mice, blood cells derived from the bone marrow contributed to the early inflammatory and to the late marrow repopulating stages of BMP4-induced bone formation, but were not present in the fibroproliferative, chondrogenic or osteogenic stages of the FOP-like lesions (Kaplan et al., 2007).
      Taken together, these findings demonstrated that bone marrow transplantation did not cure FOP in this patient, most likely because the hematopoietic cells from the bone marrow were not the source of cells that formed the FOP lesions. However, it is critical to note that normal bone marrow-derived cells were capable of stimulating HO in a genetically susceptible individual (Kaplan et al., 2007). Recent genetic experiments and bone marrow transplantation studies in FOP mouse models substantiate this finding (Chakkalakal et al., 2016; Dey et al., 2016), although a non-hematopoietically derived population of resident tissue macrophages remains a possible trigger.
      These findings are of immense research interest and vital clinical importance, and they exemplify powerfully how much can be learned by careful observation in an individual patient. They also illustrate the importance of the immune system in triggering FOP flare-ups. At present, however, the general use of potent immunosuppressive medications is not advocated in the routine management of FOP and would likely be extremely dangerous and possibly life-threatening if it were applied broadly to the FOP community. At the present time, (and until further studies are performed in appropriate animal models), this international consortium recommends against the use of chronic immunosuppressive medications in the management of FOP.
      References
      Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016
      Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, Vonner AJ, Shen Y, Mohedas AH, Lee A, Eekhoff EM, van Schie A, Demay MB, Keller C, Wagers AJ, Economides AN, Yu PB. Two tissueresident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med 2016 Nov 23;8(366):366ra163
      Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89: 347-357, 2007

11. 其他药物与治疗方法

长期使用抗血管生成剂、钙结合剂、秋水仙碱、氟喹诺酮类抗生素、矿化抑制剂、PPAR-γ激动剂、TNF-α抑制剂和华法林的案例已被个案报告或描述，结果通常不理想或含糊不清。
在一例进行性骨化性纤维发育不良（FOP）患者中，颌面外科手术被报告为改善患者生活质量，尽管HO复发。颌部手术后HO复发的风险为100%，因此应极力避免，并作为最后的管理选择。
虽然有一例成功切除FOP患者异位骨的手术报告，但不推荐这种方法，因为文献中充斥着类似手术后出现的并发症。
参考文献
  1. Benetos IS, Mavrogenis AF, Themistocleous GS, Kanellopoulos AD, Papagelopoulos PJ, Soucacos PN. Optimal treatment of fibrodysplasia ossificans progressiva with surgical excision of heterotopic bone, indomethacin, and irradiation. J Surg Orthop Adv 15: 99-104, 2006 进行性骨化性纤维发育不良的最佳治疗方法是切除异位骨、使用吲哚美辛和放疗
  1. Bocciardi R, Ravazzolo R. Is there a biological basis for treatment of fibrodysplasia ossificans progressiva with rosiglitazone? Potential benefits and undesired effects. PPAR Res 2010;2010:541927 使用罗格列酮治疗进行性骨化性纤维发育不良是否有生物学基础？
  1. Eekhoff EMW, Netelenbos JC, de Graaf P, Hoebink M, Bravenboer N, Micha D, Pals G, de Vries TJ, Lammertsma AA, Raijmakers PG, van Es RJ. Flare-Up After Maxillofacial Surgery in a Patient with Fibrodysplasia Ossificans Progressiva: An [18F]-NaF PET/CT Study and a Systematic Review. JBMR Plus 2: 55-58, 2017 进行性骨化性纤维发育不良患者颌面外科手术后的发作：一项[18F]-NaF PET/CT研究及系统评审
  1. Gatti D, Viapiana O, Rossini M, Silvano A. Rosiglitazone therapy is associated with major clinical improvements in a patient with fibrodysplasia ossificans progressiva. J Bone Miner Res 25: 1460-1462, 2010 罗格列酮治疗与进行性骨化性纤维发育不良患者的主要临床改善相关
  1. Kaplan FS, Pignolo RJ, Shore EM. Viewing FOP through rosi-colored glasses. J Bone Miner Res 25: 2295-2296, 2010 通过玫瑰色眼镜看待FOP
  1. Moore, SE, Jump A, Smiley JD. Effect of warfarin sodium therapy on excretion of 4-carboxy-L-glutamic acid in scleroderma, dermatomyositis, and myositis ossificans progressiva. Arthritis Rheum 29: 344-351, 1986 华法林钠治疗对硬皮病、皮肌炎和进行性骨化肌炎中4-羧基-L-谷氨酸排泄的影响
原文
  1. Miscellaneous Agents & Approaches in FOP
      2. The chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, mineralization inhibitors, PPAR-gamma agonists, TNF-α inhibitors and warfarin have been described anecdotally or reported with either unsatisfactory or equivocal results (Moore et al., 1986; Bocciardi & Ravazzolo, 2010; Gatti et al., 2010; Kaplan et al., 2010).
      Maxillofacial surgery has been reported in one patient with FOP and was beneficial for the patient from a quality-of-life standpoint despite recurrence of HO. There is 100% risk of recurrence of HO after jaw surgery which should be highly discouraged and remain a management choice of last resort (Eekhoff et al., 2017).
      While there has been one case report of successful surgical excision of heterotopic bone in a patient with FOP, such an approach is not recommended, as the literature is littered with casualties following similar adventures (Benetos et al., 2006).
      References
      Benetos IS, Mavrogenis AF, Themistocleous GS, Kanellopoulos AD, Papagelopoulos PJ, Soucacos PN. Optimal treatment of fibrodysplasia ossificans progressiva with surgical excision of heterotopic bone, indomethacin, and irradiation. J Surg Orthop Adv 15: 99-104, 2006
      Bocciardi R, Ravazzolo R. Is there a biological basis for treatment of fibrodysplasia ossificans progressiva with rosiglitazone? Potential benefits and undesired effects. PPAR Res 2010;2010:541927
      Eekhoff EMW, Netelenbos JC, de Graaf P, Hoebink M, Bravenboer N, Micha D, Pals G, de Vries TJ, Lammertsma AA, Raijmakers PG, van Es RJ. Flare-Up After Maxillofacial Surgery in a Patient with Fibrodysplasia Ossificans Progressiva: An [18F]-NaF PET/CT Study and a Systematic Review. JBMR Plus 2: 55-58, 2017
      Gatti D, Viapiana O, Rossini M, Silvano A. Rosiglitazone therapy is associated with major clinical improvements in a patient with fibrodysplasia ossificans progressiva. J Bone Miner Res 25: 1460-1462, 2010
      Kaplan FS, Pignolo RJ, Shore EM. Viewing FOP through rosi-colored glasses. J Bone Miner Res 25: 2295-2296, 2010
      Moore, SE, Jump A, Smiley JD. Effect of warfarin sodium therapy on excretion of 4-carboxy-L-glutamic acid in scleroderma, dermatomyositis, and myositis ossificans progressiva. Arthritis Rheum 29: 344-351, 1986

12. 支持性疗法

目前对进行性骨化性纤维发育不良（FOP）只有一种在特定地区获得批准的医疗治疗。管理主要以支持性为主。高剂量的糖皮质激素用途有限，但在处理影响附肢骨骼和下颌主要关节的早期炎症发作时最为有效，特别是在发作开始后立即使用时。口服和局部非类固醇抗炎药、环氧合酶-2抑制剂、肥大细胞稳定剂、白三烯抑制剂以及偶尔使用的静脉氨基双膦酸盐被患者报告用于管理慢性疼痛、关节症状或持续的疾病进展。这些内容在之前的部分中有讨论。
针对FOP的治疗研究集中在对ACVR1受体、ACVR1配体、BMP通路信号、异位骨形成的前骨软骨原基和疾病活动的炎症触发因素进行靶向抑制，这为未来带来了希望。
参考文献
  1. Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008 进行性骨化性纤维发育不良
  1. Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017 针对第二个骨架的硬目标：进行性骨化性纤维发育不良（FOP）的治疗前景
  1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10(S-2): 437-448, 2013 进行性骨化性纤维发育不良：诊断、管理和治疗前景
原文
  1. Supportive Treatment in FOP
      2. There is presently one approved medical treatment for FOP, but only in certain jurisdictions. Management is mainly supportive. High-dose glucocorticoids have limited use but are most effective in the management of the early inflammatory flare-ups affecting major joints of the appendicular skeleton and jaw, especially when used immediately after the onset of a flare-up. Oral and topical non-steroidal anti-inflammatory medications, cyclo-oxygenase-2 inhibitors, mast cell stabilizers, leukotriene inhibitors and occasional intravenous aminobisphosphonates are reported by patients to manage chronic pain, arthritic symptoms or ongoing disease progression (Kaplan et al., 2008; Pignolo et al., 2013). These are discussed in the prior sections.
      Research to develop treatments for FOP has focused on targeted inhibition of the ACVR1 receptor, ACVR1 ligands, BMP pathway signaling, the pre-osseous chondrogenic anlagen of HO, and inflammatory triggers of disease activity, and offers hope for the future.
      References
      Kaplan FS, LeMerrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22: 191-205, 2008
      Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017
      Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews 10(S-2): 437-448, 2013

13. 确切的FOP治疗靶点

“随着对BMP作用机制的深入了解，可能开发出能够阻断BMP途径某部分的药物，从而防止这种可怕的噩梦疾病的进展。” - Brigid Hogan (Roush, 1996)
进行性骨化性纤维发育不良（FOP）研究的终极目标是开发能够预防、停止或甚至逆转该病进展的治疗方法。在FOP中对异位骨化（HO）的预防和治疗，最终将基于四种方法中的至少一种：干扰诱导信号通路、抑制炎症触发因素、改变靶组织中的相关骨祖细胞，和/或修改组织环境，以降低其对异位骨生成的促进作用。
发现导致进行性骨化性纤维发育不良（FOP）的反复出现的杂合子错义点突变，为该病提供了一个特定的药物靶点和在关键信号通路中干预的合理切入点。FOP基因的发现将ACVR1确定为治疗FOP的易感药物靶点。在FOP中抑制BMP信号传导的可行治疗策略包括抑制RNA技术、针对ACVR1的单克隆抗体、小分子选择性信号转导抑制剂（STIs）针对ACVR1、针对炎症触发因素和骨祖细胞的小分子信号转导抑制剂、视黄酸受体伽马（RAR-γ）激动剂、抗Activin A抗体以及抑制HIF1-α/mTOR信号传导、衰老疗法药物和基因治疗。有关FOP临床试验的信息可以在以下网站找到：http://www.clinicaltrials.gov
最近的两项研究表明，抗ACVR1抗体可以加重FOP小鼠中的异位骨化。这一特性源于抗ACVR1抗体介导的突变ACVR1二聚化。相反，抗ACVR1抗体抑制了野生型ACVR1。这些数据引发了严重的安全性和有效性担忧，表明双价抗ACVR1抗体不应被视为FOP的治疗药物。相比之下，来自日本的一项最新研究显示，一种阻断性单克隆抗体可以在FOP小鼠模型中预防异位骨化，得出抗体特异性在治疗中可能至关重要的结论。
FOP中的肌肉损伤显示会导致衰老细胞积累，而衰老促进FOP肌肉向软骨形成命运的组织重编程，而不是野生型肌肉。药理学清除衰老细胞并减少与衰老相关的分泌表型（SASP）可改善FOP小鼠模型中的异位骨化。因此，衰老溶解药物为未来FOP的治疗策略提供了原则性证明。
近期对FOP新型和急需治疗的临床试验引起了广泛关注。国际FOP临床委员会（ICC）于2016年成立，旨在为FOP患者提供临床护理和研究的最佳实践的综合和协调建议。ICC的临床试验委员会制定了一份针对FOP社区特定需求的关键考虑事项清单，并得到整个ICC的认可。这些考虑事项补充了建立健全临床试验的开发和执行协议，为确保FOP患者在临床研究试验中的安全提供了基础。尽管存在风险，但也有很多收益和希望。
目前仍为时尚早，尚无法确定这些方法或方法组合中哪种最为有效，所有方法正在预临床和/或临床研究中被深入研究（www.clinicaltrials.gov；https://www.ifopa.org/ongoing_clinical_trials_in_fop）。目前在FOP领域的全球合作研究努力大多集中在这一研究领域，详细的工作和进展可在FOP合作研究项目第二十九年报中找到，以及近期的综述中。
参考文献
  1. Aykul S, Huang L, Wang L, Das NM, Reisman S, Ray Y, Zhang Q, Rothman N, Nannuru KC, Kamat V, Brydges S, Troncone L, Johnsen L, Yu PB, Fazio S, Lees-Shepard J, Schutz K, Murphy AJ, Economides AN, Idone V, Hatsell SJ. Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1. J Clin Invest 2022 Jun 15;132(12):e153792 抗ACVR1抗体通过激活进行性骨化性纤维发育不良（FOP）突变的ACVR1加剧异位骨化
  1. Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016 Palovarotene抑制异位骨化并维持携带人类ACVR1 (R206H)进行性骨化性纤维发育不良（FOP）突变的小鼠的肢体活动和生长
  1. Eekhoff EMW, de Ruiter RD, Smilde BJ, Schoenmaker T, de Vries TJ, Netelenbos C, Hsiao EC, Scott C, Haga N, Grunwald Z, De Cunto CL, di Rocco M, Delai PLR, Diecidue RJ, Madhuri V, Cho TJ, Morhart R, Friedman CS, Zasloff M, Pals G, Shim JH, Gao G, Kaplan F, Pignolo RJ, Micha D. Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles. Hum Gene Ther 33:782-788, 2022 进行性骨化性纤维发育不良的基因治疗：可行性和障碍
  1. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015 ACVR1(R206H)受体突变通过对Activin A的反应性导致进行性骨化性纤维发育不良
  1. Hino K, Horigome K, Nishio M, Komura S, Nagata S, Zhao C, Jin Y, Kawakami K, Yamada Y, Ohta A, Toguchida J, Ikeya M. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J Clin Invest 127: 3339-3352, 2017 Activin-A增强mTOR信号传导以促进进行性骨化性纤维发育不良中的异常软骨发生
  1. Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA 112: 15438-15443, 2015 进行性骨化性纤维发育不良中ACVR1的新功能
  1. Hong CC, Yu PB. Application of small molecules BMP inhibitors in physiology and disease. Cytokines Growth Factor Rev 20: 409-418, 2009 小分子BMP抑制剂在生理和疾病中的应用
  1. Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo RJ, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br J Clin Pharmacol 85: 1199-1207, 2019 进行性骨化性纤维发育不良临床试验的特殊考虑
  1. Kaplan FS, Al Mukaddam M, Shore EM. Twenty-Ninth Annual Report of the fibrodysplasia ossificans progressiva (FOP) collaborative research project. IFOPA Website & ICC Website (www.ifopa.org; www.iccfop.org), 2024 进行性骨化性纤维发育不良（FOP）协作研究项目第二十九届年报
  1. Kaplan FS, Al Mukaddam M, Baujat G. Cali A, Cho-T-J, DeCunto C, Delai P, Diecidue RJ DiRocco M, Friedman C, Grunwald Z, Haga N, Hsiao EC, Keen R, Morhart R, Netelenbos JC, Scott C, Zasloff MA, Zhang K, Eekhoff EMW, Pignolo RJ. Editorial - The twilight zone: benefit, risk & hope in clinical trials for FOP. ICCFOP.org; IFOPA.org. December 3, 2020 黄昏地带：进行性骨化性纤维发育不良临床试验中的利益、风险与希望
  1. Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E, Pignolo RJ. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 109: 276-280, 2018 关于伊马替尼美克松在进行性骨化性纤维发育不良中的早期临床观察：七例报告
  1. Kaplan J, Kaplan FS, Shore EM. Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele–specific targeting. Gene Therapy 19: 786-790, 2012 通过突变等位基因特异性靶向恢复FOP间充质前体细胞中的正常BMP信号水平和成骨分化
  1. Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017 进行性骨化性纤维发育不良的硬靶：治疗前景
  1. Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016 赋予进行性骨化性纤维发育不良免疫并捕捉异位骨化
  1. Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med 17: 420-421, 2011 破坏异位骨化并RARE启动
  1. Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Nakamura K, Ohte S, Kawaguchi Y, Takaishi K. A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders. Nat Commun 2023 May 25;14(1): 2960 一种阻断单克隆抗体揭示了与遗传疾病相关的ALK2细胞内结构域的二聚化
  1. Lees-Shepard JB, Stoessel SJ, Chandler JT, Bouchard K, Bento P, Apuzzo LN, Devarakonda PM, Hunter JW, Goldhamer DJ. An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice. J Clin Invest 2022 Jun 15;132(12):e153795 一种抗ACVR1抗体通过纤维-脂肪祖细胞加剧进行性骨化性纤维发育不良小鼠的异位骨化
  1. Maekawa H, Kawai S, Nishio M, Nagata S, Jin Y, Yoshitomi H, Matsuda S, Toguchida J. Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1. Orphanet J Rare Dis 2020 May 24;15(1):122 预防性雷帕霉素治疗改善表达人类突变ACVR1的小鼠自然发生和诱导的异位骨化
  1. Pignolo RJ, Kaplan FS. Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva. Expert Opinion on Orphan Drugs p. 1-9, 2020 进行性骨化性纤维发育不良中的药物靶点、临床试验设计和拟议的药理管理
  1. Shimono K, Tung W-e, Macolino C, Chi A, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med 17: 454-460, 2011 核内视黄酸受体-γ激动剂对异位骨化的强效抑制
  1. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genetics 38: 525-527, 2006 BMP I型受体ACVR1的重复突变导致遗传性和散发性进行性骨化性纤维发育不良
  1. Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD. Pharmacokinetics and pharmacodynamics of Garetosmab (Anti-Activin A): Results from a first-in-human phase 1 study. J Clin Pharmacol 2020 Jun 18 Garetosmab（抗Activin A）的药代动力学和药效学：首个人体阶段I研究结果
  1. Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangiavini L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res 31: 1652-65, 2016 细胞缺氧通过增强BMP信号促进异位骨化
  1. Wang H, Zhang Q, Kaplan FS, Pignolo RJ. Clearance of Senescent Cells from Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva. J Bone Miner Res 37: 95-107, 2022 清除受损肌肉中的衰老细胞可消除进行性骨化性纤维发育不良小鼠模型中的异位骨化
  1. Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 85: 1180-1187, 2019 阻止进行性骨化性纤维发育不良中的异位骨化的治疗进展
  1. Williams EP, Bagarova J, Kerr G, Xia DD, Place ES, Dey D, Shen Y, Bocobo GA, Mohedas AH, Huang X, Sanderson PE, Lee A, Zheng W, Economides AN, Smith JC, Yu PB, Bullock AN. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight 2021 Mar 11:95042 Saracatinib是进行性骨化性纤维发育不良的有效临床候选药物
  1. Yang YS, Kim JM, Xie J, Chaugule S, Lin C, Ma H, Hsiao E, Hong J, Chun H, Shore EM, Kaplan FS, Gao G, Shim JH. Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery. Nat Commun 2022 Oct 19;13(1):6175 通过AAV基因传递抑制进行性骨化性纤维发育不良中的异位骨化
原文
  1. Definitive Therapeutic Targets in FOP
      2. “With so much being discovered about how the BMPs act, it might be possible to develop drugs that would block some part of the BMP pathway and therefore prevent the progression of what is a horrible, nightmare disease.” - Brigid Hogan (Roush, 1996)
      The ultimate goal of FOP research is the development of treatments that will prevent, halt, or even reverse the progression of the condition. The prevention and treatment of HO in FOP, as in any of the more common forms of HO, will ultimately be based on at least one of four approaches: disrupting the inductive signaling pathways, suppressing the inflammatory triggers, altering the relevant osteoprogenitor cells in the target tissues, and/or modifying the tissue environment so that it is less conducive to heterotopic osteogenesis (Reviewed in Wentworth et al., 2019; Pignolo & Kaplan, 2020).
      The identification of the recurrent heterozygous missense point mutation that causes FOP in all classically affected individuals provides a specific pharmaceutical target and a rational point of intervention in a critical signaling pathway. The discovery of the FOP gene identifies ACVR1 as a susceptible pharmaceutical target for the treatment of FOP (Shore et al., 2006). Plausible therapeutic strategies to inhibiting BMP signaling in FOP include inhibitory RNA technology (Kaplan et al., 2012), monoclonal antibodies directed against ACVR1 (Kaplan et al., 2017), small molecule selective signal transduction inhibitors (STIs) of ACVR1 (Hong et al., 2009; Kaplan et al., 2017; Williams et al., 2021), small molecule signal transduction inhibitors against inflammatory triggers and osteoprogenitor cells (Kaplan et al., 2018), retinoic acid receptor gamma (RAR-γ) agonists (Shimono et al., 2011; Chakkalakal et al., 2016; Kaplan & Shore, 2011), anti-Activin A antibodies (Hatsell et al., 2015; Hino et al., 2016; Kaplan et al., 2016; Vanhoutte et al., 2020) and inhibition of HIF1-α/ mTOR signaling (Wang et al., 2016; Hino et al., 2017; Maekawa et al., 2020), senotherapeutic agents (Wang et al., 2022), and gene therapy (Eekhoff et al., 2022). Information about clinical trials on FOP can be found at: http://www.clinicaltrials.gov
      Two recent studies show that anti-ACVR1 antibodies can exacerbate heterotopic ossification in FOP mice. This property resulted from anti-ACVR1 antibody mediated dimerization of mutant ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These data raise serious safety and efficacy concerns and indicate that bivalent anti-ACVR1 antibodies should not be considered as therapeutics for FOP (Aykul et al., 2022; Lees-Shepard et al., 2022). In contrast, a recent study from Japan showed that a blocking monoclonal antibody could prevent HO in a mouse model of FOP (Katagiri et al., 2023) leading to the conclusion that antibody specificity may be critically important therapeutically.
      Muscle injury in FOP was shown to results in senescent cell accumulation, and senescence promotes tissue reprogramming toward a chondrogenic fate in FOP muscle but not wild-type muscle. Pharmacologic clearance of senescent cells and reduction in the senescence associated secretory phenotype (SASP) ameliorates HO in mouse models of FOP. Thus, senolytic drugs provide proof-of-principle as a future therapeutic strategy in FOP (Wang et al., 2022).
      There has been substantial recent interest in clinical trials for novel and urgently needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials (Hsiao et al., 2018). While there is risk, there is also much benefit and hope (Kaplan et al., 2020).
      It is still too early to determine which one of these approaches or combinations of approaches will be most effective, and all are being studied intensively in preclinical and/or clinical studies (www.clinicaltrials.gov; https://www.ifopa.org/ongoing_clinical_trials_in_fop). Much of the present worldwide collaborative research effort in FOP is focused on this area of research, and detailed accounts of the work and progress can be found in the Twenty Ninth Annual Report of the FOP Collaborative Research Project (Kaplan, Al Mukaddam, Shore et al., 2024), as well as in recent reviews.
      References
      Aykul S, Huang L, Wang L, Das NM, Reisman S, Ray Y, Zhang Q, Rothman N, Nannuru KC, Kamat V, Brydges S, Troncone L, Johnsen L, Yu PB, Fazio S, Lees-Shepard J, Schutz K, Murphy AJ, Economides AN, Idone V, Hatsell SJ. Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1. J Clin Invest 2022 Jun 15;132(12):e153792
      Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res 31: 1666-1675, 2016
      Eekhoff EMW, de Ruiter RD, Smilde BJ, Schoenmaker T, de Vries TJ, Netelenbos C, Hsiao EC, Scott C, Haga N, Grunwald Z, De Cunto CL, di Rocco M, Delai PLR, Diecidue RJ, Madhuri V, Cho TJ, Morhart R, Friedman CS, Zasloff M, Pals G, Shim JH, Gao G, Kaplan F, Pignolo RJ, Micha D. Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles. Hum Gene Ther 33:782-788, 2022
      Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303)ra137, 2015
      Hino K, Horigome K, Nishio M, Komura S, Nagata S, Zhao C, Jin Y, Kawakami K, Yamada Y, Ohta A, Toguchida J, Ikeya M. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J Clin Invest 127: 3339-3352, 2017
      Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci USA 112: 15438-15443, 2015
      Hong CC, Yu PB. Application of small molecules BMP inhibitors in physiology and disease. Cytokines Growth Factor Rev 20: 409-418, 2009
      Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo RJ, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho TJ, De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br J Clin Pharmacol 85: 1199-1207, 2019
      Kaplan FS, Al Mukaddam M, Shore EM. Twenty-Ninth Annual Report of the fibrodysplasia ossificans progressiva (FOP) collaborative research project. IFOPA Website & ICC Website (www.ifopa.org; www.iccfop.org), 2024
      Kaplan FS, Al Mukaddam M, Baujat G. Cali A, Cho-T-J, DeCunto C, Delai P, Diecidue RJ DiRocco M, Friedman C, Grunwald Z, Haga N, Hsiao EC, Keen R, Morhart R, Netelenbos JC, Scott C, Zasloff MA, Zhang K, Eekhoff EMW, Pignolo RJ. Editorial - The twilight zone: benefit, risk & hope in clinical trials for FOP. ICCFOP.org; IFOPA.org. December 3, 2020
      Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, Whitehead B, Jacobs B, Siegel DM, Keen R, Hsiao E, Pignolo RJ. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 109: 276-280, 2018
      Kaplan J, Kaplan FS, Shore EM. Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele–specific targeting. Gene Therapy 19: 786-790, 2012
      Kaplan FS, Pignolo RJ, Al Mukaddam MM, Shore EM. Hard targets for a second skeleton: therapeutic horizons for fibrodysplasia ossificans progressiva (FOP). Expert Opinion on Orphan Drugs 5: 291-294, 2017
      Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 49: 30-36, 2016
      Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med 17: 420-421, 2011
      Katagiri T, Tsukamoto S, Kuratani M, Tsuji S, Nakamura K, Ohte S, Kawaguchi Y, Takaishi K. A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders. Nat Commun 2023 May 25;14(1): 2960
      Lees-Shepard JB, Stoessel SJ, Chandler JT, Bouchard K, Bento P, Apuzzo LN, Devarakonda PM, Hunter JW, Goldhamer DJ. An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice. J Clin Invest 2022 Jun 15;132(12):e153795
      Maekawa H, Kawai S, Nishio M, Nagata S, Jin Y, Yoshitomi H, Matsuda S, Toguchida J. Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1. Orphanet J Rare Dis 2020 May 24;15(1):122
      Pignolo RJ, Kaplan FS. Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva. Expert Opinion on Orphan Drugs p. 1-9, 2020
      Shimono K, Tung W-e, Macolino C, Chi A, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med 17: 454-460, 2011
      Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genetics 38: 525-527, 2006
      Vanhoutte F, Liang S, Ruddy M, Zhao A, Drewery T, Wang Y, DelGizzi R, Forleo-Neto E, Rajadhyaksha M, Herman G, Davis JD. Pharmacokinetics and pharmacodynamics of Garetosmab (Anti-Activin A): Results from a first-in-human phase 1 study. J Clin Pharmacol 2020 Jun 18
      Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangiavini L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res 31: 1652-65, 2016
      Wang H, Zhang Q, Kaplan FS, Pignolo RJ. Clearance of Senescent Cells from Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva. J Bone Miner Res 37: 95-107, 2022
      Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 85: 1180-1187, 2019
      Williams EP, Bagarova J, Kerr G, Xia DD, Place ES, Dey D, Shen Y, Bocobo GA, Mohedas AH, Huang X, Sanderson PE, Lee A, Zheng W, Economides AN, Smith JC, Yu PB, Bullock AN. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight 2021 Mar 11:95042
      Yang YS, Kim JM, Xie J, Chaugule S, Lin C, Ma H, Hsiao E, Hong J, Chun H, Shore EM, Kaplan FS, Gao G, Shim JH. Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery. Nat Commun 2022 Oct 19;13(1):6175

14. FOP的临床试验结果

本节指南简要概述了进行性骨化性纤维发育不良（FOP）注册临床试验（clinicaltrials.gov）的同行评审和已发表结果。感兴趣的读者可参考完整的手稿。
Palovarotene
一项安慰剂对照、双盲的二期研究（NCT02190747）评估了口服生物利用度高的选择性视黄酸受体γ激动剂帕洛伐罗亭在预防进行性骨化性纤维发育不良（FOP）患者中发生异位骨化（HO）的效果。
尽管这些发现未达到统计学显著性，但支持在更大规模的研究中进一步评估帕洛伐罗亭在FOP患者中预防HO的潜力。
在**《骨与矿物研究杂志》**的一篇发表中，帕洛伐罗亭作为RARγ受体激动剂被报道能在开放标签的三期试验中减少新的异位骨化（HO）。单臂开放标签的三期MOVE试验（NCT03312634）评估了帕洛伐罗亭在FOP患者中的疗效和安全性。研究结果与未接受超出标准护理的FOP自然历史研究（NHS；NCT02322255）参与者进行比较。主要终点是与NHS参与者相比的新HO体积年化变化（通过低剂量全身计算机断层扫描[WBCT]）。十二个月的中期分析未满足无效标准。后期18个月中期分析显示，帕洛伐罗亭与NHS参与者相比，任何新HO减少的概率为99.4%。在MOVE组，新HO体积年化降低了60%，与NHS相比。所有接受帕洛伐罗亭治疗的患者均报告至少1个不良事件（AE）；97.0%报告至少1个与视黄醇相关的不良事件；29.3%报告至少1个严重不良事件，包括21/57名（36.8%）年龄小于14岁的患者出现的早期生长板闭合（PPC）/骨骼表征异常。使用WBCT的后期计算分析显示，帕洛伐罗亭治疗的患者脊椎骨矿物质密度、含量和强度均降低，脊椎骨折风险增加。因此，后期分析显示，帕洛伐罗亭在减少FOP中新HO方面有适度疗效，但在骨骼尚未成熟的患者中存在高风险的PPC。
2023年8月16日，帕洛伐罗亭获得美国食品药品监督管理局（FDA）批准用于治疗FOP，适用于年龄超过10岁的男孩和年龄超过8岁的女孩（根据全国平均身高，达到90%的身高时）。需要注意的是，帕洛伐罗亭预计不会改变急性发作的活动，因为其主要分子靶点是新异位骨化的形成。此外，由于药物相互作用的风险，帕洛伐罗亭不应与某些药物共同服用，包括四环素类药物（如四环素、道光霉素、美克霉素等）或强诱导Cyp3A4的药物。
国际进行性骨化性纤维发育不良临床委员会（ICC）于2023年8月发布了以下官方声明：
国际进行性骨化性纤维发育不良临床委员会（ICC）关于帕洛伐罗亭的声明
国际进行性骨化性纤维发育不良临床委员会（ICC）关注美国食品药品监督管理局（FDA）、欧洲药品管理局和加拿大卫生部近期关于帕洛伐罗亭用于治疗进行性骨化性纤维发育不良（FOP）的决定。ICC对此类监管决定没有直接影响，因为我们认为审查和监管过程应依据既定的科学和法律原则进行。
2023年8月16日，美国FDA宣布批准帕洛伐罗亭用于治疗FOP。帕洛伐罗亭已被其他监管机构评估，包括2022年1月加拿大卫生部的批准，以及2023年6月欧洲药品管理局的拒绝。
2023年6月，FDA顾问委员会做出了非一致的积极推荐，但对利益/风险平衡、显著的副作用风险以及对后期数据分析的依赖表示了显著的关注。
FOP是一种毁灭性的遗传疾病，进展性异常骨形成（异位骨化，HO）导致行动能力、独立性和生活质量的丧失。迄今为止，仅有症状治疗可用。帕洛伐罗亭是一种小分子视黄醇类药物，代表了首个专门批准用于减少FOP患者新HO形成的药物。
ICC已审查在2023年6月向FDA顾问委员会公开呈现的数据，以及自然历史研究（Pignolo等，Genet. Med 2022）和三期MOVE试验（Pignolo等，J Bone Mineral Res 2023）的出版物。数据的主要分析引发了对帕洛伐罗亭在阻止新HO形成方面的显著担忧，实际上因这些担忧达到了停止试验的无效标准。解盲后对数据的检查揭示了计划分析方法的缺陷。由Ipsen和FDA进行的多个后期分析建议，帕洛伐罗亭可能减少了50-60%的新HO形成。三期MOVE试验还显示，帕洛伐罗亭有显著副作用，包括年轻FOP患者早期生长板闭合的风险，以及与视黄醇类药物相关的并发症（皮疹、干燥的皮肤和眼睛、可能的骨质流失等）。
ICC成员强烈支持继续开发治疗FOP所造成毁灭性后果的疗法。
帕洛伐罗亭代表了朝着这一方向迈出的第一步，在美国、加拿大和阿联酋获得批准。然而，ICC也认为现有数据存在显著局限性——特别是对预期终身使用的药物，临床试验的短期结果不可避免；关于HO骨形成减少的确切疗效仍未解答；对长期功能结果的影响不明确；以及在儿童中可能出现的显著副作用和骨毒性。
因此，ICC建议：
  • 如果FOP患者考虑使用帕洛伐罗亭，必须与患者及其医疗团队详细讨论潜在的益处和风险，这些内容在药品说明书、MOVE试验出版物和后续出版物中有详细说明。
  • 应明确讨论额外风险，包括对骨骼健康的潜在影响（骨量流失）、皮肤/粘膜干燥及相关并发症、眼部并发症的潜在风险，以及怀孕期间胎儿畸形的风险。ICC支持对这些潜在并发症的持续密切长期跟踪。
  • 应进行帕洛伐罗亭的长期详细安全性和有效性研究，如通过注册或正式的长期研究。
  • 应根据FOP治疗指南（可在ICCFOP.org获取）结合适当的标准治疗方法和患者的医疗团队进行使用。
  • 应促进全球对帕洛伐罗亭的可负担访问，包括确保治疗费用合理。
  • 由于已知的视黄醇类药物的致畸性，患者在使用帕洛伐罗亭时应进行仔细监测，以防止怀孕。
  • 应进行潜在药物相互作用的仔细教育，包括与四环素或多西环素等抗生素的相互作用。
  • 患者不应使用非药品级别的帕洛伐罗亭。
ICC继续支持在所有临床试验和研究中进行开放讨论和数据共享，以便在研究潜在的FOP疗法时。
尽管大多数ICC成员认为帕洛伐罗亭可能对FOP患者的护理有益，但一些ICC成员对其批准和使用存在严重担忧。这些担忧包括在年轻FOP患者中生长板效应的高风险，可能导致帕洛伐罗亭不应在生长中的儿童中使用。此外，帕洛伐罗亭治疗的长期风险仍不明确，可能导致尚未确定的显著次要并发症。此外，使用帕洛伐罗亭可能影响患者服用某些药物或参与临床试验的能力。
FOP治疗指南将在ICCFOP.org上更新，提供关于帕洛伐罗亭的额外信息，一旦该药物在其批准的辖区内商业化。此外，ICC计划撰写关于帕洛伐罗亭的未来评审手稿。
Garetosmab (REGN 2477)
在《自然医学》的一篇发表中，静脉注射的加托索单抗（激活素A抑制剂）在一项小型多中心、随机、双盲、安慰剂对照的2期试验中被报告能减少进行性骨化性纤维发育不良（FOP）成人的异位骨化和发作 [LUMINA-1 (NCT03188666) ]。
患者被随机分配至加托索单抗或安慰剂组。在第1阶段，加托索单抗相较于安慰剂显示出降低异位骨化的趋势（24.6%），主要是由于几乎完全防止新病灶的出现。发作显著减少。对于在第2阶段转为使用加托索单抗的安慰剂患者，未出现新异位骨化病灶。加托索单抗与安慰剂相比，相关的不良事件更多，包括轻度复发性鼻出血、睫毛脱落和皮肤/软组织感染。总体而言，不良事件的严重程度主要为轻度。发生了5例死亡（5/44；11.4%），发生在第2阶段或开放标签扩展阶段。这些死亡与一些患者的基础病情严重程度和其他患者的既往合并症有关，且发生在开放标签/随访阶段接受8-16剂（中位数：15剂）加托索单抗后。加托索单抗减少了发作并防止了FOP患者的新异位骨化病灶。尽管报告的副作用为轻至中度，但对于这样一项小型研究，意外出现了较高的死亡人数。在开放标签期间发生了5例死亡（44例中的5例；11.4%）。尽管这些死亡被认为不太可能与加托索单抗相关，但因果关系无法排除。
参考文献
  1. Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, PlaceboControlled, Double-Blind Phase 2 Trial. J Bone Miner Res 37: 1891-1902, 2022 Palovarotene 治疗进行性骨化性纤维发育不良（FOP）：随机、安慰剂对照、双盲2期试验结果
  1. Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Keen R, Le Quan Sang KH, Mancilla EE, Marino R, Strahs A, Kaplan FS. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res 38: 381-394, 2023 在开放标签3期MOVE试验中，使用Palovarotene 减少新异位骨化（HO）
  1. Di Rocco M, Forleo-Neto E, Pignolo RJ, Keen R, Orcel P, Funck-Brentano T, Roux C, Kolta S, Madeo A, Bubbear JS, Tabarkiewicz J, Szczepanek M, Bachiller-Corral J, Cheung AM, Dahir KM, Botman E, Raijmakers PG, Al Mukaddam M, Tile L, Portal-Celhay C, Sarkar N, Hou P, Musser BJ, Boyapati A, Mohammadi K, Mellis SJ, Rankin AJ, Economides AN, Trotter DG, Herman GA, O’Meara SJ, DelGizzi R, Weinreich DM, Yancopoulos GD, Eekhoff EMW, Kaplan FS. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med 29: 2615-2624, 2023 Garetosmab 治疗进行性骨化纤维发育不良：一项随机、双盲、安慰剂对照的 2 期试验。
原文
  1. Clinical Trial Results in FOP
      2. This section of The Guidelines briefly outlines the peer reviewed, published results of registered clinical trials (clinicaltrials.gov) in FOP. Interested readers are directed to the full manuscripts.
      Palovarotene
      A placebo-controlled, double-blind trial (NCT02190747) Phase II study evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP.
      Although these findings were not statistically significant, they supported further evaluation of palovarotene for prevention of HO in FOP in larger studies (Pignolo, Baujat et al., 2022).
      In a publication in The Journal of Bone & Mineral Research, Palovarotene, an RARγ receptor agonist, was reported to reduce new heterotopic ossification (HO) in an Open-Label, Phase 3 Trial (Pignolo, Hsiao et al., 2022). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]). Twelve-month interim analyses met futility criteria. Post hoc 18-month interim analyses showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants. Annualized new HO volume was 60% lower in MOVE versus the NHS. All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for modest efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients (Pignolo, Hsiao et al., 2023).
      Palovarotene was approved for FOP by the U.S. Food & Drug Administration (FDA) on August 16, 2023, for use in boys older than 10 years of age and girls older than 8 years of age (when 90% of their height has been achieved, based on national averages). It should be noted that palovarotene is not expected to change flare activity, as the primary molecular target is the formation of new heterotopic ossification. Furthermore, palovarotene should not be taken with certain medications due to the risks of interactions, including tetracyclines (such as tetracycline, doxycycline, minocycline, etc.) or medications that are strong inducers of Cyp3A4.
      The International Clinical Council on FOP (ICC) issued the following official statement in August 2023:
      Statement Regarding Palovarotene from the International Clinical Council (ICC) on FOP
      The International Clinical Council (ICC) on FOP is aware of the recent decisions by the United States Food and Drug Administration (FDA), the European Medicines Agency, and Health Canada on the use of palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP). The ICC has no direct influence on these regulatory decisions, as we believe it is important that the review and regulatory processes play out in accordance with established scientific and legal principles.
      On August 16th, 2023, the US FDA announced the approval of palovarotene for the treatment of FOP. Palovarotene has been evaluated by other regulatory agencies, including approval by Health Canada in January 2022, and rejection by the European Medicines Agency (EMA) in June 2023.
      The FDA advisory committee in June 2023 made a non-unanimous positive recommendation, with notable concerns regarding the benefit/risk balance, significant risks of side effects, and reliance on post-hoc analyses of the data.
      FOP is a devastating genetic disease where progressive abnormal bone formation (heterotopic ossification, HO) leads to loss of mobility, independence, and quality of life. To date, only symptomatic treatments are available. Palovarotene is a small molecule in the retinoid class and represents the first drug approved specifically for decreasing new HO formation in patients with FOP.
      The ICC has reviewed the data publicly presented to the FDA advisory committee in June 2023, as well as reviewed the publications of the Natural History Study (Pignolo, et al. Genet. Med 2022) and the Phase III MOVE Trial (Pignolo et al., J Bone Mineral Res 2023). The primary analysis of the data raised significant concerns about the efficacy of palovarotene in blocking new HO formation, and in fact met the futility criteria for stopping the trial due to these concerns. Examination of the data after unblinding revealed deficiencies in the planned analysis method. Multiple subsequent post-hoc analyses, performed both by Ipsen and the FDA, suggested that palovarotene likely reduced new HO formation by 50-60%. The Phase III MOVE trial also showed that palovarotene had significant side effects, including the risk of early growth plate closure in younger patients with FOP and complications related to the retinoid class of medications (skin rash, dry skin and eyes, possible bone loss, etc.).
      The members of the ICC strongly support the continued development of therapies for treating the devastating consequences of FOP.
      Palovarotene represents a first step in that direction, with approval in the USA, Canada, and UAE. However, the ICC also feels that there are significant limitations to the existing data – specifically the necessarily short-term results of a clinical trial for a drug that is expected to be used lifelong; the still unanswered questions regarding the exact efficacy of reduction of HO bone formation; the unclear impact on long-term functional outcomes; and the potential for significant side effects and bone toxicity especially in children.
      Therefore, the ICC recommends:
      • If a patient with FOP considers palovarotene, the potential benefits and risks, as detailed in the package insert, by the MOVE trial publication, and in subsequent publications, must be discussed in detail with the patient and the patient’s medical team.
      • Additional risks should be explicitly discussed, including potential effects on bone health (loss of bone mass), skin/mucosal dryness and complications, potential for eye complications, and the risk of fetal malformations in pregnancy. The ICC supports continued close long-term follow-up of these potential complications.
      • A long term, detailed study of the safety and efficacy of palovarotene should be pursued, such as through a registry or formalized long-term study.
      • Standard-of-care therapies, as recommended by the FOP Treatment Guidelines (available at ICCFOP.org), should still be used in combination with palovarotene as appropriate, and with guidance from the patient’s medical team.
      • Worldwide affordable access to palovarotene should be facilitated, including ensuring reasonable cost for therapy.
      • Careful monitoring of patients to prevent pregnancy while on palovarotene should be required, due to the known teratogenicity of the retinoid class of medications.
      • Careful education of potential drug interactions, including with antibiotics like tetracycline or doxycycline, should be required.
      • Patients should not use non-pharmaceutical grade palovarotene.
      The ICC continues to support open discussions and data sharing in all clinical trials and studies as potential therapies for FOP are examined.
      While the majority of ICC members believe that palovarotene may have benefits for the care of patients with FOP, a number of ICC members had serious concerns about its approval and use. These concerns include the high risk of growth plate effects in young children with FOP, leading to a potential consideration that palovarotene should never be used in growing children. In addition, the long-term risks of treatment with palovarotene remain unknown, and could result in significant secondary complications that have yet to be identified. Furthermore, the use of palovarotene may impact a patient’s ability to take certain medications or participate in clinical trials.
      The FOP treatment guidelines at ICCFOP.org will be updated with additional information once palovarotene is available commercially in the jurisdictions where it has been approved. In addition, the ICC is planning a future review manuscript regarding palovarotene.”
      Garetosmab
      In a publication in Nature Medicine, intravenous garetosmab, an inhibitor of activin A, was reported to reduce heterotopic ossification and flare-ups in adults with FOP in a small multi-center, randomized, double-blind, placebo-controlled phase 2 trial [LUMINA-1 (NCT03188666) Di Rocco et al., 2023].
      Patients were randomized to garetosmab or placebo. In Period-1, there was a trend for garetosmab to decrease HO versus placebo (24.6%), primarily driven by near complete prevention of new lesions. Flareups were significantly reduced. For placebo patients transitioning to garetosmab in Period-2, no patients developed new HO lesions. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the adverse events AEs were predominantly mild in severity. Five deaths (5/44; 11.4%) occurred either in Period-2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although the reported side effects were mild to moderate, there was an unexpectedly high number of deaths for a small study. Five deaths (5 of 44; 11.4%) occurred in the open-label period. Although these were considered unlikely to be related to garetosmab, causality cannot be ruled out (Di Rocco et al., 2023).
      References
      Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, PlaceboControlled, Double-Blind Phase 2 Trial. J Bone Miner Res 37: 1891-1902, 2022
      Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, Cheung AM, De Cunto C, Delai P, Haga N, Kannu P, Keen R, Le Quan Sang KH, Mancilla EE, Marino R, Strahs A, Kaplan FS. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res 38: 381-394, 2023
      Di Rocco M, Forleo-Neto E, Pignolo RJ, Keen R, Orcel P, Funck-Brentano T, Roux C, Kolta S, Madeo A, Bubbear JS, Tabarkiewicz J, Szczepanek M, Bachiller-Corral J, Cheung AM, Dahir KM, Botman E, Raijmakers PG, Al Mukaddam M, Tile L, Portal-Celhay C, Sarkar N, Hou P, Musser BJ, Boyapati A, Mohammadi K, Mellis SJ, Rankin AJ, Economides AN, Trotter DG, Herman GA, O’Meara SJ, DelGizzi R, Weinreich DM, Yancopoulos GD, Eekhoff EMW, Kaplan FS. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med 29: 2615-2624, 2023

第五章. FOP的特殊医学考虑事项

1. 简介

患有进行性骨化性纤维发育不良（FOP）的人也可能会出现一些常见问题（如胆囊疾病、阑尾炎、感冒、耳痛等），与普通人群相似。一般来说，诊断和治疗FOP患者这些问题的最安全方法是先问：“如果这位患者没有FOP，我会如何评估他或她？”随后，可以应用“FOP过滤器”，询问：“考虑到可能的并发医疗问题的性质，以及该问题相对于FOP所带来的相对风险，有哪些诊断或治疗程序应该或不应该进行（或者是否可能有更合适的替代诊断程序）？”采用这种方法，通常可以解决诊断困境，并提供适当的护理。当仍然存在疑问时，应咨询FOP专家（见第十二章 - 作者联系方式）。
除了FOP患者可能面临的常见医疗问题外，还有许多特殊的医疗考虑事项值得特别关注，具体如下。
原文
  1. Introduction
      2. Individuals who have FOP can also develop common problems (gall bladder disease, appendicitis, colds, earaches, etc.) as with anyone in the general population. Generally, the safest way to diagnose and treat these problems in a patient with FOP is to ask the question: “How would I evaluate this patient if he or she did not have FOP?” Following that, the “FOP filter” can be applied to ask: “Given the nature of the possible intercurrent medical problem, and the relative risks that particular problem presents in relation to FOP, are there any diagnostic or treatment procedures that should or should not be undertaken (or perhaps alternative diagnostic procedures might be more appropriate)?” Using that approach, diagnostic dilemmas can often be resolved, and appropriate care delivered. When questions remain, experts on FOP should be consulted (Kaplan et al., 2018; see Section XII – Authors’ Contact Information).
      In addition to common medical problems that individuals with FOP might have, there are a number of special medical considerations for FOP patients that are worthy of very special attention. They are presented below.

2. FOP的创伤预防

预防软组织损伤和肌肉损伤仍然是进行性骨化性纤维发育不良（FOP）管理的一个重要方面。必须避免肌肉内注射。常规的儿童白喉-破伤风-百日咳疫苗通过肌肉注射接种会带来永久性异位骨化（HO）的重大风险，而动脉穿刺也是如此；相比之下，麻疹-腮腺炎-风疹疫苗通过皮下注射接种和常规静脉穿刺的风险则很小。FOP病变的活检从未被指示，并且可能导致额外的HO。选择性截肢也从未被指示。
在常规牙科护理中，最小的软组织创伤也可能引发下颌永久性强直。在对FOP患者进行牙科护理时，需要采取严格的预防措施。必须避免下颌过度拉伸和局部麻醉药物的肌肉内注射。下颌阻滞会导致肌肉创伤，从而导致HO，而局部麻醉药物对骨骼肌非常有毒。
FOP患者的跌倒可能导致严重伤害和病情加重。FOP患者往往陷入自我维持的跌倒循环。轻微的软组织创伤常常导致FOP的严重加重，从而引发HO和关节强直。由于关节强直导致的活动受限严重影响平衡机制，造成不稳定，进而导致更多跌倒。
与非FOP患者相比，FOP人群的跌倒更可能导致严重的头部损伤、失去知觉、脑震荡以及颈部和背部损伤。FOP患者往往无法使用上肢来缓冲跌倒的冲击。FOP患者在跌倒后更可能入院，并因跌倒而导致身体功能的永久性改变。在135名FOP患者中，67%的报告跌倒导致FOP的病情加重。年轻患者佩戴头盔可能有助于减少因跌倒导致的严重头部损伤的频率。
预防跌倒的措施应集中在活动调整、改善家庭安全、使用辅助行走设备（如手杖）以及使用保护性头盔。将活动转向较少身体互动的游戏可能也会有所帮助。完全避免高风险环境可能减少跌倒，但也可能影响患者的功能水平和独立性，并且对许多人来说可能不可接受。调整居住环境以减少家庭内的跌倒数量可以包括在楼梯上安装扶手、固定松散的地毯、清除通道中的物品，以及消除不平整的地面，包括门框阈值。预防因失衡导致的跌倒始于步态的稳定。使用手杖或稳定设备可能改善许多患者的平衡。对于更灵活的个体，使用滚动手杖或助步器将有助于稳定。
当发生跌倒时，应及时寻求医疗帮助，特别是当怀疑有头部或颈部损伤时。任何头部或颈部损伤在得到证明之前都应被视为严重。严重头部损伤的一些常见症状包括持续加重的头痛、头晕、嗜睡、意识模糊、虚弱、困惑或失去知觉。这些症状通常在受伤后几个小时才会出现。如果怀疑有头部或颈部损伤，FOP患者应由医疗专业人员仔细检查。
如前所述，使用泼尼松在重大软组织创伤后或围手术期应考虑作为预防措施。皮质类固醇的剂量取决于体重。泼尼松的典型剂量为1-2 mg/kg/天（最高可达100 mg），每天一次，使用不超过4天（表1）。为了对下丘脑-垂体-肾上腺轴产生最小的抑制作用，药物应在早晨服用。
参考文献
  1. Glaser DL, Rocke DM, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 346: 110-116, 1998 FOP患者的灾难性跌倒
  1. Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatrics 126: 762-764, 1995 在进行性骨化性纤维发育不良儿童中，接种白喉-破伤风-百日咳疫苗后注射部位的永久性异位骨化
  1. Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996 FOP患者局部麻醉药物注射后下颌运动严重受限
原文
  1. Injury Prevention in FOP
      2. Prevention of soft-tissue injury and muscle damage remain a hallmark of FOP management. Intramuscular injections must be avoided. Routine childhood diphtheria-tetanus-pertussis immunizations administered by intramuscular injection pose a substantial risk of permanent heterotopic ossification (HO), as do arterial punctures whereas measles-mumps-rubella immunizations administered by subcutaneous injection and routine venipuncture pose little risk (Lanchoney et al., 1995). Biopsies of FOP lesions are never indicated and will likely cause additional HO. Elective amputations are never indicated.
      Permanent ankylosis of the jaw may be precipitated by minimal soft tissue trauma during routine dental care. Assiduous precautions are necessary in administering dental care to anyone who has FOP. Overstretching of the jaw and intramuscular injections of local anesthetic must be avoided. Mandibular blocks cause muscle trauma that will lead to HO, and local anesthetic drugs are extremely toxic to skeletal muscle (Luchetti et al., 1996).
      Falls suffered by FOP patients can lead to severe injuries and flare-ups. Patients with FOP have a self-perpetuating fall cycle. Minor soft tissue trauma often leads to severe exacerbations of FOP, which result in HO and joint ankylosis. Mobility restriction from joint ankylosis severely impairs balancing mechanisms, and causes instability, resulting in more falls (Glaser et al., 1998).
      Falls in the FOP population are more likely to result in severe head injuries, loss of consciousness, concussions, and neck and back injuries, compared to people who do not have FOP. Individuals with FOP are often unable to use the upper limbs to absorb the impact of a fall. FOP patients are much more likely to be admitted to a hospital following a fall and have a permanent change in physical function because of the fall. In a group of 135 FOP patients, 67% of the reported falls resulted in a flare-up of the FOP. Use of a helmet by young patients may help reduce the frequency of severe head injuries that can result from falls (Glaser et al., 1998).
      Measures to prevent falls should be directed at modification of activity, improvement in household safety, use of ambulatory devices (such as a cane, if possible), and use of protective headgear. Redirection of activity to less physically interactive play may also be helpful. Complete avoidance of high-risk circumstances may reduce falls, but also may compromise a patient’s functional level and independence and may be unacceptable to many. Adjustments to the living environment to reduce the number of falls within the home may include installing supportive hand-railings on stairs, securing loose carpeting, removing objects from walkways, and eliminating uneven flooring including doorframe thresholds. Prevention of falls due to imbalance begins with stabilization of gait. The use of a cane or stabilizing device may improve balance for many patients. For more mobile individuals, the use of a rolling cane or a walker will assist in stabilization.
      When a fall occurs, prompt medical attention should be sought, especially when a head or neck injury is suspected. Any head or neck injury should be considered serious until proven otherwise. A few common signs and symptoms of severe head injury include increasing headache, dizziness, drowsiness, obtundation, weakness, confusion, or loss of consciousness. These symptoms often do not appear until hours after an injury. An FOP patient should be examined carefully by a healthcare professional if a head or neck injury is suspected.
      As mentioned previously, prednisone use should be considered prophylactically following major soft tissue trauma, or peri-operatively. The dose of corticosteroids is dependent upon body weight. A typical dose of prednisone is 1-2 mg/kg/day (up to 100 mg), administered as a single daily dose for no more than 4 days (Table 1). In order to have the least suppressive effect on the hypothalamic-pituitary-adrenal axis, medication should be taken in the morning.
      References
      Glaser DL, Rocke DM, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 346: 110-116, 1998
      Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatrics 126: 762-764, 1995
      Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996

3. FOP的头皮结节

头皮结节是出现在头部的发作，通常在儿童时期出现——往往是进行性骨化性纤维发育不良的第一种出生后表现。尽管头皮结节的体积常常很大且外观令人担忧，但它们在临床上并不具有重要意义。
关于头皮结节的文献报道很少。它们通常被报告为进行性骨化性纤维发育不良的第一症状，发生在新生儿期（约10%的病例），但在任何年龄都可能被低估。其发作的中位年龄为1.5岁。
临床上，头皮结节可能是单个的或多个的，且固定不动，大小变化，从核桃大小到如网球般大。它们可能是无症状的，或在开始时仅有轻微疼痛。通常，这些结节会自行出现和消退，或者在创伤或感染后，或在表面看似健康的儿童中发展。
X光检查通常不必要，但一般会显示软组织增厚，经过几个月后会出现小的骨化区域。必须避免进行活检/手术切除或细针穿刺以进行细胞学和组织学研究。对三例患者的组织病理学发现描述为：在深层皮下组织中，短纺锤形细胞增生，伴有丰富的胶原基质、散在的炎症细胞（肥大细胞和T细胞）以及大量血管。
在少数报道的病例中，头皮结节的出现与基因型之间的相关性并没有详细说明，但在多例研究中，似乎与ACVR1的R206H经典突变相关。
婴儿期出现单个或多个头皮结节是进行性骨化性纤维发育不良的重要早期迹象，可能是该病的第一次出生后发作的表现。婴儿期出现头皮结节时，应立即检查大脚趾——这一临床情境可能有助于加速进行性骨化性纤维发育不良的正确诊断。
因此，重要的是，当看到头皮结节时，必须检查脚趾！更重要的是，必须避免进行活检。可以开一些对症治疗，但不使用类固醇，因为没有关节受累。尽管它们的外观常常令人担忧，但不需要治疗。随着时间的推移，肿胀会减退，如果发生骨化，重塑是常见的，因为这些病变会融入不断生长的颅骨中。
参考文献
  1. Al Kaissi A, Kenis V, Ben Ghachem M, Hofstaetter J, Grill F, Ganger R, Kircher SG. The diversity of the clinical phenotypes in patients with fibrodysplasia ossificans progressiva. J Clin Med Res 8: 246-253, 2016 进行性骨化性纤维发育不良患者的临床表型多样性
  1. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnosis errors in FOP. Pediatrics 116: 654-661, 2005 由于FOP诊断错误导致的医源性伤害
  1. Kardile M, Nayak S, Nagaraja HS, Mishra AK. Fibrodysplasia ossificans progressiva in a four-year-old child. J Orthop Case Rep 2: 17-20, 2012 一名四岁儿童的进行性骨化性纤维发育不良
  1. Piram M, Le Merrer M, Bughin V, De Prost Y, Fraitag S, Bodemer C. Scalp nodules as a presenting sign of fibrodysplasia ossificans progressiva: a register-based study. J Am Acad Dermatol 64: 97-101, 2011 头皮结节作为进行性骨化性纤维发育不良的首发症状: 一项基于注册的研究
原文
  1. Scalp Nodules in FOP
      2. Scalp nodules are flare-ups on the head, commonly appearing in childhood – often the first post-natal manifestations of FOP. Scalp nodules are of little clinical significance despite their often large size and alarming appearance.
      Scalp nodules are noted in very few publications (Kitterman et al., 2005; Piram et al., 2011; Kardile et al., 2012; Al Kaissi et al., 2016). They are often reported as first symptom of FOP, from the neonatal period (about 10% of cases (Kitterman et al., 2005), but also may be an under-recognized symptom at any age. The median age of onset is 1.5 years (Piram et al., 2011).
      Clinically, scalp nodules may be solitary or numerous, immobile, with a variable size, from a walnut size to a great volume such as a tennis ball. They may be asymptomatic or painful only at onset. Usually, they appear and regress spontaneously, or can develop after trauma or infection, or in a child who is apparently in good health.
      Radiographs are unnecessary but generally show soft tissue thickening initially with small zones of HO after some months. Biopsies/surgical excision or fine-needle aspiration for cytological and histologic studies must be avoided. Histopathologic findings are described in three patients by Piram et al., 2011 as proliferation of short spindle-shaped cells in the deep subcutaneous tissue, with abundant collagenous stroma and scattered inflammatory cells (mast cells & T-cells) and numerous vessels.
      The correlation between their presence and the genotype is not detailed in the few reported cases but it appears that they are associated with the R206H classic mutation in ACVR1 in numerous cases studied.
      The occurrence of unique or multiple scalp nodule(s) in infancy is an important early sign of FOP and may be the first sign of a post-natal flare-up of the condition. The presence of scalp nodules during infancy should prompt immediate examination of the great toes – a clinical scenario that could appropriately accelerate the proper diagnosis of FOP.
      So, importantly, when scalp nodules are seen, the toes must be examined! Even more importantly, biopsies must not be performed. Symptomatic treatments may be prescribed but steroids are not used as no joints are involved. Despite their often alarming appearance, no treatment is necessary. Swelling subsides with time and if ossification occurs, remodeling is common as the lesions are incorporated into the growing skull.
      References
      Al Kaissi A, Kenis V, Ben Ghachem M, Hofstaetter J, Grill F, Ganger R, Kircher SG. The diversity of the clinical phenotypes in patients with fibrodysplasia ossificans progressiva. J Clin Med Res 8: 246-253, 2016
      Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnosis errors in FOP. Pediatrics 116: 654-661, 2005
      Kardile M, Nayak S, Nagaraja HS, Mishra AK. Fibrodysplasia ossificans progressiva in a four-year-old child. J Orthop Case Rep 2: 17-20, 2012
      Piram M, Le Merrer M, Bughin V, De Prost Y, Fraitag S, Bodemer C. Scalp nodules as a presenting sign of fibrodysplasia ossificans progressiva: a register-based study. J Am Acad Dermatol 64: 97-101, 2011

4. FOP的脊柱畸形

脊柱畸形在进行性骨化性纤维发育不良患者中很常见。一项针对40名FOP患者的研究显示，65%的人有脊柱侧弯的放射学证据。最初的临床异常是迅速发展的脊柱侧弯，伴有自发性出现的椎旁软组织病变。一旦形成，这些畸形会迅速导致永久性失去活动能力，并随着生长而加重脊柱畸形。
在骨骼成熟之前，脊柱一侧形成骨性桥梁会限制该侧的生长，而对侧生长则不受限制。如果骨性桥梁双侧形成且相对对称，或在骨骼成熟后形成，通常不会导致脊柱侧弯。
在FOP患者中，严重的脊柱侧弯可导致骨盆倾斜，类似于其他原因引起的脊柱侧弯，且这种倾斜会影响躯干的平衡以及站立或坐着的平衡。
在五名患者的经验中，传统的脊柱侧弯手术方法可能会严重加重FOP的病情。此外，系列中的三名患者在进行脊柱侧弯手术矫正后，脊柱曲度仍继续加重，即使在进行脊柱融合术后也是如此。其中两名患者的融合术是在后方进行的，而不是前方，因此脊柱的前向生长加重了旋转畸形。
与其他类型的脊柱侧弯相关的脊柱畸形矫正指征并不适用于FOP患者。在现有有限知识下，矫正脊柱畸形所伴随的严重并发症（尤其是在手术区域远处加重异位骨化的风险）可能超过其益处。然而，随着对FOP自然病程的了解加深和新手术技术的发展，这些旧的观点正在逐例进行仔细重新审视。
对三名快速发展下颌贴胸畸形患者的研究表明，可能需要采取更积极的外科方法来预防和/或矫正这些快速进展的畸形。
参考文献
  1. Moore R, Dormans J, Drummond DS, Shore EM, Kaplan FS, Auerbach J. Chin-on-chest deformity in patients who have fibrodysplasia ossificans progressiva (FOP). J Bone Joint Surg Am 91: 1497-1502, 2009 进行性骨化性纤维发育不良（FOP）患者的下巴贴胸畸形
  1. Shah P, Zasloff MA, Drummond, D, Kaplan FS. Spinal deformity in patients who have FOP. J Bone Joint Surg Am 76: 1442-1450, 1994 进行性骨化性纤维发育不良患者的脊柱畸形
原文
  1. Spinal Deformity in FOP
      2. Spinal deformities are common in individuals who have FOP. A study in 40 FOP patients showed that 65% had radiographic evidence of scoliosis. The initial clinical abnormality was a rapidly developing scoliosis associated with a spontaneously occurring lesion in the paravertebral soft tissues. Once established, these deformities lead to rapid, permanent loss of mobility and to progressive spinal deformity with growth (Shah et al., 1994).
      The formation of a unilateral osseous bridge along the spine prior to skeletal maturity limits growth on the ipsilateral side of the spine while growth continues uninhibited on the contralateral side. If an osseous bridge occurs bilaterally and the two bridges are relatively symmetrical, or if an osseous bridge forms after skeletal maturity, scoliosis will not result.
      Severe scoliosis in FOP can lead to pelvic obliquity, similar to that seen in scoliosis resulting from other causes, and the obliquity can impair the balance of the trunk as well as standing and/or sitting balance.
      Anecdotal experience in five patients suggests that traditional operative approaches to scoliosis in FOP patients can seriously exacerbate the disease. Furthermore, three patients in the series who had operative correction of the scoliosis continued to have progression of the spinal curve even after a spinal arthrodesis. In two of these patients, the arthrodesis was performed posteriorly and not anteriorly. Thus, continued anterior growth of the spine exacerbated rotational deformity.
      Indications for correction of spinal deformity associated with more usual types of scoliosis do not pertain to patients with FOP. With the limited knowledge available, the risks of severe complications (most notably, the exacerbation of HO at sites remote from the operative field) that are associated with correction of spinal deformity in FOP likely outweigh the benefits (Shah et al., 1994). However, with greater knowledge of the natural history of FOP and newer surgical techniques, these old assertions are undergoing careful re-examination on a case-by-case basis.
      A study of three patients with rapidly evolving chin-on-chest deformities suggests that a more aggressive surgical approach may be necessary to prevent and/or correct such rapidly progressive deformities in patients who have FOP (Moore et al., 2009).
      References
      Moore R, Dormans J, Drummond DS, Shore EM, Kaplan FS, Auerbach J. Chin-on-chest deformity in patients who have fibrodysplasia ossificans progressiva (FOP). J Bone Joint Surg Am 91: 1497-1502, 2009
      Shah P, Zasloff MA, Drummond, D, Kaplan FS. Spinal deformity in patients who have FOP. J Bone Joint Surg Am 76: 1442-1450, 1994

5. FOP的心肺功能

最近的一项自然史研究显示，携带ACVR1R206H突变的个体在心电图上出现心脏传导异常的发生率增加。在基线心电图中，传导异常的发生率为45.3%，其中大多数被归类为非特异性室内传导延迟（37.7%）。更具体地说，18岁以上患者中有22.2%出现了传导异常，这一比例显著高于之前健康人群的研究（5.9%；n = 3978）（p < 0.00001）。而18岁以下的FOP患者也有较高的传导异常发生率（62.3%）。12个月的随访数据显示与基线结果相似。传导异常与胸壁畸形、脊柱侧弯、肺功能测试结果或累积关节参与评分（CAJIS）没有相关性。对22名FOP患者的超声心动图检查显示，有8例存在结构性心脏异常，其中仅有1例与传导异常相关。
总之，FOP患者可能在心电图上表现出亚临床的传导异常，这与异位骨化无关。虽然临床上通常不认为FOP与显著的心脏疾病相关，但对于心血管风险的临床意义尚不清楚，因此了解心电图和超声心动图的变化对于FOP患者的临床护理和研究试验至关重要。进一步研究ACVR1/ALK2 R206H如何影响心脏健康将有助于阐明其潜在机制。
FOP患者可能会发展为胸腔功能不全综合征（TIS），这可能导致危及生命的并发症。FOP患者中导致TIS的特征包括：
  • 胸椎畸形伴有肋椎关节的骨性强直
  • 肋间肌、脊旁肌和腱膜的骨化
  • 进行性脊柱畸形，包括后凸侧弯或胸椎前凸
肺炎、低氧血症、高碳酸血症、肺动脉高压和右心衰竭是FOP患者中因TIS引起的主要危及生命的风险。采取预防措施以最大化肺功能、减少呼吸功能受损、预防流感和肺炎，有助于降低FOP患者因TIS导致的发病率和死亡率。应尽早邀请肺病学专家参与，并根据需要定期进行肺活量测定和睡眠研究。
FOP患者会出现胸部扩张逐渐受限，导致限制性肺病，表现为肺活量降低，但气流并无阻塞。晚期患者的胸部扩张极为有限，依赖膈肌进行吸气。因此，许多患者的低吸气容量导致低呼气流量。
因此，FOP患者易发生肺不张、分泌物潴留、低氧血症、高碳酸血症和肺炎。在TIS的影响下，所有患者的肺功能检查均异常。肺部储备减少时，胸部感染是FOP患者生命的主要危险因素。许多患者的心电图异常，显示右心室功能障碍。有研究建议，胸壁严重限制性疾病的存在与右心室异常的高发病率相关。
呼吸衰竭和肺心病是严重TIS的特征。对这一问题的详细描述指出，至少有10%的病例出现右心室肥大。肺动脉高压是常见的发现，这些作者将其归因于血管阻力增加和持续性肺泡低通气的影响。
FOP患者的呼吸问题与颈髓损伤或其他脊柱异常（如后凸侧弯）患者的呼吸肌无力所见问题相似。采用与这些其他人群相似的策略以最大限度地提高呼吸肌功能和清除分泌物，对FOP患者可能是有益的。
吸气和呼气肌肉训练应定期进行，并在确诊时开始。可以使用多种激励性肺活量计来鼓励深呼吸。吸气肌训练设备可以进行膈肌的逐步阻力锻炼。
应特别关注预防和治疗并发的胸部感染。此类措施应包括预防性接种肺炎球菌疫苗和流感疫苗（皮下注射）、胸部物理治疗，以及对早期胸部感染的及时抗生素治疗。
如果可能，应避免上腹部手术，因为这会干扰膈肌呼吸。评估睡眠呼吸暂停的睡眠研究可能有帮助。使用正压辅助呼吸设备，如BiPAP®（双水平正压呼吸）面罩，无需补充氧气也可能有帮助。夜间使用CPAP和在环境空气中进行非侵入性通气可能是有效的治疗夜间低通气/低氧血症的方法。
对于晚期TIS并在未监测情况下使用氧气的FOP患者，突发性死亡风险较高。在慢性二氧化碳潴留的情况下，突发性纠正氧分压会抑制呼吸驱动。因此，FOP患者和严重TIS患者不应在未监测的环境中使用补充氧气。
在住院期间或疾病较晚期，FOP患者可能会面临清除分泌物的困难。这可能导致肺不张、肺炎和需要气管插管的呼吸衰竭。通过适当的水合作用、愈创木脂、支气管扩张剂和粘液溶解剂等手段，可以增强分泌物的清除。如果考虑气管插管或手术，建议使用鼻纤维支气管镜进行气管插管。对于手术或介入程序，精心设计的麻醉计划至关重要。如果由于TIS严重，预计将发生呼吸衰竭，则应在气管插管和气管造口之间进行权衡。术后护理应安排在重症监护环境中进行。
在预防方面也可以采取许多措施。FOP患者通常在出生时就有胸椎关节的先天畸形，这会在异位骨出现之前就造成一定程度的胸部限制，尽管这些限制在生命早期可能不会导致任何临床问题。然而，由于这些限制，FOP患者即使在生命早期也更可能依赖膈肌呼吸。建议FOP患者在十岁之前由肺科医生进行评估，以进行基础肺功能测试和心脏超声检查。这些测试的结果将进一步指导心肺系统的预防性护理。
有多种设备可用于松动分泌物，从简单的手持设备（在呼气时造成气道壁的振动）到能够振动胸壁的衣物，再到高科技特种床（可翻转和振荡）。在使用这些设备时需谨慎，特别是对于咳嗽无力的患者，因为他们可能无法在松动后有效咳出分泌物。机械吸气-排气装置可以非侵入性地提取保留的分泌物，适用于咳嗽无效的个体。该设备可以显著提高呼气肌功能受损个体的咳嗽峰值流量。将松动分泌物的方法与排气结合使用可以防止呼吸衰竭和机械通气的需求。然而，所有震动设备在使用时应谨慎，以防引发创伤。
各种活动可以帮助增强膈肌力量，可能降低并发肺部问题的风险。除了间歇性使用激励性肺活量计外，还应鼓励其他活动，如深呼吸、游泳/水疗和唱歌，这些活动应在早期进行，可能有助于改善长期肺功能。
肺动脉高压（PH）是TIS的并发症，且是FOP的常见特征。早期症状非特异性，包括运动时呼吸困难和疲劳。在FOP患者中，如果存在严重限制性肺病或中度肺病持续时间较长，则应高度怀疑PH。如果怀疑PH，应进行经胸超声心动图检查，因为这可以非侵入性地估计肺动脉收缩压（PH时通常> 25 mm Hg）并评估左右心室的大小和功能。虽然右心导管检查可确认PH的诊断，但在已知严重限制性肺病或其他近端原因（如晚期左心病或慢性低氧）情况下，合理推迟此项检查。在可能的情况下，治疗潜在病因是PH管理的主要目标；然而，在FOP中，PH最常与限制性肺病相关，而限制性肺病因胸腔不动而难以治疗。因此，在FOP中，PH的治疗应直接针对PH本身，最好由肺科医生管理。关于使用磷酸二酯酶-5抑制剂（如西地那非或他达拉非）的经验性证据存在，应考虑作为轻至中度PH的初始口服治疗。
参考文献
  1. Bergofsky EH. Respiratory failure in disorders of the thoracic cage. Am Rev Resp Dis 119: 643–669, 1979 胸廓疾病引起的呼吸衰竭
  1. Kaplan FS, Glaser DL. Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 213-216, 2005 进行性骨化性纤维发育不良患者的胸部功能不足综合征
  1. Kaplan FS, Zasloff MA, Kitterman JA. Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 92: 686-691, 2010 进行性骨化性纤维发育不良患者的早期死亡率和心肺衰竭
  1. Kilmartin, E, Grunwald, Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: A review of 42 cases in 30 patients. Anesth Analg 118: 298301, 2014 进行性骨化性纤维发育不良患者牙科手术的全身麻醉：30名患者的42例回顾
  1. Kou S, De Cunto C, Baujat G, Wentworth KL, Grogan DR, Brown MA, Di Rocco M, Keen R, Al Mukaddam M, le Quan Sang KH, Masharani U, Kaplan FS, Pignolo RJ, Hsiao EC. Patients with ACVR1(R206H) mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2020 Jul 29;15(1):193 ACVR1(R206H)突变患者在进行性骨化性纤维发育不良的自然历史研究中，心电图上心脏传导异常的发生率增加
  1. Kussmaul WG, Esmail AN, Sagar Y, Ross J, Gregory S, Kaplan FS. Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva. Clin Orthop 346: 104-109, 1998 进展性纤维异位骨化症的肺功能和心脏功能
  1. Shah PB, Zasloff MA, Drummond D, Kaplan FS. Spinal deformity in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 76: 1442–1450, 1994 进行性骨化性纤维发育不良患者的脊柱畸形
原文
  1. Cardiopulmonary Function in FOP
      2. A recent natural history study showed that individuals with ACVR1R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram. Conduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale (CAJIS) scores. Echocardiograms from 22 patients with FOP revealed eight with structural cardiac abnormalities, only one of which correlated with a conduction abnormality (Kou et al., 2020).
      In summary, individuals with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2 R206H affects cardiac health will help elucidate the underlying mechanism (Kou et al., 2020).
      Patients with FOP develop thoracic insufficiency syndrome (TIS) that can lead to life-threatening complications. Features contributing to TIS in patients with FOP include:
      • Costovertebral malformations with orthotopic ankylosis of the costovertebral joints
      • Ossification of intercostal muscles, paravertebral muscles and aponeuroses
      • Progressive spinal deformity including kyphoscoliosis or thoracic lordosis
      Pneumonia, hypoxemia, hypercarbia, pulmonary hypertension and right-sided heart failure are the major life-threatening hazards that result from TIS in patients with FOP. Prophylactic measures to maximize pulmonary function, minimize respiratory compromise, and prevent influenza and pneumonia are helpful in decreasing the morbidity and mortality from TIS in patients with FOP (Kussmaul et al., 1998; Kaplan & Glaser, 2005; Kaplan et al., 2010). A pulmonologist should be involved early with regular spirometry assessments and sleep studies as needed.
      Individuals with FOP develop progressive limitations in chest expansion, resulting in restrictive lung disease, with reduced vital capacity but no obstruction to air flow. Those with advanced disease have extremely limited chest expansion and rely on the diaphragm for inspiration (Kussmaul et al., 1998). The low inspiratory capacity results in low expiratory flow rates, in many cases.
      Consequently, individuals with FOP are subject to atelectasis, retained secretions, hypoxemia, hypercarbia and pneumonia. All patients had abnormal spirometry secondary to TIS. Chest infection in the presence of diminished pulmonary reserve is the major hazard to life in patients with FOP. Many patients had abnormal electrocardiograms, with evidence of right ventricular dysfunction. It is suggested that the presence of severe restrictive disease of the chest wall is associated with a high incidence of right ventricular abnormalities (Kaplan et al., 2010).
      Respiratory failure and cor pulmonale are features of severe TIS (Shah et al., 1974). A detailed description of this problem (Bergofsky et al., 1979) noted right ventricular hypertrophy in at least 10% of cases. Pulmonary hypertension was a common finding, which these authors attributed to increased vascular resistance and the effects of prolonged alveolar hypoventilation.
      The respiratory problems seen in patients with FOP are similar to those seen in patients with respiratory muscle weakness such as cervical spinal cord injury, or other skeletal abnormalities such as kyphoscoliosis. Strategies similar to those used in these other populations to maximize respiratory muscle functional and clear secretions may be beneficial in those with FOP.
      Inspiratory and expiratory muscle training should be routinely practiced and started at the age of diagnosis. A variety of incentive spirometers are available to encourage deep breathing. Inspiratory muscle training devices permit progressive resistance exercise training of the diaphragm.
      Careful attention should be directed toward the prevention and therapy of intercurrent chest infections. Such measures should include prophylactic pneumococcal pneumonia and influenza vaccinations (given subcutaneously), chest physiotherapy, and prompt antibiotic treatment of early chest infection.
      Upper abdominal surgery should be avoided, if possible as it interferes with diaphragmatic respiration. Sleep studies to assess sleep apnea may be helpful. Positive pressure assisted breathing devices such as BiPAP® (Bi-level positive airway pressure) masks without the use of supplemental oxygen may also be helpful. Night CPAP and noninvasive ventilation on ambient air may be effective treatments for nocturnal hypoventilation/hypoxemia.
      Patients with FOP who have advanced TIS and who use unmonitored oxygen have a high risk of sudden death. Sudden correction of oxygen tension in the presence of chronic carbon dioxide retention suppresses respiratory drive. Patients who have FOP and severe TIS should not use supplemental oxygen in an unmonitored setting (Kaplan & Glaser, 2005; Kaplan et al., 2010).
      During hospitalizations or in more advanced disease, individuals with FOP may have trouble clearing secretions. This can lead to atelectasis, pneumonia and respiratory failure requiring endotracheal intubation. Secretion clearance is enhanced by adequate hydration, guaifenesin, bronchodilators and mucolytics, as needed. If endotracheal intubation or a surgical procedure are considered, nasal fiberoptic intubation of the trachea is recommended (Kilmartin et al. 2014). For surgical or interventional procedures, a carefully designed anesthesia plan is paramount. Planning for extubation of the trachea should be weighed against creation of tracheostomy if impending respiratory failure is expected due to the advanced TIS. Postoperative care should be assigned to an intensive care setting.
      There is also much that can be done in prevention. Individuals with FOP are often born with congenital malformations of the costovertebral joints that cause some degree of chest restriction even before the appearance of heterotopic bone, although these restrictions may not lead to any clinical problems early in life. However, because of these restrictions, individuals with FOP are more likely to rely, even early in life, on diaphragmatic breathing. It is recommended that individuals with FOP be evaluated by a pulmonologist by the end of the first decade of life in order to perform baseline pulmonary function tests and echocardiograms. The results of these tests may further help guide preventative care for the cardiopulmonary system.
      Several devices are available to loosen secretions from relatively simple handheld devices that cause vibration of the airway walls during exhalation, to garments that vibrate the chest wall to high technology specialty beds that turn and oscillate. Care must be taken when using such devices in patients with a weak cough, as they may be unable to expectorate the secretions once loosened. Use of mechanical insufflation-exsufflation can non-invasively extract retained secretions from individuals with ineffective cough. The device can dramatically increase peak cough expiratory flow in individuals with impaired expiratory muscle function. Combining a method to loosen secretions with in-exsufflation to remove them may prevent respiratory failure and the need for mechanical ventilation. However, all percussive devices should be used with caution due to risk of inducing trauma.
      Various activities can help maximize the strength of the diaphragm and perhaps decrease the risk of intercurrent pulmonary problems. In addition to the intermittent use of incentive spirometry, other activities such as deep breathing, swimming/hydrotherapy, and singing, should be encouraged at an early age and may help improve long-term pulmonary function.
      Pulmonary hypertension (PH) is a complication of TIS which is a common feature of FOP. Early symptoms are non-specific and include dyspnea on exertion and fatigue. In FOP, a high index of suspicion is warranted if severe restrictive lung disease or moderate disease exists over a prolonged period of time. If PH is suspected transthoracic echocardiography should be performed, since it permits a noninvasive estimation of pulmonary arterial systolic pressure (usually > 25 mm Hg in PH) and evaluation of both right and left heart size and function. Although right heart catheterization confirms the diagnosis of PH, it can reasonably be deferred in FOP in the setting of known severe restrictive lung disease or other proximal causes such as advanced left-sided heart disease or chronic hypoxia. When possible, treatment of the underlying condition is the primary goal of management for PH; however, in FOP, PH is most commonly associated with restrictive lung disease which is not easily treated due to immobility of the chest cavity. Therefore, in FOP, therapy for PH is directed at PH itself and is best managed by pulmonologists. Anecdotal evidence exists for the use of phosphodiesterase-5 inhibitors such as sildenafil or tadalafil, and should be considered as an initial oral therapy for mild to moderate PH.
      References
      Bergofsky EH. Respiratory failure in disorders of the thoracic cage. Am Rev Resp Dis 119: 643–669, 1979
      Kaplan FS, Glaser DL. Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 213-216, 2005
      Kaplan FS, Zasloff MA, Kitterman JA. Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 92: 686-691, 2010
      Kilmartin, E, Grunwald, Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: A review of 42 cases in 30 patients. Anesth Analg 118: 298301, 2014
      Kou S, De Cunto C, Baujat G, Wentworth KL, Grogan DR, Brown MA, Di Rocco M, Keen R, Al Mukaddam M, le Quan Sang KH, Masharani U, Kaplan FS, Pignolo RJ, Hsiao EC. Patients with ACVR1(R206H) mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2020 Jul 29;15(1):193
      Kussmaul WG, Esmail AN, Sagar Y, Ross J, Gregory S, Kaplan FS. Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva. Clin Orthop 346: 104-109, 1998
      Shah PB, Zasloff MA, Drummond D, Kaplan FS. Spinal deformity in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 76: 1442–1450, 1994

6. FOP的呼吸健康

保持良好的呼吸健康对每个人都至关重要。对于进行性骨化性纤维发育不良（FOP）患者而言，这一点尤其重要，因为FOP可能因胸廓畸形、异位骨化和脊柱侧弯而显著降低呼吸能力。
保持良好的呼吸健康涉及几个方面：
感染预防，尤其是在流感季节： 确保所有FOP患者及其家人定期洗手并使用酒精凝胶。避免前往容易传播感染的地方。如果需要接触，我们建议FOP患者佩戴简单的外科口罩，以减少吸入感染飞沫（例如打喷嚏时）。这些口罩并不是用来过滤所有病毒和细菌的，但可以在降低大飞沫接触的同时确保呼吸舒适。高质量的N95或KN95口罩也能有效减少暴露风险。
维持呼吸能力： 我们建议每天进行15-30分钟的主动呼吸活动。这些活动应感到舒适，不应引起疼痛，目的是保持膈肌和其他呼吸肌肉的健康。我们推荐的活动包括剧烈的发声（如唱歌、合唱；在淋浴时大声唱歌）、吹泡泡等。
对于某些患者，使用激励性肺活量计可以辅助剧烈的发声。这些设备可用于测量肺容量，但我们建议将其作为维持肺容量和确保肺部通气良好的工具。
选择每年接种流感疫苗的FOP患者应使用由经验丰富的医疗提供者进行的皮下注射免疫。流感疫苗不应在病情发作期间接种，并且在病情缓解后至少要等两周才能接种。无论FOP患者是否决定接种流感疫苗，所有直系亲属、家庭接触者和看护人员都应接种。
如果未能接种流感疫苗，出于任何原因，在流感季节准备好奥司他韦（达菲）是合理的预防措施。在流感出现的初期症状（如发热、发冷、咳嗽、喉咙痛、流鼻涕或鼻塞、肌肉或身体酸痛、头痛、疲劳、呕吐和腹泻）时，应立即服用第一剂奥司他韦，并立刻联系医生。
患者还应考虑接种其他呼吸疾病的疫苗，包括肺炎球菌和COVID-19。有关详细信息，请参见相应的部分。
有多种类型的激励性肺活量计和多种策略可用于维持肺功能。国际进行性骨化性纤维发育不良协会（IFOPA）根据年龄和下颌需求提供两种类型的设备。
儿童专用峰流口哨（适合幼儿）
对于幼儿，推荐使用峰流口哨。这些口哨在空气快速吹过时会发出声音。该设备最重要的部分是在吹口哨前进行深吸气，而不是实际能否发出口哨声！
患者应：
  1. 坐直或站立。
  1. 将口哨放入口中，确保嘴唇紧紧闭合。
  1. 尽可能缓慢吸气（这是最重要的部分）。屏住呼吸约10秒钟。
  1. 快速通过口哨呼气，以产生声音。
  1. 吸气和呼气之间要休息。
  1. 重复10次，中间短暂休息。
  1. 如果在任何时候感到头晕，或有任何不适或胸部不适，应立即停止。
口哨的设置应根据患者在正常日子里估计的峰流量（即应该能发出口哨声）进行。由于胸廓畸形，标准的FEV1值表在FOP中并不适用；不过，之前的肺功能测试（PFT）结果可作为参考。目标是鼓励深吸气以最小化肺不张，而不是增加峰流量。峰流口哨为儿童提供了激励。
激励性肺活量计
激励性肺活量计适用于较大儿童和成年人。市场上有多种型号，但所有型号的目标都是相同的——进行缓慢、深呼吸以扩展肺部。
患者应：
  1. 坐直在椅子或床上，或站直。
  1. 将肺活量计持在脸前，眼睛高度。有许多FOP患者由于上肢关节的强直可能无法做到这一点。他们可能需要帮助，或者将肺活量计放置得足够近，以便使用，但不必用双手握住。
  1. 用嘴唇紧紧闭合住嘴嘴，以确保密封。
  1. 慢慢完全呼气。
  1. 通过嘴巴缓慢尽可能深吸气。
  1. 活量计的活塞会在吸气时上升。
  1. 屏住呼吸10秒（此时活塞可能会下降），然后呼气。
  1. 重复10次，中间短暂休息。
  1. 如果在任何时候感到头晕，应停止并休息。
  1. 每天进行两次此例程。
参考文献
  1. Botman E, Smilde BJ, Hoebink M, Treurniet S, Raijmakers P, Kamp O, Teunissen BP, Bökenkamp A, Jak P, Lammertsma AA, van den Aardweg JG, Boonstra A, Eekhoff EMW. Deterioration of pulmonary function: An early complication in Fibrodysplasia Ossificans Progressiva. Bone Rep 2021 Feb 25;14:100758 肺功能恶化：进行性骨化性纤维发育不良的早期并发症
  1. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014 Apr 10;(4) 神经氨酸酶抑制剂用于预防和治疗健康成人和儿童的流感
  1. Shah PB, Zasloff MA, Drummond D, Kaplan FS. Spinal deformity in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg 76-A: 1442-1450, 1994 进行性骨化性纤维发育不良患者的脊柱畸形
  1. Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116. 进行性骨化性纤维发育不良患者的骨骼畸形和发育性关节病
原文
  1. Respiratory Health in FOP
      2. Strong respiratory health is important for everyone. This is particularly true for individuals with FOP since FOP can severely decrease respiratory capacity from the chest wall deformities, heterotopic ossification and scoliosis (Shah et al.,1994; Towler et al., 2020; Botman et al, 2021).
      Maintaining strong respiratory health involves a few things:
      Infection precautions, particularly during the flu season: Make sure that all FOP patients and their family members wash their hands regularly and use alcohol gel. Avoid places where infection can be easily transmitted. In the event that exposures need to occur, we recommend that individuals with FOP wear a simple surgical mask to decrease the risk of breathing in infected droplets (such as from a sneeze). These masks are not meant to filter out all viruses and infectious bacteria but will balance the need to decrease exposure to larger droplets with comfortable breathing. Alternatively, a high quality N95 or KN95 mask can be very effective in decreasing exposure.
      Maintaining respiratory capacity: We recommend 15-30 minutes per day of active respiratory activity. This should not be uncomfortable or cause pain but is meant to help keep the diaphragm and other respiratory muscles healthy. Activities that we recommend include vigorous vocalizations (i.e. singing, as in a choir; loud continuous vocal activity like singing in the shower), blowing bubbles, etc.
      For some, an incentive spirometer can complement vigorous vocalizations. These devices can be used to measure lung capacity. However, we recommend using them as a way to maintain lung capacity and make sure the lungs are well-ventilated.
      FOP patients who decide to have yearly influenza immunizations should use the subcutaneous immunization, given by an experienced provider. The flu immunization should not be given during a flareup and not until at least 2 weeks after a flare-up has resolved. Whether or not the FOP patient decides to get a flu vaccine, all immediate family members, household contacts and caretakers should be immunized.
      In the case where the flu vaccine is not obtained, for whatever reason, having a ready supply of Oseltamivir (Tamiflu) on hand during flu season is a reasonable precaution. At the first signs of the flu (fever or feeling feverish/chills, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue (tiredness), vomiting and diarrhea), one should take the first dose of Oseltamivir and then immediately contact their physician (Jefferson et al., 2014).
      Patients should also consider vaccines for other respiratory illnesses, including pneumococcus and COVID-19. See the respective sections for additional details.
      There are many types of incentive spirometers available and many different strategies for maintaining lung function. The IFOPA provides two types depending on age and jaw needs.
      Peak Flow Whistle (for young children)
      For young children, a peak flow whistle is recommended. These whistles will make a sound when air is blown fast enough through the whistle. The most important part of this device is taking the deep breath beforehand – not the actual ability to generate the whistle sound!
      The patient should:
      1. Sit upright or stand.
      1. Place the whistle in the mouth, and make sure the lips are tightly sealed
      1. Slowly inhale as much as possible (this is the most important part). Hold the breath for about 10 seconds.
      1. Exhale quickly through the whistle to generate the sound.
      1. Rest in between breaths.
      1. Repeat 10 times, with short rest breaks in between.
      1. The patient should stop if they feel dizzy at any time, or if they have any tenderness or chest discomfort.
      The whistle should be set based on the patient’s estimated peak flow on a regular day (i.e. should just be able to whistle). Standard tables with FEV1 values are not useful in FOP due to the presence of chest deformities; however, prior PFT values can serve as a guide. The goal is to encourage deep breaths to minimize atelectasis, rather than increasing peak flow. The flow whistle serves as an incentive for children.
      Incentive Spirometer
      The incentive spirometer is for older children and adults. There are many models available. The goal, however, is the same with all the models - to take slow, deep breaths to expand the lungs.
      The patient should:
      1. Sit upright in a chair or bed or stand upright.
      1. Hold the spirometer in front of the face at eye level. Many FOP patients will not be able to do this due to ankylosis of the joints in the upper extremities. They may need assistance or have the spirometer positioned close enough to use but without having to hold with both hands.
      1. Close your lips around the mouthpiece to make a seal.
      1. Slowly exhale completely.
      1. Slowly inhale thorough the mouth as deeply as possible.
      1. The piston will rise with inhalation.
      1. Hold the breath for 10 seconds (the piston may fall during this time), then exhale.
      1. Repeat 10 times, with short rest breaks in between.
      1. Stop and rest if they feel dizzy at any time.
      1. Perform this routine twice daily.
      References
      Botman E, Smilde BJ, Hoebink M, Treurniet S, Raijmakers P, Kamp O, Teunissen BP, Bökenkamp A, Jak P, Lammertsma AA, van den Aardweg JG, Boonstra A, Eekhoff EMW. Deterioration of pulmonary function: An early complication in Fibrodysplasia Ossificans Progressiva. Bone Rep 2021 Feb 25;14:100758
      Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014 Apr 10;(4)
      Shah PB, Zasloff MA, Drummond D, Kaplan FS. Spinal deformity in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg 76-A: 1442-1450, 1994
      Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116.

7. FOP患者的其他疾病免疫接种（不包括流感和COVID-19）

针对各种传染病的疫苗接种显著减少了感染疾病的发病率和死亡率。由于进行性骨化性纤维发育不良（FOP）患者易受与普通人群相同的感染疾病影响，因此疫苗接种对于FOP患者至关重要。然而，关于FOP患者的免疫接种有几个主要的考虑因素和预防措施，具体如下。
美国疾病控制与预防中心（CDC）的免疫接种实践咨询委员会（ACIP）发布了儿童、青少年和成人免疫接种推荐的图表。儿童和青少年的免疫接种图表可以在以下网址找到：https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html
成人的图表位于：https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html。此外，这些网站还提供了大量关于免疫接种的信息，包括家长友好的免疫接种图表、家长资源、成人资源、医疗专业人员资源、疫苗信息声明，以及关于COVID-19疫苗的最新临床信息。可以通过这些网站免费获得免疫接种图表的纸质版。
这些免疫接种推荐于2023年2月更新，已获得美国儿科学会、美国家庭医生学会和美国妇产科医师学会的批准。
对于大多数儿童接种的疫苗，ACIP建议进行肌肉注射（IM）。然而，由于注射部位及身体其他部位可能发生异位骨化（HO）的风险，FOP患者禁用肌肉注射。 Lanchoney及其同事报告称，DPT疫苗的肌肉注射导致27%的FOP儿童出现病情加重及后续的HO，在某些情况下还导致关节活动能力永久丧失。
此外，DPT类型疫苗的皮下（SubQ）注射也可能引起病情加重、HO和关节活动能力丧失。因此，似乎DPT类型疫苗中某些未识别的成分可能导致FOP患者无论注射方式如何，均出现病情加重和后续的HO。鉴于这些经验，建议FOP患者不要接种任何DPT类型的疫苗。
通过皮下（SubQ）途径接种的其他疫苗并未报道在进行性骨化性纤维发育不良（FOP）患者中引起病情加重或异位骨化（HO）。具体来说，尽管麻疹-腮腺炎-风疹（MMR）或麻疹-腮腺炎-风疹-水痘（MMRV）疫苗含有活病毒，但并没有报告在接种后出现病情加重的案例。
在血友病患者中，肌肉注射可能导致出血。由于这一风险，世界血友病联合会建议血友病患者进行所有疫苗接种时使用皮下途径。在大多数血友病治疗中心，推荐所有疫苗采用皮下注射是标准做法。然而，在推荐肌肉注射且对血友病患者进行皮下接种的疫苗中，目前仅有甲型肝炎（Ragni et al., 2000）、乙型肝炎（Carpenter et al., 2015）和白喉-破伤风疫苗被证明有效提供免疫。关于其他肌肉注射疫苗的皮下接种效果，目前尚无已发表的数据。
使用皮下注射几种疫苗的一个关注点是注射部位可能形成肉芽肿。这些肉芽肿被认为是对铝这种疫苗辅料成分的超敏反应。在瑞典的一项前瞻性队列研究中，Bergfors及其同事报告称，接受DPT疫苗注射的儿童中，持续发痒的肉芽肿发生率低于1%。无论是肌肉注射还是皮下注射，肉芽肿的发生率相似（Bergfors et al., 2003和2014）。此外，在血友病患者中，皮下接种的疫苗未报告出现肉芽肿。我们不知道进行性骨化性纤维发育不良（FOP）患者在任何免疫接种后是否发生过肉芽肿。
基于以上信息，似乎可以合理地建议进行性骨化性纤维发育不良（FOP）患者通过皮下注射接种所有推荐的疫苗。然而，情况比这更复杂。一些常规疫苗与白喉或破伤风疫苗的成分结合。由于尚未确定导致FOP患者病情加重和HO的DPT类型疫苗成分，FOP患者在接种时可能应避免那些与DPT疫苗成分结合的疫苗（详见下文第4和第5节）。
进行性骨化性纤维发育不良（FOP）疫苗接种建议：
以下部分列出了美国疾病控制与预防中心（CDC）免疫实践咨询委员会（ACIP）推荐用于出生至18岁人群及成年人常规免疫的疫苗，并提供了我们对进行性骨化性纤维发育不良（FOP）患者接种的注意事项。FOP的中位诊断年龄略低于六岁。因此，在确诊FOP时，许多疫苗已经通过肌肉注射（IM）接种。
一般建议：在病情加重期间，不要对FOP患者进行任何免疫接种。建议在病情临床缓解后等待6至8周再进行接种。
关于特定疫苗的建议：
  1. ACIP推荐对所有人进行皮下（SubQ）接种且对FOP患者似乎安全的疫苗：（这些疫苗不含白喉或破伤风成分。）
      • 麻疹、腮腺炎、风疹疫苗（MMR；品牌名：M-M-R II, Priorix）
      • 水痘疫苗（VAR；品牌名：Varivax）
      • 麻疹、腮腺炎、风疹、水痘疫苗（MMRV；品牌名：ProQuad）
      • 灭活脊髓灰质炎疫苗（IPV；品牌名：Ipol）
      • 23价肺炎球菌多糖疫苗（PPSV23；品牌名：Pneumovax-23）
  1. ACIP推荐进行肌肉注射（IM）但可以有效进行皮下接种且对FOP患者可能安全的疫苗：（这些疫苗不含白喉或破伤风成分。）
      • 甲型肝炎疫苗（HepA；品牌名：Havrix, VAQTA）
      • 乙型肝炎疫苗（HepB；品牌名：Energix-B, Recombivax-HB, Heplisav-B）
  1. ACIP推荐进行肌肉注射（IM），对FOP患者可能安全，但目前没有关于皮下接种有效性的数据的疫苗：（这些疫苗不含白喉或破伤风成分。）
      • 脑膜炎球菌B型疫苗（MenB；品牌名：Bexsero, Trumenba）
      • 人乳头瘤病毒疫苗（HPV；品牌名：Gardisil-9）
      • B型流感嗜血杆菌疫苗（HiB；品牌名：PedvaxHIB）。注意，这是唯一一种不与白喉或破伤风成分结合的HiB疫苗。
  1. ACIP推荐进行肌肉注射（IM），但没有关于其皮下接种有效性的数据，这些疫苗可能对FOP患者不安全，因为它们与白喉或破伤风成分结合：
      • B型流感嗜血杆菌疫苗（HiB；品牌名：Hiberix, Act HiB）
      • 脑膜炎球菌A、C、W、Y型疫苗（品牌名：Menactra, Menveo）
      • 13价肺炎球菌结合疫苗（PCV13；品牌名：Prevnar-13）
      • 15价肺炎球菌结合疫苗（PCV15；品牌名：Vaxneuvance）
      • HiB/MenC联合疫苗（品牌名：Menitorix, Menhibrix）
  1. 白喉、百日咳、破伤风类疫苗：
      2. 这些疫苗在进行性骨化性纤维发育不良（FOP）患者中并不常规推荐，因为有经验表明它们可能导致病情加重、异位骨化（HO）以及关节运动的永久丧失。因此，应采取某些预防措施以避免或治疗这些疫苗预防的疾病。然而，在某些情况下，可能需要接种疫苗以预防危及生命的疾病（见下文C4节）：
      A. 白喉在美国是罕见疾病，过去20年每年不足1例。
      如果临床怀疑为白喉，应遵循CDC（https://www.cdc.gov/diphtheria/index.html）和美国儿科学会的诊断和治疗指南，并咨询感染病专家。
      B. 百日咳对婴儿和有呼吸功能障碍的人群（在FOP中常见）构成特别风险。
      所有与FOP患者同住的家庭接触者应接种百日咳疫苗。如果发生局部百日咳疫情，FOP患者在疫情期间不应上学。如果怀疑FOP患者感染百日咳，应根据CDC（https://www.cdc.gov/pertussis/）和美国儿科学会的建议，及时开始抗生素治疗。如果家庭接触者被诊断为百日咳，则应对FOP患者给予暴露后预防治疗。
      C. 破伤风。如发生可能感染破伤风的伤口，应遵循CDC（https://www.cdc.gov/tetanus/index.html）和美国儿科学会关于“破伤风预防的伤口管理”的指南。此外，建议咨询感染病专家。应考虑对急性管理使用皮下给药的破伤风免疫球蛋白（TIG）。
      关于FOP使用破伤风免疫球蛋白（TIG）的额外考虑：
      1. 如果TIG需进行肌肉注射，应选择靠近已失去功能的关节或肌肉的注射部位。这可能是一个非常规部位。因此，如果出现病情加重，可能对活动能力的影响较小。TIG也可以皮下给药，但其有效性尚不确定。然而，最近的数据表明，免疫球蛋白在免疫抑制患者中可以有效地进行皮下给药。
      1. 由于TIG的肌肉注射可能导致病情加重，建议在注射前给予预防性泼尼松2 mg/kg/天（最高100 mg/天），持续2天。然后，每隔一天将每日剂量减少50%。请注意，这个疗程比通常的病情加重治疗短，通常为4天，每天2 mg/kg。预防性泼尼松仅建议与TIG联合使用，其他疫苗接种时则不必要。
      1. 由于肌肉注射可能引起显著的炎症，建议在注射前立即服用布洛芬，并继续按照年龄/体重适当的剂量服用7天，即使没有症状。
      1. 如果TIG不可用，唯一的选择是使用含有破伤风成分的Td疫苗，则应选择皮下注射Td疫苗，并给予FOP患者预防性泼尼松2 mg/kg/天（最高100 mg/天）持续2天。然后，每隔一天将每日泼尼松剂量减少50%。请注意，这个疗程比通常的病情加重治疗短，通常为4天，每天2 mg/kg，然后进行逐日减少。
  1. 轮状病毒疫苗（品牌名：Rotarix, RotaTeq） 是口服疫苗，含有活病毒。CDC推荐在2到6个月大的婴儿中接种这些疫苗，以预防轮状病毒引起的胃肠炎。由于大多数FOP患者在较晚年龄才被诊断，因此许多FOP患者在被诊断之前可能已经接种了这些疫苗。
  1. 登革热疫苗（品牌名：Dengvaxia） 仅推荐给9至16岁且经过实验室确认之前曾感染登革热病毒的儿童和青少年，并且生活在登革热流行地区。
  1. 其他疫苗
      2. A. COVID-19疫苗。 参见COVID疫苗部分。
      B. 霍乱疫苗（品牌名：Dukoral; Shancol; Euvichol-Plus）： 这些口服疫苗仅推荐用于以下情况：(i) 在霍乱局部传播的地区；(ii) 在高风险霍乱的人道主义危机期间；(iii) 在霍乱疫情期间。这些疫苗目前在美国没有供应。关于这些疫苗在FOP中的数据尚未公开。（https://www.cdc.gov/cholera/vaccines.html）
      C. 日本脑炎疫苗（品牌名：Ixiaro） 在一些高风险的亚洲国家常规接种。这种疫苗为肌肉注射；关于Ixiaro的皮下给药信息尚不清楚。由于日本脑炎的高死亡率和神经后遗症，计划前往亚洲的人应与医生讨论疫苗的保护效果是否超过肌肉注射带来的病情加重或HO风险。
      D. 狂犬疫苗（品牌名：Imovax; RabAvert） 是细胞培养疫苗，CDC推荐在接触狂犬病后于第0、3、7和14天接种（https://www.cdc.gov/vaccines/hcp/vis/vis-statements/rabies.html）。这两种疫苗可通过皮内给药，免疫效果和安全性与肌肉注射相同（https://www.who.int/teams/control-of-neglected-tropical-diseases/rabies/vaccinations-and-immunization）。
      E. 结核病：卡介苗（BCG）疫苗 在结核病高风险地区常规给予婴儿，以预防结核病。根据制剂，BCG可通过多点穿刺设备进行皮肤给药（https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm202934.pdf）或进行皮内注射。
      F. 伤寒疫苗（品牌名：Typhim Vi; Vivotif）： 世界卫生组织（WHO）仅建议在伤寒高风险地区接种伤寒疫苗。Typhim Vi适用于>2岁患者肌肉注射；Vivotif适用于>6岁患者口服。计划前往伤寒高风险地区的FOP患者应咨询医生，以决定伤寒的风险是否大于疫苗的风险。其他两种伤寒疫苗（Typbar Vi和Pedatyph）与破伤风类毒素结合，不应给予FOP患者。
      G. 黄热疫苗（品牌名：YF-VAX, Stamaril）。 YF-VAX推荐给9个月及以上的旅行者或居住在南美和非洲黄热传播风险地区的人。这种疫苗通过皮下给药。目前YF-VAX的供应有限。Stamaril在美国无法获得。
      H. 带状疱疹疫苗（品牌名：Shingrix; Vostarax） ACIP仅推荐50岁及以上人士接种带状疱疹疫苗以预防带状疱疹（由水痘病毒再激活引起）。有两种可用疫苗。Shingrix是一种重组疫苗，不含活病毒；Vostarax是活病毒疫苗。对于50岁及以上的FOP患者，应选择皮下给药。
      I. 呼吸道合胞病毒（RSV）。 目前有两种批准的RSV疫苗（Arexvy或Abrysvo）。这两种疫苗均为肌肉注射，不应给予FOP患者。
参考文献
  1. Bergfors E, Hermansson G, Nystrom-Kronander U, Falk L, Valter L, Trollfors B. How common are long-lasting, intensely itching vaccination granulomas and contact allergy to aluminum induced by currently used pediatric vaccines? A prospective cohort study. Eur J Pediatr 173: 1297-1307, 2014 当前使用的儿童疫苗中，持久性强烈瘙痒的疫苗肉芽肿和铝过敏的发生率有多高？一项前瞻性队列研究
  1. Bergfors E, Trollfors B, Inerot A. Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer. Vaccine 22: 64-69, 2003 使用单一制造商的吸附疫苗后，儿童中持久性瘙痒结节和延迟性超敏反应的发生率意外地高
  1. Carpenter SL, Soucie JM, Presley RJ, Ragni MV, Wicklund BM, Silvey M, Davidson H. Hepatitis B vaccination is effective by subcutaneous route in children with bleeding disorders: a universal data collection database analysis. Haemophilia 21: e39-e43, 2015 皮下接种的乙型肝炎疫苗在出血性疾病儿童中的有效性：一项普遍数据收集数据库分析
  1. Cook IF. Evidence based route of administration of vaccines. Hum Vaccin 26: 67-73, 2008 基于证据的疫苗给药途径
  1. Hawkridge A, Hatherill M, Little F, Goetz MA, Barker L, Mahomed H, Sadoff J, Hanekom W, Gaiter L. Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomized trial. BMJ 337:a2052, 2008 皮肤穿刺与皮内注射卡介苗在南非婴儿预防结核病中的有效性：随机试验
  1. Hills SL, Walter EB, Atmar RL, Fischer M. Japanese encephalitis vaccine: recommendations of the Advisory Committee on immunization practices. MMWR 19:68:1-33, 2019 日本脑炎疫苗：免疫接种实践咨询委员会的推荐
  1. Kimberlin DW, et al. Red Book: 2021-2024 Report of the Committee on Infectious Diseases (32 nd Ed). American Academy of Pediatrics. Diphtheria, pp 304-307; Pertussis, pp 578-589; Tetanus, pp 750-755, 2021 红皮书：2021-2024年传染病委员会报告（第32版）。美国儿科学会。白喉，第304-307页；百日咳，第578-589页；破伤风，第750-755页
  1. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: e654-e661, 2005 由于诊断错误导致的医源性伤害在纤维异生症中的表现
  1. Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatr 126: 762-764, 1995 纤维异生症儿童在接种白喉-破伤风-百日咳疫苗后，注射部位发生永久性异位骨化
  1. Pembroke AC and Marten RH. Unusual cutaneous reactions following diphtheria and tetanus immunization. Clin Exp Dermatol 4: 345-348, 1979 白喉和破伤风疫苗接种后出现不寻常的皮肤反应
  1. Ragni MV, Lusher JM, Koerper MA, Manco-Johnson M, Krause DS. Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with haemophilia. Haemophilia 6: 98-103, 2000 皮下接种乙型肝炎疫苗在血友病儿童中的安全性和免疫原性
  1. Ritchey AK. Administration of vaccines to infants and children with hemophilia. A survey of Region III comprehensive hemophilia treatment centers. Blood 106: 4079, 2005 给血友病婴儿和儿童接种疫苗的管理。区域III综合血友病治疗中心的调查
  1. Roush SW, Murphy TV, and the Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA 298: 2155-2163, 2007 美国疫苗可预防疾病的发病率和死亡率历史比较
  1. Schaefer BA, Gruppo RA, Mullins ES, Tarango C: Subcutaneous diphtheria and tetanus vaccines in children with haemophilia: a pilot study and review of the literature. Haemophilia 23: 904-909, 2017 血友病儿童皮下接种白喉和破伤风疫苗：一项初步研究和文献综述
  1. Srivastava A, et al. WFH Guidelines for the Management of Hemophilia, 3 rd Ed. Haemophilia 26 Suppl 6: 1-158, 2020 WFH管理指南，第三版
原文
  1. Immunizations in FOP for Diseases Other Than Influenza and Covid-19
      2. Vaccines against various infectious diseases have dramatically decreased morbidity and mortality from infectious diseases (Roush et al., 2007). Because individuals with FOP are subject to the same infectious diseases as the general population, immunizations are essential in FOP. However, there are several major considerations and precautions regarding immunization of those with FOP, and these are discussed below.
      The Advisory Committee on Immunization Practices (ACIP) of the Center for Disease Control and Prevention (CDC) has published charts with their recommendations for immunization for children, adolescents, and adults. The chart for children and adolescents can be found at: https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html
      The chart for adults is at: https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html In addition, these sites contain a wealth of other information about immunizations including Parent Friendly Immunization Charts, Resources for Parents, Resources for Adults, Resources for Health Professionals, Vaccine Information Statements, and up to date clinical information about Covid-19 vaccines. Hard copies of the Immunization Charts can be obtained for free using these sites.
      Those immunization recommendations, last updated in February 2023, have been approved by the American Academy of Pediatrics, the American Academy of Family Practitioners, and the American College of Obstetricians and Gynecologists.
      For most of the vaccines given in childhood, the ACIP recommends intramuscular (IM) administration. However, IM injections are contraindicated in FOP because of the risk of heterotopic ossification (HO) at the injection site and sometimes elsewhere in the body. Lanchoney and associates reported that IM injection of diphtheria-pertussis-tetanus (DPT) vaccines caused flare-ups and subsequent HO in 27% of children with FOP and, in some cases, permanent loss of joint motion (Lanchoney et al., 1995).
      Furthermore, subcutaneous (SubQ) injection of DPT type vaccines may also cause flare-ups, HO and loss of joint mobility (F. Kaplan, personal communication). Therefore, it seems that some unidentified component(s) of DPT type vaccines may cause flare-ups and subsequent HO in individuals with FOP regardless of route of administration. Given these experiences, it is recommended that no DPT type vaccines be given to individuals with FOP.
      Other immunizations given by the SubQ route have not been reported to cause flare-ups or HO in those with FOP. Specifically, there are no reported cases of flare-ups following subcutaneous immunization with the MMR or MMRV vaccines despite the fact that they contain live viruses.
      In individuals with hemophilia, IM injections may cause hemorrhage. Because of this risk, the World Federation for Hemophilia recommends the SubQ route for all immunizations for individuals with hemophilia (Srivastava et al., 2020). It is standard practice at most Hemophilia Treatment Centers to recommend SubQ administration of all vaccines (Ragni et al., 2000; Ritchey, 2005; Carpenter et al., 2015; Schaefer et al., 2017). However, of the vaccines recommended for IM administration and given SubQ to hemophilia patients, to date only Hepatitis A (Ragni et al., 2000), Hepatitis B (Carpenter et al., 2015), and diphtheria-tetanus (Cook, 2008; Schaefer et al., 2017) vaccines have been shown to be effective in providing immunity. There are no published data regarding effectiveness of other IM vaccines given SubQ.
      A concern for giving several vaccines SubQ has been granuloma formation at the injection site (Pembroke & Marten, 1979). These granulomas are considered to be the result of hypersensitivity to aluminum, an adjuvant to the other components of the vaccine. In a prospective cohort study in Sweden, Bergfors and associates reported that long lasting, intensely itching granulomas occurred in less than 1% of children receiving injections of DPT vaccines. The incidence of granulomas was similar whether the injections were given IM or SubQ (Bergfors et al., 2003 and 2014). Furthermore, granulomas have not been reported with SubQ vaccines administered to patients with hemophilia (Ritchey, 2005; J. Huang, personal communication). We are not aware of granuloma formation after any immunizations in individuals with FOP.
      Based on the above information, it may seem reasonable to recommend that individuals with FOP receive all their recommended immunizations by SubQ injection. However, the situation is more complicated than that. Several of the routine vaccines are conjugated with components of either diphtheria or tetanus vaccines. Because the component(s) in DPT type vaccines that cause FOP flare-ups and HO have not been identified, it may be prudent for FOP patients to avoid vaccines that are conjugated with components of DPT vaccines (See Sections 4 and 5 below).
      Recommendations for Immunization in FOP:
      The following sections list vaccines recommended by the ACIP for routine immunization of individuals from birth to 18 years of age and for adults along with our cautions regarding administration to individuals with FOP. The median age of diagnosis of FOP is just under six years (Kitterman et al., 2005). Therefore, many vaccines will have already been administered IM by the time that the person has been diagnosed with FOP.
      General Recommendation: Do not give ANY immunizations to individuals with FOP during a flareup. It would be preferable to wait 6 to 8 weeks after the flare-up has clinically resolved.
      Recommendations Regarding Specific Vaccines:
    1. Vaccines recommended by the ACIP to be given SubQ to all and appear to be safe for FOP patients: (These contain no components of diphtheria or tetanus.)
        • Measles, Mumps, Rubella Vaccine (MMR; brand names: M-M-R II, Priorix)
        • Varicella Vaccine (VAR; brand name: Varivax)
        • Measles, Mumps, Rubella, Varicella Vaccine (MMRV; brand name: ProQuad)
        • Inactivated Polio Vaccine (IPV; brand name: Ipol)
        • Pneumococcal 23-valent Polysaccharide Vaccine (PPSV23; brand name: Pneumovax-23)
    2. Vaccines recommended by the ACIP to be given IM but are effective SubQ and are probably safe for FOP patients: (These contain no components of diphtheria or tetanus.)
        • Hepatitis A Vaccine (HepA; brand names: Havrix, VAQTA)
        • Hepatitis B Vaccine (HepB; brand names: Energix-B, Recombivax-HB, Heplisav-B)
    3. Vaccines recommended by the ACIP to be given IM and are probably safe for FOP patients, but there are no data on their effectiveness when given SubQ: (These contain no components of diphtheria or tetanus.)
        • Meningococcal serogroup B Vaccine (MenB; brand names: Bexsero; Trumenba)
        • Human Papilloma Virus Vaccine (HPV; brand name:Gardisil-9)
        • Haemophilus influenzae type B vaccine (HiB: brand name: PedvaxHIB). Note that this is the only brand of HiB that is not conjugated to a component of diphtheria or tetanus.
    4. Vaccines recommended by the ACIP to be given IM, but there are no data on their effectiveness when given SubQ, and these vaccines may NOT be safe for FOP patients because they are conjugated to a component of diphtheria or tetanus:
        • Haemophilus influenzae type B vaccine (HiB; brand names: Hiberix; Act HiB)
        • Meningococcal serogroups A, C, W, Y (brand names: Menactra; Menveo)
        • Pneumococcal 13-valent conjugate vaccine (PCV13; brand name: Prevnar-13)
        • Pneumococcal 15-valent conjugate vaccine (PCV15; brand name: Vaxneuvance)
        • HiB/MenC combination vaccine (brand names: Menitorix; Menhibrix)
    5. Diphtheria, Pertussis, Tetanus type Vaccines:
        6. These vaccines are not routinely recommended in FOP because of the experience that they may cause flareups, HO, and permanent loss of joint motion (Lanchoney et al., 1995; F. Kaplan, personal communication). Therefore, certain precautions should be taken to avoid or treat the diseases that these vaccines prevent. However, there may be certain situations where the vaccine needs to be given to prevent life threatening illness (See Section C 4, below):
        A. Diphtheria is a rare disease in the United States with less than 1 case per year in the past 20 years.
        If diphtheria is suspected clinically, follow the diagnosis and treatment guidelines of the CDC (https://www.cdc.gov/diphtheria/index.html) and the American Academy of Pediatrics (Kimberlin et al., 2021, Diphtheria) and consult with an infectious disease specialist.
        B. Pertussis is a particular risk for infants and those with respiratory compromise (common in FOP).
        All household contacts of individuals with FOP should be immunized for pertussis. If there is a local outbreak of pertussis, those with FOP should not attend school during the outbreak. If pertussis is suspected in an individual with FOP, start early treatment with antibiotics as recommended by the CDC (https://www.cdc.gov/pertussis/) and the American Academy of Pediatrics (Kimberlin et al, 2021, Pertussis). If a household contact is diagnosed with pertussis, the individual with FOP should be given post-exposure prophylaxis.
        C. Tetanus. In case of a wound considered a risk for tetanus, follow the guidelines for “Wound Management for Tetanus Prevention” of the CDC (https://www.cdc.gov/tetanus/index.html) and the American Academy of Pediatrics (Kimberlin et al, 2021, Tetanus). In addition, it is recommended that consultation be obtained with an infectious disease specialist. The use of Tetanus Immune Globulin (TIG) given subcutaneously should be considered for acute management.
        Additional considerations about TIG for FOP include:
      1. If TIG is to be given IM, the injection site should be chosen to be near joints or muscles that have already lost function. This may be a non-standard site. Thus, if a flare-up develops, it is less likely to worsen mobility significantly. Alternatively, TIG can be given SubQ, but the efficacy is unknown. However, recent data in immunocompromised patients show that immunoglobulins can be effectively delivered SubQ.
      2. Because IM injection of TIG may precipitate a flare-up, give prophylactic prednisone 2 mg/kg/day (up to a maximum of 100 mg/day) for 2 days. Then taper the daily dose by 50% every other day. Note that this is shorter than the usual course for treatment of a flare-up, which is usually 4 days at 2 mg/kg/day. Prophylactic prednisone is recommended only with TIG and is not necessary for other immunizations.
      3. Because the IM injection can cause significant inflammation, give ibuprofen immediately prior to the injection and continue with standard age/weight appropriate dosing for 7 days, even if no symptoms are present.
      4. In the event that TIG is not available, and the only option is to use a Td containing vaccine, the Td vaccine should be given SubQ and the patient with FOP should be given prophylactic prednisone 2 mg/kg/day (up to a maximum of 100 mg/day) for 2 days. Then taper the daily prednisone dose by 50% every other day. Note that this is shorter than the usual course for treatment of a flare-up, which is usually 4 days at 2 mg/kg/day followed by a daily taper.
    6. Rotavirus Vaccines (brand names: Rotarix, RotaTeq) are oral vaccines that contain live virus. The CDC recommends these vaccines for infants 2 to 6 months of age to prevent gastroenteritis caused by Rotavirus. Because the majority of those with FOP are not diagnosed until later in life, many with FOP will already have received one of these vaccines before FOP has been diagnosed.
    7. Dengue Vaccine (brand name: Dengvaxia) is recommended only for children and adolescents 916 years old who have laboratory-confirmed previous dengue virus infection and are living in an area where dengue is endemic.
    8. Other Vaccines
        9. A. Covid-19 Vaccines. See section on COVID vaccines
        B. Cholera Vaccine (brand names: Dukoral; Shancol; Euvichol-Plus): These oral vaccines are recommended only for the following: (i) in areas where local transmission of cholera occurs; (ii) during humanitarian crises with a high risk of cholera; and (iii) during outbreaks of cholera. None of these vaccines are currently available in the United States. No data are available regarding these vaccines in FOP. (https://www.cdc.gov/cholera/vaccines.html)
        C. Japanese Encephalitis Vaccine (JE-Vax; brand name: Ixiaro) is routinely given in several Asian countries where there is a high risk of this disease. This vaccine is given IM; there is no information regarding SubQ administration of Ixiaro. Because of the high rates of mortality and neurologic sequelae from Japanese Encephalitis, (Hills et al, 2019), individuals planning to visit Asia should discuss with their physician whether the protective effect of the vaccine outweighs the risk of flareups or HO from the IM administration of the vaccine.
        D. Rabies Vaccine (brand names: Imovax; RabAvert) are cell culture vaccines that are recommended by the CDC and are administered on days 0, 3, 7, and 14 after exposure to Rabies (https://www.cdc.gov/vaccines/hcp/vis/vis-statements/rabies.html). Both vaccines can be given via the intradermal route which is as immunogenic and safe as IM (https://www.who.int/teams/control-of-neglected-tropical-diseases/rabies/vaccinations-andimmunization).
        E. Tuberculosis: Bacille Calmette-Guerin (BCG) Vaccine is routinely given to infants to prevent tuberculosis in countries and areas where there is a high risk for the disease. Depending on the preparation, BCG can be given percutaneously with a multiple puncture device (https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm20 2934.pdf) or injected intradermally (Hawkridge et al., 2008).
        F. Typhoid Fever vaccine (brand names: Typhim Vi; Vivotif): The World Health Organization (WHO) recommends immunization for protection against Typhoid Fever only for individuals in areas where there is a high risk for the disease. Typhim Vi is given IM for individuals >2 years of age; Vivotif is given orally for individuals >6 years of age. Individuals with FOP who plan to travel to areas where there is a high risk of Typhoid Fever should consult with their physician to decide whether the risk of Typhoid Fever is greater than the risk of the vaccine. Two other typhoid vaccines (Typbar Vi and Pedatyph) are conjugated to tetanus toxoid and should not be given to individuals with FOP.
        G. Yellow Fever Vaccine (brand names: YF-VAX, Stamaril). YF-VAX is recommended for persons age 9 months and older who are traveling to or living in areas at risk for Yellow Fever transmission in South America and Africa. This vaccine is given SubQ. At this time there is limited availability of YF-VAX. Stamaril is not available in the United States.
        H. Zoster Vaccines (brand names: Shingrix; Vostarax) The ACIP recommends Zoster Vaccine only for individuals 50 years of age and older to prevent Shingles (Herpes Zoster), which is due to reactivation of the Zoster-Varicella virus that causes Chickenpox. There are two vaccines available. Shingrix is a recombinant vaccine that contains no live virus. Vostarax is a live virus vaccine. For individuals with FOP 50 years of age and older, these vaccines should be given SubQ.
        I. Respiratory Syncytial Virus (RSV). At this time there are two approved vaccines (Arexvy or Abrysvo) for RSV. Both vaccines are administered intramuscularly and should not be given to individuals with FOP.
      References
      Bergfors E, Hermansson G, Nystrom-Kronander U, Falk L, Valter L, Trollfors B. How common are long-lasting, intensely itching vaccination granulomas and contact allergy to aluminum induced by currently used pediatric vaccines? A prospective cohort study. Eur J Pediatr 173: 1297-1307, 2014
      Bergfors E, Trollfors B, Inerot A. Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer. Vaccine 22: 64-69, 2003
      Carpenter SL, Soucie JM, Presley RJ, Ragni MV, Wicklund BM, Silvey M, Davidson H. Hepatitis B vaccination is effective by subcutaneous route in children with bleeding disorders: a universal data collection database analysis. Haemophilia 21: e39-e43, 2015
      Cook IF. Evidence based route of administration of vaccines. Hum Vaccin 26: 67-73, 2008
      Hawkridge A, Hatherill M, Little F, Goetz MA, Barker L, Mahomed H, Sadoff J, Hanekom W, Gaiter L. Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomized trial. BMJ 337:a2052, 2008
      Hills SL, Walter EB, Atmar RL, Fischer M. Japanese encephalitis vaccine: recommendations of the Advisory Committee on immunization practices. MMWR 19:68:1-33, 2019
      Kimberlin DW, et al. Red Book: 2021-2024 Report of the Committee on Infectious Diseases (32 nd Ed). American Academy of Pediatrics. Diphtheria, pp 304-307; Pertussis, pp 578-589; Tetanus, pp 750-755, 2021
      Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: e654-e661, 2005
      Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatr 126: 762-764, 1995
      Pembroke AC and Marten RH. Unusual cutaneous reactions following diphtheria and tetanus immunization. Clin Exp Dermatol 4: 345-348, 1979
      Ragni MV, Lusher JM, Koerper MA, Manco-Johnson M, Krause DS. Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with haemophilia. Haemophilia 6: 98-103, 2000
      Ritchey AK. Administration of vaccines to infants and children with hemophilia. A survey of Region III comprehensive hemophilia treatment centers. Blood 106: 4079, 2005
      Roush SW, Murphy TV, and the Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA 298: 2155-2163, 2007
      Schaefer BA, Gruppo RA, Mullins ES, Tarango C: Subcutaneous diphtheria and tetanus vaccines in children with haemophilia: a pilot study and review of the literature. Haemophilia 23: 904-909, 2017
      Srivastava A, et al. WFH Guidelines for the Management of Hemophilia, 3 rd Ed. Haemophilia 26 Suppl 6: 1-158, 2020

8. FOP的流感疫苗接种

流感（“流感”）是全球范围内导致发病率和死亡率的重要原因。对于进行性骨化性纤维发育不良患者而言，这种疾病尤其危险。每年，流感疫苗根据预测的流行病毒株生产。美国疾病控制和预防中心（CDC）建议在10月底之前接种流感疫苗。其他国家可能有不同的接种时间表和可用的疫苗类型/品牌。疫苗接种的时间应与当地医疗保健提供者确定。
流感疫苗最常见的形式是肌肉注射（IM）或以活减毒病毒的鼻用形式提供。在某些年份，可能会提供透皮和皮内流感疫苗（通过贴片通过皮肤给药或注射至皮肤下但不深入组织）。疫苗的可用性基于每年对该批疫苗进行的制造和有效性评估。
不推荐使用活减毒流感疫苗
活减毒鼻用流感疫苗（如美国的Flumist®）已被报告与部分进行性骨化性纤维发育不良患者的病情加重相。因此，不建议进行性骨化性纤维发育不良患者及其家属使用这种鼻用疫苗。
优先选择透皮或皮内疫苗（如果可用）
如果有透皮或皮内流感疫苗可用，我们建议继续使用这些途径，如我们多年所建议的。有关美国季节性流感疫苗的信息可以在CDC网站上找到：https://www.cdc.gov/flu/vaccines/index.htm
流感疫苗的皮下替代给药途径
在透皮或皮内疫苗不可用的年份，我们建议进行性骨化性纤维发育不良患者使用修改后的方案接种流感疫苗，采用皮下注射常规流感疫苗。尽管尚无明确数据表明其有效性，先前的研究表明，尽管以不同途径给药，但仍会有一定的有效性。请注意，这可能需要医生或医生办公室来施打流感疫苗，因为许多地方（如药店）不会偏离其常规的肌肉注射程序。
  • 对于儿童，应将一剂（通常为0.25毫升，具体取决于配方）的肌肉疫苗以皮下方式注射。请勿进行肌肉注射。
  • 对于成年人，可以将两剂儿童剂量（通常每剂0.25毫升）的肌肉疫苗以皮下方式注射于两个不同的部位。或者，可以将常规成人剂量（通常为0.5毫升，具体取决于配方）分成两次，在两个不同的部位进行皮下注射。这两个注射部位无需相距太远。在任何部位进行0.5毫升的皮下注射可能会不适。ICC不建议进行肌肉注射。
进行性骨化性纤维发育不良患者接种疫苗的特别注意事项
对于生活在进行性骨化性纤维发育不良患者中的所有疫苗接种，建议：
  • 选择靠近已经受到异位骨化影响的关节或肌肉群的注射部位，并选择一个如果形成异位骨骼不会导致并发症的位置。这样，如果发生病情加重，就不太可能导致活动能力的丧失。
  • 所有患者在接种疫苗时，建议同时服用一剂对乙酰氨基酚或布洛芬，以缓解疫苗可能引起的不适。
  • 疫苗接种不应在病情加重或类似症状出现后的两周内进行。建议至少等待两周，但最好等待6-8周，因为病情加重往往会在时间上聚集。这一策略旨在降低疫苗诱发后续病情加重的几率。
与进行性骨化性纤维发育不良患者同住的家庭成员和看护者应按时接种标准的肌肉注射流感疫苗。不推荐密切接触进行性骨化性纤维发育不良患者的人使用鼻用流感喷雾，因为尽管减毒病毒较弱，仍然可能导致接触者感染轻微流感。
请注意，生活在进行性骨化性纤维发育不良患者中的人应避免在活动病情加重期间接种任何疫苗——并且在之后的至少6-8周内也应如此。
抗病毒药物 – 奥司他韦/Tamiflu
如果生活在进行性骨化性纤维发育不良患者中的人或任何照顾进行性骨化性纤维发育不良患者的人出现流感症状，应该及时进行评估（包括对其他感染的评估，如COVID或RSV），并考虑抗病毒治疗（即奥司他韦，Tamiflu®）。奥司他韦仅对流感有效，对感冒或其他病毒无效。奥司他韦在感染的早期阶段效果最佳，因此在症状开始时（通常是高烧和上呼吸道症状的组合）及时就医非常重要。可能需要进行鼻拭子检测以确认流感感染。奥司他韦的保质期较短，因此我们通常建议在24小时药房“保持”处方，并在医疗保健提供者确认流感感染后立即开始使用。
每个人的感染预防
每个人都应采取日常预防措施，以防止细菌传播，具体措施可参见CDC网站：https://www.cdc.gov/flu/protect/preventing.htm。
  1. 尽量避免与生病的人密切接触。
  1. 在生病期间，尽可能限制与他人的接触，以免感染他们。
  1. 如果出现流感症状，CDC建议在发烧消退后的至少24小时内待在家中，除非需要就医或处理其他必要事务。（您的发烧应在没有使用退烧药的情况下消退24小时）。
  1. 咳嗽或打喷嚏时，用纸巾遮住鼻子和嘴巴。使用后将纸巾扔进垃圾桶。
  1. 经常用肥皂和水洗手。如果没有肥皂和水，可使用含酒精的洗手液。
  1. 避免触摸眼睛、鼻子和嘴巴。细菌通过这种方式传播。
  1. 清洁和消毒可能被流感等细菌污染的表面和物品。
  1. 有关除接种疫苗和服药之外的行动信息，请参见日常预防措施和非药物干预（NPI），了解人们和社区可以采取的措施，以帮助减缓流感等疾病的传播。
参考文献
  1. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014 Apr 10;(4) 神经氨酸酶抑制剂用于预防和治疗健康成人和儿童的流感
  1. Scarlett RF, Rocke DM, Kantanie S, Patel JB, Shore EM, Kaplan FS. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva (FOP). Clin Orthop Rel Res 423: 275-279, 2004 类流感病毒疾病与进行性骨化性纤维发育不良（FOP）病情加重
原文
  1. Immunizations for Influenza in FOP
      2. Influenza (“the flu”) is a major cause of morbidity and mortality worldwide. It is especially dangerous for those with FOP (Scarlett et al., 2004). Every year, flu vaccines are produced based on the predicted strains that will be prevalent in the following cycle. The Centers for Disease Control and Prevention (CDC) recommend flu vaccinations by the end of October in the United States. Other countries may have different schedules and types/brands of vaccines available. Timing of the vaccinations should be determined with the local health care provider.
      The most common forms of flu vaccinations are administered intramuscularly (IM) or provided as a live attenuated virus delivered in an intranasal form. In some years, transdermal and intradermal flu vaccines (given via a patch through the skin or injected just under the skin but not into the deeper tissues) may be available. Availability is based on manufacturing and effectiveness assessments that are performed yearly on that batch of vaccine.
      Live attenuated flu vaccines are not recommended
      The live attenuated intranasal form of the flu vaccine (such as Flumist ® in the United States) has been reported to be associated with flares in some patients with FOP (F. Kaplan, Personal communication). This intranasal vaccine is not recommended for patients with FOP or their family members for this reason.
      Transdermal or intradermal vaccines are preferred, when available
      If transdermal or intradermal forms of the flu vaccine are available, we recommend, as we have for many years, using those routes. Information about the seasonal influenza flu vaccine in the United States can be found on the CDC website: https://www.cdc.gov/flu/vaccines/index.htm
      Subcutaneous alternative route for flu vaccine administration
      In years when the transdermal or intradermal forms are not available, we recommend that people living with FOP receive the flu vaccine using a modified protocol where the regular flu vaccine is given subcutaneously. Although there is no clear data as to how efficacious this is, prior studies suggest that there will be some efficacy despite being administered by a different route. Note that this will likely require a physician or physician’s office to administer the flu vaccine, as many places (i.e. pharmacies) will not deviate from their normal protocol of intramuscular injection.
      • For children, have one dose (typically 0.25 ml, depending on the formulation) of the intramuscular vaccine administered subcutaneously. Do not deliver the vaccine intramuscularly.
      • For adults, either have two doses of the pediatric dose (typically 0.25 ml each) intramuscular vaccine administered subcutaneously, at two different locations. Alternatively, have the regular adult dose (typically 0.5 ml, depending on the formulation) split and administered as two separate subcutaneous injections at two different locations. The locations do not need to be far apart. Injection of 0.5 ml subcutaneously in any location may be uncomfortable. The ICC does NOT recommend to take the vaccine intramuscularly.
      Special precautions for vaccination of patients with FOP
      For all vaccinations in persons living with FOP, it is recommended that:
      • An injection site be chosen near a joint or muscle group that has already been affected by HO, and in a location that would not cause complications if heterotopic bone was to form. That way, if a flare does develop, it is less likely to result in loss of mobility.
      • For all patients, it is recommended to take a dose of acetaminophen or ibuprofen with the vaccine to help with any discomfort that the vaccine may cause.
      • Vaccinations should not be given within 2 weeks of a flare or flare-like symptoms. It is advised to wait a minimum of 2 weeks but prefer 6-8 weeks because flareups can often occur in temporal clusters. This strategy is used to decrease the chances of a vaccine inducing a subsequent flare.
      Family members living in the same home and caretakers should get the standard intramuscular flu vaccination on schedule. The nasal flu spray is NOT recommended for those in close contact with individuals living with FOP because the attenuated virus, though weaker, can still give a mild case of the flu to contacts.
      Please keep in mind that those living with FOP should avoid ANY immunizations during an active flare-up – and for at least 6-8 weeks thereafter.
      Antivirals – Oseltamivir/Tamiflu
      If a person living with FOP or anyone living with or caregiving for a person with FOP develops symptoms suggestive of the flu, they should get prompt evaluation (including evaluation for other infections, such as COVID or RSV) and consider antiviral treatment (i.e. oseltamivir, Tamiflu® ). Oseltamivir is only effective against influenza and does not work against the common cold or other viruses. The effectiveness of oseltamivir is highest in the early phase of an infection, so prompt medical attention is important when symptoms start (typically a combination of high fever and upper respiratory symptoms). Nasal swab testing may be needed to confirm infection with influenza. Oseltamivir does not have a long shelf life, so we generally recommend that a prescription be available “on hold” at a 24-hr pharmacy and that the medication be started once influenza infection has been confirmed by a medical care provider (Jefferson et al., 2014). Infection Prevention for Everyone
      Everyone should practice everyday preventive actions to stop the spread of germs as shared by the CDC on their website at https://www.cdc.gov/flu/protect/preventing.htm.
      1. Try to avoid close contact with sick people.
      1. While sick, limit contact with others as much as possible to keep from infecting them.
      1. If you are sick with flu symptoms, CDC recommends that you stay home for at least 24 hours after your fever is gone except to get medical care or for other necessities. (Your fever should be gone for 24 hours without the use of a fever-reducing medicine).
      1. Cover your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash after you use it.
      1. Wash your hands often with soap and water. If soap and water are not available, use an alcohol-based hand rub.
      1. Avoid touching your eyes, nose and mouth. Germs spread this way.
      1. Clean and disinfect surfaces and objects that may be contaminated with germs like the flu.
      1. See Everyday Preventive Actions and Nonpharmaceutical Interventions (NPIs) for more information about actions – apart from getting vaccinated and taking medicine – that people and communities can take to help slow the spread of illnesses like influenza (flu).
      References
      Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014 Apr 10;(4)
      Scarlett RF, Rocke DM, Kantanie S, Patel JB, Shore EM, Kaplan FS. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva (FOP). Clin Orthop Rel Res 423: 275-279, 2004

9. 新冠病毒（COVID-19）的预防措施与FOP患者及其家庭的指导

冠状病毒（COVID-19）大流行仍对全球人群构成重大风险，新变异株的出现使情况更加复杂。国际骨化性纤维发育不良协会（ICC）建议，FOP患者继续遵循预防措施，以防止感染导致COVID-19的SARS-CoV-2病毒。
ICC现发布对2022年5月声明的更新。本文件重点提供FOP患者在COVID-19感染和疫苗接种方面的最新信息，涵盖6个月及以上儿童的COVID-19疫苗接种批准，以及加强针和治疗建议。
建议快速变化，且因国家而异。大多数国家已结束对COVID-19的紧急法规。
ICC不对FOP患者是否应接种COVID疫苗提供具体建议。
接种疫苗的决定是个人的，基于风险和收益的平衡，应该与您的医疗团队讨论。ICC仍然建议按批准的途径接种COVID-19疫苗（即肌肉注射）。
有关FOP患者的COVID-19和COVID疫苗接种的更多信息现已发布。(链接1 和 链接2)
  • 在接受肌肉注射COVID-19疫苗的23名FOP患者中，最常见的症状为疼痛/酸痛、疲劳和肿胀。这些症状与普通人群报告的相似。在23名患者中，有1名出现了病发（flare-up），但接种COVID-19疫苗的患者均未住院。
  • 在19名COVID-19感染的FOP患者中，最常见的症状为疲劳、味觉或嗅觉丧失和咳嗽。有2名FOP患者出现了病发，3名患者住院。
现在，针对6个月及以上儿童的疫苗通常已可用。ICC不对FOP患者是否应接种COVID疫苗提供具体建议。请与您的医疗团队讨论，因为当地有关何时接种疫苗或疫苗资格的建议可能有所不同。
ICC不对加强疫苗接种提供支持或反对的建议，但如果您之前已完成疫苗接种且处于高风险区域，应考虑接种加强针。在接种加强针之前，请咨询您的医疗团队，讨论是否适合且安全接种。
FOP患者在COVID-19感染中面临高风险并发症，应与医疗团队讨论在SARS-CoV-2感染的情况下，使用单克隆抗体或抗逆转录病毒药物是否有益。
  • 单克隆抗体通过静脉注射给药，已批准用于成人和体重≥40公斤的12岁及以上儿童。应尽早开始这些治疗，并在症状出现后10天内进行。请注意，某些单克隆抗体对最新的SARS-CoV-2变种无效。
  • 抗逆转录病毒药物是已批准的药物，通常应在症状出现后的5天内使用。
  • 这些治疗的可用性和建议正在快速变化，并因国家而异。这些疗法可能在特定地区的流行株上无效。请咨询当地医疗团队以获取建议，并与您的医生讨论，确保没有药物相互作用。
如果您参与临床试验，讨论任何疫苗或治疗方案与您的研究医生非常重要。
关于FOP和COVID/SARS-CoV-2感染的临床数据已在此发布：
COVID-19对进行性骨化性纤维发育不良患者的社会和临床影响 | Orphanet Journal of Rare Diseases | 完整文本 BioMed CentralBioMed CentralSocial and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva - Orphanet Journal of Rare Diseases
Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva - Orphanet Journal of Rare Diseases

Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva - Orphanet Journal of Rare Diseases

Background COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. To better understand the impact of COVID-19 on patients with FOP, we first examined the social impact of the pandemic using data from the FOP Registry managed by the International FOP Association. We also identified patients with FOP who were exposed to or contracted the SARS-CoV-2 virus, or who received a COVID-19 vaccine, to investigate if patients with FOP were at increased risks of complications from SARS-CoV2 exposure or vaccination. Results Data from 326 individuals in 69 countries in the International FOP Association FOP Connection Registry were examined using patient-reported outcomes measurement information system (PROMIS) global health scale scores. Twenty-six (28.9%) participants aged ≥ 15 years old rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019, prior to the SARS-CoV-2 outbreak. Similar trends were noted for physical and mental health in the pediatric population. Frequency of physician visits was not changed, but a larger portion of patients reported missing dental visits in 2020 compared with 2019 (31.5% vs. 41.7%). A second cohort with 32 subjects was tracked after SARS-CoV-2 exposure or vaccination. Ten subjects were positively diagnosed with COVID-19, 15 received a COVID-19 vaccine, and seven had high-risk SARS-CoV-2 exposure but either did not have a confirmed clinical diagnosis or tested negative. Subjects who tested positive for the virus showed no major complications or increased FOP disease activity, though our sample size is very limited. Among the 15 subjects who received a COVID-19 vaccine, using the International Clinical Council on FOP guidelines for prophylaxis with ibuprofen or acetaminophen, only one person experienced flare-like activity at the injection site. Conclusions Patients with FOP showed a significant decrease in social activities that was reflective of the isolation and mobility changes in this debilitated population. In our limited cohort, the majority of the patients with FOP who tested positive for COVID-19 showed no major complications. Also, although limited in sample size, the majority of patients who received a COVID-19 vaccination and followed guidelines from the FOP International Clinical Council tolerated vaccination well. Only one person experiencing flare activity following their injection. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions.

BioMed CentralBioMed Central
关于已发布论文《COVID-19对进行性骨化性纤维发育不良患者的社会和临床影响》的后续报告 BioMed CentralBioMed CentralA follow-up report on the published paper Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva - Orphanet Journal of Rare Diseases
A follow-up report on the published paper Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva - Orphanet Journal of Rare Diseases

A follow-up report on the published paper Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva - Orphanet Journal of Rare Diseases

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder associated with increased immune activity and severe, progressive heterotopic ossification. We previously described a cohort of 32 patients with FOP who were either exposed to SARS-CoV-2 or received a COVID-19 vaccine1 and showed that these patients did not develop heterotopic ossification after COVID-19 vaccination. Here, we present additional clinical data from new subjects and additional long-term follow-up from the first cohort. We enrolled 15 new subjects between August 24th, 2021 and May 17th, 2022 and collected additional self-reported outcomes. The larger cohort with 47 individuals encompassing 49 events showed that patients with FOP exhibited no additional change in FOP disease activity or flare activity resulting from COVID-19 infection or after receipt of a SARS-CoV-2 vaccine. Thus, although any vaccination carries a risk of inducing heterotopic ossification in patients with FOP, our results show that patients with FOP who choose to receive a COVID-19 vaccination may be able to tolerate the procedure without a high risk of heterotopic ossification when following the published guidelines.

BioMed CentralBioMed Central
佩戴口罩仍是控制SARS-CoV-2传播的重要组成部分。ICC强烈建议尽可能使用合身的N95、KN95或KF94口罩，以保护佩戴者免受SARS-CoV-2感染。如果这些口罩不可用或不舒适，则佩戴三层外科口罩是次优选择。
ICC注意到近期有研究表明，疫苗的皮下注射仍可能诱导出足够的疫苗反应。然而，这项研究可能通过浅层肌肉注射方式给药。此外，文献中有多个报告提到COVID疫苗的皮下注射引发严重反应。皮下给药的COVID疫苗的有效性尚未得到证实。因此，ICC继续建议遵循制造商的疫苗接种指导，并且不通过皮下途径接种肌肉注射的COVID疫苗。
如果您决定接种COVID疫苗或加强针，我们建议：
  • 与您的医生讨论计划，审查任何潜在的过敏反应或之前的反应（如过敏性休克），以便在接种疫苗前考虑。
  • 如果您参与临床试验或研究，讨论任何疫苗或治疗方案与您的研究医生非常重要。
  • 按照推荐的途径和剂量接种疫苗（即当前可用疫苗的肌肉注射IM）。通过皮下途径接种IM疫苗的安全性和有效性尚不明确，可能导致意外的炎症反应或免疫反应不良，目前不推荐这种方式。
  • 如果可能，在已经融合的部位接种疫苗，因为疫苗似乎会引起局部反应（如手臂疼痛和肿胀）。例如，如果您的左髋或右肩已融合，建议在这些部位周围的肌肉中接种。
  • 与其他疫苗一样，FOP患者在接种疫苗前应至少无发作2周。
  • 由经验丰富的护士、医生或药剂师进行注射。
  • 使用最短的针头（根据临床场所而异）。临床医生应了解FOP患者在注射部位可能有隐匿的异位骨化和肌肉萎缩，尽量避免直接在已有异位骨的旁边注射。
  • 在接种疫苗前，准备好布洛芬或对乙酰氨基酚。同时，准备好应对发作的泼尼松方案。
  • FOP患者在接种COVID疫苗后报告的症状与普通人群的报告相似（低热、头痛、肌肉酸痛、疲劳等）。
  • 确保您的医生熟悉ICC治疗指南，特别是在疫苗接种和发作管理方面（见下文）。通知您的医生您计划接种疫苗的时间。
  • 在注射当天：
    • 您所在的当地团队可能不允许您在注射前服用布洛芬或对乙酰氨基酚（因为他们可能首先会筛查COVID症状）。
    • 接种后，可能会有一个短暂的观察期。
    • 观察期结束后，在接下来的48小时内，无论您的症状如何，都请按照标签说明服用布洛芬（每天2到3次）或对乙酰氨基酚（每天2到3次）。
    • 注意休息和保持水分。
    • 如果出现发作，请联系您的医生以获取指导。您可能需要进行短期泼尼松治疗，但这需要与类固醇的免疫抑制作用相平衡。通常的发作剂量为泼尼松2 mg/kg/天，最多100 mg，持续4天；您的医生可能会根据您的症状建议从较低剂量开始。
    • 即使接种了疫苗，您仍然需要继续保持社交距离，佩戴口罩，并适当地洗手。
ICC不能保证这些步骤能有效预防并发症。接种COVID疫苗的FOP患者中已有报告出现发作或类发作活动。所有药物和治疗都有风险，因此在决定疫苗是否适合您时，与医生讨论您的具体情况非常重要。
确保完成推荐的全部免疫接种方案（例如，如果疫苗推荐接种2剂，则务必接种两剂）。
与您的医生讨论是否需要接种加强针，以及这是否适合您，例如覆盖本地的SARS-CoV-2变种。这是一个积极研究的领域，因此随着ICC获取更多信息，相关建议将会更新。
疫苗的开发如何改变现状？
疫苗的开发和分发对COVID疫情产生了重大影响。
疫苗效果和变种的出现是全球范围内持续研究的热点领域，该领域正在快速发展。
疫苗所赋予的免疫持续时间尚不清楚，但似乎并非终身有效。
ICC建议FOP患者的家庭成员和护理人员在安全可用的情况下接种SARS-CoV-2疫苗。
疫苗接种后可能需要超过2周才能显示出任何效果，因此接种后并没有立即的保护。此外，疫苗并不提供对SARS-CoV-2病毒的绝对免疫，可能对所有形式的SARS-CoV-2病毒都无效。
接种疫苗的人仍需继续佩戴口罩、保持手部卫生和保持社交距离。
请与当地医疗提供者讨论任何经过当地批准的疫苗和加强针的益处和风险。
在与您家以外的人在一起时，保持社交距离和佩戴口罩是非常重要的。
FOP患者或护理人员检测SARS-CoV-2阳性后的建议
请通知您的初级保健医生以帮助协调护理。
遵循您所在地区的隔离/检疫指南，包括所需的时间和程序。所有人，包括检测结果为阳性的SARS-CoV-2患者，应始终佩戴口罩以避免传播。
对于检测结果为阴性但有类似症状的患者，应进行流感检测。
FOP患者在COVID-19感染中面临高并发症风险，应与医疗团队讨论在SARS-CoV-2感染情况下使用单克隆抗体或抗病毒药物是否有益。治疗的主要目的是减少呼吸并发症，因为FOP患者呼吸并发症风险高且插管困难。然而，您所在地区可能对这些药物的获取有限。请与您的医生讨论这些药物是否适合您。
  • 单克隆抗体通过静脉注射给药，已获批准用于成人和体重≥40公斤的儿童（≥12岁）。这些干预措施应尽早开始，并在症状出现10天前进行。
  • 抗病毒药物是经批准用于治疗COVID-19的药物。通常应在症状出现后5天内给予。
  • 这些治疗的可用性和推荐正在迅速变化，并因国家而异。请咨询您当地的医疗团队。
  • 在开始抗病毒治疗之前，与您的医生讨论任何潜在的药物相互作用。
参考文献
  1. Kou S, Kile S, Kambampati SS, Brady EC, Wallace H, De Sousa CM, Cheung K, Dickey L, Wentworth KL, Hsiao EC. Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2022 Mar 4;17(1):107 COVID-19对进行性骨化性纤维发育不良患者的社会和临床影响
  1. Wallace H, Lee RH, Hsiao EC. A follow-up report on the published paper Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2023 Mar 20;18(1):61 关于已发表论文《COVID-19对进行性骨化性纤维发育不良患者的社会和临床影响》的后续报告
原文
  1. Coronavirus (COVID-19) Precautions & Guidance for FOP Patients & Families
      2. The Coronavirus (COVID-19) pandemic continues to pose a significant risk to the population worldwide with new variants of SARS-CoV-2 virus that are emerging. The ICC recommends that people living with FOP continue to follow precautionary measures to prevent infection from SARS-CoV-2, the virus that causes the COVID-19 illness.
      The ICC is providing this update to the prior statement in May 2022. This document focuses on updated information reporting on COVID-19 infection and vaccination in FOP patients, approval on COVID-19 vaccination in children aged 6 months and above, as well as boosters and treatment.
      The recommendations are changing rapidly and are country specific. Most countries have ended their emergency regulations for COVID-19.
      The ICC does not provide recommendations on whether a patient with FOP should or should not receive a COVID vaccine.
      The decision to take a vaccine is a personal one and based on the balance of risks and benefits, and this should be discussed with your medical team. ICC continues to recommend that COVID-19 vaccines be administered that same route that it was approved (i.e., intramuscular).
      Additional information about COVID-19 and COVID vaccination in patients with FOP is now published. (https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02246-4 and https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02638-0)
      • Amongst 23 FOP patients who received intramuscular COVID-19 vaccination. Most common symptoms were pain/soreness, tiredness and swelling. These symptoms are similar to those reported by the general population. One out of 23 developed a flare-up. No patients who received the COVID-19 vaccine were hospitalized.
      • Amongst 19 FOP patients with COVID-19 infection. Most common symptoms were fatigue, loss of taste or smell and cough. Two out 19 FOP patient developed flare ups and 3 patients were hospitalized.
      Vaccines are now generally available for children age 6 months or over. ICC does not provide recommendations on whether a patient with FOP should or should not receive a COVID vaccine. Discuss with your medical team, as local recommendations on when to take a vaccine or eligibility for a vaccine may vary.
      ICC does not provide recommendations for or against the booster vaccination, but boosters should be considered if you completed vaccinations previously and are in a high risk area. Please consult with your medical team prior to receiving the booster to discuss if a booster is appropriate and safe.
      Patients with FOP are at high risk of complications with COVID-19 infection and should discuss with their medical team if use of monoclonal antibodies or anti-retroviral medications would be beneficial, in the event of a SARS-CoV2 infection.
      • Monoclonal antibodies are given intravenously and are approved for adults and pediatric patients (≥12 years of age weighing ≥40 kg). Those interventions should be started as early as possible and before 10 days of symptoms onset. Note that some monoclonal antibodies are not effective against the newest strains of SARS-CoV2.
      • Anti-retrovirals are pills that have been approved. These should generally be administered within 5 days of symptoms onset.
      • Availability and recommendations of the use of these treatments are rapidly changing and country specific. Some of these therapies may not work against strains prevalent in a particular region. Please consult with your local medical team for recommendations o Discuss with your doctors to make sure there are no medication interactions
      If you are in a clinical trial, it is important to discuss any vaccines or therapies with your study doctors.
      Clinical data about FOP and COVID/SARS-CoV2 infections are published here:
      Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva | Orphanet Journal of Rare Diseases | Full Text (biomedcentral.com)
      https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02246-4
      A follow-up report on the published paper Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressive (biomedcentral.com)
      https://ojrd.biomedcentral.com/articles/10.1186/s13023-023-02638-0
      Masking continues to be an important component of controlling the spread of SARS-CoV-2. The ICC strongly recommends the use of tight fitting N95, KN95, or KF94 masks whenever possible to protect the wearer from infection by SARS-CoV-2. If these masks are not available or uncomfortable, then wearing a 3-layer surgical mask would be the next best choice.
      The ICC is aware of a recent publication suggesting that the use of subcutaneous injection of the vaccine could still induce adequate vaccine response. However, this study likely delivered the vaccine via a shallow intramuscular route. Furthermore, there are multiple reports in the literature of severe reactions to subcutaneous injection of the COVID vaccine. Efficacy of subcutaneous delivery of a COVID vaccine remains unproven. Therefore, the ICC continues to recommend following the manufacturers’ directions for vaccination and NOT taking intramuscular COVID vaccines by the subcutaneous route.
      If you decide to take the COVID vaccine or booster, we recommend:
      • Discuss your plans with your doctor. Review any potential allergies or prior reactions like anaphylaxis that you should consider before taking the vaccine.
      • If you are in a clinical trial or study, it is important to discuss any vaccines or therapies with your study doctors.
      • Take the vaccine via the recommended route and dose (i.e., intramuscular (IM) for the currently available vaccines). Safety and efficacy of taking an IM vaccine through the subcutaneous route is not known and could cause a more unexpected inflammatory responses or poor immune reactions and is currently not recommended.
      • If possible, take the vaccine in a location that is already fused, as the vaccines all appear to induce some local site reaction (arm pain and swelling). For example, if your left hip or right shoulder are fused, you should use the muscle around those sites.
      • As with other vaccines, patients with FOP should be flare free for at least 2 weeks prior to receiving the vaccine.
      • Have the injection done by an experienced nurse, physician, or pharmacist.
      • Use the shortest needle available (this varies with clinical site). The clinician should be aware that patients with FOP may have hidden HO and thinned muscle at the site of the injection. Avoid injecting directly next to existing HO bone if possible.
      • Prior to the vaccination, have ibuprofen or acetaminophen available. Also, have a course of prednisone for flares available.
      • The symptoms reported by patients with FOP after a COVID vaccination are similar to those reported for the general population (low grade fever, headache, muscle aches, fatigue, etc.).
      • Make sure your physician is familiar with the ICC Treatment guidelines, specifically on vaccinations and flare management (see below). Notify your physician you plan to do the vaccine, and when.
      • On the day of the injection:
        • Your local team may not allow you to take ibuprofen or acetaminophen prior to the injection (this is because they may screen for COVID symptoms first).
        • After you receive your injection, there may be a brief observation period.
        • After that is completed, take ibuprofen (2 to 3 times/day) or acetaminophen (2-3 times/day) following the label instructions, for the next 48 hrs, regardless of your symptoms.
        • Rest and stay hydrated.
        • In the event of a flare, contact your physician for guidance. You may need to do a short course of prednisone, but this needs to be balanced with the immunosuppressive effects of steroids. The usual flare dosing is prednisone 2 mg/kg/day up to 100 mg, for 4 days; your physician may recommend starting at a lower dose, depending on your symptoms.
        • Even if you take the vaccine, you still need to continue physical distancing, wearing masks, and appropriate hand washing
      The ICC can’t guarantee that these steps will “work” to prevent complications. Flare or flare-like activity has been reported in patients with FOP who receive a COVID vaccine. All medications and treatments have risk, so it is important to discuss your specific situation with your doctor as you decide whether the vaccine is appropriate for your situation.
      Make sure that you complete the full immunization regimen recommended (i.e., do both doses if the vaccine recommends 2 doses)
      Discuss with your physician if you should do a booster and if that is appropriate for you, such as to cover local SARS-CoV2 variants. This is an area of active investigation so will need to be updated as the ICC receives more information.
      How does the development of a vaccine change things?
      The development and distribution of vaccines have had a major impact on the COVID pandemic.
      Vaccine outcomes and the emergence of variants are areas of intense ongoing study worldwide, and the field continues to rapidly evolve.
      The duration of immunity conferred by the vaccines is unknown but does not seem to be lifelong.
      The ICC recommends that FOP family members and caregivers be fully vaccinated for SARS-CoV2 if safely available for them.
      Vaccinations can take 2+ weeks to show any efficacy, so there is no protection immediately after vaccination. In addition, vaccines do not confer absolute immunity to the SARS-CoV-2 virus, and may not have activity against all forms of the SARS-CoV-2 virus.
      Anyone who receives a vaccine should still continue with masking, hand hygiene, and physical distancing.
      Please discuss with your local care providers regarding benefits and risk of any locally approved vaccines and boosters.
      It’s very important to maintain social distancing and wearing a mask when around members outside your household
      Recommendations if a patient with FOP or caregiver tests positive for SARS-CoV2
      Notify your primary care physician to help coordinate care.
      Follow your local guidelines for isolation/quarantine and the needed durations and procedures. Everyone, including the person with the positive SARS-CoV2, should wear a mask at all times to avoid transmission.
      Patients who are negative for SARS-CoV2 but have similar symptoms should be tested for influenza.
      Patients with FOP are at high risk of complications with COVID-19 infection and should discuss with their medical team if use of monoclonal antibodies or anti-retroviral medications would be beneficial, in the event of a SARS-CoV-2 infection. The main reason for treatment would be to reduce respiratory complications, as patients with FOP are at high risk of breathing complications and are difficult to intubate. However, access to these medications may be limited in your area. Please discuss with your physician if these medications are an option and appropriate for you.
      • Monoclonal antibodies are given intravenously and are approved for adults and pediatric patients (≥12 years of age weighing ≥40 kg). Those interventions should be started as early as possible and before 10 days of symptoms onset.
      • Anti-retrovirals are pills that have been approved for treatment of COVID-19. These should generally be administered within 5 days of symptoms onset.
      • Availability and recommendations of the use of these treatments are rapidly changing and country specific. Please consult with your local medical team.
      • Discuss with your physician about any potential medication interactions prior to starting anti-viral therapies
      References
      Kou S, Kile S, Kambampati SS, Brady EC, Wallace H, De Sousa CM, Cheung K, Dickey L, Wentworth KL, Hsiao EC. Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2022 Mar 4;17(1):107
      Wallace H, Lee RH, Hsiao EC. A follow-up report on the published paper Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2023 Mar 20;18(1):61

10. FOP的急性和慢性疼痛管理

根据IFOPA患者登记系统，近90%的进行性骨化性纤维发育不良患者都有疼痛诉说。FOP中急性疼痛的主要原因源于肌肉骨骼，包括发作、暂时性滑囊炎、骨软骨瘤的炎症、肌肉疲劳和异位骨折。
急性疼痛管理最重要的方面是区分因发作引起的急性疼痛与其他病因。在一项关于FOP发作自然历史的研究中，最痛苦的发作发生在髋关节和膝关节。对FOP患者的定量感官测试显示出显著的热痛和机械痛的超敏感性，提示存在一种新的神经性疼痛表型。
基于对FOP急性髋痛的临床和放射学发现的近期评估，可以提出一种针对急性关节或关节周围疼痛的算法方法（图示）。在初始的短期类固醇治疗后，如果停止用药后没有反弹症状，这是进一步治疗决策的关键节点。缺乏反弹症状（即疼痛诉说的消失）表明疼痛的病因与发作无关。然而，停药后症状持续或加重，则强烈提示发作可能是导致疼痛的原因。受累关节的普通放射线照片对管理急性关节周围疼痛可能会有所帮助。
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进行性骨化性纤维发育不良（FOP）中慢性疼痛的常见原因包括神经病变、关节炎、晚期FOP中的广泛慢性疼痛综合征，以及其他疼痛原因，如胃肠道疼痛（见胃肠问题部分）。慢性疼痛的处理方法依赖于区分神经病性和伤害性感染的病因。神经病性疼痛源于神经系统的损伤或病理，可能是中枢性或外周性。在FOP中，神经病变是神经病性疼痛的主要原因，通常与神经压迫综合征和/或神经损伤有关，并可能由与FOP病因内在相关的外周或中枢神经系统现象引起。伤害性感染的疼痛则是由威胁或引发实际组织损伤的刺激所引起。在FOP中，伤害性感染的主要原因是肌肉骨骼疼痛（例如，背痛、肌筋膜疼痛综合征、踝痛）、炎症性疼痛以及由机械/压迫性原因引起的疼痛（例如，由于异位骨膨胀引起的内脏疼痛）。
应将疼痛管理的一般原则应用于FOP中的慢性疼痛治疗。最佳的方法是针对已知的疼痛病因进行治疗，并在病因不明确时，合理尝试了解至少疼痛的类型。最佳效果通常来自多种方法的协调使用，这些方法通过多学科团队进行协调。一些辅助性非药物疗法在疼痛管理中可能是有效的。最后，抑郁症的治疗可能会提供与纠正情绪障碍无关的疼痛缓解。
慢性疼痛的治疗基于神经病性和伤害性成分的区分。在非FOP疼痛综合征的疼痛管理指南中，关于神经病性疼痛的一线药物包括钙通道α2-δ配体（如加巴喷丁或普瑞巴林）或三环类抗抑郁药。选择性血清素-去甲肾上腺素再摄取抑制剂（SNRIs）被视为一线或二线药物（如度洛西汀、文拉法辛），尽管它们可能比三环类抗抑郁药更受青睐。在三环类抗抑郁药中，副作用概况似乎更倾向于次胺类三环药物（如去甲替林和去甲丙氨酸），尽管其他三环类药物（如阿米替林）的疗效是相同的。由于不到一半的神经病性疼痛患者会对单一药物产生反应，通常需要联合治疗。然而，关于联合治疗的疗效和安全性证据较少。可以使用的其他二线药物包括曲马多和其他抗癫痫药（如卡马西平或奥卡西平）。考虑到滥用潜力以及激活肥大细胞和全身性组胺释放是阿片类药物（特别是可待因和美托洛尔）的常见副作用，因此在FOP中应将阿片类药物视为三线选择。适当时，可以将局部药物用作辅助治疗。
伤害性疼痛的药物治疗首先要评估可能禁忌、限制或引起注意的风险因素，这些因素与非甾体抗炎药（NSAIDs）的使用相关，这是治疗的主要手段。风险因素包括老年、肾脏、肝脏、心血管疾病或风险、消化性溃疡和糖皮质激素使用。后者与FOP直接相关，系统性NSAIDs不应与类固醇同时使用。在评估风险因素后，伤害性疼痛管理的下一步是评估疼痛水平。轻度至中度疼痛可以最初通过局部药物（见局部药物部分）和/或对乙酰氨基酚/扑热息痛进行治疗。
无法通过局部药物或对乙酰氨基酚/扑热息痛控制的疼痛应使用非甾体抗炎药（NSAIDs）联合质子泵抑制剂或COX-2抑制剂治疗，并可加或不加对乙酰氨基酚/扑热息痛。关于对乙酰氨基酚的最大安全每日剂量存在争议，但3克到3.25克的每日剂量似乎在安全的最大范围内。
对中度至重度疼痛且没有炎症成分或具有NSAID使用风险因素的患者，应先使用对乙酰氨基酚/扑热息痛，如果疼痛控制不佳，则可转为三环类抗抑郁药。对于具有炎症成分的中度至重度疼痛，初始应使用NSAIDs联合质子泵抑制剂或COX-2抑制剂，并可加或不加对乙酰氨基酚/扑热息痛。使用COX-2抑制剂可能减少NSAIDs引起的胃肠道毒性。如果疼痛控制不佳，也可以使用三环类抗抑郁药。如果疼痛伴有痉挛成分，短期内可以考虑加用巴克洛芬或其他肌肉松弛剂（见肌肉松弛剂部分）。基于上述原因，在FOP中，阿片类药物也应被视为管理伤害性疼痛的三线选择。
FOP中的急性和慢性疼痛有很多原因，每个个体在制定有效治疗方案之前都必须经过仔细评估。许多FOP的发作，尤其是髋关节和膝关节周围的发作，极其疼痛，可能需要在使用非甾体抗炎药、COX-2抑制剂和/或口服或静脉注射糖皮质激素的基础上，短期使用良好监测的麻醉镇痛药。其他类型的暂时性疼痛综合征可能由神经病变、暂时性滑囊炎、骨软骨瘤炎、关节炎和肌肉疲劳等急性发作引起，仅举几例。
迄今为止，关于FOP在发作及静止非发作疾病阶段的疼痛与情绪健康动态仍然知之甚少。为了阐明FOP中疼痛的发生和影响，一项研究分析了参与国际FOP注册的99名患者在30个月期间填写的患者报告结果测量信息系统问卷（Peng等，2019）。研究观察到，中度至重度疼痛（≥4，0-10疼痛评分）通常与发作相关（56-67%），但令人惊讶的是，30-55%的患者在非发作状态下也经历了相似的疼痛水平。此外，无论发作状态如何，FOP患者的疼痛严重程度与情绪健康、身体健康和总体生活质量呈负相关。这些发现强烈表明，需要更深入地理解FOP在发作和静止期间的疼痛和情绪健康。
那些具有广泛肌肉骨骼来源的慢性疼痛患者可能需要由疼痛管理专家主导的更专业的疼痛管理程序。应努力最小化慢性不适并最大化身体和认知功能。在大多数情况下，应避免使用麻醉药物，以减少对这些药物的依赖风险。虽然有些患者在疾病进程的后期可能需要长期使用麻醉镇痛药，但应仔细监测，以避免便秘和呼吸抑制。
替代或补充疗法的使用尚未得到充分研究，但可能提供减少系统性疼痛药物使用的选项。疼痛神经科学教育可能是有用的，并已被证明在各种疼痛类型中是一种有效的干预。由于可能造成组织损伤，不建议使用针灸。
应考虑其他补充或整合医学技术用于疼痛管理，包括生物反馈、治疗性水疗、治疗性放松、自我催眠、认知行为疗法、轻柔按摩/指压和医疗大麻（在可用的情况下）。应与主治医生讨论这些疗法，以确保与其他药物或疗法没有不良相互作用或患者的禁忌症。此外，像指压和轻柔按摩等程序需要以不增加创伤风险或诱发发作的方式进行。请与主治医生或当地疼痛管理团队讨论，寻求推荐可信赖的补充或整合医学从业者。
对于那些有更严重慢性疼痛管理问题的患者，咨询疼痛管理专家可能会有所帮助，建议进行此类咨询。
医疗大麻
在FOP患者中，偶尔使用医疗大麻的现象是已知的。这类药物由大麻属植物的亚种衍生出的化合物组成，通过吸入、吞咽以及涂抹于皮肤或口腔黏膜来发挥潜在的益处。截至撰写本文时，美国有33个州和哥伦比亚特区设有授权用于特定医疗条件的大麻使用项目，各国的规定各不相同。大多数州允许其用于多种疾病，FOP相关的情况包括恶病质/消瘦综合征、肌肉痉挛、严重和慢性疼痛，以及严重恶心。在美国，临床医生并不处方医疗大麻，而只是为符合州项目条件的患者提供认证。
国家科学院、工程院和医学院（NASEM）对大麻及其类 cannabinoid 的健康影响进行了全面评估。NASEM报告显示，有确凿或实质证据表明大麻或类 cannabinoid 对成人的慢性疼痛、止吐以及改善肌肉痉挛有效。慢性疼痛是个体使用医疗大麻的最常见原因；然而，其使用应作为综合症状管理策略的一部分，而不是单一的疼痛控制方式，这突显了持续其他治疗的重要性。在此背景下，值得注意的是，医疗大麻的使用与显著降低的阿片类药物过量死亡率相关。
自然存在的植物类 cannabinoid 的口服提取物，口服给药的 Δ9-四氢大麻酚（THC）和 nabiximols（THC与 cannabidiol [CBD] 的组合）是通常使用的形式，但合成类 cannabinoid 也可用。在不同的制剂中，关于临床有效性的证据仅能针对吸烟或蒸汽化的植物花、植物衍生的口服 THC、THC-CBD 组合和合成 THC 进行。NASEM 指出，大麻吸烟与呼吸系统疾病、机动车碰撞（MVCs）、后代出生体重低以及精神分裂症或其他精神病之间存在实质性证据关联。在考虑对25岁以下患者使用医疗大麻时应谨慎，因为大脑发展持续到该年龄，而大麻对认知表现的潜在长期影响尚不清。此外，由于园艺技术、药物提取方法和药物递送方式的差异，从州级项目获得的医疗大麻产品的可用证据也难以推广。
参考文献
  1. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010 [published correction appears in JAMA Intern Med. 2014;174(11):1875]. JAMA Intern Med 174: 1668-1673, 2014 医疗大麻法律与美国1999-2010年阿片类镇痛药过量死亡率的关系
  1. Belendiuk KA, Baldini LL, Bonn-Miller MO. Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders. Addict Sci Clin Pract 2015; 10:10 关于大麻治疗常见州批准的医疗和精神疾病安全性和有效性的叙述性综述
  1. Blunk JA, Schmelz M, Zeck S, Skov P, Likar R, Koppert W. Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 98: 364-370, 2004 阿片类药物引起的肥大细胞激活和血管反应并非通过μ-阿片受体介导：一项在人体皮肤进行的体内微透析研究
  1. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14: 162, 2015 成人神经性疼痛的药物治疗：一项系统评估与荟萃分析
  1. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc 90: 532, 2015 神经性疼痛：诊断和治疗原则
  1. Heard K, Green JL, Bailey JE, et al. A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol. Aliment Pharmacol Ther 26: 283, 2007 一项随机试验以确定在适度饮酒者中，10天服用对乙酰氨基酚（扑热息痛）期间丙氨酸氨基转移酶的变化
  1. Kan L, Kitterman JA, Procissi D, Chakkalakal S, Peng CY, McGuire TL, Goldsby RE, Pignolo RJ, Shore EM, Kaplan FS, Kessler JA. CNS demyelination in fibrodysplasia ossificans progressiva. J Neurol 259: 2644-2655, 2012 FOP中的中枢神经系统脱髓鞘
  1. Kan L, Lounev VY, Pignolo RJ, Duan L, Liu Y, Stock SR, McGuire TL, Lu B, Gerard NP, Shore EM, Kaplan FS, Kessler JA. Substance P signaling mediates BMP-dependent heterotopic ossification. J Cell Biochem 112: 2759-2772, 2011 生物活性物质P信号介导BMP依赖的异位骨化
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP). Bone 109: 115-119, 2018 FOP中的急性单侧髋痛
  1. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva (FOP). Best Practice & Research – Clinical Rheumatology 22: 191-205, 2008 进行性骨化性纤维发育不良（FOP）。最佳实践与研究 – 临床风湿病学
  1. Louw A, Zimney K, Puentedura EJ, Diener I. The efficacy of pain neuroscience education on musculoskeletal pain: A systematic review of the literature. Physiother Theory Pract 32: 332-355, 2016 疼痛神经科学教育对肌肉骨骼疼痛的有效性：文献的系统评估
  1. Mantick N, Bachman E, Baujat G, Brown M, Collins O, De Cunto C, Delai P, Eekhoff M, Zum Felde R, Grogan DR, Haga N, Hsiao E, Kantanie S, Kaplan F, Keen R, Milosevic J, Morhart R, Pignolo R, Qian X, di Rocco M, Scott C, Sherman A, Wallace M, Williams N, Zhang K, Bogard B. The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 109: 285-290, 2018 FOP连接注册：一个国际患者资助的进行性骨化性纤维发育不良注册设计
  1. McCormack K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 59: 9, 1994 非甾体抗炎药与脊柱的痛觉处理
  1. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press, 2017 大麻及其类 cannabinoid 的健康影响：当前证据状态及研究建议
  1. Peng K, Cheung K, Lee A, Sieberg C, Borsook D, Upadhyay J. Longitudinal evaluation of pain, flare-Up, and emotional health in fibrodysplasia ossificans progressiva: Analyses of the international FOP registry. JBMR Plus 2019 Mar 1;3(8):e10181. FOP中的疼痛、发作与情感健康的纵向评估：国际FOP注册的分析
  1. Peng K, Karunakaran KD, Labadie R, Veliu M, Cheung C, Lee A, Yu PB, Upadhyay J. Suppressed prefrontal cortex oscillations associate with clinical pain in fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2021 Jan 30;16(1):54. 抑制的前额皮质振荡与FOP中的临床疼痛相关联
  1. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine 33:1766, 2008 用于下背痛的非甾体抗炎药：更新的Cochrane评估
  1. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284: 1247, 2000 赛乐克与非甾体抗炎药在骨关节炎和类风湿性关节炎中的胃肠毒性：CLASS研究：一项随机对照试验
  1. Yu X, Ton AN, Niu Z, Morales BM, Chen J, Braz J, Lai MH, Barruet E, Liu H, Cheung K, Ali S, Chan T, Bigay K, Ho J, Nikolli I, Hansberry S, Wentworth K, Kriegstein A, Basbaum A, Hsiao EC. ACVR1activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans. Pain 164: 4358, 2023. ACVR1激活突变导致人类神经性疼痛和感觉神经元高兴奋性
原文
  1. Acute & Chronic Pain Management in FOP
      2. General Considerations
      According to the IFOPA Patient Registry (Mantick et al., 2018), almost 90% of individuals with FOP have pain complaints. Major causes of acute pain in FOP are musculoskeletal in origin and include flare-ups, transient bursitis, inflammation of osteochondromas, muscle fatigue, and fracture through heterotopic bone.
      The most important aspect of acute pain management is distinguishing acute pain due to flare-ups versus other etiologies. In a study on the natural history of flare-ups in FOP (Pignolo et al, 2016), the most painful flare-ups occur in the hips and knees. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity, suggesting a novel neuropathic pain phenotype (Yu et al., 2023).
      Based on a recent evaluation of clinical and radiographic findings of acute hip pain in FOP (Kaplan et al., 2018; see section on Differential diagnosis of hip pain), an algorithmic approach to acute joint or periarticular pain may be proposed (Figure). After an initial brief course of steroids to empirically treat for a possible flare-up, observation for rebound symptoms with discontinuation is the critical node for further treatment decisions. The absence of rebound symptoms (i.e., resolution of pain complaints) suggests that the etiology for pain is not related to a flare-up. The presence of continued or worsening symptoms after discontinuation, however, strongly suggests a flare-up as the likely cause. Plain radiographs of the involved joint can be helpful in the management of acute periarticular pain.
      notion image
      Common causes of chronic pain in FOP include neuropathies, arthritis, generalized chronic pain syndrome in advanced FOP, and other causes of pain such as gastrointestinal pain (see section on gastrointestinal issues). The approach to chronic pain relies on distinguishing between neuropathic and nociceptive etiologies. Neuropathic pain results from damage to or pathology within the nervous system and can be central or peripheral. In FOP, neuropathies are the major cause of neuropathic pain, related to entrapment syndromes and/or nerve damage, and may be caused by peripheral or central nervous system phenomena intrinsically related to the cause of FOP (Kan et al., 2011; Kan et al., 2012; Peng et al., 2021; Yu et al, 2023). Nociceptive pain is caused by stimuli that threaten or provoke actual tissue damage. In FOP, the major causes of nociceptive pain are musculoskeletal pain (e.g., back pain, myofascial pain syndrome, ankle pain), inflammatory pain, and pain due to mechanical/compressive causes (e.g., visceral pain from expanding HO).
      General principles of pain management should be applied to the treatment of chronic pain in FOP. The best approach is to target the etiology of the pain, whenever known, and to make reasonable attempts at understanding at least the type of pain when the etiology is unknown. Optimal outcomes often result from multiple approaches utilized in concert, coordinated via a multidisciplinary team. Some adjuvant, nonpharmacologic modalities can be effective in pain management. Finally, treatment of depression may provide pain relief separate from correction of the mood disorder.
      Treatment of chronic pain is based on neuropathic versus nociceptive components. There is consensus among guidelines on pain management of non-FOP pain syndromes that first-line agents for neuropathic pain include either calcium channel alpha 2-delta ligands (e.g., gabapentin or pregabalin) or tricyclic antidepressants (Gilron et al., 2015; Finnerup et al., 2015). Serotonin norepinephrine uptake inhibitors (SNRIs) are identified as either first or second-line agents (e.g., duloxetine, venlafaxine), although they may be preferred to tricyclic antidepressants. Among the tricyclic antidepressants, side effect profiles appear to favor the secondary amine tricyclics (e.g., nortriptyline and desipramine), although the efficacy is the same for other tricyclics such as amitriptyline. Combination therapy is often required, because less than half of patients with neuropathic pain will respond to a single agent. However, evidence is scant regarding the efficacy and safety of combination treatment. Other second-line agents that may be used include tramadol and other antiepileptics (e.g., carbamazepine or oxcarbazepine). Opioids should be considered a third-line option in FOP, both because of abuse potential and the fact that activation of mast cells and the systemic release of histamine are common side effects of opioids, especially codeine and meperidine (Blunk et al., 2004). Topical agents can be used as adjunctive therapy as appropriate.
      The pharmacologic approach to nociceptive pain first begins with an evaluation of risk factors that may contraindicate, limit, or otherwise call attention to the possibility of potential side effects related to the use of non-steroidal anti-inflammatory agents (NSAIDS), the mainstay of treatment (McCormack, 1994; Roelofs et al., 2008). Risk factors include advanced age, renal, hepatic, cardiovascular disease or risk, peptic ulcer, and glucocorticoid use. The latter is directly applicable to FOP, and systemic NSAIDS should not be used concomitantly with steroids. After risk factor evaluation, the next step to nociceptive pain management is an assessment of pain level. Mild to moderate pain can initially be treated with topical agents (see section on Topical Agents) and/or acetaminophen/paracetamol.
      Pain not controlled by topical agents or acetaminophen/paracetamol should be managed with NSAIDs plus a proton-pump inhibitor or COX-2 inhibitor with or without acetaminophen/paracetamol. There is controversy over the maximal safe daily dose of acetaminophen, but a 3g to 3.25g daily dose appears to be within a safe maximal range (Heard et al., 2007).
      Treatment of moderately severe to severe pain without an inflammatory component or with risk factors for NSAID use should begin with acetaminophen/paracetamol and advanced to tricyclic antidepressants if pain is not adequately controlled. Moderately severe to severe pain with an inflammatory component should be initially treated with NSAIDs plus a proton-pump inhibitor or COX-2 inhibitor with or without acetaminophen/paracetamol. Use of COX-2 inhibitors may decrease the likelihood of gastrointestinal toxicity from NSAIDs (Silverstein et al., 2000). Tricyclic antidepressants can also be used if pain is not adequately controlled. The addition of baclofen or other muscle relaxant may be appropriate for a short period of time if there is a spasmodic component to the pain (see section on Muscle Relaxants). For the reasons stated above, opioids should also be considered a third-line option in FOP for the management of nociceptive pain.
      There are many causes of acute and chronic pain in FOP, and each individual must be carefully evaluated before effective treatment can be planned and implemented (Kaplan et al., 2008). Many FOP flare-ups, especially those around the hips and knees, are extremely painful and may require a brief course of well-monitored narcotic analgesia in addition to the use of non-steroidal anti-inflammatory medications, COX-2 inhibitors, and/or oral or IV glucocorticoids. Other types of transient pain syndromes may be caused by neuropathies resulting from acute flare-ups, transient bursitis, inflammation of osteochondromas, arthritis and muscle fatigue, to mention only a few.
      To date, much remains unknown regarding the dynamics of pain and emotional health in FOP during flareup and also quiescent, non-flare-up disease phases. In order to elucidate the occurrence and effect of pain in FOP, a study analyzed patient-reported outcomes measurement information system-based questionnaires completed by 99 patients participating in the international FOP Registry over a 30-month period (Peng et al., 2019). The study observed that while moderate to severe pain (≥4, 0-10 pain scale) was commonly associated with flare-ups (56-67%), surprisingly, 30-55% of patients experienced similar pain levels during non-flare-up states. Furthermore, independent of the flare-up status, the severity of pain in FOP patients was found to be inversely correlated with emotional health, physical health and overall quality-of-life. These findings strongly suggest the need for an improved understanding of pain and emotional health in FOP during flare-up and quiescent periods (Peng et al., 2019).
      Those with chronic pain of diffuse musculoskeletal origin may require more specialized pain management programs directed by pain management specialists. Attempts should be made to minimize chronic discomfort and maximize physical and cognitive function. In most cases, narcotic agents should be avoided to minimize the risk of dependency on these agents. While some may require chronic narcotic analgesics late in the course of their disease process, attempts should be made to monitor this carefully to avoid constipation and respiratory suppression.
      Use of alternative of complementary therapies have not been well investigated but may provide options for reducing systemic pain medication use. Pain neuroscience education may be useful and has been shown to be an effective intervention in all types of pain (Louw et al., 2016). Acupuncture is not recommended due to the potential for tissue trauma.
      Other complementary or integrative medicine techniques for pain management should be considered, including the use of biofeedback, therapy pools, therapeutic relaxation, auto-hypnosis, cognitive behavioral therapy, gentle massage/acupressure, and medicinal marijuana (where available). These therapies should be discussed with the treating physician to ensure that there are no adverse interactions with other medications or therapies, or contraindications for an individual patient. Also, procedures such as acupressure and gentle massage need to be performed in a way that does not increase the risks of trauma or inducing a flare. Please discuss with the primary care physician or local pain management team for referrals to a reputable complementary or integrative medicine practitioner.
      For those with more chronic pain management issues, a consultation with a pain management specialist may be helpful and is recommended.
      Medical Cannabis
      Anecdotal use of medical cannabis among patients with FOP is known to occur. This class of drugs is represented by a group of compounds derived from the subspecies of the plant genus Cannabis and delivered for potential beneficial effects through inhalation, swallowing, and topical application to skin or buccal mucosa. At the time of this writing, 33 U.S. states and the District of Columbia have programs authorizing cannabis use for specific medical conditions, with varying regulations in other countries. Most states allow its use for a variety of conditions, with those most related to FOP including cachexia/wasting syndrome, muscle spasticity, severe and chronic pain, and severe nausea (Belendiuk et al., 2015). In the U.S., clinicians do not prescribe medical cannabis but only certify for the condition that qualifies patients under state programs.
      The National Academies of Sciences, Engineering, and Medicine (NASEM) conducted a comprehensive review on the health effects of cannabis and cannabinoids (NASEM, 2017). The NASEM reported conclusive or substantial evidence that cannabis or cannabinoids are effective for chronic pain in adults, as anti-emetics, and for improvement of muscle spasticity. Chronic pain is the most common reason individuals use medical cannabis; however, its use needs to be part of a comprehensive symptom management strategy rather than a single modality for pain control, underscoring the importance of continuing other therapies. In this context, it is noteworthy that use of medical cannabis has been associated with significantly lower opioid overdose mortality rates (Bachhuber et al., 2014).
      Oral cannabis extracts from naturally occurring phytocannabinoids, orally administered Δ9Tetrahydrocannabinol (THC) and nabiximols (combination THC-cannabidiol [CBD]) are the usually administered forms, but synthetic cannabinoids are also available. Among the different preparations, evidence-based claims regarding clinical efficacy can only be made for smoked or vaporized plant flower, plant-derived oral THC, THC-CBD combinations, and synthetic THC. However, the NASEM noted that there is substantial evidence for an association between cannabis smoking and respiratory disease, motor vehicle collisions (MVCs), lower birth weight of offspring, and schizophrenia or other psychoses (NASEM, 2017). Caution should be exercised when considering medical cannabis for patients under the age of 25 years because brain development continues until this age, and the potential lasting impact of cannabis on cognitive performance is unknown (NASEM, 2017). Also, it is difficult to extrapolate available evidence on medical cannabis given the differences in products obtained from state-run programs due to horticultural techniques, drug extraction methods, and drug delivery modalities.
      References
      Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010 [published correction appears in JAMA Intern Med. 2014;174(11):1875]. JAMA Intern Med 174: 1668-1673, 2014
      Belendiuk KA, Baldini LL, Bonn-Miller MO. Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders. Addict Sci Clin Pract 2015; 10:10
      Blunk JA, Schmelz M, Zeck S, Skov P, Likar R, Koppert W. Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 98: 364-370, 2004
      Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14: 162, 2015
      Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc 90: 532, 2015
      Heard K, Green JL, Bailey JE, et al. A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol. Aliment Pharmacol Ther 26: 283, 2007
      Kan L, Kitterman JA, Procissi D, Chakkalakal S, Peng CY, McGuire TL, Goldsby RE, Pignolo RJ, Shore EM, Kaplan FS, Kessler JA. CNS demyelination in fibrodysplasia ossificans progressiva. J Neurol 259: 2644-2655, 2012
      Kan L, Lounev VY, Pignolo RJ, Duan L, Liu Y, Stock SR, McGuire TL, Lu B, Gerard NP, Shore EM, Kaplan FS, Kessler JA. Substance P signaling mediates BMP-dependent heterotopic ossification. J Cell Biochem 112: 2759-2772, 2011
      Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP). Bone 109: 115-119, 2018
      Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia ossificans progressiva (FOP). Best Practice & Research – Clinical Rheumatology 22: 191-205, 2008
      Louw A, Zimney K, Puentedura EJ, Diener I. The efficacy of pain neuroscience education on musculoskeletal pain: A systematic review of the literature. Physiother Theory Pract 32: 332-355, 2016
      Mantick N, Bachman E, Baujat G, Brown M, Collins O, De Cunto C, Delai P, Eekhoff M, Zum Felde R, Grogan DR, Haga N, Hsiao E, Kantanie S, Kaplan F, Keen R, Milosevic J, Morhart R, Pignolo R, Qian X, di Rocco M, Scott C, Sherman A, Wallace M, Williams N, Zhang K, Bogard B. The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 109: 285-290, 2018
      McCormack K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 59: 9, 1994
      National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press, 2017
      Peng K, Cheung K, Lee A, Sieberg C, Borsook D, Upadhyay J. Longitudinal evaluation of pain, flare-Up, and emotional health in fibrodysplasia ossificans progressiva: Analyses of the international FOP registry. JBMR Plus 2019 Mar 1;3(8):e10181.
      Peng K, Karunakaran KD, Labadie R, Veliu M, Cheung C, Lee A, Yu PB, Upadhyay J. Suppressed prefrontal cortex oscillations associate with clinical pain in fibrodysplasia ossificans progressiva. Orphanet J Rare Dis 2021 Jan 30;16(1):54.
      Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine 33:1766, 2008
      Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284: 1247, 2000
      Yu X, Ton AN, Niu Z, Morales BM, Chen J, Braz J, Lai MH, Barruet E, Liu H, Cheung K, Ali S, Chan T, Bigay K, Ho J, Nikolli I, Hansberry S, Wentworth K, Kriegstein A, Basbaum A, Hsiao EC. ACVR1activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans. Pain 164: 4358, 2023.

11. FOP的神经问题

FOP患者常报告神经症状。为了确定FOP患者中神经症状的流行率及其特征，国际FOP协会（IFOPA）对470名患者进行了全球调查，使用了一份关于神经症状的问卷。调查共收到168份回复（105名女性，63名男性；年龄范围1.5-68岁），来自30个国家，占IFOPA成员的36%。
其中86名（51%）患者报告了慢性神经症状。与普通人群相比，神经性疼痛（NP）的流行率显著增加（p < 0.001），在女性中比男性高出十倍（女性15%，男性1.6%）。在有神经性疼痛的患者中，94%报告了其他感觉异常。复发性严重头痛（HA）的流行率为26%，与普通人群相似，但FOP女性的流行率（36%）几乎是男性的四倍。神经性疼痛、头痛和其他感觉异常在青春期后的女性中显著更高；33%的女性报告症状在月经期间加重。23%的患者报告在FOP发作期间神经症状加重。三名FOP患者（1.8%）报告了肌阵挛，这一流行率远高于普通人群（p < 0.001）。这一全球调查表明，FOP患者中神经症状很常见。这些症状可能与BMP信号传导在中枢和/或外周神经系统的失调有关。在涉及FOP患者的IFOPA注册研究中也观察到了类似的发现。
为了进一步阐明这些非典型神经症状，评估了与FOP相关的两种BMP信号失调的小鼠模型，通过非侵入性磁共振成像（MRI）研究及组织学和免疫组化方法检测潜在的中枢神经系统病理。在一个模型中，BMP4在神经元特异性烯醇化酶启动子的控制下过表达；第二个模型是在ACVR1中的经典FOP突变的敲入。对四名FOP患者的MRI扫描进行了回顾性检查。在这两种小鼠模型中，一致观察到中枢神经系统的脱髓鞘病变和局部炎症变化，但在野生型对照组中没有发现。在四名检查的FOP患者中也发现了中枢神经系统的白质病变。
这些发现表明，BMP信号的失调扰乱了靶组织的正常稳态，包括中枢神经系统，其中局部脱髓鞘可能表现为FOP患者常见的神经症状。虽然大多数FOP患者的中枢神经系统病变是偶然发现的、无症状的且得到良好补偿，但一些严重FOP变异中一致的发育发现支持了BMP信号过度活跃可能对中枢神经系统的发育和修复产生影响的假设。
此外，研究表明，ACVR1基因在感受疼痛和刺激信号的神经元（痛觉感受器）中非常重要。携带ACVR1 R206H突变的人类诱导多能干细胞（iPSCs）在刺激下表现出增加的活性，这支持了FOP患者中神经性疼痛的临床发现。
总结来说，FOP患者报告了更高的神经问题发生率，包括在FOP发作期间和以外的疼痛。应仔细探讨疼痛的来源。患有神经性疼痛的患者可能会从某些药物类别中受益，如加巴喷丁和普瑞巴林——药物的适用性和选择应与患者的医生讨论。此外，经历慢性疼痛的FOP患者应考虑寻求临床疼痛管理团队进行评估和治疗。最后，一些FOP患者报告慢性头痛。如果头痛持续，患者应转诊至神经科医生，以获得详细评估和治疗建议。
参考文献
  1. Kan L, Kitterman JA, Procissi D, Chakkalakal S, Peng C-Y, McGuire TL, Goldsby RE, Pignolo RJ, Shore EM, Kaplan FS, Kessler JA. CNS demyelination in fibrodysplasia ossificans progressiva. J Neurol 259: 2644-2655, 2012 中枢神经系统的脱髓鞘在进行性骨化性纤维发育不良中的表现
  1. Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167A: 2265-2271, 2015 进行性骨化性纤维发育不良的严重变异（ACVR1c.772G>A; R258G）中的多系统受累：两例患者的报告
  1. Kitterman JA, Strober JB, Kan L, Rocke DM, Cali A, Peeper J, Snow J, Delai PLR, Morhart R, Pignolo RJ, Shore EM, Kaplan FS. Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. J Neurol 259: 2636-2643, 2012 进行性骨化性纤维发育不良患者的神经症状
  1. Severino M, Bertamino M, Tortora D, Morana G, Uccella S, Bocciardi R, Ravazzolo R, Rossi A, Di Rocco M. Novel asymptomatic CNS findings in patients with ACVR1/ALK2 mutations causing fibrodysplasia ossificans progressiva. J Med Genet 53: 859-864, 2016 ACVR1/ALK2突变引起的进行性骨化性纤维发育不良患者的新型无症状中枢神经系统发现
  1. Yu X, Ton AN, Niu Z, Morales BM, Chen J, Braz J, Lai MH, Barruet E, Liu H, Cheung K, Ali S, Chan T, Bigay K, Ho J, Nikolli I, Hansberry S, Wentworth K, Kriegstein A, Basbaum A, Hsiao EC. ACVR1activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans. Pain 164: 4358, 2023 ACVR1激活突变导致人类神经性疼痛和感觉神经元过度兴奋
原文
  1. Neurological Issues in FOP
      2. Neurological symptoms are commonly reported by patients with FOP. To determine the prevalence of neurological symptoms and their characteristics in individuals with FOP, a worldwide survey was conducted of the 470 patient members of the International FOP Association (IFOPA) using a questionnaire about neurological symptoms. There were 168 responses (105 females, 63 males; age 1.5-68 years) from 30 countries representing 36% of IFOPA members.
      Chronic neurological symptoms were reported by 86 (51%). Prevalence of neuropathic pain (NP) was significantly increased (p < 0.001) compared to the general population, and tenfold more common in females (15%) than males (1.6 %). Of those with NP, 94 % reported other sensory abnormalities. Prevalence of recurrent severe headaches (HA) (26 %) was similar to that in the general population, but prevalence in females with FOP (36%) was almost fourfold greater than in males. Prevalence of NP, HA, and other sensory abnormalities was substantially higher in post-pubertal females; 33 % reported symptoms worsened during menstrual periods. Worsening of neurological symptoms during FOP flare-ups was reported by 23%. Three patients with FOP (1.8%) reported myoclonus, prevalence much greater than reported in the general population (p < 0.001). This worldwide survey indicated that neurological symptoms are common in FOP. These symptoms are plausibly related to dysregulated BMP signaling in the central and/or peripheral nervous systems (Kitterman et al., 2012). Similar findings were present in a study involving patients with FOP who were enrolled in the IFOPA Registry (Yu, et al., 2023).
      To further elucidate these atypical neurologic symptoms, two mouse models of dysregulated BMP signaling relevant to FOP were evaluated for potential CNS pathology through non-invasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 was over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of the classic FOP mutation in ACVR1. MRI scans of four FOP patients were retrospectively examined. Demyelinated lesions and focal inflammatory changes of the CNS in both mouse models were consistently observed but not in wild-type controls. CNS white matter lesions were also found in each of the four FOP patients examined.
      These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP (Kan et al., 2012). While most CNS lesions in FOP patients are incidental, asymptomatic and wellcompensated, consistent developmental findings in the CNS in some of the severe FOP variants support the hypothesis that over-activity of BMP signaling may have consequences for development and repair of the CNS (Kaplan et al., 2015; Severino et al., 2016).
      In addition, studies have shown that the ACVR1 gene is important in nociceptors (cells that sensing pain and irritant signals). Human induced pluripotent stem cells (iPSCs) carrying the ACVR1 R206H mutation showed increased activity in response to irritant stimuli, supporting the clinical finding of nociceptive pain in patients with FOP.
      Practically and in summary, patients with FOP have reported a higher incidence of neurological concerns including pain both during and outside of an FOP flare-up. The sources of pain should be carefully explored. Patients having neuropathic pain may benefit from certain classes of medications, such as gabapentin and pregabalin – the appropriateness and choice of medications should be discussed with the patient’s physicians. In addition, patients with FOP who experience chronic pain should consider having a clinical pain management team for evaluation and treatment. Finally, some individuals with FOP report chronic headaches as noted above. If headaches persist, patients should be referred to a neurologist, who can make recommendations for detailed evaluation and treatment.
      References
      Kan L, Kitterman JA, Procissi D, Chakkalakal S, Peng C-Y, McGuire TL, Goldsby RE, Pignolo RJ, Shore EM, Kaplan FS, Kessler JA. CNS demyelination in fibrodysplasia ossificans progressiva. J Neurol 259: 2644-2655, 2012
      Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167A: 2265-2271, 2015
      Kitterman JA, Strober JB, Kan L, Rocke DM, Cali A, Peeper J, Snow J, Delai PLR, Morhart R, Pignolo RJ, Shore EM, Kaplan FS. Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. J Neurol 259: 2636-2643, 2012
      Severino M, Bertamino M, Tortora D, Morana G, Uccella S, Bocciardi R, Ravazzolo R, Rossi A, Di Rocco M. Novel asymptomatic CNS findings in patients with ACVR1/ALK2 mutations causing fibrodysplasia ossificans progressiva. J Med Genet 53: 859-864, 2016
      Yu X, Ton AN, Niu Z, Morales BM, Chen J, Braz J, Lai MH, Barruet E, Liu H, Cheung K, Ali S, Chan T, Bigay K, Ho J, Nikolli I, Hansberry S, Wentworth K, Kriegstein A, Basbaum A, Hsiao EC. ACVR1activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans. Pain 164: 4358, 2023

12. FOP的发育性关节病和退行性关节病

进行性骨化性纤维发育不良不仅是一种进行性异位骨化的疾病，还伴随着广泛且严重的发育性关节病及相关的退行性关节病。
在Towler及其同事的一项研究中，在所有年龄组中，轴骨和附肢骨骼中普遍存在发育性关节病的证据。关节的非对称性狭窄和软骨下硬化，作为退行性关节炎的放射学特征，在正常位置的骨骼关节中普遍存在。
FOP患者的髋关节常常畸形且发育不良。所有年龄组的FOP患者的髋关节和膝关节中，骨刺（骨赘）很常见。肋椎关节、脊柱的椎间关节以及近端胫腓关节经常出现部分或完全的关节内强直（融合），特别是在13岁之后。13岁之后，脊柱、骶髂关节和下肢的退行性关节表型尤为明显。
因此，相关的退行性关节病在多个部位发生，从青少年时期开始，并在一生中持续进展。这些表型似乎与异位骨形成无关，暗示ACVR1在退行性关节病的发展和进展中可能发挥作用。因此，ACVR1突变对FOP患者的正常骨骼的影响不仅限于大脚趾的畸形，还包括形态缺陷和发育性关节病。这些发现对于理解FOP的自然病史、治疗与FOP相关的关节炎（尤其是在青少年和成年期）以及设计和评估新兴治疗的临床试验具有重要意义。
参考文献
  1. Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 130: 115116, 2020 进行性骨化性纤维发育不良患者的骨骼畸形和发育性关节病
原文
  1. Developmental Arthropathy and Degenerative Joint Disease in FOP
      2. FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease.
      In a study by Towler and colleagues (Towler et al, 2020), widespread evidence of developmental arthropathy was found throughout the axial and appendicular skeleton in all age groups. Asymmetric narrowing and subchondral sclerosis, radiographic hallmarks of degenerative arthritis, were present throughout the joints of the normotopic skeleton.
      The hips of FOP patients were frequently malformed and dysplastic. Osteophytes (bone spurs) were common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints throughout the spine, and proximal tibio-fibular joints frequently showed partial or total intra-articular ankylosis (fusion), particularly after age 13. Degenerative joint phenotypes after age 13, were found particularly in the spine, sacroiliac joints, and lower limbs.
      Thus, associated degenerative joint disease occurs at multiple sites, starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease. Thus, the effects of ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. These findings have extraordinary relevance for understanding the natural history of FOP, for treating the arthritis associated with FOP throughout life (especially in adolescence and adulthood) and for designing and evaluating clinical trials with emerging therapeutics.
      References
      Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 130: 115116, 2020

13. FOP的髋关节疼痛鉴别诊断

髋关节的急性发作是进行性骨化性纤维发育不良（FOP）中最令人担忧且致残的并发症之一。在一项最新研究中，对25名出现急性单侧髋关节疼痛的经典FOP患者进行了评估。所有25名患者的临床历史均怀疑为髋关节发作，并且对为期四天的高剂量口服泼尼松有良好反应。十名患者（40%）在停用泼尼松后七天内经历了疼痛和/或僵硬的反弹症状，随后都出现了异位骨化或受影响髋关节的活动度降低。而14名在口服泼尼松治疗后症状得到持续缓解的患者则没有出现异位骨化或活动度下降。
入院时的偶发放射学发现是多因素的，包括近端股骨的骨软骨瘤（18/25; 72%）、退行性关节炎（17/25; 68%）、发育性髋关节发育不良（15/25; 60%）、之前存在的异位骨化（12/25; 48%）、关节内滑膜骨软骨瘤（8/25; 32%）或通过既存异位骨的创伤性骨折（1/25; 4%）。发育性关节病理可能会干扰对FOP髋关节疼痛的临床评估。
怀疑髋关节发生易于骨化的发作时，最有用的检测方式是缺乏对短期口服泼尼松的持续反应。通过超声或磁共振成像评估软组织水肿显示出在识别易于骨化的发作方面的前景，值得在前瞻性研究中进一步分析；然而，平片X光能够可靠地识别与发作无关的髋关节疼痛的可能原因。有趣的是，在FOP患者中，大多数非手术治疗的骨折愈合时很少出现发作、活动受限或异位骨化。
参考文献
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP). Bone 109: 115-119, 2018 进行性骨化性纤维发育不良（FOP）中的急性单侧髋关节疼痛
  1. Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res 481: 2447-2458, 2023 大多数在进行性骨化性纤维发育不良患者中非手术治疗的骨折愈合时很少出现发作、异位骨化和活动丧失
原文
  1. Differential Diagnosis of Hip Pain in FOP
      2. Flare-ups of the hips are among the most feared and disabling complications of FOP. In a recent study (Kaplan et al, 2018), 25 consecutive individuals with classic FOP who presented with acute unilateral hip pain were evaluated. All 25 individuals were suspected of having a flare-up of the hip based on clinical history and a favorable response to a four-day course of high-dose oral prednisone. Ten individuals (40%) experienced rebound symptoms of pain and/or stiffness within seven days after discontinuation of prednisone and all ten subsequently developed HO or decreased mobility of the affected hip. None of the 14 individuals who experienced sustained relief of symptoms following a course of oral prednisone experienced HO or decreased mobility.
      Incidental radiographic findings at the time of presentation were multifactorial and included osteochondromas of the proximal femur (18/25; 72%), degenerative arthritis (17/25; 68%), developmental hip dysplasia (15/25; 60%), previously existing HO (12/25; 48%), intra-articular synovial osteochondromatosis (8/25; 32%) or traumatic fractures through pre-existing heterotopic bone (1/25; 4%). Developmental joint pathology may confound clinical evaluation of hip pain in FOP.
      The most useful modality for suspecting an ossification-prone flare-up of the hip was lack of sustained response to a brief course of oral prednisone. Evaluation of soft tissue edema by ultrasound or magnetic resonance imaging showed promise in identifying ossification-prone flare-ups and warrants further analysis in prospective studies; however, plain radiographs were able to reliably identify the likely causes of hip pain unrelated to flare-up. Interestingly, most fractures treated nonoperatively in individuals with FOP heal with few flareups, impaired mobility, or heterotopic ossification (Lindborg et al., 2023).
      References
      Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP). Bone 109: 115-119, 2018
      Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res 481: 2447-2458, 2023

14. FOP的肢体肿胀

进行性骨化性纤维发育不良（FOP）患者常常出现肢体肿胀的问题，但关于这种并发症的了解较少。在一项已发表的研究中，详细回顾了大量FOP患者的病历，以确定肢体肿胀的流行率和自然历史。几乎所有病例的急性肢体肿胀与该疾病的发作相关。上肢的急性肿胀通常呈局部和结节状，而下肢的急性肿胀则更为弥漫。组织病理学评估中观察到的强烈血管生成和水肿可能在肢体肿胀的发病机制中起着作用。此外，肢体的近端病变可能导致远端淋巴引流的机械性阻塞，从而加重肿胀。
急性FOP发作时出现的急性和往往严重的肢体肿胀归因于早期FOP病变中可见的强烈炎症、血管生成和毛细血管渗漏。与急性FOP发作相关的肢体肿胀可能会增长到异常且令人担忧的大小，导致神经和组织淋巴管的血管外压迫。下肢出现如此大规模的急性肿胀可能引发对深静脉血栓症的严重担忧。
大规模的组织水肿可能在急性肿胀开始后的3-6个月内持续。随着纤维软骨组织逐渐成熟为软骨骨组织，最终转变为骨，肿胀会减轻。在接下来的六个月内，肿胀可能缓慢回退或持续存在为慢性肢体肿胀。随着下肢的骨骼肌被异位骨取代，正常的肌肉泵动作用消失，进一步加剧淋巴淤滞和依赖性水肿。关节的逐步强直不可避免地继续进行，导致活动能力下降，进一步增加静脉和淋巴淤滞及依赖性水肿。
当淋巴水肿发生时，避免感染和淋巴水肿-蜂窝织炎-淋巴水肿的恶性循环至关重要。与淋巴水肿相关的链球菌性蜂窝织炎可能会表现出严重的症状和发病率。对受影响肢体的预防性皮肤护理，以防止溃疡、皮炎、软化和足癣，也对减少微生物进入途径很重要。蜂窝织炎的发作可能损害淋巴系统，并使其更易复发。
一些患有晚期FOP的下肢患者除了淋巴水肿外，还可能有静脉淤滞。由于先前的发作导致的严重畸形和关节强直，排除深静脉血栓症的确切研究可能难以获得和解读。决定给患者使用抗凝药物时，应有充足的深静脉血栓症证据。在FOP患者中，急性上肢肿胀的鉴别诊断并不如急性下肢肿胀的鉴别诊断那么困难。目前尚无法解释FOP病变的区域外观差异，但这可能与影响腱膜和筋膜平面的机械因素有关。
在FOP患者中，肢体肿胀往往难以有效治疗。非甾体抗炎药和糖皮质激素通常没有效果。大多数患者对支撑袜的耐受性差，而由于主要关节的强直，抬高受影响肢体往往是不可能的。在能够耐受的情况下，支撑袜可能有帮助。气动压缩装置的使用尚未经过评估。此外，许多人报告在淋巴水肿门诊治疗后有偶然的有益效果。
淋巴水肿治疗有两种不同类型。Vodder方法在门诊中最为常用，而Chikly方法则涉及“映射”淋巴流动，并可能利用替代通路重新引导淋巴流动，对于那些异位骨和/或持续发作可能干扰正常淋巴流动渠道的FOP患者来说可能更有用。淋巴水肿门诊还可以为患者提供控制淋巴水肿的资源，强烈推荐。
参考文献
  1. Al Niaimi F, Cox N. Cellulitis and lymphoedema: A vicious cycle. J Lymphoedema 4: 38-42, 2009 蜂窝织炎与淋巴水肿：恶性循环
  1. Chikly, BJ. Manual techniques addressing the lymphatic system: origins and development. J Am Osteopathic Association 105: 457-464, 2005 针对淋巴系统的手法技术：起源与发展
  1. Chikly, BJ. Lymph Drainage Therapy (LDT) Manual Lymphatic Mapping and its Clinical Applications to Lymphedema. The National Lymphedema Network (NLN) Publication 12(3), 2000 淋巴引流疗法（LDT）手动淋巴映射及其在淋巴水肿中的临床应用
  1. Moriatis JM, Gannon FH, Shore EM, Bilker W, Zasloff M, Kaplan FS. Limb swelling in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 336: 247-253, 1997 进行性骨化性纤维发育不良患者的肢体肿胀
原文
  1. Limb Swelling in FOP
      2. Limb swelling is a common problem in patients who have FOP, yet little is known about this complication. In a published study, detailed medical records were reviewed on a large group of FOP patients to determine the prevalence and natural history of limb swelling (Moriatis et al., 1997). Acute swelling of the limbs occurred in association with flare-ups of the condition in nearly all cases. Acute swelling in the upper limbs was focal and nodular in contrast to acute swelling in the lower limbs, which was more diffuse. The intense angiogenesis and edema seen on histopathologic evaluation of preosseous FOP lesions may play a role in the pathogenesis of the limb swelling. In addition, proximal lesions in the limb may cause a mechanical blockage of distal limb lymphatic drainage thus exacerbating the swelling.
      The acute and often severe limb swelling seen with acute flare-ups of FOP is ascribed to the intense inflammation, angiogenesis and capillary leakage demonstrable in the early FOP lesions. Limb swelling associated with an acute FOP flare-up may grow to extraordinary and alarming size and lead to extravascular compression of nerves and tissue lymphatics. The appearance of such massive acute swelling in the lower limbs can provoke serious considerations of a deep vein thrombosis.
      Massive tissue edema may last for 3-6 months after the onset of acute swelling. As fibrocartilaginous tissue matures into chondro-osseous tissue and finally into bone, swelling diminishes. During the following six months, swelling may regress slowly or may persist as chronic limb swelling. As skeletal muscle in the lower limbs is replaced by heterotopic bone, the normal pumping action of the muscle is lost, further exacerbating lymphatic stasis and dependent edema. Progressive ankylosis of the joints continues inexorably and loss of mobility ensues, further increasing venous and lymphatic stasis and dependent edema (Moriatis et al., 1997).
      When lymphedema occurs, it is critical to avoid infections and the vicious cycle of lymphedema-cellulitislymphedema. Streptococcal cellulitis associated with lymphedema can be aggressive with severe symptoms and morbidity. Prophylactic skin care of the affected limb in preventing ulcers, dermatitis, macerations and tinea pedis is also important in reducing the portal of entry for micro-organisms. Episodes of cellulitis can damage the lymphatic system and predispose to recurrent episodes of cellulitis (Al Niaimi & Cox, 2009).
      Some patients who have advanced FOP involving the lower limbs have venous stasis in addition to lymphedema. Definitive studies to exclude deep vein thrombosis may be difficult to obtain and interpret due to severe existing deformity and joint ankylosis from previous flare-ups. A decision to anticoagulate a patient should not be made without substantial evidence of deep vein thrombosis. The differential diagnosis of acute upper limb swelling is not nearly as difficult as is the differential diagnosis of acute lower limb swelling in patients who have FOP. Differences in the regional appearance of the FOP lesions cannot be explained at the present time but may be due to mechanical factors affecting aponeuroses and fascial planes (Moriatis et al., 1997).
      Limb swelling is often difficult to treat effectively in patients who have FOP. Non-steroidal antiinflammatory medications and glucocorticoids generally have not been effective. Support stockings are poorly tolerated by most patients, and elevation of the affected limbs is often impossible because of ankylosis of the major joints, especially later in the disease process. When tolerated, support stockings may be helpful. The use of pneumatic compression devices has not been evaluated. Additionally, many have reported anecdotal beneficial effects following treatments at lymphedema clinics.
      There are two different types of lymphedema therapy. The Vodder method is most often used in clinics, though the Chikly method, which involves “mapping” the lymph flow and potentially using alternate pathways to reroute the lymph flow, may be more useful for FOP patients for whom HO and/or on-going flare-ups may interfere with the normal channels of lymph flow (Chikly et al., 2000; Chikly et al., 2005). Lymphedema clinics can also provide patients with resources to help control lymphedema and are highly recommended.
      References
      Al Niaimi F, Cox N. Cellulitis and lymphoedema: A vicious cycle. J Lymphoedema 4: 38-42, 2009
      Chikly, BJ. Manual techniques addressing the lymphatic system: origins and development. J Am Osteopathic Association 105: 457-464, 2005
      Chikly, BJ. Lymph Drainage Therapy (LDT) Manual Lymphatic Mapping and its Clinical Applications to Lymphedema. The National Lymphedema Network (NLN) Publication 12(3), 2000
      Moriatis JM, Gannon FH, Shore EM, Bilker W, Zasloff M, Kaplan FS. Limb swelling in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 336: 247-253, 1997

15. FOP患者的压疮

在进行性骨化性纤维发育不良（FOP）患者中，皮肤破损和压疮是常见且令人困扰的问题。皮肤破损可能是由于在正常或异位骨上的压力增加所致。
压疮可能突然发生，快速恶化且难以治疗。预防措施包括：
  • 足够的营养
  • 每日皮肤检查
  • 经常变换姿势
  • 使用减压床垫或床铺
  • 使用减压敷料或垫子。如果在皮肤发红但没有开放性伤口的早期阶段发现压疮，治疗会容易得多。涉及开放性伤口的压疮则需要更多的护理。
一旦发现问题，遵循以下建议：
  • 经常变换位置，并使用专门设计的减压垫。
  • 保持该区域清洁以防感染。I期伤口（无开放性皮肤）可以用温水和温和肥皂轻轻清洗。更严重的情况应使用生理盐水清洗，生理盐水可在药店购买。避免使用如过氧化氢或碘酒等抗菌剂，这些可能会损伤皮肤并延迟愈合。
  • 特别注意皮肤褶皱处，保持干燥。这些区域对FOP患者尤其困难，因为空气流通较少。保持这些区域干燥非常重要，使用薄的超细纤维毛巾等简单措施会有帮助。
  • 使用能保护伤口并促进愈合的特殊敷料。常见品牌包括Tegaderm和Duoderm。这些敷料有助于保持伤口湿润（促进细胞生长），同时保持周围组织干燥。它们不应用于可能感染的病变上。
  • 温泉浴可以帮助保持皮肤清洁，自然去除死组织。
  • 如有必要，可以去除受损的组织。伤口需无死组织和/或感染组织才能正确愈合。即使在FOP中，也有几种安全的方法可以做到这一点。
  • 在绝对必要时，可以在皮质类固醇覆盖下去除穿透骨。
  • 与伤口护理团队的协调非常重要。
参考文献
  1. Boyko TV, Longaker MT, Yang GP. Review of the Current Management of Pressure Ulcers. Adv Wound Care 7: 57–67, 2018 现行压疮管理的综述
  1. Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: a systemic review. JAMA 296: 974-984, 2006 预防压疮：系统评价
原文
  1. Pressure Ulcers in FOP
      2. Skin breakdown and pressure sores are common and troublesome problems in individuals who have advanced FOP. Skin breakdown can occur from increased pressure over normotopic or heterotopic bone.
      Pressure ulcers can develop suddenly, progress rapidly, and be difficult to treat (Reddy et al., 2001; Boyko et al., 2018). Preventive measures include:
      • Adequate nutrition
      • Daily skin inspections
      • Frequent changes in position
      • Use of a pressure-reducing mattress or bed
      • Use of pressure-reducing dressings or cushions. If a pressure sore is detected at an early stage when the skin is erythematous but there is no open sore, it will be much easier to treat. Pressure sores involving open wounds require considerably more care.
      Follow these suggestions as soon as a problem is identified:
      • Change positions frequently and use special cushions designed to relieve pressure.
      • Keep the area clean to prevent infection. A stage I wound (no open skin) can be gently washed with water and mild soap. Anything more serious should be washed with saline (salt) solution, which can be obtained from a pharmacy. Avoid using antiseptics such as hydrogen peroxide or iodine which can damage the skin and delay healing.
      • Pay special attention to the folded areas of the skin and keep them free of moisture. These areas may be especially problematic for FOP patients when little air can circulate. Keeping these areas dry is very important and simple measures like the use of a thin microfiber washcloth can be helpful.
      • Use a special dressing/bandage that protects wounds and helps promote healing. Name brands include Tegaderm and Duoderm. These dressings help keep the wound moist (to promote cell growth) while keeping the surrounding tissue dry. They should not be used on lesions that might be infected.
      • Whirlpool baths can be helpful because they help keep the skin clean and naturally remove dead tissue.
      • If necessary, damaged tissue can be removed. A wound needs to be free of dead and/or infected tissue to heal properly. There are several ways that this can be done safely, even in FOP.
      • Perforating bone may be removed under corticosteroid coverage when absolutely necessary.
      • Coordination with a wound care team is important.
      References
      Boyko TV, Longaker MT, Yang GP. Review of the Current Management of Pressure Ulcers. Adv Wound Care 7: 57–67, 2018
      Reddy M, Gill SS, Rochon PA. Preventing pressure ulcers: a systemic review. JAMA 296: 974-984, 2006

16. 皮肤病与FOP

皮肤是人体最大的器官，常常反映系统性疾病及其后果，为诊断提供线索。多年来，医生和研究人员注意到进行性骨化性纤维发育不良（FOP）与一些皮肤、头发和指甲疾病之间的联系。尽管这些轶事性的皮肤病发现的许多方面将在未来研究中探讨，但可以大致将这些疾病分为四种主要类型：
  • 与FOP后果相关的皮肤病——如不动、身体姿势、血液循环不良。
  • 与药物使用相关的皮肤病（如泼尼松、非甾体抗炎药、止痛药和参与临床试验的药物）。
  • 与FOP本身相关的皮肤病——与基因突变和信号通路有关。
  • 对每个FOP个体独特的皮肤病——遗传、环境和/或职业因素。
与FOP后果相关的皮肤病
压疮是FOP患者常见的皮肤问题。异位骨可能会阻塞皮肤的血供并形成溃疡。重要的是通过缓冲易受压的骨突出部位，及时治疗发现的压疮，以避免此问题。
异位骨常常跨越关节，形成难以到达和清洁的身体褶皱，创造了发生成群性皮肤损伤及真菌和细菌感染的有利条件。医疗专业人员必须注意这些潜在情况，并尽量减少导致败血症的严重感染风险。
异位骨还可能导致血液和淋巴管的循环受限，造成供氧不足的皮肤变得干燥和湿疹样。建议避免热水淋浴、高温和含月桂基硫酸酯的肥皂。同时，建议使用皮肤保湿剂。应咨询皮肤科医生关于可能使用类固醇和抗生素的事宜。
一些晚期FOP患者在没有摩擦或创伤的情况下报告出现水疱。这可能是由于淋巴循环受限。如果淋巴压力升高，可能形成充满透明淋巴液的紧张水疱。
淋巴管的压迫也可能导致淋巴水肿，极端情况下可导致肢体的大象病伴随溃疡和疣状病变。超声检查有助于排除深静脉血栓。
与药物使用相关的皮肤病
皮肤、指甲和头发可能会受到某些药物的影响。虽然许多药物可能导致问题，但抗炎药和止痛药是最常见的罪魁祸首。FOP患者由于频繁使用止痛或抗炎药，出现皮疹或荨麻疹并不少见。药物反应可以表现为多形性红斑（皮肤和粘膜上的病变）、固定色素性红斑、荨麻疹、单形性痤疮或汗疱症等。
即使是短期使用泼尼松，也可能导致皮肤问题，包括痤疮、皮肤和头发变薄、面部潮红、多毛、妊娠纹或伤口愈合不良。一些正在临床试验中测试的药物也会对皮肤产生影响。帕洛维汀可能导致皮肤和粘膜干燥、类视黄醇性皮炎、嘴唇干裂以及易感染等。加瑞托珠单抗可能导致睫毛脱落、痤疮、毛囊炎、脓疱和脓肿等。
与FOP本身相关的皮肤病——与基因突变和信号通路有关
FOP不仅仅是一种骨病。基因突变如何影响各种身体系统仍然 largely unknown。皮肤表现及其与FOP的关联仍在研究中。然而，已经有一些常见特征被轶事性观察到：
发作。在FOP发作期间，受影响区域的皮肤可能会变得敏感、红肿或发热。当异位骨形成时，皮肤看起来光滑，触摸时感觉坚硬，并伴有脱发。避免与皮肤疾病如硬皮病混淆是重要的。在这里，我们再次强调大脚趾畸形和进行性异位骨化发展的诊断重要性，这些是经典FOP的标志性临床发现。
头皮结节。头皮结节可能在儿童期出现，通常会自发消失。
脱发。脱发偶尔被报告为FOP的症状，尤其是严重FOP变异体。患者还报告其他与头发相关的问题（眉毛稀疏、体毛减少和变轻等）。这些额外特征也可能是FOP未被充分报告的症状。
对昆虫叮咬的过敏反应。这可能与FOP中系统性肥大细胞反应性增加有关。
罕见的皮肤肿瘤。默克尔细胞癌（罕见、侵袭性、恶性原发性皮肤神经内分泌肿瘤）在某些FOP患者中偶尔被发现，可能与终身使用类固醇或日晒有关。
其他皮肤异常。某些FOP患者中还注意到其他皮肤异常，从皮肤色素沉着到与免疫相关的病症如脂溢性皮炎等。
显然，需要在更广泛的FOP群体中评估这些皮肤问题，以确定FOP中与皮肤相关疾病的流行率和风险。
对每个FOP个体独特的皮肤病——遗传、环境和/或职业因素
对FOP患者的皮肤评估需要谨慎和全面。尽管上述症状可能出现在FOP中，但它们的相对流行率仍不清楚。
参考文献
  1. Blaszczyk M, Majewski S, Brzezinska-Wcislo L, Jablonska S. Fibrodysplasia ossificans progressiva. Eur J Dermatol 13: 234-237, 2003 进行性骨化性纤维发育不良
  1. Kang S, Masayuki A, Bruckner AL, Enk AH, Margolis DJ, McMichael AJ. Fitzpatrick's Dermatology, 9th edition, 2019 菲茨帕特里克皮肤病学，第9版
  1. McFarland GS, Robinowitz B, Say B. Fibrodysplasia ossificans progressive presenting as fibrous scalp nodules. Cleve Clin Q 51: 549-552, 1984 进行性骨化性纤维发育不良以纤维性头皮结节呈现
  1. Moriatis JM, Gannon FH, Shore EM, Bilker W, Zasloff MA, Kaplan FS. Limb swelling in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 336: 247-253, 1997 进行性骨化性纤维发育不良患者的肢体肿胀
  1. Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016 进行性骨化性纤维发育不良发作的自然史：全面的全球评估.
  1. Pignolo RJ, Wang H, Kaplan FS. Fibrodysplasia ossificans progressiva: a segmental progeroid syndrome. Frontiers in Endocrinology 10 (Article 908): 1-8, 2020 进行性骨化性纤维发育不良：一种分段性早衰综合症
原文
  1. Dermatology & FOP
      2. The skin is the largest organ of the human body, and often reflects systemic diseases and their consequences, providing clues to diagnosis. Over many years, doctors and researchers have noticed a connection between FOP and some skin, hair, and nail conditions. Although many aspects of these anecdotal dermatologic findings will be the subjects of future studies, it is possible to state that these conditions can be roughly divided in 4 main types:
      • Dermatologic conditions related to a consequence of FOP – immobility, position of the body, poor blood circulation.
      • Dermatologic conditions related to the use of drugs (prednisone, NSAIDs, analgesics, and drugs involved in clinical trials).
      • Dermatologic conditions related to FOP itself – linked to the genetic mutation and signaling pathway.
      • Dermatologic conditions unique to each individual with FOP – genetic, environmental, and/or occupational.
      Dermatologic conditions related to a consequence of FOP
      Pressure ulcers are a common skin problem that is often seen in individuals with FOP. Heterotopic bone can occlude the blood supply to the skin and create an ulcer. It is important to avoid this problem by cushioning vulnerable bony prominences and treating pressure ulcers as soon as they are found.
      Heterotopic bone often crosses joints, creating body folds that are exceedingly difficult to reach and clean, creating fertile fields for the development of intertriginous lesions, as well as fungal and bacterial infections. Health care professionals must be aware of these possible conditions and minimize the risk of serious infections that can lead to sepsis (Kang et al., 2019).
      Heterotopic bone can also lead to compromised circulation as the compression of blood and lymphatic vessels creates poorly oxygenated skin that becomes dry and eczematous. Avoiding hot showers, hot temperatures, and soaps containing lauryl sulfates is recommended. Also, skin moisturizers are recommended. A dermatologist should be consulted about the possible use of steroids and antibiotics (Kang et al., 2019).
      Some patients with advanced FOP have reported blisters in the absence of friction or trauma. This may occur from compromised lymphatic circulation. If lymphatic pressure is elevated, tense blisters containing transparent lymphatic fluid may form.
      The compression of lymphatic vessels can also be the cause of lymphedema and in extreme cases elephantiasis of the limb with ulcers and verrucous lesions. An ultrasound examination can help to rule out deep venous thrombosis (Moriatis et al., 1997).
      Dermatologic conditions related to the use of medications
      Skin, nails, and hair can be affected by the use of certain medications. Many medications can be implicated, but anti-inflammatories and analgesics are the most common culprits. It is not uncommon that FOP patients have skin rashes or hives due to the frequent use of drugs for pain relief or inflammation. Reactions to drugs can manifest as polymorphic erythema (with lesions on the skin and mucous membranes), fixed pigmented erythema, urticaria (hives), monomorphic acne or dyshidrosis, among others (Kang et al., 2019).
      The use of prednisone, even for short periods of time, can also cause skin issues that include acne, skin and hair thinning, facial erythema, hirsutism, stria, or impaired wound healing. Some medications that are being tested in clinical trials also have influences on the skin. Palovarotene can cause dryness of the skin and mucous membranes, retinoid dermatitis, dry lips, and tendency to skin infections, among others. Garetosmab can cause madarosis, acne, folliculitis, furunculus, carbuncles and abscesses.
      Dermatologic conditions related to FOP itself – linked to the genetic mutation and signaling pathway
      FOP is not just a bone disease. The way in which the genetic mutation affects the various body systems is still largely unknown. Dermatologic manifestations and their ties to FOP are still being investigated. However, some common features have been anecdotally observed:
      Flare-ups. During FOP flare-ups, the skin over the affected area may be tender, erythematous or warm (Pignolo et al., 2016). When heterotopic bone has formed, the skin can look glossy and feel hard upon touch, with loss of hair. It is important to avoid confusion with dermatologic diseases such as scleroderma, among others. Here again, we stress the diagnostic importance of the malformation of the great toes and the development of the progressive heterotopic ossification – signature clinical findings of classic FOP (Blaszczyk et al., 2003).
      Scalp nodules. Scalp nodules may appear during childhood. They usually disappear spontaneously (McFarland et al., 1984).
      Hair loss. Hair loss has occasionally been reported as a symptom of FOP, especially with severe FOP variants. Patients also report other hair-related issues (sparse eyebrows, less and lighter body hair. etc.).These additional features may also be under-reported symptoms of FOP (Pignolo et al., 2020).
      Hypersensitivity to insect bites. This may be related to increased systemic mast cell reactivity in FOP (Pignolo et al., 2020).
      Rare skin tumors. Merkel cell carcinoma (rare, aggressive, malignant primary cutaneous neuroendocrine tumor) has been noted rarely in some FOP patients – possibly related to lifelong corticosteroid use or sun exposure (Kang et al., 2019).
      Other skin abnormalities. Other skin abnormalities ranging from skin discoloration to immune-related conditions such as seborrheic dermatitis have been noted in some FOP patients.
      Clearly, there is a tremendous need to evaluate these dermatologic issues in the wider FOP community in order to determine the prevalence and risk of skin-related conditions in FOP.
      Dermatologic conditions unique to each individual with FOP – genetic, environmental, and/or Occupational
      Dermatological evaluation of a patient with FOP needs to be careful and comprehensive. Although the items above may be noted in FOP, their relative prevalence is unknown.
      References
      Blaszczyk M, Majewski S, Brzezinska-Wcislo L, Jablonska S. Fibrodysplasia ossificans progressiva. Eur J Dermatol 13: 234-237, 2003
      Kang S, Masayuki A, Bruckner AL, Enk AH, Margolis DJ, McMichael AJ. Fitzpatrick's Dermatology, 9th edition, 2019
      McFarland GS, Robinowitz B, Say B. Fibrodysplasia ossificans progressive presenting as fibrous scalp nodules. Cleve Clin Q 51: 549-552, 1984
      Moriatis JM, Gannon FH, Shore EM, Bilker W, Zasloff MA, Kaplan FS. Limb swelling in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 336: 247-253, 1997
      Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016
      Pignolo RJ, Wang H, Kaplan FS. Fibrodysplasia ossificans progressiva: a segmental progeroid syndrome. Frontiers in Endocrinology 10 (Article 908): 1-8, 2020

17. FOP的趾甲内生（嵌甲）

嵌甲，尤其是大脚趾的嵌甲，在进行性骨化性纤维发育不良（FOP）患者中很常见。 由于先天性足部和指甲畸形、趾尖行走的压力、不当修剪指甲、不合脚的鞋子以及使用视黄醇类药物，FOP患者更容易出现嵌甲。嵌甲可能导致疼痛、不适，甚至使患者无法承重受影响的足部，同时增加感染的风险。
预防嵌甲的方法包括以90度角修剪指甲（并且不要剪得太短；指甲必须在甲床上方）以及减轻趾部的压力（使用合适的鞋子）。
甲真菌病是一种常见的指甲真菌感染，可能导致嵌甲。免疫系统减弱（使用类固醇）、外伤和循环问题都可能促使真菌进入指甲。可以观察到指甲的颜色变化和增厚，指甲可能变形并嵌入。对嵌甲的治疗通常是在皮肤科医生的指导下使用抗真菌药物。
根据严重程度，可能需要对嵌甲进行各种干预。对于轻微疼痛和轻度炎症的症状，非侵入性程序如更换鞋子、温水浸泡、使用抗菌剂和非处方局部抗生素（如百多邦和多粘菌素B软膏）可能就足够了。口服抗生素用于治疗继发的细菌感染。在更严重的情况下，可能需要转诊给皮肤科医生或伤口专家。在某些情况下，已安全地对FOP患者进行趾甲周围肉芽组织的电灼切除。
原文
  1. Ingrown Toenails in FOP
      2. Ingrown toenails, especially of the big toe, are common with people living with FOP. Patients with FOP are predisposed to ingrown toenail due to congenital foot and nail malformations, pressure from toe walking, improper nail trimming, poorly fitting shoes and retinoid medications. Ingrown toenails can lead to pain, discomfort and inability to bear weight on the affected foot as well as to an increased risk of infection.
      Prevention of ingrown toenails includes cutting the nail at a 90 degree angle to the toe (and never too short; the nail must be above the nail bed) and removing pressure on the toe (using appropriate shoes).
      Onychomycosis is a common fungal infection of the nail that can cause ingrown nails. Weakened immune system (use of steroids), trauma, and circulatory issues can facilitate the entrance of fungus into the nail. It is possible to observe changes in color and thickening of the nail that can be deformed and ingrown. The treatment for ingrown nails is antifungal drugs under the direction of a dermatologist.
      Depending on the severity, various interventions might be necessary for ingrown toenail. For symptoms of mild pain and minimal inflammation, noninvasive procedures like changes in shoes, warm water soaks, antiseptics and over-the-counter topical antibiotics (like Bacitracin and Polymyxin B creams) might suffice. Oral antibiotics are used to treat superimposed bacterial infections. In more severe cases, referral to a dermatologist/wound specialist is warranted. In certain instances, removal of granulomatous tissue around the toenail by cauterization has been performed safely in FOP patients.

18. FOP的骨折

FOP患者由于跌倒风险增加、活动能力降低以及使用泼尼松而更容易发生正常骨和异位骨的骨折。已在美国、加拿大和澳大利亚获批的Palovarotene（SOHONOS）也被显示可降低骨密度，可能与骨折风险增加相关（SOHONOS处方信息）。
在FOP中，骨折可发生在正常骨和异位骨。异位骨的骨折常见且愈合迅速。抬高、休息、夹板固定以及局部冰敷通常对控制疼痛和肿胀有帮助，如有需要可补充急性使用麻醉性镇痛药。正常骨的骨折需谨慎评估，处理方式与其他患者相同。大多数骨折采用闭合复位和夹板固定即可。开放复位或内部固定很少必要，且可能导致异位骨化的快速发生。在骨质疏松的情况下，愈合可能会延迟。
在一项回顾性研究中调查了非手术治疗骨折后FOP的发作、异位骨化形成和运动能力丧失的程度。研究者提出了以下问题：（1）骨折中有多少比例的影像学证据表明骨痂形成或不愈合？（2）因骨折而出现FOP发作的临床症状患者占多少比例？（3）多少比例的骨折出现异位骨化的影像学证据？（4）多少比例的患者在骨折后失去运动能力？
研究者对31名患者（13名男性，18名女性；年龄范围5至57岁，中位年龄22岁）进行回顾性分析，这些患者在20年期间共发生了41例正常骨的骨折，均为非手术治疗，并在骨折后至少随访18个月，最长可达20年。每位患者的临床记录由相关医师审查，并记录了每个骨折的以下数据：生物性别、ACVR1基因致病变异、骨折时年龄、骨折机制、骨折部位、初始治疗方式、骨折时的泼尼松使用情况（根据FOP治疗指南进行发作预防）、患者在骨折后的发作情况、随访的骨折影像（如可用）、骨折后至少6周确定的异位骨化形成情况以及患者报告的运动丧失。25名患者中有76%（31例中的41例）提供了骨折后的影像资料。
在事件发生后6周，97%（30/31）骨折的影像学愈合得到确认。一名患者发生了位移性髌骨骨折和异位骨化，且为无痛不愈合。三名患者（7%；3/41）在骨折固定后的几天内报告了骨折部位或附近的疼痛和/或肿胀，可能指示特定部位的FOP发作。这三名患者在骨折一年后与骨折前状态相比报告了残余的运动丧失。随访影像中10%（3/31）的骨折发生了异位骨化。患者报告的运动丧失在骨折中出现的比例为10%（4/41）。其中两名患者报告了明显的运动丧失，而另两名患者则报告关节完全固定（关节强直）。
大多数FOP患者的非手术治疗骨折愈合时发作和异位骨化的发生率很低，且运动能力得以保留，这表明骨折修复与异位骨化之间存在脱钩，后者是由炎症诱导的两种软骨内骨化过程。这些发现强调了考虑FOP患者骨折的非手术治疗的重要性。由于骨畸形和异位骨化，评估FOP患者的骨密度和骨质量具有挑战性。在骨折愈合后，对于发生低创伤/脆性骨折的患者应考虑使用双膦酸盐治疗。值得注意的是，一名髋关节骨折患者在使用Palovarotene治疗后仍然发展出异位骨化，尽管目前尚不清楚Palovarotene治疗是否降低了异位骨化的程度。
参考文献
  1. Einhorn TA, Kaplan FS. Traumatic fractures of heterotopic bone in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 308: 173-177, 1994 进行性骨化性纤维发育不良患者的异位骨创伤性骨折
  1. Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res 481: 2447-2458, 2023 大多数进行性骨化性纤维发育不良患者的非手术治疗骨折愈合时发作、异位骨化和运动丧失的发生率很低
  1. Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016 FOP急性发作的自然病史：一项综合性全球评估
  1. Singh S, Kidane J, Wentworth KL, Motamedi D, Morshed S, Schober AE, Hsiao EC. Surgical management of bilateral hip fractures in a patient with fibrodysplasia ossificans progressiva treated with the RAR-γ agonist palovarotene: a case report. BMC Musculoskelet Disord 2020 Apr 3;21(1):204 进行性骨化性纤维发育不良患者双侧髋关节骨折的外科管理，使用RAR-γ激动剂Palovarotene治疗：病例报告
原文
  1. Fractures in FOP
      2. Individuals with FOP are at increased risk of fractures of both the normotopic and heterotopic skeleton due to the increased risk of falls, immobility and prednisone use. Palovarotene (SOHONOS), approved in USA, Canada, and Australia has also been shown to decrease bone mineral density and could be associated with increased risk of fractures (SOHONOS prescribing information).
      In FOP, fractures can occur in both normotopic and heterotopic bone (Pignolo et al., 2016). Fractures of heterotopic bone occur commonly and heal rapidly (Einhorn & Kaplan, 1994). Elevation, rest, splinting, and local application of ice are often helpful in controlling pain and swelling and may be supplemented by acute use of narcotic analgesia, if needed. Fractures of normotopic bone need to be carefully evaluated, as in any patient. Closed reduction and splinting is sufficient for most fractures. Open reduction or internal fixation is rarely warranted and can lead to rapid onset of HO. Healing may be delayed in osteoporotic bone.
      In a retrospective study, Kaplan et al. (2023) examined the extent to which non-operative treatment of a fracture leads to an FOP flare-up, HO formation and loss of mobility. The authors asked: (1) What proportion of the fractures had radiographic evidence of union or nonunion (2) What proportion of patients had clinical symptoms of an FOP flare-up because of the fracture? (3) What proportion of fractures developed radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture?
      The authors retrospectively analyzed 31 patients (13 males, 18 females; ages 5 to 57 years, median age 22 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively from five continents over a 20-year period and followed for a minimum of 18 months after the fracture and for as long as 20 years. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention, patient-reported flare-ups after the fracture, follow-up radiographs of the fracture if available, HO formation as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients.
      Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. A painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. Three patients [7%; (3 of 41) of fractures] reported increased pain and/or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flare-up. The same three patients reported a residual loss of motion one year after the fracture compared with their prefracture status. Ten percent (Three of 31) of the fractures for which follow-up radiographs were available developed HO. Patient-reported loss of motion occurred in 10% (4 of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosed).
      Most fractures treated nonoperatively in individuals with FOP healed with a paucity of flare-ups and HO and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering non-operative treatment for fractures in individuals with FOP. Bone mineral density and bone quality evaluation in FOP is challenging due to bone deformity and HO. Consider bisphosphonate treatment in patients who have sustained a low trauma/fragility fracture after the fracture has healed. Notably, on patient with hip fracture treated with palovarotene still developed HO, although it is unclear if the amount of HO was lowered due to palovarotene treatment (Singh et al., 2020).
      References
      Einhorn TA, Kaplan FS. Traumatic fractures of heterotopic bone in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 308: 173-177, 1994
      Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, De Cunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility. Clin Orthop Relat Res 481: 2447-2458, 2023
      Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016
      Singh S, Kidane J, Wentworth KL, Motamedi D, Morshed S, Schober AE, Hsiao EC. Surgical management of bilateral hip fractures in a patient with fibrodysplasia ossificans progressiva treated with the RAR-γ agonist palovarotene: a case report. BMC Musculoskelet Disord 2020 Apr 3;21(1):204

19. FOP的颞下颌关节半脱位

由于关节畸形，FOP患者可能会常见半脱位。大多数半脱位是慢性的，从出生时就存在，例如大脚趾的跖趾关节常见半脱位。然而，有些可能会更急性。
颞下颌关节（TMJ）没有发作的迹象，且闭合突然，提示可能存在机械问题，如急性半脱位或下颌骨脱位，而不是发作。这可以通过CT扫描排除。FOP患者TMJ半脱位的关键历史线索是没有发作和闭合的突然性。尽管通常会感到疼痛，但在FOP中可能会减轻。我们现在知道，许多FOP关节存在不同程度的畸形，而不仅仅是大脚。下颌的发育异常尚未得到足够重视。
FOP患者的TMJ容易出现问题，这可能与上述发育异常有关。FOP的TMJ通常不正常形成， mandibular condyles常常扁平，关节盘（类似于膝盖）通常也畸形。我们很少要求FOP患者最大程度地张口，但如果要求的话，会发现他们的张口功能不正常。如果有良好的功能性开口，但未达到最大开口，则分配CAJIS为零。
如果TMJ没有半脱位或脱位且已经融合，不要强行张口。大多数患者适合吃多次小餐和泥状食物——这虽然不是理想的，但可以忍受。很少有患者需要鼻胃管，但那些需要的通常也能很好地适应。FOP患者的深覆盖咬合常常有助于进食。如有必要，可以拔掉后牙，以帮助牙齿的接触、进食和减少呕吐的恐惧。
参考文献
  1. Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan; 130:115116 进行性骨化性纤维发育不良患者的骨骼畸形和发育性关节病
原文
  1. Temporomandibular Subluxations in FOP
      2. Subluxations may be common in FOP due to joint malformations. Most are chronic and present from birth such as the common subluxation of the metatarsophalageal joint of the great toe. However, some may be more acute.
      The absence of temporomandibular joint (TMJ) flare-ups and the suddenness of closure suggests a mechanical problem such as acute subluxation or dislocation of the jaw – rather than a flare-up. This is relatively easy to rule out with a CT scan of the TMJ. The key historical clue to subluxation of the TMJ in FOP is the absence of flare-up and the suddenness of closure. It is often painful, but may be less so in FOP. We now know that many FOP joints are malformed to various degrees - not just the great toe (Towler et al., 2020). The developmental anomalies of the jaw have received very little attention.
      The TMJ in FOP patients is prone to develop problems. This may be due to developmental abnormalities as mentioned above. The TMJ in FOP does not form normally. The mandibular condyles are often flat and the menisci (similar to the knee) are often malformed. We rarely ask FOP patients to open their mouth maximally, but if we did, we would see that this does not occur normally. We assign a CAJIS of zero if there is good functional opening (but not maximal because we don’t test it).
      If the TMJ is not subluxed or dislocated and if it is fused, do not try to force it open. Most patients do well with multiple small meals and puréed foods - not ideal - but bearable. Very few need a naso-gastric tube, but those who do tend to tolerate it well. The overbite of FOP can often help with access to eating. If necessary, back teeth can be removed to help with dental access, eating, and fear of vomiting.
      References
      Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan; 130:115116

20. FOP的营养、钙和维生素D指南

FOP患者因多种因素（如胃肠问题、下颌关节强直、恶心和食欲不振）而面临较高的营养和维生素缺乏风险。
充足的营养对FOP患者尤为重要，以防止严重的体重减轻、上肠系膜动脉综合征和压疮。对于下颌关节强直的患者，建议转介营养师；在特殊情况下，患者可能需要使用喂食管。理想体重由于身高测量和BMI计算的不准确而难以确定，但我们建议监测体重，并在发现非自愿性体重减轻（6-12个月内超过5%的体重）时及时处理。
FOP患者可能也会有维生素缺乏，包括维生素D缺乏，尤其是当他们大部分时间待在室内时。钙的摄入也可能不足，因为有误解认为这会进一步加重异位骨化。
我们建议患者根据2011年医学研究所的指导，获得推荐的钙摄入量（RDA），即18-50岁成年人每天1000毫克元素钙。建议通过饮食（如牛奶、奶酪、酸奶或钙强化食品如橙汁和杏仁奶）来摄入钙，限制钙补充剂不超过每天600毫克。过量的钙摄入，特别是以补充剂形式，可能增加肾结石的风险，而FOP患者容易出现肾结石。同时，FOP患者保持适当的水分摄入也很重要，以避免肾结石。
我们还建议患者根据2011年医学研究所的指导，获得维生素D的RDA，即18-50岁成年人每天600个单位的维生素D3。建议测量血清25-OH-维生素D，并根据需要补充，以维持水平>20-30 ng/dl。血清中低水平的25-OH维生素D与骨软化症/佝偻病相关，可能增加正常骨折的风险。此外，低维生素D水平增加了在静脉给药双膦酸盐后低钙血症的风险。
参考文献
  1. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC. The National Academies Press, 2011 《钙和维生素D的膳食参考摄入量》
  1. Mantick N, Bachman E, Baujat G, Brown M, Collins O, De Cunto C, Delai P, Eekhoff M, Zum Felde R, Grogan DR, Haga N, Hsiao EC, Kantanie S, Kaplan FS, Keen R, Milosevic J, Morhart R, Pignolo RJ, Qian X, Di Rocco M, Scott C, Sherman A, Wallace M, Williams N, Zhang K, Bogard B. The FOP connection registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 109: 285-290, 2018 FOP连接注册：为进行性骨化性纤维发育不良设计的国际患者赞助注册
  1. Smith B, Hakim-Zargar M, Thomson J. Low body mass index: a risk factor for superior mesenteric artery syndrome in adolescents undergoing spinal fusion for scoliosis. J Spinal Disord Tech 22: 144-148, 2009 低体重指数：在接受脊柱融合术的青少年中是上肠系膜动脉综合征的风险因素
  1. Wong CJ. Involuntary weight loss. Med Clin North Am 98: 625-43, 2014 非自愿性体重减轻
原文
  1. Nutrition, Calcium & Vitamin D Guidelines in FOP
      2. Patients with FOP are at high risk of nutritional and vitamin deficiencies due to multiple factors, including but not limited to gastrointestinal issues, ankylosed jaw, nausea and poor appetite (Mantick et al., 2018).
      Adequate nutrition is especially important in FOP patients to prevent severe weight loss, Superior Mesenteric Artery (SMA) syndrome and pressure ulcers. For patients with an ankylosed jaw, we recommend referral to a nutritionist; in extenuating situations, patients might need a feeding tube. Ideal weight will be difficult to determine due to inaccurate height measurements and BMI calculation, but we recommend monitoring weight and addressing unintentional weight loss (>5% of weight over 6-12 months) as soon as it is noted (Wong et al., 2014).
      FOP patients can also have vitamin deficiencies, including vitamin D deficiency, especially if they spend most of their time indoors. Calcium intake could also be suboptimal due to the misconception that it could further worsen heterotopic ossification.
      We recommend that patients obtain the recommended dietary allowance (RDA) of calcium as per Institute of Medicine 2011 guidelines, which would be 1,000 mg of elemental calcium daily for adults, age 18-50 years old. We recommend that calcium intake be obtained using diet (example milk, cheese, yoghurt or food items fortified with calcium like orange juice and almond milk) and limit calcium supplements to no more than 600 mg daily. Excessive calcium intake, especially in the form of supplements, can increase the risk of kidney stones which patients with FOP are prone to develop. It is also important for patients with FOP to maintain adequate hydration to avoid kidney stones.
      We recommend that patients also obtain the RDA for vitamin D as per the Institute of Medicine 2011 guidelines, which would be 600 units of Vitamin D3 daily for adults, age 18-50 years old. We recommend measuring serum 25-OH-vitamin D and repleting as needed to maintain a level >20-30 ng/dl. Low 25-OHvitamin D levels in the serum are associated with osteomalacia/rickets that could lead to increased risk of normotopic bone fracture. In addition, low vitamin D levels increase the risk of hypocalcemia after administration of intravenous bisphosphonates.
      References
      Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC. The National Academies Press, 2011
      Mantick N, Bachman E, Baujat G, Brown M, Collins O, De Cunto C, Delai P, Eekhoff M, Zum Felde R, Grogan DR, Haga N, Hsiao EC, Kantanie S, Kaplan FS, Keen R, Milosevic J, Morhart R, Pignolo RJ, Qian X, Di Rocco M, Scott C, Sherman A, Wallace M, Williams N, Zhang K, Bogard B. The FOP connection registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 109: 285-290, 2018
      Smith B, Hakim-Zargar M, Thomson J. Low body mass index: a risk factor for superior mesenteric artery syndrome in adolescents undergoing spinal fusion for scoliosis. J Spinal Disord Tech 22: 144-148, 2009
      Wong CJ. Involuntary weight loss. Med Clin North Am 98: 625-43, 2014

21. FOP的预防性口腔保健

FOP患者的颞下颌关节（TMJ）存在发育异常。自发或创伤后颞下颌关节的强直在FOP中很常见，导致严重的残疾，使进食困难并影响口腔卫生。必须非常小心，以免引发TMJ的急性发作。咬肌的骨化导致最大口开度减小，而颧骨弓的骨化则导致最大口开度增大。因此，骨化的位置会影响口开度的程度。
在FOP患者中，管理任何形式的口腔疾病风险至关重要，特别是在儿童时期。预防龋齿或牙周病的发展对于避免长期的牙齿和口腔并发症至关重要。
建议所有FOP患者饮用氟化水。建议使用高剂量氟化牙膏（当个体能够吐出时），同时使用氟化凝胶和漱口水，以帮助预防需要修复的牙齿护理。无法吐出的儿童可以使用一米粒大小的普通氟化牙膏。
频繁的牙线清洁和刷牙对FOP患者是必要的，但随着FOP进展，由于开口受限，可能会变得困难。使用小头的超声波、电动或电池供电牙刷、水牙线和牙线棒可能有助于口腔卫生。如果建议使用这些工具，请咨询您的口腔健康专业人士，以获得适当的最佳使用技巧。
对于开口足够的FOP患者，可以使用正常的牙科工具进行治疗，但在牙科手术中必须非常小心，以防止TMJ过度伸展。在颞下颌关节强直的患者中，专业工具和特殊牙刷可能有帮助，但通常限于对颊面进行使用。抗菌和氟化漱口水可能是唯一能接触到舌面和腭面的方法。
对于有明显龋齿的患者，推荐使用38%银氟化物（SDF）作为非手术治疗方法。强烈建议在乳牙和恒牙中使用玻璃离子体密封剂。SMART（银改良无创技术）也可以使用。部分去除龋齿且不使用麻醉并放置玻璃离子体修复材料通常足以支持直到乳磨牙脱落。
对于需要轻微修复程序的FOP患者，可以在牙科诊所进行，使用浸润或韧带间麻醉或激光（但绝不能使用下颌阻滞），可以在不使用术前泼尼松的情况下完成治疗。该方法需要在术前评估最大口开度，并放置比最大开口小3-4毫米的Molt或McKesson口撑。频繁的间歇有助于减少软组织的压力和损伤。多次预约是可行的，但建议在预约之间间隔两周。
对于有口腔卫生维护困难或牙龈炎的患者，鼓励使用氯己定漱口水。氯己定通常每日使用一次，使用6周后每月再使用一次。长期使用氯己定可能导致牙齿变色。
对于有高龋齿风险或维护口腔卫生困难的患者，可以请求牙医专业涂抹氟化物涂层或生物可降解氟化树脂。氟化物涂层应每年涂抹3-4次，通常与银氟化物（SDF）结合使用。有充足证据表明，这些方法在抑制牙齿去矿化方面是有效的。建议对这些患者进行至少三个月的专业随访。对于早期邻接损伤发展的患者，建议使用树脂浸润技术，并结合使用氟化物涂层和/或SDF。
强烈建议FOP患者进行唾液测试。应进行定性和定量评估。应对静息和刺激时的唾液流量以及缓冲能力进行基线测量，尤其是在患者使用任何药物时。许多FOP临床试验药物会导致口干。如果患者的静息和刺激唾液流量不足，食用任何食物后定期用水漱口是有帮助的。唾液替代品也可能有帮助。对于可能存在低pH或无法缓冲的患者，使用MI Paste、牙膏或无定形酪蛋白磷酸盐（ACP）可能有益，同时使用含木糖醇的口香糖和漱口水。根据原产国，还可能有其他针对药物诱导的口干症的产品。
任何可以降低口腔健康恶化风险的活动都应得到实施。本部分重点讨论疾病的药物治疗而非手术治疗。这在FOP患者中尤为重要，因为进行侵入性牙科治疗可能会引发急性发作。
以下是一些建议：
3岁以下儿童患者：
  • 最晚在一岁时进行第一次口腔健康专业检查。
  • 每次哺乳或喂奶后进行口腔清洁。
  • 使用米粒大小的氟化牙膏，特别是在非氟化地区生活的儿童。
  • 尽量减少软性致龋食物的摄入。糖是普遍存在的，许多常见的儿童食品中含有糖。例如，酸奶可能含有过多的糖。
  • 对于高风险儿童，建议每年涂氟两次。
3岁以上儿童患者：
  • 评估口腔疾病的发展风险，如果风险较高，建议每三个月进行一次专业检查。如果无法做到这一点，开始使用高剂量氟化牙膏（米粒大小）并进行频繁的每日刷牙和使用牙线。
5岁以上儿童患者（能吐出牙膏的）：
  • 开始使用氟化牙膏；如果风险高，使用高剂量氟化牙膏，并每年至少进行2-3次专业涂氟。
  • 继续监测并指导低糖饮食。
  • 大多数儿童在10-11岁之前无法有效使用牙线，因此需要帮助。可以使用牙线辅助工具。但家长应注意交叉污染，并确保在每次使用牙线后冲洗牙线棒。
  • 监测鼻呼吸或口呼吸——打鼾或磨牙。口呼吸可能导致口面部发育异常，并增加口腔疾病的风险。
  • 对于正常开口的患者，可以使用普通牙科工具进行治疗，但需小心避免过度拉伸TMJ和相关肌肉。创伤和缺氧是已知的FOP发作诱因。
  • 牙齿矫正——（见牙齿矫正部分）
  • 对于有龋齿的患者，考虑使用银氟化物（SDF）、部分龋齿去除的理念（智能修复）结合玻璃离子体和霍尔冠。所有这些应用均不需要使用局部麻醉。
青少年和成年人：
  • 对于口腔开口正常且风险较低的患者，建议定期护理，包括刷牙、使用牙线、氟化牙膏和饮食监测。每年进行两次专业检查应足够。
  • 牙齿矫正（见牙齿矫正部分）
  • 对于任何口腔疾病高风险的患者，应尽可能每三个月就诊一次。
  • 对于有口腔开口减少、颌部功能障碍或保持良好口腔卫生困难的患者，建议以下措施：
    • 高剂量氟化牙膏
    • 唾液检测（定性和定量），并根据结果进行适当干预
    • 在任何初期病变（龋齿）上涂抹38%银氟化物（SDF），然后使用高氟含量的玻璃离子氟化物、木糖醇漱口水
    • 监测并尽量减少糖的摄入
    • 使用氯己定漱口水或涂层
    • 氟化涂层
    • 对于轻微的邻接病变——使用SDF和/或树脂渗透技术及氟化涂层
    • 刷牙和牙线辅助工具。电动牙刷、小头水牙线和牙线棒都是示例。
      • 电动牙刷应根据每个品牌的具体建议正确使用。然而，刷牙的指导原则在所有品牌中通常相似：应让牙刷执行刷牙动作，只需将牙刷放在要清洁的区域，而不需做额外的圆形或前后移动。
      对于有部分或完全颞下颌关节（TMJ）强直的患者，尤其是那些在进食时将食物推向一侧的患者，建议每餐后漱口，并在漱口后至少等待30分钟再刷牙。目前已知，口腔微生物群的质量和口腔酸度显著影响牙釉质和牙龈。
    • CMP（MI膏）
    • 含木糖醇的口香糖。
参考文献
  1. Carvalho DR, Farage L, Martins BJ, Speck-Martins CE, Craniofacial findings in fibrodysplasia ossificans progressiva: computerized tomography evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111: 499-502, 2011 进行性骨化性纤维发育不良的颅面发现：计算机断层扫描评估。口腔外科、口腔医学、口腔病理学、口腔放射学及根管治疗
  1. Connor JM & Evans DA. Extra-articular ankylosis in fibrodysplasia ossificans progressiva. Br J Oral Surg 20: 117-121, 1982 进行性骨化性纤维发育不良的关节外强直
  1. Donly KJ. Fluoride Varnishes. J Calif Dental Assoc 31: 217-219, 2003 氟化物涂层
  1. Gao SS, Zhao IS, Hiraishi N, Duangthip D, Mei ML, Lo ECM, Chu CH. Clinical trials of silver diamine fluoride in arresting caries among children: A Systematic Review. JDR Clin Trans Res 1: 201-210, 2016 银氟化物在儿童龋齿治疗中的临床试验：系统评价
  1. Hujoel PP, Hujoel MLA, Kotsakis GA. Personal oral hygiene and dental caries: A systematic review of randomised controlled trials. Gerodontology May, 2018 个人口腔卫生与龋齿：随机对照试验的系统评价
  1. Innes NPT et al: Managing carious Lesions: Consensus recommendations and terminology. Advances in Dental Research 28: 49-57, 2016 龋齿病变的管理：共识建议与术语
  1. Lin R, Hildebrand T, Donly KJ. In vitro remineralization associated with a bio-erodible fluoridated resin and a fluoride varnish. Am J Dentist 22: 203-205, 2009 与生物可腐蚀氟化树脂和氟化涂层相关的体外再矿化
  1. Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996 在接受局部麻醉注射后的进行性骨化性纤维发育不良患者中，颌部运动严重受限
  1. Nussbaum BL. Dental care for patients who are unable to open their mouths. Dental Clin North Am 53: 323-328, 2009 对无法张嘴患者的牙科护理
  1. Nussbaum BL, Grunwald Z, Kaplan FS. Oral and dental healthcare and anesthesia for persons with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 239-242, 2005 进行性骨化性纤维发育不良患者的口腔和牙科护理及麻醉
  1. Pitts N, Zero D. White paper on dental caries prevention and management: fdiworldental.org/media/93783/2016-fdi_cpp-white_paper.pdf, 2016 龋齿预防和管理的白皮书
  1. Renton P, Parkin SF, Stamp TC. Abnormal temporomandibular joints in fibrodysplasia ossificans progressiva. Br J Oral Surg 230: 31-38, 1982 进行性骨化性纤维发育不良的颞下颌关节异常
  1. Schoenmaker T, Dahou Bouchankouk A, Özkan S, Gilijamse M, Bouvy-Berends E, Netelenbos C, Lobbezoo F, Eekhoff EMW, de Vries TJ. Limitations of Jaw Movement in Fibrodysplasia Ossificans Progressiva: A Review. Front Med (Lausanne). 2022 Mar 22;9:852678 进行性骨化性纤维发育不良的颌部运动限制：综述
  1. Wong A, Subar PE, Young DA. Dental Caries: An update on dental trends and therapy. Adv Pediatr 64: 307-330, 2017 龋齿：牙科趋势和治疗的最新进展
  1. Young JM, Diecidue RJ, Nussbaum BL. Oral management in a patient with fibrodysplasia ossificans progressiva. Spec Care Dentist 27: 101-104, 2007 进行性骨化性纤维发育不良患者的口腔管理
原文
  1. Preventive Oral Healthcare in FOP
      2. Individuals with FOP have developmental anomalies of the temporomandibular joints (TMJs) (Connor & Evans, 1982; Renton et al., 1982; Carvalho et al., 2011). Spontaneous or post-traumatic ankylosis of the TMJs is common in FOP and leads to severe disability with resultant difficulties in eating and poor oral hygiene. Great care must be taken not to provoke flare-ups of the TMJ (Luchetti et al., 1996). Ossification of the masseter muscle results in the smallest mouth opening and ossification of the zygomatic arch results in the largest mouth opening. Thus, the location of the HO impacts the extent of the mouth opening (Schoenmaker et al., 2022).
      Managing the risk of any form of oral disease is essential in patients with FOP, especially during childhood years (Young et al., 2007). Preventing development of caries or periodontal disease is crucial to prevent long-term dental and oral complications in patients with FOP.
      Fluoridation of water is suggested for all patients who have FOP. The use of high dose fluoride toothpaste (once an individual can spit) is recommended along with use of fluoride gels and rinses to help prevent the need for restorative dental care (Hujoel et al., 2018). Children who are unable to spit can use a rice size grain of normal fluoridated toothpaste.
      Frequent flossing and brushing are necessary in patients with FOP, as in anyone, but may be difficult due to limited jaw opening as FOP progresses. Ultrasonic, electric, or battery-powered toothbrushes with small heads, water picks and floss wands may also help with dental hygiene. If these are suggested, please check with your oral health professional on appropriate and best technique to use these devices.
      Patients with FOP who have sufficient mouth opening can be treated with normal dental instruments as in unaffected individuals, but great care must be exercised to prevent overstretching of the TMJs during dental procedures. In patients who have ankylosed TMJs, professional instrumentation and special toothbrushes may be helpful, but are often limited to use on the buccal surfaces. Antimicrobial and fluoride rinses may be the only method to reach the lingual and palatal surfaces (Nussbaum et al., 2005).
      For patients who have frank cavitation, the use of 38% Silver Diamine Fluoride (SDF) is recommended as a non-surgical treatment approach. Use of glass ionomer sealants in both primary and permanent dentition is highly recommended (Slayton et al., 2018). SMART (Silver modified atraumatic technique) technique may also be used. Partial caries removal with no anesthesia and placement of a glass ionomer restoration can often suffice until a primary molar exfoliates (Innes et al., 2016; Wong et al., 2017).
      For FOP patients with frank cavitation requiring minor restorative procedures that can be performed in a dental office using infiltration or inter-ligamentary anaesthesia or lasers (but never mandibular blocks), treatment can be accomplished without the use of pre-procedure prednisone. This approach requires preprocedure assessment of maximum mouth opening and placement of a molt or McKesson mouth prop 3-4 mm less than the maximum opening. Frequent intermissions are beneficial to limit stress and injury to soft tissue. Multiple appointments are possible. However, two-week intervals between appointments are suggested.
      In patients who have difficulty maintaining oral hygiene or who have gingivitis, chlorhexidine rinses are encouraged. Chlorhexidine is normally used once daily for 6 weeks and then once daily for one week a month. Long-time use of chlorhexidine can result in staining of teeth.
      Patients with a high risk of dental caries or difficulty in maintaining good oral hygiene may request that their dentist professionally apply fluoride varnish or a bio-erodible and fluoride resin. Fluoride varnish should be applied 3-4 times a year – often in conjunction with silver diamine fluoride (SDF) (Gao et al., 2016). There is good evidence that these modalities are effective in inhibiting tooth demineralization (Donly, 2003; Lin et al., 2009; Pitts & Zero, 2016; Slayton et al., 2018). A minimum three months’ professional follow-up for these patients is suggested. For patients who have early stages of interproximal lesion development use of a resin infiltration technique plus the use of a fluoride varnish and/or SDF is suggested (Slayton et al., 2018).
      Saliva testing is highly recommended for patients with FOP. Qualitative and quantitative evaluations should be done. Salivary flow both resting and stimulated, and buffering capacity should be performed as a baseline and if a patient is on any medication. Many of the FOP clinical trial drugs will cause dry mouth. If a patient has inadequate resting and stimulated saliva flow, habitual rinsing with water after any food intake is helpful. Saliva substitutes may also be helpful. For patients who may have a low pH or inability to buffer use of MI Paste, Tooth Mousse or Amorphous Casein Phosphate – ACP may be beneficial as will use of xylitol containing gum and or rinses (Pitts & Zero, 2016). Other products for MIX (medication induced xerostomia) may also be available dependent on country of origin.
      Any activity that can minimize the risk of oral health degradation should be implemented. The focus on this section is the pharmacologic treatment of disease rather than surgical. This is especially important in someone with FOP where doing invasive dental treatment can trigger flare-ups.
      The following is a list of such suggestions:
      Pediatric patients under 3 years of age:
      • First visit to an oral health professional - by latest, one year of age.
      • Begin oral sanative cleaning after each breast or bottle feeding.
      • Use rice size grain of fluoridated toothpaste especially if living in a non-fluoridated area.
      • Minimize use of soft cariogenic foods. Sugar is ubiquitous and present in many foods commonly given to children. Yoghurt is a good example of a food that may contain an excess of sugar.
      • Fluoride varnish suggested twice annually for children at high risk.
      Pediatric patients over 3 years of age:
      • Assess risk of development of oral disease, and if high risk 3 monthly professional appointments suggested. If this is not possible, begin use of high dose fluoride toothpaste (rice size grain) and frequent daily brushing and flossing.
      Pediatric patients over 5 years of age (who can spit):
      • Begin use of fluoride toothpaste – if high risk, use high dose fluoride toothpaste and provide professionally applied fluoride varnish a minimum of 2-3 times a year.
      • Continue to monitor and direct diet that is low in sugar.
      • Most children do not have the ability to floss effectively until 10-11years of age and would benefit from assistance. Floss aids can be used. However, parent should be aware of cross contamination and be sure to rinse a floss wand after flossing each tooth area.
      • Monitor nasal or mouth breathing – snoring or grinding. Mouth breathing can cause altered oral facial development and increase risk for oral disease.
      • Patients with normal mouth opening can be treated with normal dental instruments however, care should be taken to prevent overstretching of the TMJ and musculature. Trauma and anoxia are known triggers for FOP episodes.
      • Orthodontics – (see section on orthodontics)
      • For patients who have carious lesions consider the use of SDF, partial caries removal concept (smart restorations) with the use of glass ionomers and Hall Crowns. None of these applications require the use of local anesthesia.
      Adolescents and Adults:
      • In patients who have normal mouth opening and are at low risk – regular care, brushing, flossing, fluoridated toothpaste, and dietary monitoring are suggested. Bi-annual professional visits should be sufficient.
      • Orthodontics (see section on orthodontics)
      • Any patient who is at high risk for oral disease should be seen at least every three months, if possible.
      • For patients with any decrease in mouth opening, jaw dysfunction, or difficulty in maintaining good oral hygiene, the following are recommended:
        • High dose fluoride toothpaste
        • Saliva testing – (qualitative and quantitative) and appropriate intervention based on results
        • Silver diamine fluoride (SDF) 38% application on any beginning lesion (cavity) followed by placement of a high fluoride containing glass ionomer fluoride, xylitol rinses
        • Monitor and minimize sugar intake
        • Use of chlorhexidine rinses or varnish
        • Fluoride varnishes
        • For minimal interproximal lesions – SDF – and or resin infiltration techniques and fluoride varnish
        • Brushing and flossing aids. Electric toothbrushes with small heads, water pics and floss wands are examples.
          • The electric toothbrush should be used appropriately according to the specific recommendations of each brand. However, the brushing guidelines are generally similar across all brands: one should let the toothbrush perform the brushing motions and simply position the brush at the area to be cleaned without making additional circular or back-and-forth movements.
          For patients with partial or total ankylosis of the temporomandibular joint, especially those who push food to one side of the mouth to eat, the recommendations are to rinse the mouth after each meal and to wait at least 30 minutes after rinsing before brushing the teeth. It is now understood that the quality of the microbiome and acidity of the oral cavity significantly impact the enamel and gums.
        • CMP (MI paste)
        • Xylitol containing gum.
      References
      Carvalho DR, Farage L, Martins BJ, Speck-Martins CE, Craniofacial findings in fibrodysplasia ossificans progressiva: computerized tomography evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111: 499-502, 2011
      Connor JM & Evans DA. Extra-articular ankylosis in fibrodysplasia ossificans progressiva. Br J Oral Surg 20: 117-121, 1982
      Donly KJ. Fluoride Varnishes. J Calif Dental Assoc 31: 217-219, 2003
      Gao SS, Zhao IS, Hiraishi N, Duangthip D, Mei ML, Lo ECM, Chu CH. Clinical trials of silver diamine fluoride in arresting caries among children: A Systematic Review. JDR Clin Trans Res 1: 201-210, 2016
      Hujoel PP, Hujoel MLA, Kotsakis GA. Personal oral hygiene and dental caries: A systematic review of randomised controlled trials. Gerodontology May, 2018
      Innes NPT et al: Managing carious Lesions: Consensus recommendations and terminology. Advances in Dental Research 28: 49-57, 2016
      Lin R, Hildebrand T, Donly KJ. In vitro remineralization associated with a bio-erodible fluoridated resin and a fluoride varnish. Am J Dentist 22: 203-205, 2009
      Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996
      Nussbaum BL. Dental care for patients who are unable to open their mouths. Dental Clin North Am 53: 323-328, 2009
      Nussbaum BL, Grunwald Z, Kaplan FS. Oral and dental healthcare and anesthesia for persons with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 239-242, 2005
      Pitts N, Zero D. White paper on dental caries prevention and management: fdiworldental.org/media/93783/2016-fdi_cpp-white_paper.pdf, 2016
      Renton P, Parkin SF, Stamp TC. Abnormal temporomandibular joints in fibrodysplasia ossificans progressiva. Br J Oral Surg 230: 31-38, 1982
      Schoenmaker T, Dahou Bouchankouk A, Özkan S, Gilijamse M, Bouvy-Berends E, Netelenbos C, Lobbezoo F, Eekhoff EMW, de Vries TJ. Limitations of Jaw Movement in Fibrodysplasia Ossificans Progressiva: A Review. Front Med (Lausanne). 2022 Mar 22;9:852678
      Wong A, Subar PE, Young DA. Dental Caries: An update on dental trends and therapy. Adv Pediatr 64: 307-330, 2017
      Young JM, Diecidue RJ, Nussbaum BL. Oral management in a patient with fibrodysplasia ossificans progressiva. Spec Care Dentist 27: 101-104, 2007

22. 拔出智齿

智齿拔除的考虑因素：
  • 当智齿已萌出且与邻近的磨牙及某些神经等结构接近时。
  • 若智齿可能导致未来并发症或部分萌出时。
警告：在具有正常颌功能的进行性骨化性纤维发育不良患者中，拔除智齿始终存在引发炎症或颌关节强直的风险，即使采取了严格的预防措施。因此，智齿早期拔除的相对风险和益处必须根据个体情况进行评估。
拔除技术：
如果患者的下颌融合，可以采用颊侧方法进行拔除。如果口腔开启正常，则可以采用常规方法进行智齿拔除。
为了进食和呕吐的牙齿拔除：
对于下颌融合的患者，考虑单侧拔除上下颌的前磨牙或磨牙，这样可以同时满足进食和呕吐的需求。同时，也需要考虑后牙的状态以及维持清洁程序的能力。有时可能需要双侧拔除。
抗生素：
通常建议使用抗生素进行预防，但需谨慎审查，因为某些抗生素在参与临床试验的患者中是禁忌的。请与主治医生确认患者是否参与临床试验，以及适合使用的抗生素。
皮质类固醇：
在进行性骨化性纤维发育不良患者中，智齿拔除时进行皮质类固醇预防是必要的，具体细节见第二部分。
原文
  1. Extraction of Wisdom Teeth
      2. Wisdom teeth may be considered for extraction if:
      • The wisdom teeth have erupted and if they are in close proximity to the adjacent molar and certain nerves among other structures.
      • It is determined that the wisdom teeth may present future complications and or is partially erupted.
      WARNING: Wisdom teeth extraction in FOP patients with normal jaw function always carries the risk of flare-ups and or ankylosis of the jaw, even with assiduous precautions. Thus, the relative risks and benefits of early removal of wisdom teeth must be considered on an individual basis.
      Technique for removal:
      If the patient has a fused jaw, a buccal approach may be used for the extraction. If the mouth opening is normal, removal of the wisdom teeth may be performed using a normal approach.
      Removal of teeth for eating and emesis:
      For a patient with a fused jaw, removing the premolars or molars unilaterally in both the upper and lower jaw might be considered and would allow both feeding and emesis to occur. It is also important to take into consideration the state of the posterior teeth, and ability to maintain cleaning procedures. Sometimes bilateral extractions might be indicated.
      Antibiotics:
      Prophylaxis with antibiotics is always suggested but must be carefully reviewed as certain antibiotics are contraindicated in patients who are enrolled in clinical trials. Please check with the primary physician to ascertain if the patient is enrolled in a clinical trial and what would be the appropriate antibiotic to use.
      Corticosteroids:
      Corticosteroid prophylaxis is imperative with wisdom teeth extraction in individuals with FOP as outlined in Section-2

23. 正畸与FOP

大多数人寻求正畸治疗是出于美观和功能的考虑。对于进行性骨化性纤维发育不良（FOP）患者，自我形象与普通人群一样重要。对于口腔开合正常或接近正常的FOP患者，可以安全地进行正畸治疗。
FOP患者常常出现下颌发育不良伴随上颌深覆盖，因此可能需要考虑正畸治。然而，许多患者发现，深覆盖有助于进食和维持口腔及牙齿卫生。后牙和前牙的交叉咬合可能影响颞下颌关节（TMJ），应予以矫正。对于功能正常且前牙开放咬合小于15毫米的儿童，不建议进行正畸治疗，因为深覆盖在TMJ最终融合时有助于营养摄入和后续的牙齿护理。
考虑到正畸治疗时，应缩短就诊时间，以减少对TMJ的压力。
同时，建议采用非拔牙治疗。为避免FOP患者需要拔牙，可能需要对前牙进行美学上的整齐，而后牙的拥挤可暂不处理。后牙拥挤可能比拔牙引发的急性发作和TMJ融合风险更为可取。使用隐形正畸可能更具优势，因为其产生的力量远低于传统正畸，且日常口腔卫生维护更为简便。目前已有口内扫描技术可用于特别难以取模的患者。关于正畸力量与牙齿移动及异位骨化（HO）之间关系的数据尚缺乏。大多数病例报告表明，FOP患者可以进行正畸治疗。
参考文献
  1. Hammond P, Suttie M, Hennekam RC, Allanson J, Shore EM, Kaplan FS. The face signature of fibrodysplasia ossificans progressiva. Am J Med Genet 158A: 1368-1380, 2012 进行性骨化性纤维发育不良的面部特征
  1. Levy CE, Berner TF, Bendixen R. Rehabilitation for individuals with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 251-256, 2005 针对进行性骨化性纤维发育不良患者的康复治疗
  1. Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996 在进行性骨化性纤维发育不良患者中，局部麻醉后出现严重的下颌运动限制
  1. Slayton RL, Urquhart O, Araujo MWB, Fontana M, Guzmán-Armstrong S, Nascimento MM, Nový BB, Tinanoff N, Weyant RJ, Wolff MS, Young DA, Zero DT, Tampi MP, Pilcher L, Banfield L, CarrascoLabra A. Evidence -based clinical practice guideline on non-restorative treatments for carious lesions. A report from the American Dental Association. JADA 149: 837-849, 2018 关于龋齿病变非修复性治疗的循证临床实践指南
原文
  1. Orthodontics & FOP
      2. Most people seek orthodontic care for aesthetic and functional reasons. For the FOP population, self-image is as important as in the general population. Orthodontic therapy can be safely performed on patients with FOP who have normal or nearly normal oral opening (Luchetti et al., 1996).
      Patients who have FOP often develop mandibular hypoplasia with a maxillary overbite and, therefore, orthodontic therapy may be considered (Hammond et al., 2012). However, many patients find that the overbite provides a means of access for eating as well as for oral and dental hygiene. Posterior and anterior dental cross-bites can influence the TMJs and should be corrected. For children with functional TMJs and with anterior open bites that are less than 15 mms, orthodontics is not recommended as the overbite will facilitate nutrition and subsequent dental care if the TMJ does eventually ankylose.
      When orthodontic care is considered, brief appointment times should be used to lessen stress on the TMJs.
      The use of non-extraction therapy is also recommended. To prevent the need for extractions in FOP patients, it may be advisable to align the anterior segments for aesthetics, leaving posterior dental crowding untreated. Crowded posterior teeth may be a better alternative than the risks of flare-up and TMJ ankylosis that can accompany an extraction (Levy et al., 1999). Use of Invisalign orthodontics may be advantageous as forces generated are far less than with traditional orthodontics and daily maintenance of oral health is considerably easier. Intra-oral scanning techniques are now available that can be used especially useful for patients who have difficulty with impressions. Data on the relation between orthodontic forces and tooth movement and HO is lacking. Most case reports identify that orthodontics can be performed in patients with FOP.
      References
      Hammond P, Suttie M, Hennekam RC, Allanson J, Shore EM, Kaplan FS. The face signature of fibrodysplasia ossificans progressiva. Am J Med Genet 158A: 1368-1380, 2012
      Levy CE, Berner TF, Bendixen R. Rehabilitation for individuals with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 251-256, 2005
      Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996
      Slayton RL, Urquhart O, Araujo MWB, Fontana M, Guzmán-Armstrong S, Nascimento MM, Nový BB, Tinanoff N, Weyant RJ, Wolff MS, Young DA, Zero DT, Tampi MP, Pilcher L, Banfield L, CarrascoLabra A. Evidence -based clinical practice guideline on non-restorative treatments for carious lesions. A report from the American Dental Association. JADA 149: 837-849, 2018

24. FOP下颌下的急性发作

下颌下的急性发作是所有急性发作中最令人担忧的一种，因为它们可能导致呼吸和吞咽困难。然而，单独发生在该区域的急性发作很少会影响下颌运动。由于下颌下急性发作对重要功能的影响，值得特别关注。
Janoff等人在1996年对进行性骨化性纤维发育不良（FOP）患者的下颌下肿胀进行了全面研究。107名患者中，有12名（11%）出现了下颌下的异位骨化，最初被误诊为腮腺炎、血管神经性水肿、脓肿、单核细胞增多症或肿瘤。研究对象包括2名男性和10名女性，年龄从6到47岁（平均21岁）。经过严格的预防措施，10名患者幸存下来。一名需要紧急气管切开和通气支持的患者也存活了下来。另一名患者因长期吞咽困难而导致消瘦死亡。
有效的治疗方案包括对下颌下急性发作的早期识别、营养支持和糖皮质激素治疗。对于FOP患者，下颌下肿胀可能成为医疗急症，需要采取强化预防措施，以避免临床严重恶化。这些措施包括避免对病变的操作、气道监测和吸入预防。下颌下肿胀应被视为FOP的一个可变特征，具有重要的潜在临床后果。
Leavitt等（2009）的一例孤立病例报告指出，下颌下急性发作可能造成困扰，并危及气道或吞咽。作者指出，FOP患者常常下颌运动有限，并伴随牙科问题，牙科专业人员常误将FOP患者的下颌下急性发作诊断为牙脓肿或牙源性感染。更糟的是，对口腔、头部或颈部软组织的任何操作都会加速炎症并加重下颌下区域的急性发作临床问题。
对FOP患者的下颌下急性发作进行正确诊断至关重要，以便能够采取强化预防措施，避免临床严重恶化。在处理FOP患者的下颌下急性发作时，重要的挑战是有效管理急性症状和相关不适，同时避免干预可能加重病变的情况。
根据我们丰富的临床经验，建议如下：
  1. 所有治疗进行性骨化性纤维发育不良（FOP）患者的医生应意识到，急性下颌下肿胀可能是该疾病的表现，任何年龄段均可发生，且在病情快速进展的儿童中尤为常见。
  1. FOP的诊断应告知主治医生，以便在患者的基础疾病背景下管理急性下颌下病变。
  1. 必须避免对急性病变的操作，因为即使是轻微的创伤也可能导致气道受损的严重加重。
  1. 如果可能，急性下颌下急性发作的患者应保持头部抬高，以降低气道阻塞的风险。
  1. 急性下颌下急性发作的患者在急性肿胀阶段应密切监测，如有气道阻塞的危险，应立即住院。
  1. 食物应为泥状或半固体。清液在急性下颌下发作期间常引发窒息，因为受影响的肌肉负责在口底移动舌头。
  1. 应鼓励患者频繁进食，以减少体重下降。
  1. 还应考虑额外的高热量食品补充剂。
  1. 应采取严格的预防措施以防止食物误吸。
  1. 在急性下颌下发作的早期治疗中，应考虑使用高剂量口服糖皮质激素。首选的糖皮质激素是泼尼松，剂量为2 mg/kg体重（最多100 mg），在急性发作的最早迹象出现时每日口服一次，持续四天。尽管这些急性发作持续时间不超过其他部位的急性发作，但下颌下区域发作的功能性后果可能需要更长的糖皮质激素治疗课程，或者在停止使用激素后，如果严重的软组织肿胀复发，则需要第二个激素疗程。如果使用第二个四天的高剂量糖皮质激素，应在接下来的两到三周内逐渐减量。在停止糖皮质激素治疗后，可以考虑在接下来的6-8周内使用非甾体抗炎药或COX-2抑制剂。
参考文献
  1. Janoff, HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996 进行性骨化性纤维发育不良患者的下颌下肿胀
  1. Leavitt BD, Teeples TJ, Viozzi CF. Submandibular space swelling in a patient with fibrodysplasia ossificans progressiva: a diagnostic dilemma. J Oral Maxillofac Surg 67: 668-673, 2009 进行性骨化性纤维发育不良患者的下颌下腔肿胀：一个诊断难题
原文
  1. Submandibular Flare-ups in FOP
      2. Submandibular flare-ups are among the most concerning of all flare-ups due to their potential for causing difficulties in breathing and swallowing. Rarely, however, does jaw movement become affected by flareups isolated to this region. Due to their significance for vital functions, submandibular flare-ups warrant special attention (Janoff et al., 1996; Leavitt et al., 2009).
      A comprehensive study of submandibular swelling in patients with FOP was undertaken by Janoff et al. and published in 1996. Twelve (11%) of 107 patients who were studied had submandibular HO that was mistaken initially in seven of the patients for mumps, angioneurotic edema, abscess, mononucleosis, or neoplasm. Two male patients and ten female patients ranging in age from 6-47 years (mean: 21 years) were studied. Ten patients survived following assiduous precautionary measures. One patient who required emergency tracheostomy and ventilatory support also survived. Another patient died of inanition from chronic swallowing difficulty.
      An effective treatment program includes early identification of the submandibular flare-up, nutritional support, and glucocorticoid therapy. Submandibular swelling in patients who have FOP can be a medical emergency and requires intensive precautionary measures to avoid catastrophic clinical deterioration. These measures include avoidance of lesional manipulation, airway monitoring, and aspiration precautions. Submandibular swelling should be recognized as a variable feature of FOP with important potential additional clinical consequences (Janoff et al., 1996).
      An isolated case report of submandibular swelling in a patient with FOP (Leavitt et al., 2009) notes that submandibular flare-ups can be troublesome and endanger the airway or swallowing. The authors note that patients with FOP often have limited jaw movement and associated dental problems and that dental professionals often misdiagnose FOP patients with submandibular flare-ups as having dental abscesses or odontogenic infection. Making matters worse, any manipulation of the soft tissues of the mouth, or the head, or neck will hasten inflammation and worsen the clinical problem of flare-ups in the submandibular region.
      Patients with submandibular flare-ups of FOP must be properly diagnosed so that intensive precautionary measures to avoid catastrophic clinical deterioration can be instituted. An important challenge in the care of patients with a submandibular flare-up of FOP is to effectively manage the acute symptoms and associated discomfort while avoiding meddlesome intervention that will likely exact the lesion.
      Based on our extensive clinical experience, we recommend the following:
      1. All physicians who treat patients with FOP should be aware that acute submandibular swelling may be a manifestation of the disease at any age and can occur during childhood in patients with rapid disease progression.
      1. Diagnosis of FOP should be communicated to the attending physician so that the acute submandibular lesion can be managed in the context of the patient’s underlying disease.
      1. Manipulation of acute lesions must be avoided because even minor trauma can lead to catastrophic exacerbation with airway compromise.
      1. Patients having an acute submandibular flare-up should sleep with their head elevated, if possible, to decrease the risk of airway obstruction.
      1. Patients with an acute submandibular flare-up should be monitored closely during the acute swelling phase and should be hospitalized immediately in the event of pending obstruction of the airway.
      1. Food should be pureed or semi-solid. Clear liquids often provoke choking episodes during submandibular flare-ups as the involved muscles are those that move the tongue at the floor of the mouth.
      1. Patients should be encouraged to eat frequently to minimize weight loss.
      1. Additional high calorie food supplements should also be considered.
      1. Assiduous precautions should be undertaken to prevent food aspiration.
      1. High dose oral glucocorticoids should be considered in the very early treatment of acute submandibular flare-ups. The glucocorticoid of choice is prednisone, and the dose is 2 mg/kg of bodyweight (up to 100 mg) taken per oral once daily for four days at the earliest sign of an acute flare-up. While these flare-ups do not last longer than flare-ups at other locations, the functional consequences of flare-ups in the submandibular region may warrant a longer glucocorticoid treatment course or a second course of steroids if severe soft tissue swelling recurs after cessation of steroid use. If a second four-day course of high dose glucocorticoids is used, the steroids should be tapered slowly over the next two to three weeks. Following discontinuation of the glucocorticoid therapy, non-steroidal anti-inflammatory medications or a COX-2 inhibitor can be considered for the next 6-8 weeks.
      References
      Janoff, HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996
      Leavitt BD, Teeples TJ, Viozzi CF. Submandibular space swelling in a patient with fibrodysplasia ossificans progressiva: a diagnostic dilemma. J Oral Maxillofac Surg 67: 668-673, 2009

25. 吞咽与FOP

吞咽可能是一些进行性骨化性纤维发育不良（FOP）患者面临的最困难问题之一。吞咽机制复杂，涉及颅神经和周围神经，以及舌头的外部肌肉（这些肌肉常常在下颌区的发作中受到影响），还包括罕见的FOP对食管上三分之一骨骼肌的影响。因此，慢性吞咽困难（吞咽困难）可能表现为机械性吞咽困难、食物误吸、咳嗽、反复肺炎（由于误吸）、管理分泌物的困难、极度不适、焦虑和对进食的恐惧，以及逐渐的体重下降和随之而来的营养不良。
如果存在慢性吞咽问题，应进行吞咽测试，并咨询耳鼻喉科医生、FOP专家及FOP麻醉专家。可能需要使用胃肠喂养管（GTubes）来绕过严重失调的吞咽机制，这通常能够被很好地耐受。
参考文献
  1. Janoff HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996 进行性骨化性纤维发育不良患者的下颌肿胀
原文
  1. Swallowing and FOP
      2. Swallowing may be among the most difficult of problems for some individuals with FOP. The swallowing mechanism is complex and involves cranial and peripheral nerves as well as the extrinsic muscles of the tongue (which are often involved in flare-ups of the submandibular space) as well as rare FOP involvement of the skeletal muscles of the upper third of the esophagus. As a result, chronic dysphagia (difficulty with swallowing) may manifest with mechanical difficulty in swallowing, aspiration of food, coughing, recurrent pneumonia (due to aspiration), difficulty in managing secretions, extreme discomfort, anxiety, and fear of eating as well as progressive weight loss and resultant malnutrition.
      If chronic swallowing problems exist, swallowing tests as well as consultation with ENT, and FOP specialists as well as FOP-Anesthesia specialists should be obtained. Gastrointestinal feeding tubes (GTubes) may be necessary to bypass the severely dysregulated swallowing mechanism and are generally well-tolerated.
      References
      Janoff HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg 114: 599-604, 1996

26. FOP的牙科麻醉

进行性骨化性纤维发育不良（FOP）患者与其他患者一样，应该在最佳麻醉条件下接受牙科治疗，以确保无痛的治疗过程。
因此，强烈建议使用局部牙科麻醉，明确指出禁止进行下颌神经阻滞，因为这将导致翼肌的骨化和颞下颌关节的迅速强直。
在下颌后磨牙区，进行浸润麻醉是困难的。在下颌乳牙中，通过牙槽骨进行浸润麻醉可以获得成功。对小病变使用硬组织激光可以避免使用麻醉。
如果小心实施，间隙浸润麻醉可能会有所帮助。然而，在某些患者中，这种局部麻醉可能不可行。FOP患者可能需要全身麻。
颈椎融合、颞下颌关节的强直、胸腔不足综合症、限制性胸壁疾病以及对口腔创伤的敏感性，使气道管理和麻醉变得复杂，并对FOP患者构成生命威胁。
在一家机构对接受全身麻醉以治疗复杂牙科程序的FOP患者进行的回顾性病例分析显示。
即使是简单的程序，如果患者无法充分张口，即使是细致的护理也可能成为手术不安全的来源（误吞/误吸），迫使团队在全身麻醉下进行护理。
三十名患者接受了42次全身麻醉。全身麻醉通常是在气道通过清醒的纤维支气管镜插管得到保障后诱导的。针对FOP患者的牙科程序，可以安全地施行全身麻醉，同时注意气道管理和围手术期护理，采用多学科的综合方法。清醒的鼻部纤维支气管镜插管应被视为气道管理的首选。大多数患者可以在牙科手术当天出院。
这一大规模病例系列表明，通过多学科的综合方法，FOP患者的牙科手术可以安全地进行全身麻醉。鉴于文献中关于困难气道管理的报告及多种医学专业的常规使用，我们建议FOP患者在能够提供多学科综合护理的机构接受治疗。
麻醉师应在手术前对患者进行评估，最好是在手术当天之前。耳鼻喉科医生应在手术期间随时待命，以协助气道管理，并在必要时进行紧急气管切开。每个病例中应有牙医和口腔颌面外科医生参与，以便在一个全身麻醉的环境中进行全面的口腔修复和拔牙，这样对患者来说更安全、更方便。
可能还需要其他医疗从业者，如儿科医生、家庭医学医生、心脏病专家、肺病专家和重症监护医师。
应将清醒的鼻部纤维支气管镜插管视为气道管理的首选。在这个病例系列中选择全身麻醉（GA）并使用气管内管有几个原因。
首先，在牙科手术中，尤其是下颌神经阻滞，常规注射局部麻醉药应避免，因为这些可能引发急性发作并导致颞下颌关节的融合。
其次，如果患者张口受限，口腔进入可能会很困难。如果在一名未插管、下颌融合的患者口腔内掉落了牙齿碎片，可能无法取回。气管内管提供了必要的气道保护。
第三，牙医和口腔颌面外科医生可能需要在特伦德伦堡位（Trendelenburg position指患者仰卧，身体的下半部分抬高，通常将腿部抬高到比心脏高的位置）下保持较长时间。这种体位可能导致患者不适，并在有既往肺部疾病的患者中造成呼吸问题。
体位考虑非常重要；患者的身体通常处于固定状态。所有压力点必须进行垫衬，颈部应得到支撑。如果患者的颈椎处于屈曲状态，往往需要采用较陡的特伦德伦堡体位以获得足够的牙科暴露。特伦德伦堡体位的考虑包括为患者的肩部垫衬，并将患者固定在手术床上，以确保他们的身体在手术台上不移动。
第四，我们建议在围手术期给予皮质类固醇，以预防和减轻急性发作。根据当前指南，应在手术开始前给予为期4天的围手术期皮质类固醇治疗。
总之，对FOP患者的围手术期管理应采用多学科综合的方法作为标准护理。患者应预先接受皮质类固醇治疗，并仔细安排手术体位。对FOP患者的牙科手术可以安全实施全身麻醉；清醒的鼻部纤维支气管镜插管被建议作为气道管理的首选。大多数患者可以在牙科手术当天出院。
有关FOP患者全身麻醉的术前咨询，请联系：
Zvi Grunwald 博士.
The James D. Wentzler Professor and Chairman Emeritus
Department of Anesthesiology
Thomas Jefferson University and Hospitals
111 South 11th Street, Suite G-8490
Philadelphia, PA 19107, USA
Tel: 215-955-6161
Cell: 215-206-7362
Fax: 215-923-5507
Email: [email protected]
参考文献
  1. Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg 118: 298-301, 2014 进行性骨化性纤维发育不良患者的牙科手术全身麻醉：对30例患者42个病例的回顾
  1. Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996 进行性骨化性纤维发育不良患者在局部麻醉注射后出现的严重下颌运动受限
  1. Nussbaum BL, Grunwald Z, Kaplan FS. Oral and dental healthcare and anesthesia for persons with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 239-242, 2005 进行性骨化性纤维发育不良患者的口腔和牙科护理及麻醉
  1. Nussbaum BL, O’Hara, I, Kaplan FS. Fibrodysplasia ossificans progressiva: report of a case with guidelines for pediatric dental and anesthetic management. ASDC J Dent Child 63: 448-450, 1996 进行性骨化性纤维发育不良：一例病例报告及儿童牙科和麻醉管理指南
原文
  1. Dental Anesthesia in FOP
      2. Patients with Fibrodysplasia Ossificans Progressiva (FOP), like all other patients, should be able to receive dental care under the best possible anesthetic conditions, ensuring pain-free treatment.
      Therefore, local dental anesthesia is highly recommended making it clear that Mandibular blocks are forbidden as they will lead to ossification of the pterygoid muscles and rapid ankylosis of the TMJ (Luchetti et al., 1996).
      Infiltration anesthesia is difficult in the mandibular posterior molar areas of permanent teeth. Successful anesthesia in mandibular primary teeth can be achieved by infiltration through the alveolar bone. Use of a hard tissue laser can preclude the use of anesthesia especially in small lesions.
      Interligamentary infiltration may be helpful, if performed carefully. However, in some patients, this type of local anesthesia may not be possible. General anesthesia (GA) may be needed for dental care in patients with FOP (Nussbaum et al., 1996; Nussbaum et al., 2005).
      Cervical spine fusion, ankylosis of the TMJ, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks in individuals with FOP.
      A retrospective chart review was conducted at one institution of patients with FOP who underwent GA for treatment of complex dental procedures (Kilmartin et al., 2014).
      Even for simple procedures, if the patient does not open his or her mouth sufficiently, even vigilant care can be a source of operative insecurity (ingestion/inhalation), forcing the team to perform care under general anesthesia.
      Thirty patients underwent 42 general anesthetics. GA was induced most commonly after the airway was secured by an awake fiberoptic intubation. GA can be administered safely to patients with FOP for dental procedures with attention to airway management and perioperative care using a multidisciplinary approach. An awake nasal fiberoptic intubation should be considered the first choice for airway management. Most patients can be discharged home on the same day as their dental procedure.
      This large case series demonstrates that GA for dental procedures can be safely accomplished in patients with FOP using a multidisciplinary approach. Because of the difficult airway management reports in the literature and the routine use of numerous medical specialties, we recommend that patients with FOP are cared for at an institution where a multidisciplinary approach is possible.
      An anesthesiologist should evaluate the patient preoperatively, preferably before the day of the procedure. An otolaryngologist should be immediately available during the procedure to assist with airway management and perform an emergency tracheostomy if needed. A dentist and an oral maxillofacial surgeon should be involved in each case so that a comprehensive oral rehabilitation with tooth extractions can occur under one GA setting, which is safer and more convenient for the patient.
      Other medical practitioners, such as pediatricians, family medicine physicians, cardiologists, pulmonologists, and intensivists, may be required.
      An awake nasal fiberoptic intubation should be considered the first choice for airway management. There are several reasons for choosing GA with an endotracheal tube in this case series.
      First, routine injections of local anesthetic for dental procedures, especially mandibular blocks, should be avoided because they can precipitate flare-ups and cause fusion of the TMJ.
      Second, oral access can be difficult if a patient has decreased mouth opening. If a tooth fragment were dropped in the mouth of an unintubated patient with a fused jaw, it could be impossible to retrieve. An endotracheal tube provides needed airway protection.
      Third, the dentist and the oral and maxillofacial surgeon may need Trendelenburg positioning for long periods of time. This positioning may cause patient discomfort and result in respiratory compromise, especially in patients with pre-existing pulmonary disease.
      Positioning consideration is essential; patients’ bodies are often fused in a rigid position. All pressure points must be padded, and the neck supported. If a patient’s cervical spine is fused in flexion, a steep Trendelenburg positioning is often needed for adequate dental exposure. Positioning considerations for Trendelenburg include padding the patients’ shoulders and securing the patients to the bed to ensure that their bodies do not shift on the operating room table.
      Fourth, we recommend the administration of perioperative corticosteroids to prevent and mitigate flareups. A 4-day perioperative corticosteroid course should be administered according to the current guidelines and begin before the start of the procedure.
      In summary, a multidisciplinary approach to the perioperative management of patients with FOP should be the standard of care. Patients should be pretreated with corticosteroids and carefully positioned for surgery. GA can be safely administered to FOP patients for dental procedures; an awake nasal fiberoptic intubation is suggested as the first choice for airway management. Most patients can be discharged home on the same day as their dental procedure.
      For pre-op consultation on GA for FOP patients, please contact:
      Zvi Grunwald, M.D.
      The James D. Wentzler Professor and Chairman Emeritus
      Department of Anesthesiology
      Thomas Jefferson University and Hospitals
      111 South 11th Street, Suite G-8490
      Philadelphia, PA 19107, USA
      Tel: 215-955-6161
      Cell: 215-206-7362
      Fax: 215-923-5507
      Email: [email protected]
      References
      Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg 118: 298-301, 2014
      Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS. Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: 21-25, 1996
      Nussbaum BL, Grunwald Z, Kaplan FS. Oral and dental healthcare and anesthesia for persons with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 239-242, 2005
      Nussbaum BL, O’Hara, I, Kaplan FS. Fibrodysplasia ossificans progressiva: report of a case with guidelines for pediatric dental and anesthetic management. ASDC J Dent Child 63: 448-450, 1996

27. FOP的全身麻醉

颈椎融合、颞下颌关节强直、胸腔功能不全综合症、限制性胸壁疾病以及对口腔创伤的敏感性，使得进行性骨化性纤维发育不良（FOP）患者的气道管理和麻醉变得复杂，并带来生命危险。由于气道管理的挑战，FOP患者在大多数手术中需要全身麻醉（GA），这是一项极为复杂的事务。
GA可以安全地施用于FOP患者，前提是关注气道管理和围手术期护理，并采用多学科方法。应将清醒的鼻腔纤维支气管插管视为气道管理的首选。
鉴于文献中对气道管理的困难报告和多个医疗专业的常规使用，我们建议FOP患者在能够提供多学科护理的机构接受治疗。
麻醉师应在术前评估患者，最好是在手术当天之前。耳鼻喉科医生在手术过程中应随时待命，以协助气道管理，并在需要时进行紧急气管切开。其他医疗人员，如儿科医生、家庭医学医生、心脏病专家、肺病专家和重症监护医生，也可能是必需的。
总之，对FOP患者的围手术期管理应采用多学科的方法作为护理标准。患者应在手术前接受皮质类固醇治疗，并仔细定位。建议将清醒的鼻腔纤维支气管插管作为气道管理的首选。即使是小手术，也应安排在大型医院进行，但对于个别患者，可以考虑同日出院。如果考虑术后住院，随访应安排在重症监护环境中。
有关FOP患者GA的术前咨询，请联系：
Zvi Grunwald, M.D.
The James D. Wentzler Professor and Chairman Emeritus Department of Anesthesiology Thomas Jefferson University and Hospitals 111 South 11th Street, Suite G-8490 Philadelphia, PA 19107, USA Tel: 215-955-6161:
Cell: 215-206-7362 Fax: 215-923-5507 Email: [email protected]
术前准备
在手术日期之前，与麻醉师进行术前会面和交流，对于确保安全顺利的全身麻醉过程至关重要。麻醉师应熟悉进行性骨化性纤维发育不良（FOP），了解影响患者的疾病程度，并仔细规划围手术期的麻醉护理。
对于疾病进展较为严重的患者，如有胸腔功能不全综合症、多关节显著强直、以及活动能力受限和合并症的患者，麻醉师应计划组建一个多学科团队，至少包括一名麻醉师和一名有急救气道管理经验的外科医生。与患者及其家属分享麻醉计划，有助于缓解他们的担忧，并促进手术当天的合作。
麻醉师对FOP患者所需的特殊护理和技能，可能在周边医院或社区医院无法提供。在这种情况下，转诊医生、患者和家属应寻求转诊到具备经验丰富的FOP患者护理能力的大型医疗中心，以便麻醉师可以进行鼻腔纤维支气管插管。
我们建议在大多数手术过程中使用围手术期皮质类固醇，以预防和减轻相关的发作。应根据当前指南，在手术当天开始四天的术后皮质类固醇治疗——在手术开始之前。
术中管理
定位：定位非常重要，因为患者的身体往往以僵硬的姿势融合。所有压力点必须进行垫护，并支持颈部。Trendelenburg体位的考虑包括对患者肩部的垫护以及将患者固定在手术台上，以确保他们的身体在手术过程中不会移动。额外的垫护将有助于减少手术过程中软组织的创伤。手术台应根据患者的需要进行调整。
监测：大多数手术程序都需要常规监测（心电图、非侵入性血压、脉搏血氧饱和度、呼气末二氧化碳和体温）。显著的合并症、较长的手术过程或受损的心肺系统可能需要额外的监测。在上肢在内收和屈曲状态下强直的患者，施加血压袖带可能会困难或不可能。袖带可施加在下肢，袖带下方放置一层薄垫可减少袖带频繁充气对肢体的影响。
静脉通路：细致的静脉穿刺和短期施加止血带通常是安全的。留置静脉或动脉导管可能会导致插入部位形成骨化通道，因此应选择适合手术的最小静脉导管进行插入。
全身麻醉和镇静：对于患有进行性骨化性纤维发育不良（FOP）的患者，全身麻醉的施用和保持气道通畅是特别具有挑战性的事项，应仔细规划。已有关于全身麻醉的指南报道。
医生和患者可能会倾向于在办公室或门诊设施中使用镇静技术进行小手术。然而，气道紧急情况的灾难性风险远远超过这种选择的潜在好处。手术应仅在具备必要技能和支持系统的设施中进行。对于疾病进展较为严重的患者，即使是小手术（如肠镜检查、牙科手术）也建议在大型医疗中心进行全身麻醉，并通过鼻腔纤维支气管插管确保气道安全。
能张嘴的患者：对于能够张嘴的患者，直接喉镜检查时必须避免过度拉伸颞下颌关节。仔细定位患者及其头部，保持“嗅闻”体位并使用Glidescope（GlideScope®视频喉镜；GVL®）在最小开口的情况下是确保气道的一种方法。使用喉罩气道（LMA）应谨慎评估。在紧急情况下进行气管插管极具挑战性，可能导致显著的 morbidity 和 mortality（详见Kilmartin et al., 2014）。
无法张嘴的患者：对于颈椎融合、开口受限或颞下颌关节强直的患者，进行气管插管的口腔通道不可行的。对于这些患者，建议在轻度镇静下进行清醒的纤维光纤鼻气管插管。可考虑使用Dexmedetomidine。这应由经验丰富的麻醉团队进行。团队应由两名经验丰富的麻醉师组成。应有一名备份外科医生（通常是耳鼻喉科医生）在场，并准备好急救气管切开器具。进行鼻腔纤维支气管插管时应注意对鼻子的血管收缩剂的使用，并从小号润滑鼻咽管开始逐渐增加至32-34 Fr。
所有接受插管的患者应接受预防性类固醇治疗（静脉注射甲基泼尼松龙50 mg每6小时一次，随后在能耐受口服时开始口服泼尼松减量），以降低致命气道肿胀和水肿的风险。
围手术期疼痛管理和区域麻醉
大多数FOP患者在胸腰部有严重的骨化，无法接受脊椎或硬膜外镇痛。此外，这种方法可能导致灾难性的发作。
接受术前镇痛药物（包括阿片类药物）的患者可能会给麻醉师带来显著的术中管理挑战。应考虑使用静脉注射氯胺酮。应尽量减少阿片类药物的使用，以避免术后呼吸抑制。与外科医生讨论后建议使用对乙酰氨基酚和非类固醇抗炎药物。术后疼痛管理应使用静脉药物。使用患者自控镇痛（PCA）装置的患者应在任何时候都接受补充氧气，并仔细监测氧合情况。对于能张嘴的患者应开具口服药物。
有关全身麻醉的所有问题，请联系Dr. Zvi Grunwald（请见上文）。
参考文献
  1. Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg 118: 298-301, 2014 对于进行性骨化性纤维发育不良患者的牙科手术全身麻醉：30名患者42例病例的回顾
  1. Tumolo M, Moscatelli A, Silvestri G. Anaesthesia management of child with fibrodysplasia ossificans progressiva. Br J Anaesth 97: 701-703, 2006 进行性骨化性纤维发育不良儿童的麻醉管理
原文
  1. General Anesthesia in FOP
      2. General Considerations
      Cervical spine fusion, ankylosis of the TMJ, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks in individuals with FOP. Due to the challenges of airway management, general anesthesia (GA) is needed for most procedures in FOP patients and is an exceedingly complex issue (Kilmartin et al., 2014)
      GA can be administered safely to patients with FOP with attention to airway management and perioperative care using a multidisciplinary approach. An awake nasal fiberoptic intubation should be considered the first choice for airway management.
      Because of the difficult airway management reports in the literature and the routine use of numerous medical specialties, we recommend that patients with FOP are cared for at an institution where a multidisciplinary approach is possible.
      An anesthesiologist should evaluate the patient preoperatively, preferably before the day of the procedure. An otolaryngologist should be immediately available during the procedure to assist with airway management and perform an emergency tracheostomy if needed. Other medical practitioners, such as pediatricians, family medicine physicians, cardiologists, pulmonologists, and intensivists, may be required.
      In summary, a multidisciplinary approach to the perioperative management of patients with FOP must be the standard of care. Patients should be pretreated with corticosteroids and carefully positioned for surgery. An awake nasal fiberoptic intubation is suggested as the first choice for airway management. Even minor procedures should be scheduled to a major hospital setting, however same day discharge may be considered for individual patients. If postoperative admission is considered follow up should be assigned to an intensive care setting.
      For pre-op consultation on GA for FOP patients, please contact:
      Zvi Grunwald, M.D.
      The James D. Wentzler Professor and Chairman Emeritus Department of Anesthesiology Thomas Jefferson University and Hospitals 111 South 11th Street, Suite G-8490 Philadelphia, PA 19107, USA Tel: 215-955-6161:
      Cell: 215-206-7362 Fax: 215-923-5507 Email: [email protected]
      Pre-operative preparation
      A preoperative visit and meeting with the anesthesiologist prior to the date of surgery is crucial for conducting a safe and smooth general anesthesia course. The anesthesiologist should become familiar with FOP, learn about the extent of the disease affecting the individual patient, and carefully plan the perioperative anesthesia care.
      In the case of a patient presenting with advanced disease, thoracic insufficiency syndrome, significant ankylosis of multiple joints, and/or limited mobility and co-morbidities, the anesthesiologist should plan to assemble a multidisciplinary team consisting at least of an anesthesiologist and a surgeon experienced in emergency airway management. Sharing the anesthesia plan with the patient and the family is useful to diffuse apprehension and foster cooperation on the day of surgery.
      The special care and the skills required by the anesthesiologist to treat an FOP patient may not be available at peripheral locations or community hospitals. In these situations, the referring physician, the patient, and the family should seek referral to a major medical center with practitioners who are skilled in the care of FOP patients and the anesthesiologist can perform nasal fiberoptic intubation of the trachea.
      We recommend the administration of perioperative corticosteroids to prevent and mitigate flare-ups associated with most surgical procedures. A four-day postoperative corticosteroid course should be administered according to the current guidelines and begin on the day of surgery - before the start of the procedure.
      Intra-operative management
      Positioning: Positioning consideration is essential as patients’ bodies are often fused in a rigid position. All pressure points must be padded, and the neck supported. Positioning considerations for Trendelenburg include padding the patients’ shoulders and securing the patients to the operating room table to ensure that their bodies do not shift during the surgical procedure. Extra padding will help minimize soft tissue trauma during the surgical procedure. The operating room table should be adjusted according to patient’s needs.
      Monitoring: Routine monitoring is required for most surgical procedures (ECG, non-invasive blood pressure, pulse oximetry, end-tidal CO2 , and temperature). Significant co-morbidities, lengthy surgical procedures, or a compromised cardio-respiratory system may require additional monitors. In patients whose upper limbs are ankylosed in adduction and flexion, the application of a blood pressure cuff may be difficult or impossible. The cuff may be applied on the lower extremity. A thin layer of padding under the cuff may reduce the impact of the frequent inflations of the cuff on the extremity.
      Intravenous access: Careful venipuncture and short-term application of a tourniquet are usually benign. Indwelling intravenous or arterial catheters may rarely lead to the formation of an ossified tract at the site of insertion. Therefore, the smallest intravenous catheter appropriate for the procedure should be selected for insertion.
      General anesthesia and sedation: The administration of general anesthesia and the maintenance of a patent airway are particularly challenging matters in patients who have FOP, and should be planned with exacting care. Guidelines for general anesthesia have been reported (Kilmartin et al., 2014).
      Physicians and patients may be tempted to use sedation techniques and perform minor surgical procedures at an office-based or out-patient facility. The risks of catastrophic airway emergencies far outweigh the potential benefits of this option. Procedures should be performed only at facilities equipped with the skills and support systems necessary for a safe outcome. For patients with advanced disease, it is recommended that even minor procedures (colonoscopies, dental procedures) be performed at a major medical center under general anesthesia with a secured airway by nasal fiberoptic endotracheal intubation.
      Patients who can open the mouth: In patients who are able to open the mouth, it is imperative to avoid over-stretching the TMJ during direct laryngoscopy. Careful positioning of the patient and the head, maintenance of a sniffing position and the use of a Glidescope (GlideScope ® Video laryngoscope; GVL® ) with minimal mouth opening is one approach of securing the airway. The use of a laryngeal mask airway (LMA) should be seriously questioned. Establishing endotracheal intubation under emergency conditions is extremely challenging resulting in significant morbidity and mortality (Reviewed in Kilmartin et al., 2014).
      In cases where adequate mouth opening is questionable, an awake fiberoptic nasotracheal intubation is recommended.
      Patients who cannot open the mouth: In patients who present with fusion of the cervical vertebrae, limited mouth opening, or ankylosis of the TMJ, oral access for endotracheal intubation is not possible. For these patients, an awake fiberoptic nasotracheal intubation under light sedation is recommended. Dexmedetomidine may be a reasonable choice. This should be performed by welltrained anesthesia teams who are experienced with this type of procedure (Tumolo et al., 2006; Kilmartin et al., 2014). The team should consist of two experienced anesthesiologists. A back-up surgeon (usually an otorhinolaryngologist) experienced in performing tracheostomies should be present with an immediately available tracheotomy tray. Nasal fiberoptic endotracheal intubation is performed with attention to administration of vasoconstrictors to the nose and the use of lubricated nasopharyngeal tubes starting with a small one and increasing the diameter up to 32-34 Fr.
      All patients who undergo intubation should receive prophylactic steroids (methylprednisolone 50 mg iv q6 hrs, followed by oral prednisone taper once tolerating oral intake) to decrease the risk of fatal airway swelling and edema.
      Perioperative pain management and regional anesthesia
      Most patients with FOP present with advanced ossifications at the thoraco-lumbar area precluding access to spinal or epidural analgesia. Furthermore, such an approach can lead to catastrophic flareups.
      Patients who are receiving preoperative pain medications including opioids may present significant intraoperative management challenge to the anesthesiologist. The use of intravenous ketamine should be considered. The use of opioids should be minimized to avoid postoperative respiratory depression. The use of acetaminophen and nonsteroidal anti-inflammatory medication is advised after discussion with the surgeon. Postoperative pain management should be accomplished with intravenous medications. Patients using patient controlled analgesia (PCA) devices should receive supplemental oxygen with careful monitoring of oxygenation at all times. Oral medications should be prescribed to patients who can open the mouth.
      All questions regarding general anesthesia should be directed to Dr. Zvi Grunwald (please see above).
      References
      Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg 118: 298-301, 2014
      Tumolo M, Moscatelli A, Silvestri G. Anaesthesia management of child with fibrodysplasia ossificans progressiva. Br J Anaesth 97: 701-703, 2006

28. FOP可接受/低风险的医疗处置

在进行性骨化性纤维发育不良（FOP）患者中，避免软组织创伤非常重要，因为这可能导致炎症发作和快速进展的骨化，最终造成受影响区域的永久运动丧失。FOP患者的所有侵入性程序都存在风险。尽管FOP患者偶尔需要进行医疗程序，但可接受/低风险程序的范围尚未明确，因此进行任何程序时必须考虑潜在的风险和收益。
注射和静脉穿刺
应避免肌肉注射和免疫接种，因为它们可能导致永久性运动丧失。皮内或皮下注射被认为是可接受的。在患者经历活跃的炎症发作或在炎症发作后的两周内，不应进行免疫接种。关于冠状病毒疫苗接种，请参见COVID-19相关部分。
局部麻醉可能存在风险，但在需要时，可接受用于皮肤科程序，如去除痣。对于其他适应症，请直接咨询FOP专家。有关牙科使用，请参见牙科麻醉部分。
可以安全地从皮下静脉进行血液采样。外周静脉插管如果不造成创伤也被认为是安全的。虽然在没有并发症的情况下放置股静脉和桡动脉导管的报告存在，但这被认为风险极高。动脉插管会导致骨化，通常被禁止，除非对患者护理至关重要。PICC导管在FOP患者中使用，但因活动能力下降或解剖限制，深静脉血栓形成（DVT）的风险增加。此外，PICC导管在插入部位也可能增加骨化的风险。
手术和其他侵入性程序
在许多FOP儿童中，柔软的软组织肿块最初主要发生在头部、颈部或背部。在没有FOP的先前诊断的情况下，临床医生往往怀疑肿瘤，导致高比例的活检和/或切除手术，随之而来的骨。已经报道了进行骨化去除或矫正肢体或躯干畸形的骨科手术，但大多数手术都会导致骨化和运动/畸形加重，即使在围手术期使用了防止炎症和骨化的药物。
关于其他侵入性程序的报告有限，安全性尚未确定。对于难治性发热的婴儿进行常规的腰穿导致了炎症发作。紧急剖腹手术治疗腹膜炎未引起骨化。有报道显示，物理治疗可能导致永久性并发症。然而，可接受的物理治疗程序范围尚未确定。应避免被动关节活动度练习以获得额外的关节活动范围，但温和的主动运动可能是允许的。
参考文献
  1. Kitterman JA. Kantanie S, Rocke DM, Kaplan FS: Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: e654-e661, 2005 由于诊断错误造成的医源性伤害在进行性骨化性纤维发育不良中的表现
  1. Liu JX, Hu R, Sun Y, Jiang H: General anesthesia in fibrodysplasia ossificans progressiva: a case report and clinical review. Int J Clin Exp Med 7: 1474-1479, 2014 进行性骨化性纤维发育不良中的全身麻醉：病例报告及临床回顾
  1. Okamoto N, Tazaki T, Shintakuya R, Hirano T, Sasaki M, Takahashi S, Nakamitsu A. Fibrodysplasia ossificans progressiva with two emergency laparotomies: A case report. Int J Surg Case Rep 73: 196-198, 2020 进行性骨化性纤维发育不良患者的两次紧急剖腹手术：病例报告
  1. Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB: Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neurosurg Pediatr 1: 9194, 2008 腰椎穿刺和手术干预在未诊断的进行性骨化性纤维发育不良儿童中的应用
原文
  1. Acceptable/Low Risk Procedures in FOP
      2. In FOP, it is important to avoid soft-tissue trauma as it is likely to induce flare-ups and rapidly progressive HO, with resultant permanent loss of motion in the affected area (Kitterman et al., 2005). All invasive procedures in an FOP patient carry risk. Although patients with FOP must occasionally undergo medical procedures, the range of acceptable/low risk procedures remains undefined, so performing any procedure must be judged considering the potential risks and the benefits.
      Injection and Venipuncture
      Intramuscular injections and immunizations should be avoided because they can lead to permanent loss of movement (Kitterman et al., 2005). Intradermal or subcutaneous injections are considered acceptable. No immunizations should be given while the patient is experiencing an active flare-up or within 2 weeks of a flareup. For coronavirus vaccinations, please see section on COVID-19.
      Local anesthesia can be risky but may be acceptable for dermatologic procedures such as mole removal, if needed. For other indications, please consult directly with an FOP expert. For dental use, please see section on dental anesthesia.
      Blood sampling can be safely performed from subcutaneous veins. Peripheral intravenous catheterization is also considered safe, if atraumatic. Placing femoral vein and radial artery catheters without any complications is reported (Liu et al., 2014), but is considered very high risk. Arterial catheterization will cause HO and is routinely forbidden unless critical for patient care. PICC lines have been used in patients with FOP but have an increased risk of deep vein thrombosis (DVT; due to decreased mobility or anatomic restriction). Also, PICC lines may have an increased risk of HO at the insertion site.
      Surgery and Other Invasive Procedures
      In many children with FOP, tender soft-tissue masses initially develop mainly on the head, neck, or back (Kitterman et al., 2005). Without the previous diagnosis of FOP, clinicians tend to suspect neoplasm, leading to high rates of biopsy and/or resection surgery, with subsequent HO (Kitterman et al., 2005, Zaghloul et al., 2014). Orthopedic surgeries to remove HO or to correct deformities in the extremities or trunk have been reported, but most of them lead to HO and worsening of motion/deformity, even though medications to prevent inflammation and ossification were used perioperatively.
      Reports on other invasive procedures are limited and the safety is not established. Lumbar puncture as a routine work-up for an intractable fever in an infant led to flare-up (Zaghloul et al., 2014). Emergent laparotomy for peritonitis evoked no HO (Okamoto et al., 2020). Physiotherapy is reported to induce permanent complications (Kitterman et al., 2005). However, the range of acceptable physiotherapy procedures has not been established. Passive range of motion exercises to gain additional range of joint motion should be avoided, but gentle active exercise may be permitted.
      References
      Kitterman JA. Kantanie S, Rocke DM, Kaplan FS: Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116: e654-e661, 2005
      Liu JX, Hu R, Sun Y, Jiang H: General anesthesia in fibrodysplasia ossificans progressiva: a case report and clinical review. Int J Clin Exp Med 7: 1474-1479, 2014
      Okamoto N, Tazaki T, Shintakuya R, Hirano T, Sasaki M, Takahashi S, Nakamitsu A. Fibrodysplasia ossificans progressiva with two emergency laparotomies: A case report. Int J Surg Case Rep 73: 196-198, 2020
      Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB: Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neurosurg Pediatr 1: 9194, 2008

29. FOP的听力障碍

听力障碍是进行性骨化性纤维发育不良（FOP）的常见特征，约50%的患者受影响。其发作通常在儿童期，可能是缓慢进展的。听力损失通常是传导性，可能由于中耳骨化所致，但在某些患者中，听力障碍则具有神经性。一般而言，FOP儿童应每两年进行一次听力评估，如有必要可更频繁地检查。助听器通常有帮助，可以减少因听力损失而导致的发展问题。急性听力损失通常与FOP无关，应促使对其他原因进行评估。
参考文献
  1. Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressive. Am J Audiol 8: 29-33, 1999 进行性骨化性纤维发育不良患者的传导性听力损失
原文
  1. Hearing Impairment in FOP
      2. Hearing impairment is a common feature of FOP and occurs in approximately 50 percent of patients. The onset is usually in childhood and may be slowly progressive. Hearing loss is usually conductive in nature and may be due to middle ear ossification, but in some patients, the hearing impairment is neurologic in nature. Children with FOP should generally have audiology evaluations every other year; more often, if necessary. Hearing aids are often helpful and can diminish developmental problems due to hearing loss (Levy et al., 1999). Acute hearing loss is not usually associated with FOP and should prompt evaluation for other causes.
      References
      Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressive. Am J Audiol 8: 29-33, 1999

30. FOP的胃肠道问题

根据国际进行性骨化性纤维发育不良协会（IFOPA）登记处收集的基础数据，近28%的患者报告至少有一个与胃和消化相关的健康问题。腹痛是最常见的症状，占所有参与者的约18%，其次是胃食管反流和恶心的症状。17岁以上的女性腹痛最为严重。18岁及以上男性中，有多达19%的人报告吞咽困难。成年女性中，食欲不振最为普遍。成人患者中，约10%有直肠症状，包括便秘，且这一比例是18岁以下患者的两倍多。严重腹泻的投诉约占5%。食物消化困难和间歇性呕吐的投诉分别占所有登记参与者的约7.5%和9%。总体而言，受胃肠道问题影响最大的亚组是成年女性，而受影响最小的亚组是18岁以下女性。
功能性胃肠疾病，包括消化不良和肠易激综合症，与低级别的粘膜炎症相关，主要由肥大细胞、嗜酸性粒细胞和上皮内淋巴细胞主导，这表明局部免疫介导现象与FOP中的一些胃肠道投诉之间可能存在联系。据说，对于这些症状，使用肥大细胞抑制剂在一些特定病例中提供了缓解。
目前尚不清楚这些投诉的发生率是否高于一般人群，或与之在人口统计学上匹配，或者这些投诉的病因是否因FOP的诊断而不同。
Ahn等人报告了一名FOP患者，其表现为慢性腹痛、食欲减退、胆汁性呕吐和体重下降，最终被诊断为上肠系膜动脉综合征。上肠系膜动脉综合征是一种罕见病症，其特点是由于肠系膜脂肪不足，导致主动脉和上肠系膜动脉压迫十二指肠第三部分，进而导致十二指肠阻塞。在任何有持续体重下降、胃肠道症状和胆汁性呕吐的FOP患者中，应考虑临床怀疑SMA综合征。在FOP中，SMA综合征常常因脊柱侧弯、活动受限和下颌关节融合而加剧，导致热量摄入不足。尽管SMA由于其罕见性和多样化的症状而难以诊断，但在FOP患者中考虑SMA综合征的诊断非常重要。腹部CT扫描可以确。在FOP中，SMA综合征的治疗应首先采取保守措施。可以插入鼻胃管以减压十二指肠或胃。应考虑通过静脉营养或鼻空肠管进行体重增加。如果可能，可以将患者置于俯卧或左侧卧位，以减轻对十二指肠的压力。侵入性程序可能会诱发发作，因此仅在绝对必要时进行。
参考文献
  1. Ahn TY, Han JB, Bae JY, Woo SH. Superior mesenteric artery syndrome in a patient with fibrodysplasia ossificans progressiva. Bone Rep 2023 Jul 20;19:101702 上肠系膜动脉综合征在一名患有进行性骨化性纤维发育不良患者中的表现
  1. Mantick N, Bachman E, Baujat G, Brown M, Collins O, De Cunto C, Delai P, Eekhoff M, Zum Felde R, Grogan DR, Haga N, Hsiao E, Kantanie S, Kaplan F, Keen R, Milosevic J, Morhart R, Pignolo R, Qian X, di Rocco M, Scott C, Sherman A, Wallace M, Williams N, Zhang K, Bogard B. The FOP connection registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 109: 285-290, 2018 FOP连接登记处：为进行性骨化性纤维发育不良设计的国际患者赞助登记处
  1. Wouters MM, Vicario M, Santos J. The role of mast cells in functional GI disorders. Gut 65: 155-168, 2016 肥大细胞在功能性胃肠疾病中的作用
原文
  1. Gastrointestinal Issues in FOP
      2. According to baseline data collected by the IFOPA Registry (Mantick et al, 2018) almost 28% of all patients report at least one health issue related to the stomach and digestion. Abdominal pain was the most common complaint, accounting for about 18% of all participants, followed by symptoms of gastrointestinal reflux and nausea. Abdominal pain was highest in females over the age of 17. Difficulty swallowing was reported in up to 19% of males age 18 years or older. Loss of appetite was most common among adult females. Rectal complaints, including constipation, was present in about 10% of adult patients, more than twice as much compared to those under the age of 18. Severe diarrhea was a complaint in approximately 5% of patients. Trouble digesting food and complaints of intermittent vomiting represented about 7.5% and 9% of all registry participants, respectively. Overall, the subgroup most affected by gastrointestinal issues is adult females, and the subgroup least affected is females under the age of 18.
      Functional gastrointestinal disorders, including dyspepsia and irritable bowel syndrome, have been associated with low-grade mucosal inflammation dominated by mast cells, eosinophils and intraepithelial lymphocytes (Wouters et al., 2016), suggesting a possible link between local immune-mediated phenomena and some gastrointestinal complaints in FOP. Anecdotally, the use of mast cell inhibitors for these complaints has provided relief of symptoms in selected, otherwise unresponsible cases.
      It is unclear at the present time if the prevalence of these complaints is greater than those in the general population, demographically matched, or if the etiologies of these complaints differ based on the diagnosis of FOP.
      Ahn et al reported a patient with FOP who had chronic abdominal pain, decreased appetite, biliary vomiting, and weight loss leading to the diagnosis of superior mesenteric artery (SMA) syndrome (Ahn et al., 2023). SMA syndrome is a rare condition in which the third part of the duodenum is compressed by the aorta and superior mesenteric artery due to a paucity of peri-mesenteric fat, resulting in duodenal obstruction. Clinical suspicion of SMA syndrome should be considered in any FOP patient who has persistent weight loss, gastrointestinal symptoms, and biliary vomiting. In FOP, SMA syndrome is often amplified by scoliosis, immobility and ankylosis of the jaw leading to poor caloric intake. Although SMA is difficult to diagnose due to its infrequency and diverse symptoms, it is important to consider the diagnosis of SMA syndrome in patients with FOP. Abdominal CT scan can be diagnostic (Ahn et al., 2023). Treatment of SMA syndrome in FOP should first be conservative. A nasogastric tube can be inserted for decompression of the duodenum or stomach. Weight gain through intravenous nutrition or a nasal-jejunal tube should be considered. If possible, the patient can be placed in a prone or left lateral position to decrease pressure on the duodenum. Invasive procedures can potentially trigger flare-ups, so they should only be performed when absolutely necessary (Ahn et al., 2023).
      References
      Ahn TY, Han JB, Bae JY, Woo SH. Superior mesenteric artery syndrome in a patient with fibrodysplasia ossificans progressiva. Bone Rep 2023 Jul 20;19:101702
      Mantick N, Bachman E, Baujat G, Brown M, Collins O, De Cunto C, Delai P, Eekhoff M, Zum Felde R, Grogan DR, Haga N, Hsiao E, Kantanie S, Kaplan F, Keen R, Milosevic J, Morhart R, Pignolo R, Qian X, di Rocco M, Scott C, Sherman A, Wallace M, Williams N, Zhang K, Bogard B. The FOP connection registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 109: 285-290, 2018
      Wouters MM, Vicario M, Santos J. The role of mast cells in functional GI disorders. Gut 65: 155-168, 2016

31. 肾结石与FOP

临床观察促使对国际骨化性纤维发育不良协会（IFOPA）患者成员进行全球调查，评估肾结石的疾病负担。 该调查考察了FOP患者肾结石形成的风险因素，并为这一已经严重影响生活的疾病提供了预防结石的基础。
尽管存在地域差异，FOP患者的肾结石发生率大约是普通人群的两倍。久坐不动加上骨代谢增加是该人群肾结石形成的重要风险因素。目前尚无对FOP患者结石成分的综合研究。
在本研究中，低纤维饮食是唯一显著增加该人群肾结石风险的饮食因素，尽管水摄入不足和动物蛋白摄入过多也与此状况相关。历史上有尿路感染的FOP患者更容易发展为肾结石。体外冲击波碎石术、输尿管镜取石、经皮肾镜取石和激光碎石术等治疗方法均已被采用，但尚无长期数据来评估这些治疗方法的安全性或有效性。
理想情况下，预防肾结石的建议应当被提出。随着FOP患者的活动能力逐渐下降，这一点变得愈发重要。患者应：
  • 饮用足够的水，以保持每日尿量超过两升。
  • 用全麦面包替代白面包，并食用天然纤维谷物。
  • 限制维生素C和富含草酸食物的摄入。
  • 避免在食物中添加盐。
  • 获取推荐的膳食钙摄入量（RDA），即18至50岁成年人每日摄入1,000毫克元素钙。
参考文献
  1. Gupta RR, Delai PLR, Glaser DL, Rocke DM, Al Mukaddam M, Pignolo RJ, Kaplan FS. Prevalence and risk factors for kidney stones in fibrodysplasia ossificans progressiva. Bone 109: 120-123, 2018 进行性骨化性纤维发育不良患者肾结石的流行率及风险因素
原文
  1. Kidney Stones & FOP
      2. Clinical observations prompted a worldwide survey of patient-members of the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) on the disease burden of kidney stones. The survey examined risk factors for the development of kidney stones in FOP patients and provided a basis for prevention of stones in this already devastating disease (Gupta et al., 2018).
      Although geographical variation exists, patients with FOP have approximately a two-fold higher prevalence of kidney stones than the general population. Immobilization coupled with increased bone turnover is a significant risk factor in the development of kidney stones in this population. There has been no comprehensive study of stone composition in FOP patients.
      A low-fiber diet was the only dietary factor in this study to significantly increase the risk of developing kidney stones in this population, although deficient water intake and excess animal protein intake were associated with the condition. FOP patients with a history of urinary tract infections are at increased risk for developing kidney stones. Extracorporeal shock wave lithotripsy, uteroscopic stone removal, percutaneous nephrolithotomy, and laser lithotripsy have all been used as treatment modalities, but there are no long-term data to evaluate the safety or efficacy of one treatment over another.
      Ideally, recommendations to prevent kidney stones are made. This becomes increasingly important as FOP patients become progressively more immobilized. Patients should (Gupta et al., 2018):
      • Drink sufficient water to keep the urine volume above two liters daily.
      • Substitute whole wheat bread for white bread and eat natural fiber cereals.
      • Limit their intake of Vitamin C and oxalate-rich foods.
      • Refrain from adding salt to their food.
      • Obtain the recommended dietary allowance (RDA) of calcium, which would be 1,000 mg of elemental calcium daily for adults, age 18-50 years old.
      References
      Gupta RR, Delai PLR, Glaser DL, Rocke DM, Al Mukaddam M, Pignolo RJ, Kaplan FS. Prevalence and risk factors for kidney stones in fibrodysplasia ossificans progressiva. Bone 109: 120-123, 2018

32. FOP的康复问题

随着进行性骨化性纤维发育不良（FOP）患者的关节退行性疾病加重和异位骨形成，关节活动范围逐渐丧失，最终导致几乎完全失去行动能力。在这一过程能够停止或逆转之前，康复方法应着重于保持和促进独立性，促进日常生活中的活动和参与。职业治疗和职业教育咨询可能非常有用。虽然鼓励进行保护性主动活动范围的练习，如温水水疗，但必须避免被动活动范围（由患者以外的人进行的运动，即由操作者在没有患者肌肉辅助的情况下进行的关节运动），因为这可能加重FOP，导致进一步的功能丧失和疼痛。尽管存在广泛的异位骨化和逐步的残疾，大多数FOP患者依然过着富有成效和充实的生活。
许多因疾病进展而加重的限制可以通过合理的康复得到改善。
职业治疗干预：穿衣可以通过拉头衫和衬衫、弹性腰带、魔术贴闭合、袜子穿戴器（将袜子放在附有绳索的套筒上）、弹性鞋带，以及长柄鞋拔和取物器来实现。升高的马桶座、定制角度的厕所、床边尿壶（适用于男性或女性）和坐浴盆都有助于如厕。加宽的门口、浴缸和淋浴椅（可能需要根据个人需求进行定制）和扶手可以提高浴室的安全性和可达性。长柄海绵、梳子或改良的取物器、电动牙刷、水冲牙器和吸引装置有助于保持清洁和个人卫生。
在餐桌上，战略性放置的凳子和升高的平台、长柄餐具和吸管都能提供帮助。餐前准备可以通过电动罐头和瓶子开启器、带刺的切菜板（用于固定食物）和旋转架（懒人转盘）来便利。对于咀嚼能力有限的人，可以将食物磨碎或搅拌成泥。
根据疾病进展的阶段，拐杖、助行器、拐杖或定制鞋可能是重要的行走辅助工具。应考虑请经验丰富的矫形技师制作适应性鞋和鞋垫。对于限制更严重的患者，电动轮椅可能是必要的。电动轮椅的考虑因素包括定制座椅、座椅升降、前后倾斜和倾斜功能。配备笔记本电脑支架的膝上托盘可以支持工作和学习的参与。
职业和教育问题： 因为即使是轻微的创伤也可能触发致残性异位骨化，因此鼓励智力追求和计算机技能作为身体活动的替代选择是明智的。《2004年残疾人教育改善法案》（IDEA 2004）是美国的一项法律，要求为残疾儿童提供公平、负责任和优质的教育。这要求公立学校系统为每个残疾儿童提供个性化教育计划，并在限制最少的环境中接受教育。儿童有权享受职业、物理和语言治疗以及课堂辅助服务（如有必要）。各州必须提供某种职业康复服务，帮助残疾人进入或留在劳动市场。
交通和家庭改造： 车辆可以根据需要定制以适应FOP电动轮椅。可以安装坡道和升降机，提高车顶，降低车地板，安装新的控制装置和电动机，使车辆能够“跪下”，降低离地间隙以方便进出。
家庭改造包括消除或减少室内台阶，安装扶手以及外部和内部坡道，加宽走廊，改造可无障碍的浴室和厨房。
环境控制单元（可以集成到智能手机应用中）可以远程操作电器、门和电视。为促进睡眠，提供倾斜桌床，这种床可以从垂直旋转到水平，特殊的床垫和垫层可以重新分配压力，以提供舒适感并保护皮肤完整性。
性与生育： 性亲密行为需要谨慎和体贴。可能需要使用枕头和垫子来支持不寻常和僵硬的姿势。对于性活跃者或考虑进行性活动的人，特别是那些参与临床试验或正在使用实验性药物的人，进行遗传咨询和避孕讨论是必要的。
娱乐疗法： 娱乐疗法可能有助于更有意义地利用闲暇时间。心理学家、社会工作者和其他心理健康顾问可以帮助受影响的个人及其家庭成员适应FOP带来的限制和不便。创意艺术疗法（艺术治疗、音乐治疗、舞蹈/运动治疗、戏剧治疗、诗歌治疗）利用基于艺术的方法和创意过程，旨在改善残疾和疾病，优化健康和福祉。
许多康复治疗方法可以通过远程医疗，至少部分地直接在家中提供。
水疗（温水水疗）使个人能够在安全、低冲击的环境中进行主动活动范围、心肺和抗阻运动。温水可以帮助缓解疼痛。池边的进入和退出可能需要改良的升降机、电梯或坡道。
离子透析涉及通过表皮引入局部应用的生理活性离子（醋酸、类固醇），使用连续直流电。传闻显示，醋酸离子透析可能有助于恢复FOP患者部分失去的下颌关节活动范围。
有关FOP患者康复的问题，请联系：
Charles Levy, MD
Adjunct Associate Professor, Department of Physical Therapy Research Scholar, Center for Arts in Medicine University of Florida 426 SW 43 rd Terrace Gainesville, Florida 32607, USA Email: [email protected]
参考文献
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale for fibrodysplasia ossificans progressiva (FOP). Bone 109: 123-128, 2018 进行性骨化性纤维发育不良（FOP）的累积类比关节受累评分
  1. Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP). Bone 109: 150-161, 2018 行性骨化性纤维发育不良（FOP）患者的纵向自我报告活动能力评估
  1. Levy CE, Berner TF, Bendixen R. Rehabilitation for individuals with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 251-256, 2005 进行性骨化性纤维发育不良患者的康复治疗
  1. Levy CE, Berner TF, Sandhu PS, McCarty B, Denniston MA. Mobility challenges and solutions for fibrodysplasia ossificans progressiva. Arch Phys Med Rehab 80: 1349-1353, 1999 进行性骨化性纤维发育不良患者的活动挑战与解决方案
  1. Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016 进行性骨化性纤维发育不良的发作自然史：全面的全球评估
  1. Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint -specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 109: 124-133, 2018 进行性骨化性纤维发育不良（FOP）中特定关节功能受损的风险
原文
  1. Rehabilitation Issues in FOP
      2. As degenerative joint disease advances and heterotopic bone accumulates in FOP, range of motion is progressively lost, leading to near complete immobility (Pignolo et al., 2016; Kaplan et al., 2017; Kaplan et al., 2018; Pignolo et al., 2018). Until this process can be halted or reversed, the focus of rehabilitation approaches should be on preserving and promoting independence and enabling activity and participation in daily living. Occupational therapy and vocational education consultations may be extremely useful. Although protected active range of motion such as warm water hydrotherapy is encouraged, passive range of motion (motion performed by someone other than the patient in other words, a movement of a joint carried out by an operator without aid of the patient's muscles) must be avoided, as it risks exacerbation of FOP with further loss of function and pain. Despite widespread HO and progressive disability, most individuals with FOP lead productive and fulfilling lives (Levy et al., 1999; Levy et al., 2005).
      Many of the limitations exacerbated by disease progression can be ameliorated with thoughtful rehabilitation.
      Occupational Therapy Interventions: Dressing may be enabled with pullover shirts and blouses, elastic waistbands, Velcro closures, sock donners (devices where the sock is placed over a cuff attached to a cord), elastic shoelaces, and long handled shoehorns and reachers. Raised toilet seats, custom-angled commodes, bedside urinals (shaped for men or women), and bidets all enable toileting. Widened doorways, tub and bath benches (which may need to be customized to fit the individual) and grab bars increase bathroom safety and accessibility. Long-handled sponges, combs, or modified reachers, electric toothbrushes, water pics, and suction devices help insure cleanliness and personal hygiene.
      Strategically placed stools and elevated platforms, long-handled eating utensils and straws, help at the dinner table. Meal preparation may be facilitated by electrical can and jar openers, cutting boards with spikes to hold food while it is prepared or cut, and rotating shelves (Lazy Susans). For individuals with limited ability to masticate, food may be ground-up or pureed.
      Depending on the stage of disease progression, canes, walkers, crutches, and/or custom shoes may be essential aids to ambulation. The assistance of thoughtful orthotists to fabricate adaptive shoes and inserts should be considered. For more severe limitations, power wheelchairs may be necessary. Considerations for power wheelchairs include customized seating, power seat elevation and depression, anterior and posterior tilt and recline functions. Lap trays with mounts for laptop computers allow participation in work and school.
      Vocational and Educational Issues: Because even minor trauma can trigger disabling HO, it is sensible to encourage intellectual pursuits and computer skills as alternatives to physical activity. The Individuals with Disabilities Education Improvement Act of 2004 (IDEA 2004) is a law in the United States that mandates equity, accountability and excellence in education for children with disabilities. This requires public school systems to provide each disabled child with an individualized educational plan, and an education in the least restrictive environment. Children are entitled to occupational, physical and speech therapy as well as classroom aides, if indicated. Each state is required to offer some sort of vocational rehabilitation to help people with disabilities enter or remain in the work force.
      Transportation and Home Modification: Vans can be customized to accept an FOP power chair. Ramps and lifts can be installed, roofs can be raised, floors can be lowered, new controls and motors can be installed to allow the van to “kneel”, lowering ground clearance to ease ascent into a van.
      Home modifications include elimination or minimization of indoor steps, installation of grab bars as well as exterior and interior ramps, widened hallways, accessible bathrooms and kitchens.
      Environmental control units (which may be integrated as smart phone applications) operate appliances, doors, and televisions remotely. To facilitate sleep, there are tilt table beds that rotate from vertical to horizontal, specialized mattresses and overlays to redistribute pressure to provide comfort and protect skin integrity.
      Sexuality and reproduction: Physical acts of sexual intimacy require tact and thoughtfulness. Pillows and bolsters may be necessary to support unusual and inflexible postures. Genetic counseling and discussion of contraception are warranted for the sexually active or those who are considering such activity, especially if they or a partner are in a clinical trial and/or on an investigational agent.
      Recreational therapy: Recreational therapy may be helpful in making meaningful use of leisure time. Psychologists, social workers and other mental health counselors can help affected individuals and family members with adjustment to the limitations and inconveniences imposed by FOP. Creative arts therapies (art therapy, music therapy, dance/movement therapy, drama therapy, poetry therapy) use arts-based methods and creative processes for the purpose of ameliorating disability and illness and optimizing health and wellness.
      Many of these rehabilitation treatment approaches can be delivered, at least in part, directly to the home via telehealth.
      Aquatic therapy (warm water hydrotherapy) allows individuals to perform active range of motion, cardiopulmonary, and resistive exercise in a safe, low impact environment. Warm water can facilitate pain relief. Modified lifts, elevators or ramps may be necessary for pool entry and exit.
      Iontophoresis involves the introduction of topically applied physiologically active ions (acetic acid, steroids) through the epidermis using continuous direct current. Anecdotal reports suggest that acetic acid iontophoresis may help restore some lost temporomandibular joint range of motion in FOP.
      For questions on rehabilitation for FOP patients, please contact:
      Charles Levy, MD
      Adjunct Associate Professor, Department of Physical Therapy Research Scholar, Center for Arts in Medicine University of Florida 426 SW 43 rd Terrace Gainesville, Florida 32607, USA Email: [email protected]
      References
      Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale for fibrodysplasia ossificans progressiva (FOP). Bone 109: 123-128, 2018
      Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP). Bone 109: 150-161, 2018
      Levy CE, Berner TF, Bendixen R. Rehabilitation for individuals with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3: 251-256, 2005
      Levy CE, Berner TF, Sandhu PS, McCarty B, Denniston MA. Mobility challenges and solutions for fibrodysplasia ossificans progressiva. Arch Phys Med Rehab 80: 1349-1353, 1999
      Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31: 650-656, 2016
      Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint -specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 109: 124-133, 2018

33. 辅助工具、助行器具和适应措施（AADAs）

AADAs对全球健康的影响
辅助工具、助行器具和适应措施（AADAs）常被进行性骨化性纤维发育不良（FOP）患者使用。在一项针对来自54个国家的299名FOP患者的研究中，基于国际FOP协会（IFOPA）全球注册的数据，发现AADAs的使用随着年龄段的增长而增加，但在所有参与者中，性别对AADAs的使用没有显著影响。0–<9岁年龄组的AADAs中位数为2.0，9–15岁年龄组为7.5，而>15岁年龄组为13.0。最常用的AADAs，各自被超过40%的参与者使用，包括洗浴助手、饮水吸管、取物器和记忆泡沫床垫。某些AADAs的使用与整体健康评分的改善相关，包括定制的电动轮椅、饮水器、便携式尿壶、药丸粉碎器、无障碍淋浴、便携式坐厕、空气流动床垫、家庭入口坡道、自动灯、定制柜台、耐用地板、遥控入口、适应性键盘、适应性椅子、特殊电子设备、适用于电动轮椅的改装车辆、无障碍宽门、语音激活计算机软件、打字棒以及通常不包括在设备中的屏幕键盘。
AADAs的预期指导
预测某一FOP患者何时首次经历日常生活活动的障碍，以及何时需要AADAs来缓解这一障碍是很困难的。然而，根据至少10%的IFOPA全球注册参与者的使用情况，可以对在疾病自然进程中可能需要的AADAs类型提供预期指导（见表）。对不同年龄组AADAs使用情况的评估提供了一些高级别建议：（1）许多AADAs在所有年龄组中都很有价值，包括洗浴助手、兼职家庭个人护理助手、饮水吸管、取物器、定制衣物、记忆泡沫床垫和枕头、所有门口的地面门槛以及定制家具；（2）在个人护理工具和辅助器具中，穿衣棒和助听器在9岁时分别变得非常有用或必要；（3）许多浴室辅助器具和设备在9岁时被频繁使用；（4）15岁后通常需要家庭适应；（5）职业治疗和用于维持肺功能的设备在整个生命周期内都是有用的。
辅助工具、助行器具和适应措施（AADAs）
小于9岁
9岁~15岁
大于15岁
移动辅助设备
ㅤ
ㅤ
有价值
拐杖/拐杖
ㅤ
有价值
有价值
手动轮椅
ㅤ
ㅤ
有价值
电动滑板车
ㅤ
ㅤ
有价值
定制电动轮椅
ㅤ
ㅤ
有价值
适应电动轮椅的车辆（坡道、升降机或车顶改装）
ㅤ
ㅤ
有价值
FOP特定护理助理（有偿或无偿）
ㅤ
ㅤ
ㅤ
洗澡助理
有价值
有价值
有价值
兼职家庭个人护理助理
有价值
有价值
有价值
全职个人学校助理（有偿或无偿）
有价值
ㅤ
ㅤ
饮食工具
ㅤ
ㅤ
ㅤ
改装餐具
有价值
ㅤ
有价值
定制高度餐桌
有价值
ㅤ
有价值
定制餐椅
ㅤ
有价值
有价值
饮用吸管
有价值
有价值
有价值
食物搅拌机
ㅤ
ㅤ
有价值
个人护理工具/辅助设备
ㅤ
ㅤ
ㅤ
助听器
ㅤ
有价值
有价值
伸手器
有价值
有价值
有价值
穿衣棒
ㅤ
有价值
有价值
定制服装
有价值
有价值
有价值
标准鞋垫以提供支持
ㅤ
ㅤ
有价值
定制鞋底
ㅤ
ㅤ
有价值
便携式尿壶（男用和女用）
ㅤ
ㅤ
有价值
改装梳子、刷子、洗澡工具、牙刷、剃须刀或化妆工具
ㅤ
ㅤ
有价值
药丸粉碎器
ㅤ
ㅤ
有价值
带年费紧急会员的医疗警报手环
ㅤ
ㅤ
有价值
定制牙科护理工具
有价值
ㅤ
有价值
浴室辅助设备
ㅤ
ㅤ
ㅤ
无障碍淋浴间
ㅤ
ㅤ
有价值
淋浴座椅/椅子
ㅤ
有价值
有价值
残疾人高度马桶
ㅤ
ㅤ
有价值
洗净便器（按钮式冲洗）
ㅤ
有价值
ㅤ
升降座便器
ㅤ
ㅤ
有价值
适应性洗手池台面、高度、水龙头手柄或管道
ㅤ
有价值
有价值
淋浴扶手
ㅤ
有价值
有价值
淋浴手持喷头
ㅤ
有价值
有价值
浴室扶手
ㅤ
ㅤ
有价值
卧室辅助设备
ㅤ
ㅤ
ㅤ
记忆泡沫床垫
有价值
有价值
有价值
记忆泡沫枕头
有价值
有价值
有价值
带电动升降系统的床
ㅤ
有价值
有价值
空气流通床垫
ㅤ
ㅤ
有价值
床边安全栏杆
ㅤ
有价值
有价值
灯光、窗帘和/或百叶窗的遥控设备
ㅤ
有价值
有价值
家庭适应性改造
ㅤ
ㅤ
ㅤ
所有门口的门槛
有价值
有价值
有价值
宽门道以便轮椅通行
ㅤ
有价值
有价值
家庭内永久性内置坡道
ㅤ
ㅤ
有价值
便携坡道供家庭、办公室或旅行使用
ㅤ
ㅤ
有价值
定制家具
有价值
有价值
有价值
厨房、浴室或工作区的定制台面
ㅤ
ㅤ
有价值
升降椅
ㅤ
ㅤ
有价值
耐用/易于清洁的地板以承受轮椅重量
ㅤ
ㅤ
有价值
儿童保护用的软垫地板
有价值
ㅤ
ㅤ
组合紧急火灾/一氧化碳探测器和911警报系统
ㅤ
有价值
有价值
工作环境适应
ㅤ
ㅤ
ㅤ
定制桌子
ㅤ
ㅤ
有价值
定制工作站
ㅤ
ㅤ
有价值
使用无障碍卫生间设施
ㅤ
ㅤ
有价值
技术适应
ㅤ
ㅤ
ㅤ
改装键盘（小型、摇杆或定制）
ㅤ
有价值
有价值
无线键盘和鼠标
ㅤ
有价值
有价值
改装支架用于计算机使用
ㅤ
ㅤ
有价值
屏幕键盘（通常不是设备的一部分）
ㅤ
ㅤ
有价值
运动与休闲适应
ㅤ
ㅤ
ㅤ
保护头盔
有价值
ㅤ
ㅤ
改装自行车
有价值
ㅤ
ㅤ
其他改装休闲设备
ㅤ
有价值
ㅤ
学校适应
ㅤ
ㅤ
ㅤ
改装桌子
有价值
ㅤ
有价值
改装椅子
有价值
ㅤ
ㅤ
学习用特殊电子设备
ㅤ
有价值
ㅤ
改装课程
ㅤ
有价值
ㅤ
日常生活医疗疗法
ㅤ
ㅤ
ㅤ
物理治疗
ㅤ
有价值
有价值
水疗
ㅤ
有价值
有价值
职业治疗
有价值
有价值
有价值
呼吸练习用的PEP面罩或肺活量计
有价值
有价值
有价值
基于IFOPA全球注册中心的数据和299名个体的反馈。阴影表示至少有10%的受访者使用AADA
ㅤ
ㅤ
ㅤ
实践经验表明，患者和家庭在面临身体限制时寻求辅助工具、助行器具和适应措施（AADAs），而不是在预见到这种限制之前。这种反应性行为在患者已经经历疾病进展带来的极大挑战时，增加了额外的压力。这通常是社会支持系统的结果，尽管出于良好意图，却使得依赖行为得以延续，而不是通过尽早使用AADAs来促进独立活动。减少支持性行为、鼓励患者通过AADAs使用独立的一个方法是，在实际需要之前引入这些工具或适应措施，并在全家人的支持下将其可视化。例如，可以给一个尚未失去行动能力的孩子提供一个取物器，并与他轮流从洗衣篮中挑选袜子。这样，接受和使用工具或适应措施的可能性会更大，因为在实际需要之前，给予了情感和身体调整的时间。引入AADAs的机会窗口必须考虑到通常的事件顺序——从初步限制到限制、初始的AADAs抗拒和缓慢的接受。这种预期规划有可能为患者提供更多成功使用AADAs的机会，从而改善应对技能、增强适应能力、提高情商和整体的社会情感健康。
最常推荐的AADAs
根据医疗支持人员和FOP社区成员对国际FOP协会（IFOPA）的咨询和询问，以下被认为是一些最常使用的AADAs。有关AADAs咨询和个性化支持，请访问 www.ifopa.org/ability_toolbox_program。
最常见的幼儿AADAs：
  • 保护头盔（头盔、减冲头带），以保护在摔倒时的头部和面部
  • 步态训练器，帮助学习走路时保持平衡
  • 提供额外缓冲和支持的适应性婴儿推车，方便社区出行
  • 安全的地面游戏用地垫和护角
  • 水槽龙头延长器，缩短洗手时的伸手距离
  • “鼻子杯”——边缘有一部分去除的杯子，使得喝水时不需要头部伸展
  • 可弯曲的泡沫管握把，以改善餐具、牙刷和/或铅笔的握持角度和抓握能力
最常见的学龄儿童和年轻成人AADAs：
  • 穿衣棒和长柄鞋拔，帮助穿衣
  • 具有额外拉链、魔术贴或磁性闭合的适应性服装
  • 可以旋转的适应性桌椅，允许尽管颈部活动受限仍能获得全面视野
  • 可调高度的适应性桌子，以适应适应性座椅或轮椅
  • 台面倾斜板，以支持更轻松的观看和书写角度
  • 键盘打字辅助工具
  • “叫我”棒或视觉辅助工具，代替孩子在课堂上举手
  • 豆袋椅，提供在地面上更舒适的坐姿
  • 个性化教育计划，以允许学校内所需的适应（灵活座位、延长测试时间、在上课间过渡时提前释放以避免拥挤走廊和跌倒风险、体育课期间的替代活动、专业人员协助）
  • 适应性自行车和休闲装备
  • 上厕所擦拭辅助工具
  • 洗发工具
  • 紧急ID手链，以通知急救人员、学校员工和/或雇主有关FOP诊断和禁忌症
最常见的成人AADAs：
  • 加长的餐具和适应性餐具（高边盘子以便于舀取、带尖刺的盘子在切割时保持食物固定）
  • 洗澡和卫生工具，适应性梳子/刷子、适应性剃须刀、适应性化妆工具
  • 适应性马桶（坐浴盆马桶、马桶升高器、支持用的扶手或侧杆、便携式马桶和尿壶）
  • 淋浴椅和零级入水（“无障碍”）淋浴
  • 拐杖、Lofstrand拐杖或滚动助行器，帮助步行时保持平衡
  • 电动滑板车，帮助长距离移动
  • 为无法行走者定制的电动轮椅及轮椅配件（如托盘、手机和平板电脑支架、杯架、根据上肢位置定制的操控杆）
  • 防止压疮的坐垫和座位解决方案
  • 轮椅通道坡道，包括永久和便携式，使轮椅用户能够进入家庭环境和公共空间
  • 可接入的面包车，专为运输轮椅用户设计
FOP患者倾向于使用市场上可用的AADAs以及他们个人为满足特定需求而制作的自制工具。AADAs的知识和可获取性在全球范围内差异很大，因此鼓励患者发挥创造力和解决问题的心态，以产生应对行动挑战的解决方案，对他们的独立性至关重要。日常物品如衣架、胶带、木杆或棍子，以及管道或管材可以用来构建帮助患者伸手、抓取、推拉以完成任务的工具，这表明市场上昂贵的AADAs可以被模拟，并且通常并非必要。虽然建议将患者推荐给IFOPA以获得AADAs支持，但也建议寻求国家FOP组织的意见，以获取特定国家的资源，因为AADAs的可用性、成本、医疗援助和进口限制因地理位置而异。
在线AADAs资源描述
除了通过互联网搜索、适应性设备目录和相关健康专业人士的推荐来寻找AADAs之外，IFOPA网站上还提供了一系列可用的在线AADAs资源，网址为 https://guidebook.ifopa.org/。在线指南中的AADAs可以下载并打印，供无法访问网络的人使用，并且整个资源具有使用谷歌翻译的翻译功能。该资源是一个不断变化的AADAs库，反映了FOP社区中工具使用的当前趋势，并在发现新工具并提交给IFOPA时进行更新。
对于在线指南中列出的AADAs以外的个性化支持，建议医疗专业人士将患者推荐至：
医疗专业人士还可以请求常用AADAs的样品演示工具包，以便在门诊访问期间与家庭分享。
参考文献
  1. Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, DeCunto C, Al Mukaddam M, Hsiao EC, Baujat G, Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z, Haga N, Keen R, Levi B, Morhart R, Scott C, Sherman A, Zhang K, Kaplan FS. Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry. Bone 2020;134:115274 国际进行性骨化性纤维发育不良（FOP）协会全球注册的自我报告基线表型
原文
  1. Aids, Assistive Devices, and Adaptations (AADAs)
      2. Effects on global health by use of AADAs
      Aids, assistive devices and adaptations (AADAs) are frequently used by individuals with FOP. In a study on 299 FOP patients from 54 countries, based on data from the International FOP Association (IFOPA) Global Registry, there was an increase in the use of AADAs by age groups, but no difference on the basis of gender for all participants (Pignolo et al., 2020). The median number of AADAs was 2.0 for the 0–<9 years age group, 7.5 for the 9–15 years age group, and 13.0 for the>15 years age group. The most commonly used AADAs, each by >40% of all participants, were bathing attendants, straws for drinking, reaching sticks, and memory foam bed mattresses. The use of some AADAs were associated with improvement in global health scores, including customized motorized wheelchairs, drinking draws, portable urinals, pill crushers, roll-in showers, portable commodes, airflow mattresses, ramps for home entry, automatic lights, customized counters, durable flooring, remote control entry, adaptive keyboards, adaptive chairs, special electronics, adapted vehicles for motorized wheelchairs, wide doorways for wheelchair access, voice activated computer software, typing sticks, and onscreen keyboards not normally part of devices.
      Anticipatory guidance for AADAs
      It is difficult to predict when a given individual with FOP will first experience impairment in activities of daily living that can be mitigated by AADAs. However, based on use by at least 10% of IFOPA Global Registry participants, it is possible to give anticipatory guidance on the type of ADAAs that are likely to be required over the natural course of the disease (Table). Evaluation of AADA use among age groups provides several high-level recommendations: (1) Several AADAs are valuable across all age groups, including bathing attendants, part-time home personal care attendants, straws for drinking, reaching sticks, customized clothing, memory foam bed mattresses and pillows, floor level thresholds on all door-ways, and customized furniture; (2) Among personal care tools and aids, dressing sticks and hearing aids become very helpful or required, respectively, beginning at 9 years of age; (3) Many bathroom aids and devices are frequently employed by age 9; (4) Home adaptations are generally required after the age of 15; (5) Occupational therapy and devices used to preserve pulmonary function are useful over the entire life span.
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      Practical experience suggests that patients and families seek AADAs when a physical limitation demands remediation and support rather than in anticipation of such limitation. This reactionary behavior causes excessive stress in a time when the patient is already experiencing extreme challenges of overcoming new limitations from the progression of the disease. This is often the result of social support systems that, although well intentioned, enable dependent behaviors rather than empower independent activities through the early utilization of AADAs. An approach to reduce enabling behaviors and encourage patient independence through AADA use is to introduce the tool or adaptation prior to its need, in a setting where it is visible and promoted by the entire family. For example, providing a child (who has not yet lost mobility) with a reaching device and taking turns with them picking out socks from the laundry basket. In this way there is a greater chance for acceptance and use of the tool or adaptation because time is given for the emotional and physical adjustment period before the need is actually realized. The window of opportunity for introduction of an AADA must be considered in light of the usual sequence of events—from prelimitation, to limitation, initial AADA resistance, and slow acceptance. This anticipatory planning has the potential to provide patients with increased opportunities for success using AADAs leading to improved coping skills, greater resiliency, increased emotional intelligence and overall social-emotional well-being as the disease progresses.
      Most commonly recommended AADAs
      The following have been identified as some of the most commonly used AADAs based on consultations and inquiries made by medical support staff and FOP community members, respectively, to the IFOPA. For AADA consultations and personalized support go to www.ifopa.org/ability_toolbox_program.
      Most common Early Childhood AADAs:
      • Protective headgear (helmets, impact-reducing headbands) to protect the head and face during falls
      • Gait trainers to assist with balance when learning to walk
      • Adaptive strollers that provide extra cushion and support for community transportation
      • Floor padding and bumpers for safe floor play
      • Sink faucet extenders to shorten the reaching distance when washing hands
      • “Nosey” cups – cups with a section of rim removed to make space for the nose so that head extension is not necessary for drinking
      • Bendable foam tubing grips to improve grasp and holding angle of flatware, toothbrushes, and/or pencils
      Most common School-Aged and Young Adult AADAs:
      • Dressing sticks and long-reach shoehorns to assist with dressing
      • Adaptive clothing with additional zippers, Velcro, or magnetic closures
      • Adaptive desk chairs that swivel to allow full visual field despite reduced neck mobility
      • Adaptive desk with adjustable height to accommodate adaptive seating or wheelchairs
      • Table-top slant boards to support easier viewing and writing angles on assignments/documents
      • Keyboard typing aids
      • “Pick Me” stick or visual aid to extend in lieu of child raising hand to be called upon in class
      • Bean bag chairs for more comfortable seating when on the floor
      • Individualized Educational Plans to allow for necessary accommodations in school (flexible seating, longer test durations, early release when transitioning between classes to avoid crowded hallways and risk of falls, alternate activities during Physical Education classes, para-professional assistance)
      • Adaptive bicycles and recreational gear
      • Toilet wiping aids
      • Hair washing tools
      • Emergency ID bracelets to inform First Responders, school staff, and/or employers of FOP dx and contraindications
      Most common Adult AADAs:
      • Extended eating utensils and adaptive dishware (high-sided plates for easier scooping, plates with spikes to hold food in place while cutting)
      • Bathing and hygiene tools, adaptive combs/brushes, adaptive shavers, adapted cosmetic make-up applicators
      • Adapted toilets (Bidet toilet seats, toilet risers, grab bars or side rails for support, portable commodes and urinals)
      • Shower chairs and zero-entry (“roll-in”) showers
      • Canes, Lofstrand crutches or rolling walkers to assist with balance when walking
      • Motorized scooters to assist with mobility for extended distances
      • Custom motorized wheelchairs for non-ambulators and wheelchair accessories (i.e. trays, mounts for cell phones and tablets, cup holders, custom-placed joystick controls based on upper extremity positioning)
      • Cushions and seating solutions to prevent pressure sores
      • Wheelchair access ramps, both permanent and portable, allowing access into home environments and public spaces
      • Accessible vans for transporting wheelchair users
      Individuals with FOP tend to use AADAs available in the marketplace as well as homemade tools they have personally crafted for their individual needs. Knowledge and accessibility of AADAs vary greatly across the globe; therefore, encouraging patients to use creativity and a problem-solving mindset to generate solutions to their mobility challenges is vital to their success with independence. Everyday items such as coat hangers, duct tape, dowel rods or sticks, and pipe or tubing can be used to construct a tool that helps a patient reach, scratch, push and pull in order to complete a task, demonstrating that expensive AADAs found in the marketplace can be simulated and are often not necessary. While referring patients to the IFOPA for support with AADAs is encouraged, it is also recommended to seek input from the national FOP organizations for country-specific resources as availability of AADAs, cost, healthcare assistance, and importing restrictions vary greatly by geographic location.
      Description of online resources for AADAs
      In addition to finding AADAs through internet searches, adaptive equipment catalogs and recommendations from allied health professionals, there is a collection of online resources for AADAs available on the IFOPA website at https://guidebook.ifopa.org/. The AADAs in the Online Guidebook can be downloaded and printed for those without web access, and the entire resource has a translation feature using Google Translate. This resource is an ever-changing library of AADAs reflecting the current trends of tool use in the FOP community throughout the world and is updated as new tools are discovered and submitted to the IFOPA.
      For individualized support beyond AADAs listed in the Online Guidebook, medical professionals are encouraged to refer patients to:
      Medical professionals may also request a sample demonstration kit of commonly used AADAs for their office to share with families during office visits.
      References
      Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, DeCunto C, Al Mukaddam M, Hsiao EC, Baujat G, Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z, Haga N, Keen R, Levi B, Morhart R, Scott C, Sherman A, Zhang K, Kaplan FS. Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry. Bone 2020;134:115274

34. FOP群体中的女性健康

我们观察到，进行性骨化性纤维发育不良（FOP）女性可能出现多种月经异常，包括原发性闭经（即15岁后未开始月经周期）、继发性闭经（即月经初潮后缺失3-6个月）、月经周期不规律以及导致月经过多的子宫肌瘤。
我们建议对所有出现原发性和继发性闭经的女性进行评估，并考虑使用雌激素（+/- 孕激素）进行激素替代治疗以促进骨骼健康。口服或经皮贴片在FOP女性中安全用于激素替代。应避免使用宫内避孕器（IUD）。肌肉注射或植入避孕药物是绝对禁忌。
对于月经过多并且有卫生顾虑的女性，可以使用口服避孕药来减少或停止月经周期。激素替代可能增加血栓风险；开始口服避孕药的风险和益处需要与当地医疗提供者讨论。目前没有数据显示口服避孕药或激素替代会增加发作风险。
许多成年FOP女性报告有子宫肌瘤（平滑肌瘤）的病史；在FOP中的确切流行率尚未完全确定。根据2023年9月的IFOPA注册数据，19名女性受访者中有9名（47%）报告有子宫肌瘤病史。子宫肌瘤是女性最常见的良性盆腔肿瘤。根据年龄、种族以及识别子宫肌瘤的方法（症状、超声波或病理），报告的流行率变化极大。一项回顾性研究对277,821名年龄在18至65岁之间的女性进行观察，发现总体流行率接近10%。在一项外科研究中，77%的切除子宫中发现了子宫肌瘤。子宫肌瘤的管理将取决于症状。可以使用激素药物（口服避孕药、GnRH激动剂）来减少出血。非甾体抗炎药（例如布洛芬）可以用来减轻疼痛和月经过多。氨甲环酸可以减少出血。
如果可能，应避免对FOP患者进行侵入性和外科手术。如果医疗上有必要，可以在多学科团队的指导下进行子宫切除。
口服避孕药在FOP中并不是禁忌。然而，一些患者在使用周期性口服避孕药时报告了发作活动的变化。可以考虑使用仅含孕激素的药物或减少子宫内膜脱落周期的版本（例如Seasonale避孕药，每年4次月经）。
参考文献
  1. Ho M, Park BY, Rosenblum NG, Al Mukaddam M, Kaplan FS, Kucherov V, Hubosky SG, Kane G, Desai V, Kramer MR, Ku BS, Schwenk ES, Baratta JL, Harshavardhana D, Grunwald Z. Surgical and Radiological Management of Complicated Uterine Leiomyoma Aided by 3D Models in a Patient with Fibrodysplasia Ossificans Progressiva. Am J Case Rep 2021 Jun 10;22:e931614. 复杂子宫平滑肌瘤的外科和放射学管理，借助3D模型在进行性骨化性纤维发育不良患者中的应用
  1. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 94: 435-438, 1990 子宫平滑肌瘤的发生频率
  1. Yu O, Scholes D, Schulze-Rath R, Grafton J, Hansen K, Reed SD. A US population-based study of uterine fibroid diagnosis incidence, trends, and prevalence: 2005 through 2014. Am J Obstet Gynecol 2018 Dec;219(6):591.e1-591.e8. 美国基于人群的子宫肌瘤诊断发生率、趋势和流行率研究：2005年至2014年
原文
  1. Women’s Health in FOP
      2. We have observed that women with FOP can have various menstrual abnormalities ranging from primary amenorrhea (i.e., lack of initiation of menstrual cycle after the age of 15 years), secondary amenorrhea (i.e., absent menstrual for 3-6 months after the onset of menarche), irregular menstrual cycles and uterine fibroids leading to heavy menstrual cycles.
      We recommend evaluation for all women with primary and secondary amenorrhea and consider hormonal replacement therapy with estrogen (+/- progesterone) for bone health. Oral or transdermal patches have been used safely in women with FOP for hormonal replacement. Intra-uterine devices (IUDs) should be avoided. Intramuscular injections or implanted contraceptives are absolutely contraindicated.
      For women with heavy menstrual cycles and concern for hygiene, oral contraceptive can be used to decrease or stop the menstrual cycle. Hormonal replacement can be associated with increased risk of blood clots; risks and benefits of starting oral contraception needs to be discussed with their local providers. No data exist to suggest that oral contraceptive/hormone replacement increase the risk of flare-ups.
      Many adult women with FOP have reported a history of uterine fibroids (leiomyoma); the exact prevalence in FOP is yet to be fully determined. Based on the IFOPA registry from September 2023, 9/19 (47%) of the female respondents (age range 19-56 years) reported history of uterine fibroids. Uterine fibroids are the most common benign pelvic tumor in females. Reported prevalence is extremely variable depending on the age and race of the cohort as well as methods for identifying uterine fibroid (symptoms, ultrasound, or pathology). A retrospective study reviewing charts of 277,821 women age range 18–65 years followed at Kaiser Permanente noted an overall prevalence of nearly 10% (Yu et al., 2018). In a surgical study, the prevalence of uterine fibroid was noted in 77% of surgically removed uteri (Cramer and Patel, 1990). Management of uterine fibroid will depend on the symptoms. Hormonal medications (oral contraception, GnRH agonist) can be used to decrease bleeding. NSAIDs (example Ibuprofen) can be used to decrease pain and menstrual bleeding. Tranexamic acid can decrease bleeding.
      Invasive and surgical procedures should be avoided in patients who have FOP, if possible. If medically necessary, hysterectomies can be performed under the guidance of a multi-disciplinary team (Ho et al., 2021).
      Oral contraceptives are not contraindicated in FOP. However, some patients have reported changes in their flare activity when on cyclic oral contraceptives. Formats such as progestin-only pills or versions with fewer endometrial shedding cycles (such as Seasonale Contraceptive Oral, with 4 periods/year) may be useful to consider.
      References
      Ho M, Park BY, Rosenblum NG, Al Mukaddam M, Kaplan FS, Kucherov V, Hubosky SG, Kane G, Desai V, Kramer MR, Ku BS, Schwenk ES, Baratta JL, Harshavardhana D, Grunwald Z. Surgical and Radiological Management of Complicated Uterine Leiomyoma Aided by 3D Models in a Patient with Fibrodysplasia Ossificans Progressiva. Am J Case Rep 2021 Jun 10;22:e931614.
      Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 94: 435-438, 1990
      Yu O, Scholes D, Schulze-Rath R, Grafton J, Hansen K, Reed SD. A US population-based study of uterine fibroid diagnosis incidence, trends, and prevalence: 2005 through 2014. Am J Obstet Gynecol 2018 Dec;219(6):591.e1-591.e8.

35. FOP的怀孕问题

决定是否要孩子是个人或夫妻可以做出的最重要和严肃的生活决定之一。由于进行性骨化性纤维发育不良（FOP）是一种遗传性疾病，任何患有FOP的人（无论男女）都可能对将FOP突变传给孩子感到担忧。如果父母有FOP，孩子患FOP的机会为50%。女性则有额外的问题需要考虑。除了任何女性在怀孕期间可能面临的常见风险外，患有FOP的女性还有额外的关注事项，这些都必须仔细考虑。
怀孕在FOP中是罕见的；然而，FOP女性怀孕是可能的。然而，怀孕和分娩对母亲和孩子都存在重大威胁生命的风险，并带来了独特的管理挑战。如果FOP女性考虑怀孕，产前咨询是必不可少的。
由于胸壁疾病引起的呼吸困难，FOP在怀孕后期会导致问题，这与肋椎关节的发育异常和胸部肌肉及腹壁的进行性异位骨化有关。在产前和产时期间，可能需要仔细监测，包括呼吸功能测试，以确定是否需要呼吸支持。
即使胎儿没有受影响，怀孕对FOP母亲也构成重大风险。尽管数据稀少，怀孕与FOP相关的初步风险之一是流产风险或在自发早产后面临的重大早产风险，这可能与怀孕后期遇到的胎儿窘迫有关。如果预计在怀孕36周之前分娩，必须进行类固醇治疗以促使胎儿肺成熟。
另一个重大风险是血栓栓塞，这在FOP的严重不动性加上怀孕的高凝状态下被加剧。在怀孕最后三个月，常常发生下肢水肿，进一步增加了这一危及生命的并发症的风险，因此在整个怀孕期间考虑使用预防性低分子量肝素是必要的。
除了对FOP母亲的重大风险外，怀孕还对未出生的孩子增加了显著风险，包括FOP（50%）、早产、胎儿窘迫以及因需要全身麻醉而带来的并发症风险。与FOP相关的母亲特定风险之一是怀孕期间的发作。长期使用高剂量的糖皮质激素和非甾体抗炎药可能对胚胎和胎儿有毒性，使用时应尽可能避免。
流产、分娩和产前护理的管理由于与FOP相关的特定风险而面临重大困难。由于严重的骨盆畸形以及腰椎、髋关节和骶髂关节的融合，阴道分娩对FOP女性而言非常危险。在达到可存活年龄后，剖宫产是唯一相对安全的分娩方式。剖宫产后出现需要输血和/或子宫切除的子宫出血已有报道。
除了分娩相关的身体问题外，麻醉选择也成为挑战，因为区域麻醉和全身麻醉都有技术难度。由于已有的异位骨化，区域麻醉在技术上非常困难，而且在硬膜外阻滞后可能会引发新的异位骨化发作。全身麻醉时，气管插管可能因气管环的骨化和过度拉伸下颌的危险而变得困难。此外，由于颈部旁脊椎关节在儿童期就开始骨化，年轻FOP患者无法伸展颈部。使用清醒的纤维支气管镜鼻气管插管被发现是唯一安全的选择。在分娩时，应该有一支熟练于高风险婴儿复苏的团队。
许多报告描述了手术后FOP的加重。然而，在其他案例中（五次手术，包括两次子宫切除术），腹壁没有形成异位骨化。建议在择期手术时及手术后3天使用泼尼松或其静脉等效药物，如果没有其他禁忌症。早期合理使用皮质类固醇是基于其强大的抗炎作用以及对FOP发作中炎症诱因重要性的逐渐认识。
在一项回顾性案例系列中，Forrest及其同事描述了三位女性在10年间在同一机构分娩早产儿。这些案例在确保气道和进行剖宫产时带来了独特的麻醉和产科技术挑战。重要的是，每位患者在围手术期接受了糖皮质激素以预防进一步的异位骨化，并需要多学科管理以实现最佳结果。
虽然在基因发现后，试管婴儿、胚胎植入前基因检测、胚胎选择和代孕在理论上是可能的，但尚未有关于FOP的相关报道。产前基因诊断有可能用于排除FOP。
总之，尽管FOP女性怀孕是可能的，但FOP对母亲和孩子构成重大威胁生命的风险，如果孩子出生时患有此疾病，则对整个家庭也会造成生活上的改变。此外，参与临床试验期间绝对禁忌怀孕。FOP的怀孕绝不应在没有严肃考虑和家庭规划的情况下进行。应尽力避免意外怀孕。如有需要，可获得独立的基因咨询。如果发生怀孕，必须在高风险怀孕中心获得指导和护理。
参考文献
  1. Davidson BN, Bowerman RA, La Ferla JJ. Myositis ossificans progressiva and pregnancy. A therapeutic dilemma. J Reprod Med 30: 945-947, 1985 进行性骨化性肌炎与怀孕
  1. Du J, Huang LL, Tan YQ, Cheng DH, Li SF, Li LY, Lu GX. Mutation analysis and prenatal exclusion of fibrodysplasia ossificans progressiva in a Chinese fetus. Genet Test Mol Biomarkers 2010 Jan 10 中国胎儿的进行性骨化性纤维发育不良的突变分析与产前排除
  1. Forrest AD, Vuncannon DM, Ellis JE, Grunwald Z, Kaplan FS. Fibrodysplasia Ossificans Progressiva and Pregnancy: A Case Series and Review of the Literature. Case Rep Obstet Gynecol 2022 Sep 16;2022:9857766 进行性骨化性纤维发育不良与怀孕：案例系列及文献综述
  1. Fox S, Khoury A, Mootabar H, Greenwald EF. Myositis ossificans progressiva and pregnancy. Obstet Gynecol 69 (Pt 2): 453-455, 1987 进行性骨化性肌炎与怀孕
  1. Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg 118: 298-301, 2014 患有进行性骨化性纤维发育不良患者的牙科手术全身麻醉：30例患者中的42个案例回顾
  1. Muglu JA, Garg A, Pandiarajan T, Shore EM, Kaplan FS, Uchil D, Dickson MJ. Pregnancy in fibrodysplasia ossificans progressiva. Obstet Med 5: 35-38, 2012 进行性骨化性纤维发育不良的怀孕
  1. Thornton YS, Birnbaum SJ, Lebowitz, N. A viable pregnancy in a patient with myositis ossificans progressiva. Am J Obstet Gynecol 156: 577-578, 1987 患有进行性骨化性肌炎的患者的可行怀孕
原文
  1. Pregnancy Issues in FOP
      2. The decision to have a child is one of the most important and serious life decisions an individual or couple can make. Because FOP is an inherited disease, anyone (man or woman) with FOP will have similar concerns about passing the FOP mutation to his/her child. If a parent has FOP, the chance that the child will have FOP is fifty percent. Women, specifically, have additional matters to consider. In addition to the usual risks that any woman might encounter during pregnancy, a woman with FOP has additional concerns that must be carefully considered (Davidson et al., 1985; Fox et al., 1987; Thornton et al., 1987; Muglu et al., 2012; Forrest et al., 2022).
      Pregnancy is a rare event in FOP; however, it is possible for a woman with FOP to carry a child (Muglu et al., 2012). However, pregnancy and childbirth have substantial life-threatening risks to both the mother and child and present unique management challenges. If pregnancy is contemplated by a woman with FOP, pre-pregnancy counseling is mandatory.
      FOP results in breathing difficulties during the latter part of pregnancy because of restrictive chest wall disease due to developmental anomalies in the costovertebral joints and progressive HO in the chest muscles and abdominal wall. Careful monitoring including respiratory function tests may be required during the antepartum and intrapartum course to establish any requirement for respiratory support.
      A pregnancy, even with an unaffected fetus, poses substantial risks to a mother with FOP. Although data are scant, one of the initial risks of pregnancy associated with FOP is a risk of miscarriage or substantial risk of premature birth following spontaneous preterm labor and may be secondary to fetal distress encountered during the later stages of pregnancy. Steroid administration for fetal lung maturity is imperative if delivery is anticipated before 36 weeks of gestation (Muglu et al., 2012).
      Another substantial risk is thromboembolism, which is exacerbated by severe immobility of FOP in addition to the hyper-coagulable state of pregnancy. The added constraint of lower limb edema that invariably occurs in the last trimester of pregnancy further increases the risk of this life-threatening complication and warrants consideration of the use of prophylactic low-molecular-weight heparin throughout the duration of pregnancy (Muglu et al., 2012).
      In addition to substantial risk to a mother with FOP, pregnancy also poses substantially increased risks to the unborn child including the risk of FOP (50%), prematurity, fetal distress and the risk of complications from requisite general anesthesia. One of the specific risks to the mother associated with FOP is a flare-up during pregnancy. The chronic use of high-dose glucocorticoids and non-steroidal anti-inflammatory medications has potential embryonic and fetal toxicity, and their use should be avoided, when possible.
      The management of miscarriage, delivery and antenatal care poses substantial difficulties because of the specific risks associated with FOP. Vaginal delivery is perilous in a woman with FOP due to severe pelvic deformity as well as fusion of the lumbar spine, hip joints and sacroiliac joints. Delivery by caesarean section is the only relatively safe mode of delivery after the age of viability is achieved (Muglu et al., 2012). Uterine bleeding needing transfusion and/or hysterectomy after caesarean have been reported (Forrest et al, 2022).
      In addition to the physical problems associated with delivery, the choice of anesthesia becomes a challenge due to technical difficulties with both regional and general anesthesia. Regional anesthesia is technically difficult due to pre-existing heterotopic bone and the danger of precipitating new episodes of HO following an epidural block. Similar problems, including ossification in tracheal rings and the danger of overstretching the jaw, may cause difficult intubation during general anesthesia. Also, it is impossible to extend the neck in young adults with FOP due to orthotopic ankylosis of the cervical paravertebral joints that ossify in childhood, even before the appearance of HO. The use of awake fiberoptic nasotracheal intubation was found to be the only safe option. At delivery, there should be a team skilled in resuscitation of high-risk infants (Muglu et al., 2012; Kilmartin et al., 2014).
      Many reports describe exacerbation of FOP following surgical procedures. However, in other cases (five surgical operations including two hysterectomies), no HO formed in the abdominal wall. The use of prednisone or intravenous equivalent at the time of elective surgery and three days following surgery is recommended if there are no other contraindications. The rational use of corticosteroids early in the course of an FOP flare-up is based primarily on its potent anti-inflammatory effects and on emerging knowledge of the importance of inflammatory triggers in FOP flare-ups (Muglu et al., 2012).
      In a retrospective case series, Forrest and colleagues describe three women who delivered preterm infants at one institution during a 10-year time span (Forrest et al., 2022). These cases posed unique anesthetic and obstetric technical challenges, particularly when securing the airway and performing cesarean delivery. Importantly, each patient received perioperative glucocorticoids for prevention of further heterotopic ossification and required multidisciplinary management for optimal outcomes.
      Although in vitro fertilization, pre-implantation genetic testing, embryo selection and surrogate motherhood are theoretically possible now after the gene discovery, that sequence has not been reported for FOP. Prenatal genetic diagnosis could potentially be used to exclude FOP (Du et al., 2010).
      In summary, although pregnancy in women with FOP is possible, FOP poses major life-threatening risks to mother and child as well as life altering consequences to the entire family if a child is born with this condition. In addition, pregnancy is absolutely contraindicated during participation in a clinical trial. Pregnancy in FOP should never be undertaken without serious consideration and family planning. Unwanted pregnancies should be assiduously avoided. Independent genetic counseling is available, if desired. Should a pregnancy occur, guidance and care at a high-risk pregnancy center are imperative.
      References
      Davidson BN, Bowerman RA, La Ferla JJ. Myositis ossificans progressiva and pregnancy. A therapeutic dilemma. J Reprod Med 30: 945-947, 1985
      Du J, Huang LL, Tan YQ, Cheng DH, Li SF, Li LY, Lu GX. Mutation analysis and prenatal exclusion of fibrodysplasia ossificans progressiva in a Chinese fetus. Genet Test Mol Biomarkers 2010 Jan 10
      Forrest AD, Vuncannon DM, Ellis JE, Grunwald Z, Kaplan FS. Fibrodysplasia Ossificans Progressiva and Pregnancy: A Case Series and Review of the Literature. Case Rep Obstet Gynecol 2022 Sep 16;2022:9857766
      Fox S, Khoury A, Mootabar H, Greenwald EF. Myositis ossificans progressiva and pregnancy. Obstet Gynecol 69 (Pt 2): 453-455, 1987
      Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg 118: 298-301, 2014
      Muglu JA, Garg A, Pandiarajan T, Shore EM, Kaplan FS, Uchil D, Dickson MJ. Pregnancy in fibrodysplasia ossificans progressiva. Obstet Med 5: 35-38, 2012
      Thornton YS, Birnbaum SJ, Lebowitz, N. A viable pregnancy in a patient with myositis ossificans progressiva. Am J Obstet Gynecol 156: 577-578, 1987

36. 变异型FOP

[摘自“FOP变异：它们是什么、谁拥有它们以及它们对您意味着什么？由Frederick S. Kaplan医学博士和Eileen M. Shore博士撰写”]
在我们开始接诊FOP患者近35年前，很快就发现所有患者都有两个共同特征：畸形的大脚趾和进行性异位骨化。这两个特征显然是经典FOP的特征。
随着接诊患者的增多，我们注意到个体间脚趾畸形的差异，以及异位骨化的进展速度。例如，有些人有短而弯曲的大脚趾；有些人有短而直的大脚趾；还有些人则有较长的大脚趾，有些则为正常长度。但每个人都有脚趾畸形——通常表现为大脚趾关节缺失或畸形，这在体检、X光或两者中均可明显发现。同样，我们也观察到FOP异位骨化的进展速度差异——有些人进展得非常快，而另一些人则非常缓慢，还有一些则以较均匀的速度进展。就像任何人群中的其他特征一样，FOP展现出一种自然变异，定义了常态的极限。
然而，有时我们会看到一些患者的特征明显超出“正常”范围——即使对于FOP患者来说也是如此。这一特征最常涉及大脚趾。在这些个体中，我们开始识别出两个群体：一组有几乎正常或完全正常外观的大脚趾；另一组则有极为严重的脚趾畸形，涉及手脚的其他指头。在更“严重”的群体中，我们观察到其他器官系统的额外发育异常。我们将这两组异常个体称为“FOP变异”——一些轻微，一些严重。
我们观察到大约97%的FOP异位骨化患者为“经典FOP”，而约3%为“FOP变异”。其中约一半的FOP变异患者（1.5%）为轻微临床变异，另一半患者（1.5%）为严重变异。这些观察基于临床评估，并在FOP基因发现之前。
在发现FOP基因后，我们检查了所有患者的FOP基因DNA序列。值得注意的是，几乎所有被诊断为“经典FOP”的患者——无论其疾病严重程度如何——都具有相同的杂合子错义激活FOP突变：[ACVR1c.617G>A; p.R206H]。
同样，所有被我们临床识别为“FOP变异”的患者则有不同的杂合子错义激活突变在ACVR1基因中。
换句话说，临床诊断为“经典FOP”的患者在FOP基因中具有相同的“经典突变”[ACVR1c.617G>A; p.R206H]，而所有被临床诊断为“FOP变异”的患者则在FOP基因中具有“变异突变”。
许多人会问：“轻微变异的异位骨化是否更轻微，严重变异的异位骨化是否更严重？”答案是：“有时，但不一定。”一些轻微脚趾变异的患者有较晚的发作和较温和的异位骨化过程，而一些严重脚趾变异的患者则有较早的发作和较严重的异位骨化过程。但变异性很大——正如在“经典FOP”患者中异位骨化的发作和严重程度一样，即使是在经典FOP的同卵双胞胎中。 “FOP变异”的最重要临床特征是大脚趾的畸形——要么远不如“经典FOP”患者严重，要么远比“经典FOP”患者严重。
尽管临床评估在确定“经典FOP”与“FOP变异”的临床状态中极为重要，但在分子层面上确定FOP的确切类型的唯一方法是通过基因检测和FOP基因的DNA序列分析。明确而言，是否为“经典FOP”或“FOP变异”的绝对决定性因素是ACVR1（FOP）基因的确切基因序列。如果某人具有常见的ACVR1c.617G>A; p.R206H突变，则他们就是“经典FOP”。如果他们在ACVR1基因中有变异的遗传突变，则他们是“FOP变异”。目前已发现约20种FOP基因的变异。
通过DNA测序评估FOP基因（ACVR1）可在遗传实验室中进行，通过从血液样本中获得的DNA。分析可以由您的医生安排。
基因分型是参与所有临床研究的要求，并且对于适当的临床和遗传咨询非常重要。
请记住，FOP变异比经典FOP更为罕见。有些ACVR1变异目前仅在全球一两名患者中发现，因此难以预测FOP随时间的进展。对于其他变异，可能有少数受影响的个体在世界范围内，因此我们对FOP变异可能的进展有更多了解。
那么，这对拥有FOP变异的人意味着什么？
第一，我们对FOP变异的了解较少，因此不确定性也更大；但我们和其他科学家正开始了解ACVR1变异突变如何影响细胞功能，以及它们与经典ACVR1突变的异同（Haupt et al., 2018; Mucha et al., 2018; Allen et al., 2020）。ACVR1基因中突变的确切位置和特征（ACVR1蛋白的蓝图；经典与变异）为我们合作的结构生物学家提供了信息，以更好地理解FOP中ACVR1的受损功能。这一洞察对于开发结构模型和针对导致所有形式FOP的致残性异位骨化的损伤和过度活跃的开关的失活方法至关重要。
第二，无论某人是“经典FOP”还是“FOP变异”，所有人都有骨形成BMP信号通路的过度活跃，因此有形成异位骨的倾向。
第三，无论某人是“经典FOP”还是“FOP变异”，他们在出生后形成异位骨的过程是相同的。
第四，对于FOP的总体预防措施对于经典FOP和FOP变异患者是相同的。
第五，对于症状管理的应对措施在经典FOP和FOP变异患者中是相同的。
第六，一些开发FOP药物的方法是特定于突变的，而其他方法则针对FOP中共同的异位骨形成过程。
第七，具体阻断过度活跃的ACVR1受体（由FOP基因编码）的方法应适用于FOP变异和经典FOP。
第八，新的临床试验可能最初仅限于经典FOP患者——然后，如果适用，再扩展到FOP变异患者——主要基于监管要求。
第九，我们正在全力以赴，尽快以人道的方式为FOP变异患者开放适用的临床试验。这正在进行中。
第十，最后，所有FOP患者——无论是经典还是变异FOP——都是小而强大的全球FOP社区的一部分。每个FOP患者之间都有共同的联系。所有FOP患者必须团结在一起，齐心协力，互相学习。知识将引领更好的治疗方案和治愈方案，无论是“经典FOP”还是“FOP变异”。
参考文献
  1. Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020 进行性骨化性纤维发育不良突变ACVR1在发育中的斑马鱼中通过多种方式信号传递
  1. Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1mutations. Bone 109: 232-240, 2018 进行性骨化性纤维发育不良ACVR1突变的可变信号活性
  1. Huning I & Gillessen-Kaesbach. Fibrodysplasia Ossificans Progressiva: Clinical Course, Genetic Mutations and Genotype-Phenotype Correlations. Molec Syndromology 5: 201-211, 2014 进行性骨化性纤维发育不良：临床过程、遗传突变与基因型-表型相关性
  1. Kaplan FS, Groppe JC, Xu M, Towler OW, Grunvald E, Kalunian K, Kallish S, Al Mukaddam M, Pignolo RJ, Shore EM. An ACVR1 R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva. Am J Med Genet A 188: 806-817, 2022 两个轻微进行性骨化性纤维发育不良家族中的ACVR1 R375P致病变异
  1. Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167: 2265-2271, 2015 一种严重变异的进行性骨化性纤维发育不良（ACVR1c.772G>A; R258G）涉及多个系统：两例患者的报告
  1. Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009 经典和非典型进行性骨化性纤维发育不良表型由BMP I型受体ACVR1中的突变引起
  1. Mucha BE, Hashiguchi M, Zinski J, Shore EM, Mullins MC. Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone 109: 225-231, 2018 导致人类进行性骨化性纤维发育不良（FOP）的变异BMP受体突变在斑马鱼中表现出BMP配体无关的受体激活
原文
  1. FOP Variants
      2. [Adapted from “FOP Variants: What Are They, Who Has Them & What Do They Mean for You? By Frederick S. Kaplan, M.D. and Eileen M. Shore, Ph.D.”]
      When we started seeing FOP patients, nearly 35 years ago, it quickly became obvious that everyone shared two features: malformed big toes and progressive HO. These were clearly two characteristic clinical features, and they defined classic FOP.
      As we saw more patients, we recognized variability in the toe malformation that individuals had, as well as differences in the rate of progression of HO. For example, some had short, bent big toes; others had short, straight big toes; others still had long big toes, and some were of normal length. But everyone had a toe malformation – most commonly characterized by a missing or malformed joint in the big toe that was obvious on physical examination, radiographs or both. Likewise, we noted variability in the rate of progression of the FOP HO – some progressed very rapidly while others progressed very slowly, and still others progressed at a more even pace. Much like other traits in any population, FOP showed a natural variation that defined the limits of the norm.
      Occasionally though, we saw someone who had a feature of FOP that was WAY outside of the “normal” range – even for those with FOP. This defining feature most often involves the big toes. Among these individuals, we began to recognize two groups: One group had nearly normal or completely normal-looking big toes. The other group had extremely severe toe malformations that involved other digits in the feet and the hands. In the more “severe” group, we observed additional developmental abnormalities in other organ systems. We refer to these two groups of outliers as “FOP variants” – some mild, some severe.
      Approximately 97% of individuals that we have seen with FOP HO had “classic FOP”, and approximately 3% of individuals were “FOP variants.” About half the patients with FOP variants (1.5%) had a mild clinical variant and about half the patients (1.5%) had a severe variant. Again, these observations were based on clinical evaluation and preceded the discovery of the FOP gene.
      After we discovered the FOP gene, we examined the DNA sequence of the FOP gene in all patients who we had seen. Remarkably, nearly every single patient who was diagnosed as having “classic FOP” – regardless of where they were on the spectrum of disease severity – had the same exact heterozygous missense activating FOP mutation: [ACVR1c.617G>A; p.R206H].
      As remarkable, every single patient who we had identified clinically as an “FOP variant” had a different heterozygous missense activating mutation in the ACVR1 gene.
      In other words, those with “classic FOP” as the clinical diagnosis had the same “classic mutation” in the FOP gene [ACVR1c.617G>A; p.R206H], while everyone clinically diagnosed as an “FOP variant” had a “variant mutation” in the FOP gene.
      While many will ask, “Is the HO less severe in the less severe variants and more severe in the more severe variants?” The answer is: “Sometimes, but not necessarily.” Some of the patients with mild toe variants have a later onset and a milder course of HO and some of the patients with severe toe variants have an earlier onset and more severe course of HO. But there is wide variability – just as there is in the onset and severity of HO in the patients with “classic FOP,” even among identical twins with classic FOP. The most important defining clinical feature of the “FOP variants” is the malformation of the big toes – either far less severe or far more severe than the patients with “classic FOP”.
      Although the clinical assessment is extremely important in assigning a clinical status of “classic FOP” vs. “FOP variant”, the only way to ascertain the exact type of FOP at a molecular level is by genetic testing and DNA sequence analysis of the FOP gene. To be clear, the absolute defining factor in whether someone has “classic FOP” or an “FOP variant” is the exact genetic sequence of the ACVR1 (FOP) gene. If someone has the commonly shared ACVR1c.617G>A; p.R206H mutation, then they have “classic FOP”. If they have a variant genetic mutation in the ACVR1 gene, then they have an “FOP variant”. So far, there are approximately 20 identified variants in the FOP gene.
      The evaluation of the FOP gene (ACVR1) by DNA sequencing can be conducted in a genetics laboratory through DNA obtained from a blood sample. The analysis can be arranged by your physician.
      Genotyping is required for enrollment into all clinical studies and is important for proper clinical and genetic counseling.
      Keep in mind that FOP variants are much rarer than classic FOP. Some of the ACVR1 variants have so far been found in only one or two affected individuals in the world, so it is difficult to make predictions about the course of FOP over time. With other variants, there may be a few affected individuals in the world, so we know a little bit more about the course that FOP variant may take over time.
      So, what does this all mean for someone who has an FOP variant?
      First, we have less knowledge and therefore less certainty about the FOP variants than we do about classic FOP; but we and other scientists are beginning to learn more about how ACVR1 variant mutations affect cell functions and how they are similar to and different from the classic ACVR1 mutation (Haupt et al., 2018; Mucha et al., 2018; Allen et al., 2020). The exact location and characteristic of the mutation in the ACVR1 gene (blueprint for the ACVR1 protein; classic vs. variant) informs the structural biologists with whom we work and collaborate to better understand the damaged workings of ACVR1 in FOP. That insight is critical to developing structural models and approaches to inactivating the damaged and overactive switch that leads to disabling HO in all forms of FOP.
      Second, regardless whether someone has “classic FOP” or an “FOP variant”, all have over-activity of the bone forming BMP signaling pathway and thus the tendency to form heterotopic bone.
      Third, whether someone has “classic FOP” or an “FOP variant”, the process by which they form heterotopic bone after birth is the same.
      Fourth, the general precautions for FOP are the same for patients with classic FOP and FOP variants.
      Fifth, the symptomatic management of flare-ups is the same for patients with classic FOP and FOP variants.
      Sixth, some of the approaches to develop medications for FOP are mutation-specific while others target the broad process of HO common to both.
      Seventh, approaches to specifically block the overactive ACVR1 receptor (encoded by the FOP gene) should be applicable to FOP variants as well as classic FOP.
      Eighth, new clinical trials will likely be limited at first to patients who have classic FOP – and then later, if applicable, to those with FOP variants – based primarily on regulatory requirements.
      Ninth, every measure and pressure are being exerted to open-up applicable clinical trials to patients with FOP variants as quickly and humanly possible. This is being done right now.
      Tenth, and finally, all patients with FOP – classic and variant FOP – are part of the small but powerful worldwide FOP community. There is a common thread that unites everyone with FOP. All with FOP must stay together, speak with one voice, and learn from each other. Knowledge will lead to better treatments and a cure for all of those with FOP regardless of whether one has “classic FOP” or an “FOP variant”.
      References
      Allen, RS, Tajer B, Shore EM, and Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife 9:e53761, 2020
      Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1mutations. Bone 109: 232-240, 2018
      Huning I & Gillessen-Kaesbach. Fibrodysplasia Ossificans Progressiva: Clinical Course, Genetic Mutations and Genotype-Phenotype Correlations. Molec Syndromology 5: 201-211, 2014
      Kaplan FS, Groppe JC, Xu M, Towler OW, Grunvald E, Kalunian K, Kallish S, Al Mukaddam M, Pignolo RJ, Shore EM. An ACVR1 R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva. Am J Med Genet A 188: 806-817, 2022
      Kaplan FS, Kobori JA, Orellana C, Calvo I, Rosello M, Martinez F, Lopez B, Xu M, Pignolo RJ, Shore EM, Groppe JC. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1c.772G>A; R258G): a report of two patients. Am J Med Genetic A 167: 2265-2271, 2015
      Kaplan FS, Xu M, Seemann P, Connor M, Glaser DL, Carroll L, Delai, P, Fastnact-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Morhart R, Pauli RM, Reardon W, Zaidi SA, Zasloff M, Mundlos S, Groppe J, Shore EM. Classical and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Human Mutation 30: 379-390, 2009
      Mucha BE, Hashiguchi M, Zinski J, Shore EM, Mullins MC. Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone 109: 225-231, 2018

37. FOP对患者及其家庭的影响

最近的一项国际疾病负担调查（NCT04665323）评估了进行性骨化性纤维发育不良（FOP）对患者及其家庭成员的身体、生活质量（QoL）和经济影响。来自15个国家的患者协会邀请其成员参与，符合条件的包括FOP患者及其家庭成员。调查于2021年1月18日至4月30日在线提供，支持11种语言。参与者回答了测量关节功能、生活质量、医疗服务和生活适应利用、个人支出、就业和旅行的评估。
调查共收到463份回复（患者219份；家庭成员244份）。对于患者，关节功能下降与生活质量降低和对生活适应的更大依赖相关。近一半的主要护理人员在健康/心理福祉方面感受到轻度至中度的影响。大多数主要护理人员和患者（≥18岁）表示，FOP影响了他们的职业选择。该调查的数据将有助于理解FOP对患者和家庭成员的影响，识别未满足的需求，优化护理，并改善对FOP社区的支持。
参考文献
  1. Al Mukaddam M, Toder KS, Davis M, Cali A, Liljesthröm M, Hollywood S, Croskery K, Grandoulier AS, Böing EA, Whalen JD, Kaplan FS. The impact of fibrodysplasia ossificans progressiva (FOP) on patients and their family members: results from an international burden of illness survey. Expert Rev Pharmacoecon Outcomes Res 22: 1199-1213, 2022 进行性骨化性纤维发育不良（FOP）对患者及其家庭成员的影响：来自国际疾病负担调查的结果
原文
  1. Impact of FOP on Patients and Family
      2. A recent international burden of illness survey (NCT04665323) assessed physical, quality of life (QoL), and economic impacts of FOP on patients and family members (Al Mukaddam et al., 2022). Patient associations in 15 countries invited their members to participate; individuals with FOP and their family members were eligible. The survey was available online, in 11 languages, from 18 January-30 April 2021. Participants responded to assessments measuring joint function, QoL, healthcare service and living adaptation utilization, out-of-pocket costs, employment, and travel.
      The survey received 463 responses (patients, n = 219; family members, n = 244). For patients, decreased joint function was associated with reduced QoL and greater reliance on living adaptations. Nearly half of primary caregivers experienced a mild to moderate impact on their health/psychological wellbeing. Most primary caregivers and patients (≥18 years) reported that FOP impacted their career decisions. Data from this survey will aid understanding of the impact of FOP on patients and family members as well as identifying unmet needs, optimizing care, and improving support for the FOP community.
      References
      Al Mukaddam M, Toder KS, Davis M, Cali A, Liljesthröm M, Hollywood S, Croskery K, Grandoulier AS, Böing EA, Whalen JD, Kaplan FS. The impact of fibrodysplasia ossificans progressiva (FOP) on patients and their family members: results from an international burden of illness survey. Expert Rev Pharmacoecon Outcomes Res 22: 1199-1213, 2022

38. FOP的未满足需求

对进行性骨化性纤维发育不良（FOP）患者未满足需求的细致关注至关重要，以防止潜在的医源性伤害并优化护理。FOP患者常常面临漫长的诊断过程、自我倡导的负担以及新的护理路径的挑战。
在全球范围内，FOP患者也面临着诊断和专科护理获取不平等的问题，因此，注册信息、临床试验以及来自患者协会的基本支持的获取也存在差异。国际进行性骨化性纤维发育不良协会（IFOPA；www.ifopa.org）、国际FOP临床委员会（ICC；www.iccfop.org）以及各国FOP组织致力于提供信息，促进专家临床指导的获取，培育患者赋权，资助FOP研究和/或与研究界建立有意义的合作。非营利组织Tin Soldiers全球FOP患者搜索项目旨在识别并为FOP患者提供诊断和护理的途径，特别是在服务不足的社区中。
这些全球性倡议以及日益广泛使用的远程医疗和数字平台为改善护理和研究的关键获取提供了机会。区域和国际组织在提升全球FOP社区中所触及者的生活质量方面发挥着重要作用。然而，全球范围内，在提高医疗专业人员对FOP的认识、识别FOP患者、缩短诊断时间以及确保最佳护理、支持和临床研究的获取等基本问题上仍然存在挑战。
参考文献
  1. Pignolo RJ, Bedford-Gay C, Cali A, Davis M, Delai PLR, Gonzales K, Hixson C, Kent A, Newport H, Robert M, Scott C, Kaplan FS. Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective. Orphanet J Rare Dis 17:168, 2022 当前进行性骨化性纤维发育不良（FOP）患者护理中的挑战与机遇：来自国际多方利益相关者的视角
原文
  1. Unmet Needs in FOP
      2. Assiduous attention to the unmet needs of individuals with FOP is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP. Individuals with FOP often face the frustration of long diagnostic journeys, the burden of self-advocacy and the navigation of novel care pathways.
      Globally, patients with FOP are also confronted with inequities in access to diagnosis and specialist care, and consequently, unequal access to registries, clinical trials, and essential support from patient associations. Organizations such as the International Fibrodysplasia Ossificans Progressiva Association (IFOPA; www.ifopa.org), the International Clinical Council on FOP (ICC; www.iccfop.org), and national FOP organizations work to provide information, facilitate access to expert clinical guidance, nurture patient empowerment, fund FOP research and/or foster meaningful collaborations with the research community. The non-profit Tin Soldiers Global FOP Patient Search program aims to identify and provide a pathway to diagnosis and care for individuals with FOP, particularly in underserved communities.
      Such global initiatives and the increasingly widespread use of telemedicine and digital platforms offer opportunities to improve vital access to care and research. Regional and international organizations play an important role in improving the quality of life of those they reach in the global FOP community. However, globally, fundamental issues remain around raising awareness of FOP among healthcare professionals, identifying individuals with FOP, reducing time to diagnosis, and ensuring access to best practice in care, support, and clinical research (Pignolo, Bedford-Gay et al., 2022).
      References
      Pignolo RJ, Bedford-Gay C, Cali A, Davis M, Delai PLR, Gonzales K, Hixson C, Kent A, Newport H, Robert M, Scott C, Kaplan FS. Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective. Orphanet J Rare Dis 17:168, 2022

第六章. 当前治疗考虑事项

目前，针对进行性骨化性纤维发育不良（FOP）的治疗手段有限。该疾病的稀有性、病程的变异性以及临床表现的波动性在评估实验疗法时带来了相当大的不确定性。
在评估每种治疗时，我们重点关注药物的已知作用机制，以及其与FOP提出的发病机制的相关性。对每种药物的使用考虑基于当前的监管批准，或在没有批准的情况下，权衡使用每种药物治疗FOP时的临床不确定性与充分安全地控制该疾病的致残症状（特别是在急性发作期间）的同情需求。每种药物被根据其在III期临床试验结果和批准用途、实验性或案例经验以及药物安全性资料的知识分类为四类之一。
监管批准药物：已获得至少一个监管机构（如美国食品药品监督管理局FDA）批准的药物。
示例：长期和间歇性使用palovarotene（SohonosTM）
这些药物被广泛用于控制FOP急性发作时的症状（如肿胀和疼痛）或慢性关节病，通常副作用较小。
I类药物：
示例：短期使用高剂量皮质类固醇，非甾体抗炎药（NSAIDs）和COX-2抑制剂。
这些药物在FOP的不同方面有理论上的应用，已获得其他疾病的治疗批准，并且具有有限且良好描述的效果。
II类药物：
示例：白三烯抑制剂（Montelukast）、肥大细胞稳定剂（Cromolyn）、氨基双磷酸盐（Pamidronate；Zoledronate）、特定的酪氨酸激酶抑制剂（Imatinib）、Janus激酶抑制剂（Tofacitinib）或IL-1β抑制剂（Canakinumab）。
III类药物：
研究性和新药物示例：选择性ACVR1/ALK2信号转导抑制剂、靶向激活素或MMP-9的单克隆抗体。
治疗FOP患者的医生应牢记，迄今为止，以上药物（或任何其他药物）尚未证明能够改变FOP的自然病程。
我们强调，本报告反映了作者在各种症状调节药物类别方面的经验和观点，仅作为这一有争议的治疗领域的指南。尽管每位FOP患者都有一些共同的身体特征，但个体之间的差异可能会影响所讨论的任何药物或药物类别的潜在益处或风险。是否使用或停用特定药物的决定最终应由患者及其医生共同作出。
I类药物可以考虑用于涉及主要肢体骨骼主要关节的急性发作，建议立即使用泼尼松，以2 mg/kg/天（最多100 mg）的剂量进行单次每日用药，最多四天。为了获得最佳效果，泼尼松应在发作开始后的24小时内开始使用，此时对应急性和强烈淋巴细胞浸润骨骼肌的早期阶段。如果发作已超过两天，泼尼松通常效果较差。如果发作对药物有反应，但在停用泼尼松后复发，可以考虑重复四天的疗程，并随后逐渐减量十天。通常不应将泼尼松用于胸部或躯干的发作，因为难以判断新发作的确切开始时间。长期或慢性使用皮质类固醇没有益处，可能加速异位骨化（HO），并对身体有害，不应考虑。此外，慢性或长期使用可能抑制垂体-肾上腺轴，导致长期有害影响。泼尼松的使用仅用于抑制或中止急性FOP急性发作早期的炎症事件，并可能抑制FOP发作早期阶段骨骼肌的随后的死亡。
当停用泼尼松时（或考虑治疗已有超过48小时的发作时），可以考虑使用非甾体抗炎药进行对症治疗。可以使用环氧合酶-2（COX-2）抑制剂代替传统的NSAID（见表1）。与所有非甾体抗炎药一样，应采取胃肠道预防措施。如果考虑长期使用COX-2抑制剂，应监测血清肝肾功能测试。在有心血管疾病病史的FOP患者或严重失能或完全不具备行走能力的老年FOP患者中，使用COX-2抑制剂应谨慎。
II类药物可在医生的判断下谨慎考虑。
III类药物正在开发中，正在临床试验中，尚未普遍使用。
原文
At the present time, there are limited treatments for FOP. The disorder’s rarity, variable severity, and fluctuating clinical course pose substantial uncertainties when evaluating experimental therapies.
In evaluating each treatment, we have focused on the known mechanism of action of the drug as it relates to the proposed pathogenesis of FOP. Consideration for use of each medication was made based on current regulatory approval, or if no approval, balancing the clinical uncertainty of each agent when used to treat FOP against the compassionate need to control the disabling symptoms of the disease adequately and safely, especially during flare-ups. Each pharmacologic agent was classified into one of four categories based on Phase 3 clinical trial results and approved use, experimental or anecdotal experience with the drug, as well as knowledge of each drug’s safety profile.
Regulatory-approved: Medications that have been approved by at least one regulatory authority (e.g., U.S. Federal Drug Administration, or FDA).
Examples: Chronic and episodic use of palovarotene (SohonosTM )
Medications that have been widely used to control symptoms of acute flare-ups in FOP (swelling and pain), or chronic arthropathy - with generally minimal side effects.
Class I:
Examples: Short-term use of high-dose corticosteroids, and use of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors.
Medications that have theoretical application to various aspects of FOP, are approved for the treatment of other disorders, and have limited and well-described effects.
Class II:
Examples: Leukotriene inhibitors (Montelukast), mast cell stabilizers (Cromolyn), aminobisphosphonates (Pamidronate; Zoledronate), specific tyrosine kinase inhibitors (Imatinib), Janus kinase inhibitors (Tofacitinib), or IL-1β inhibitors (Canakinumab).
Class III:
Investigational and new drugs Examples: Selective ACVR1/ALK2 signal transduction inhibitors, monoclonal antibodies targeting Activin or MMP-9.
PHYSICIANS TREATING PATIENTS WHO HAVE FOP SHOULD KEEP IN MIND THAT NONE OF THESE MEDICATIONS (OR ANY OTHER MEDICATIONS TO DATE) HAVE BEEN PROVEN TO ALTER THE NATURAL HISTORY OF FOP
We emphasize that this report reflects the authors’ experience and opinions on the various classes of symptom-modifying medications and is meant only as a guide to this controversial area of therapeutics. Although there are common physical features shared by every person who has FOP, there are differences among individuals that may alter the potential benefits or risks of any medication or class of medications discussed here. The decision to use or withhold a particular medication must ultimately rest with an individual patient and his or her physician.
Class I Medications can be considered for acute flare-ups involving the major joints of the major appendicular skeleton, the immediate use of prednisone at a dose of 2 mg/kg/day (up to 100 mg) can be considered as a single daily dose for a maximum of four days. For maximal beneficial effect, the prednisone should be started within 24 hours of the onset of a flare-up, which corresponds to the earliest phase of acute and intense lymphocytic infiltration into skeletal muscle. If the flare-up is more than two days old, prednisone is generally less effective. If the flare-up responds to the medication but recurs when the prednisone is discontinued, a repeat 4-day course with a subsequent 10-day taper can be considered. Prednisone should generally not be used for flare-ups on the chest or trunk, as it is difficult to judge the exact onset of a new flare-up. Prolonged or chronic use of corticosteroids is of no benefit, may accelerate heterotopic ossification (HO), is harmful systemically, and should not be considered. Furthermore, suppression of the pituitary-adrenal axis is likely to occur with chronic or long-term use and can have longterm harmful effects. The use of prednisone is meant only to suppress or abort the early inflammatory events of an acute FOP flare-up, and potentially suppress the subsequent death of skeletal muscle in the earliest stages of an FOP flare-up.
When prednisone is discontinued (or if a flare-up existing for more than 48 hours is being considered for treatment), symptomatic treatment may be considered with a non-steroidal anti-inflammatory agent. A cyclooxygenase-2 (COX-2) inhibitor can be used instead of a traditional NSAID (Table 1). As with all nonsteroidal anti-inflammatory medications, gastrointestinal precautions should prevail. If long-term use of the COX-2 inhibitors is considered, serum liver and kidney function tests should be monitored. COX-2 inhibitors should be used with caution in FOP patients with a history of cardiovascular disease or in older FOP patients who are severely immobilized or completely non-ambulatory.
Class II Medications can be considered with caution, at the physicians’ discretion.
Class III Medications are under development, being tested in clinical trials and are not yet available for general use.

第七章. 药物类别（表1）

已获得监管批准的药物:
通用药物
商品名
类别
作用机制和机理
剂量
主要副作用
帕罗伐汀(Palovarotene)
Sohonos TM 美国、加拿大和澳大利亚获批 Sohonos 教育计划，任何希望开处方 Sohonos 的医疗专业人员必须完成该计划。教育计划材料可以在以下网址找到：Support and Resources
Support and Resources

Support and Resources

According to the International Clinical Council (ICC) Guidelines, a multidisciplinary approach is essential to providing optimal patient care and lessening the chance for potentially harmful interventions.1

RAR-γ 激动剂
抑制异位软骨发生
适用于14岁及以上的成人和儿童患者： 每日5毫克。当开始使用加量治疗时停止每日用药。14岁及以上成人和儿童的加量治疗剂量为每日20毫克，持续4周，随后为每日10毫克，持续8周（总共12周的加量治疗），即使症状提前缓解，也要遵循此方案。然后恢复每日5毫克的常规剂量。 如果在加量治疗期间，患者原有的加量部位明显恶化或在新部位出现新的加量，需重新开始12周的加量治疗，剂量为每日20毫克。对于在12周结束时尚未缓解的加量症状，可以每4周延长10毫克的每日剂量，直到加量症状缓解为止。 如果在恢复每日5毫克剂量后出现新的发作症状，可以重新开始发作剂量。 对于14岁以下的患者（女性8-13岁，男性10-13岁）：剂量根据体重进行调整，包括预防性和发作剂量。 请参见处方信息：d2rkmuse97gwnh.cloudfront.net
d2rkmuse97gwnh.cloudfront.net

d2rkmuse97gwnh.cloudfront.net

处方信息可以在以下网址找到：www.accessdata.fda.gov
www.accessdata.fda.gov

www.accessdata.fda.gov

 患者用药指南可以在IpsenCares网站（ipsencares.com）找到：d2rkmuse97gwnh.cloudfront.net
d2rkmuse97gwnh.cloudfront.net

d2rkmuse97gwnh.cloudfront.net

 早期骨骺闭合：使用SOHONOS可能会发生早期骨骺闭合。在开始SOHONOS治疗之前，评估基础骨骼成熟度，并在生长中的儿童患者中监测线性生长。 建议生长中的儿童患者在开始治疗之前进行生长和骨骼成熟度的基线评估，并在达到骨骼成熟或最终成年身高之前，每6到12个月进行持续的临床和影像学监测。 粘膜皮肤不良反应：使用SOHONOS可能出现干燥皮肤、嘴唇干燥、瘙痒、皮疹、脱发、红斑、皮肤剥落和干眼症。可使用皮肤软化剂、防晒霜和人工泪液进行预防或治疗。一些患者可能需要减少剂量。 代谢性骨病：可能出现脊椎骨矿物质含量和骨密度降低。需定期通过放射学方法评估脊椎骨折。 精神疾病：使用SOHONOS可能出现抑郁、焦虑、情绪变化以及自杀念头和行为。如患者出现新的或加重的症状，请联系医疗服务提供者。 夜盲症：可能发生，驾驶时在夜间危险。 妊娠：可能对胎儿造成伤害。
I类药物:
通用药物
商品名
类别
作用机制和机理
剂量
主要副作用
泼尼松（片剂） 泼尼松龙（液体）
Deltasone
皮质类固醇
减少淋巴细胞和巨噬细胞的招募及组织浸润；强效抗炎药：减少炎症、肿胀和水肿，尤其是在涉及下颌、喉咙和主要关节时。
对于涉及主要关节的急性发作，口服（PO）每天早晨一次，剂量为每千克体重2毫克，持续4天（最大剂量为100毫克/天）。发作通常是由于过度使用和软组织损伤引起的。泼尼松（Prednisone）– 每千克体重1-2毫克（口服），每天一次，持续3-4天，以防止严重软组织损伤后的发作。可以重复使用4天，然后逐渐减量，持续最长可达2周。 - 不要在轻微的碰撞或瘀伤后使用。 - 不要用于涉及胸部或背部的发作（参见正文）。 - 在牙科或外科手术过程中按指示预防性使用泼尼松。 对于影响呼吸或吞咽的下颌区域的发作，也可以使用更长时间的治疗并逐渐减量。 泼尼松或泼尼松龙应在发作发生后的24小时内开始使用，以获得最佳效果。 （药物应与食物一起服用）。 对于频繁发作且需要长期类固醇治疗的患者，应考虑使用双磷酸盐以防止类固醇引起的骨质疏松症（参见正文）。 对于生活在地方性流行地区的患者，可能需要采取抗寄生虫预防措施。 另外，可以考虑高剂量静脉皮质类固醇（甲基泼尼松龙或泼尼松龙钠）治疗，但必须在住院期间进行，以监测高血压等潜在副作用。 静脉皮质类固醇治疗的方案如下： 每天7-15 mg/kg的甲基泼尼松龙或20-30 mg/kg的泼尼松龙钠，连续三天静脉给药。 有些人 prefer每隔一天给药，因为一些患者对这种方式的耐受性更好。例如： 第1天：20-30 mg/kg的甲基泼尼松龙静脉给药 第2天：不使用药物 第3天：20-30 mg/kg的甲基泼尼松龙静脉给药 第4天：不使用药物 第5天：20-30 mg/kg的甲基泼尼松龙静脉给药 甲基泼尼松龙或泼尼松龙钠的总日剂量不得超过1000 mg。
~ 痤疮 ~ 肾上腺抑制 ~ 髋关节无血管坏死 ~ 白内障 ~ 慢性依赖 ~ 库欣综合征 ~ 糖尿病 ~ 青光眼 ~ 生长迟缓 ~ 高血压 ~ 免疫抑制 ~ 骨质疏松 ~ 胃溃疡 ~ 皮肤淤伤 ~ 睡眠和情绪障碍 ~ 体重增加
布洛芬
Advil/Motrin
非甾体抗炎药（非特异性COX-1和COX-2抑制剂）
抗炎和抗血管生成；在发作期间缓解症状；通过抑制炎症前列腺素的产生，具有潜在的预防作用。
儿童：根据需要，每6小时口服4-10毫克/千克。 成人：根据需要，每6小时口服200-800毫克。药物必须随餐服用。
~ 胃肠道出血 ~ 肾功能受损
吲哚美辛
Indocin
非类固醇抗炎药（非特异性COX-1和COX-2抑制剂）
抗炎和抗血管生成；在发作期间缓解症状；通过抑制炎症前列腺素的产生，具有潜在的预防作用。
儿童：口服每日2-4 mg/kg；或每日150-200 mg（以较少者为准）；分为三次服用。 成人：口服50 mg，每日三次；或使用Indocin-SR（缓释剂型），剂量为每日75 mg，口服每日两次。 药物必须与食物一起服用。
~ 胃肠道出血 ~ 肾功能受损
塞来昔布
Celebrex
COX-2抑制剂
抗炎和抗血管生成；在发作期间缓解症状；通过抑制炎症前列腺素的产生，具有潜在的预防作用。
儿童和成人：维持剂量为每日口服100-200 mg，具体由医生决定。 对于急性和慢性发作，剂量不得超过每平方米250 mg的最大抗血管生成剂量，或每千克6 mg（以较低者为准；四舍五入到最接近的100 mg的倍数），且每日总剂量不得超过600 mg，持续时间不超过16个月。药物应与含脂肪的小吃一起服用，以达到最佳吸收效果。
~ 胃肠道出血 ~ 肾功能受损 ~ 存在心血管和脑血管风险的顾虑 ~ 不适用于已知对磺胺类药物过敏的患者或对阿司匹林敏感的哮喘患者
II类药物:
通用药物
商品名
类别
作用机制和机理
剂量
主要副作用
孟鲁司特
Singulair
白三烯受体拮抗剂
阻断炎症介质；与环氧合酶抑制剂具有互补作用。
儿童：（2-5岁）：睡前口服4毫克；6-14岁：睡前口服5毫克 成人：睡前口服10毫克
~ 通常耐受性良好。很少发生：血管神经性水肿、头痛、流感样综合症、疲劳、腹痛；可能与行为/情绪变化、自杀念头和行为以及自杀相关。应监测患者的行为和情绪变化。
色甘酸钠
Gastrocrom
肥大细胞稳定剂
减少肥大细胞脱颗粒，但在胃肠道的吸收较差。若长期使用，可能更有效。
儿童：（0-2岁）：每日20毫克/公斤，口服，分为四次；（2-12岁）：每日100毫克，口服，分为四次。 成人：每日200毫克，口服，分为四次。
~ 一般来说，耐受性极好。很少出现：喉咙刺激、喉咙干燥、咳嗽、苦味。
帕米膦酸钠
Aredia
氨基二膦酸盐
抗血管生成；可能具有抗炎作用；潜在抑制早期血管生成性纤维增生病变；在正常骨骼中降低骨重建的作用得到充分证实，并能保护正常骨骼免受长期间歇性高剂量糖皮质激素的显著骨质疏松影响。
儿童（2-3岁）：以每公斤体重0.75毫克的剂量，通过缓慢静脉输注，持续三天； 对于3岁以上的儿童、青少年和成年人：以每公斤体重1.0毫克的剂量，持续三天。 药物应每天缓慢输注，持续4-5小时。 注意：在第一个治疗周期的第一天，患者必须接受一半的剂量。如出现发热，应给予标准的对乙酰氨基酚治疗。 3天的治疗周期每年不得超过4次。有关稀释说明，请参见文本。 在接受帕米膦酸盐治疗之前，患者应检查以下血液检测：血清钙、磷、白蛋白、碱性磷酸酶、25-羟基维生素D、BUN、肌酐、CBC。 所有患者在接受帕米膦酸盐治疗期间及治疗后应每日补充足够的膳食钙和维生素D，且持续进行。
通常耐受性良好。在肾功能不全时禁用。 ~在静脉输注帕米膦酸盐期间，常见急性期反应表现为发热、全身不适和肌肉疼痛，可能持续18-24小时。预处理使用对乙酰氨基酚可能减轻症状。 ~如出现发热或其他急性期反应症状，应给予标准的对乙酰氨基酚治疗。 ~帕米膦酸盐不应用于低钙血症患者，因为可能导致抽搐，并且在FOP患者中后续管理低钙血症可能非常困难。 所有接受帕米膦酸盐治疗的患者应每日补充钙和维生素D（不仅仅在输注日，而是每天持续至少两周）。在儿童中频繁高剂量使用氨基双膦酸盐可能导致骨质增生以及可能的低能量股骨骨折。 另请参见文本中关于下颌骨坏死的注意事项。
唑来膦酸
Zometa
氨基二膦酸盐
抗血管生成；可能具有抗炎作用；潜在抑制早期血管生成性纤维增生病变；在正常骨骼中降低骨重建的作用得到充分证实，并能保护正常骨骼免受长期间歇性高剂量糖皮质激素的显著骨质疏松影响。
所有患者在接受唑来膦酸治疗期间及治疗后应每日补充足够的膳食钙和维生素D，且持续进行。 儿童和青少年：安全性和有效性尚未确定。 成年人：静脉注射5毫克，至少持续15分钟。 针对肾功能和肝功能损害、血液系统毒性和非血液系统毒性进行剂量调整。
~ 预先服用对乙酰氨基酚可以减轻症状。如出现发热或其他急性反应症状，请给予标准的对乙酰氨基酚治疗。 ~ 唑来膦酸不应用于低钙血症患者，因为可能导致手足抽搐，而在FOP患者中后续管理可能困难。 ~ 所有接受唑来膦酸治疗的患者应每日补充足够的钙和维生素D（不仅仅是在输注日，而是持续至少两周）。 ~ 在儿童中频繁高剂量使用氨基二膦酸盐可能导致骨质增生和可能的低能量股骨骨折。 另请参见文本中关于下颌骨坏死的注意事项。 ~迄今为止尚未进行随机安慰剂对照试验以证明疗效；一项病例系列表明可能对减少发作强度有益，但数据是个案报告。
伊马替尼
格列卫-Gleevec
选择性酪氨酸激酶抑制剂
阻断 c-Kit、HIF-1α、PDGFRα 和多种 MAP 激酶的非靶向效应（Kaplan 等，2018；Kaplan 等，2021）。
伊马替尼应始终在成人或儿童肿瘤学家或风湿病医生的指导下开处方。
最常见的副作用 骨髓抑制：可能导致骨髓抑制（贫血、中性粒细胞减少和血小板减少），通常发生在治疗的头几个月内。中性粒细胞减少的中位持续时间为2到3周；血小板减少的中位持续时间为2到4周。治疗的前一个月每周监测血常规，第二个月每两周监测，之后根据临床需要进行监测。 液体潴留/水肿：伊马替尼常与液体潴留、体重增加和水肿相关（风险随着剂量增加和年龄超过65岁而增加）。 胃肠道毒性：伊马替尼具有中等的呕吐潜力；可能建议使用抗呕吐药物以防止恶心和呕吐。可能导致胃肠道刺激；建议与食物和水一起服用以减少刺激。 肝毒性：可能出现肝毒性；在治疗开始前和之后每月监测肝功能（转氨酶、胆红素和碱性磷酸酶），或根据需要进行监测。 肾毒性：伊马替尼与肾功能下降相关；可能与治疗持续时间有关。
托法替尼
Xeljanz
JAK抑制剂
JAK抑制剂代表了一类新的疾病修饰抗风湿药物（DMARDs），具有抗炎特性，并获得FDA批准用于治疗特发性青少年关节炎以及其他风湿病和溃疡性结肠炎。 在Nikishina等人于2023年进行的一项FOP病例系列中，5名患者中有4名（80%）的IL-1RA水平下降，而1名（20%）的水平上升，表明在FOP中，其作用机制至少部分与抑制炎症细胞因子相关。
在Nikishina等人于2023年发表的FOP病例系列中发现，5毫克每日两次（口服给药）具有益处，文献来源为《儿科风湿病学》21:1-9，BioMed CentralBioMed CentralSuccessful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva - Pediatric Rheumatology
Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva - Pediatric Rheumatology

Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva - Pediatric Rheumatology

Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways.

BioMed CentralBioMed Central
 该药物也有延释制剂（XR），剂量为每日11毫克，或更高的诱导剂量为每日两次10毫克或每日一次22毫克（XR），持续8周。此外，还有1毫克/毫升的口服溶液可供使用。
FDA黑框警告：严重感染、死亡率、恶性肿瘤、重大不良心血管事件（MACE）和血栓形成 ~已报告因细菌、分枝杆菌、侵袭性真菌、病毒或其他机会性病原体引起的严重且有时致命的感染。 ~在50岁及以上、具有至少一种心血管风险因素的患者中，观察到更高的全因死亡率，包括突发性心血管死亡。 ~在临床研究中观察到恶性肿瘤，包括淋巴瘤和实体癌。 ~在接受治疗的患者中发生血栓形成，包括肺栓塞（PE）、深静脉血栓（DVT）和动脉血栓，其中一些导致死亡。 ~观察到如血管神经性水肿和荨麻疹等反应，可能反映出药物过敏反应。 ~已观察到实验室异常，包括淋巴细胞减少、 neutropenia（中性粒细胞减少）、贫血和肝酶升高。 ~应避免使用活疫苗。避免在已有胃肠道狭窄的情况下使用。 ~关于在怀孕、哺乳期的使用信息非常有限，并且对患有FOP的成人使用信息也有限。 在开始治疗前，评估高风险感染，包括结核病筛查。 在糖尿病和肝功能不全患者中使用时需谨慎，同时应注意与非甾体抗炎药（NSAIDs）的联合使用。
卡那单抗
Ilaris
IL-1β 抑制剂
抗体可阻断IL-1β促炎细胞因子。此药已获得FDA批准，用于治疗4岁及以上儿童的CAPS、Muckle-Wells综合征和FCAS。在Haviv等人于2024年进行的FOP无对照病例系列中，4名患者的发作活性减少了61~89%。
遵循FMF的给药方案。在体重<40公斤时，起始剂量为每4周2 mg/kg，可以增加到4 mg/kg。对于体重>40公斤的患者，起始剂量为每4周150 mg。最大剂量为每4周300 mg皮下注射（这是用于FMF的最大剂量）。
增加严重感染的风险。 在开始之前，应评估高风险感染，包括结核筛查。 活疫苗是禁忌的。 关于在妊娠或哺乳期间使用的信息尚无，且在FOP成人中的使用信息有限。
III类药物：
通用药物
商品名
类别
作用机制和机理
剂量
主要副作用
ACVR1/ALK2信号转导抑制剂 (STI)
塞卡替尼 (Saracatinib)（阿斯利康；STOPFOP研究小组）
信号转导抑制剂
阻断 ACVR1/ALK2 信号转导
目前不适用；正在进行的 II 期临床试验。
见：IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva AssociationOngoing Clinical Trials in FOP
Ongoing Clinical Trials in FOP

Ongoing Clinical Trials in FOP

Clinical trials are an integral part of drug development and are required before a medicine can be available by prescription.

IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva Association
ACVR1/ALK2信号转导抑制剂 (STI)
IPN60130（Ipsen）FALKON 试验。
信号转导抑制剂
阻断 ACVR1/ALK2 信号转导
目前不适用；正在进行的 II 期临床试验。
见：IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva AssociationOngoing Clinical Trials in FOP
Ongoing Clinical Trials in FOP

Ongoing Clinical Trials in FOP

Clinical trials are an integral part of drug development and are required before a medicine can be available by prescription.

IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva Association
ACVR1/ALK2信号转导抑制剂 (STI)
INCB000928 (Incyte) PROGRESS 试验
信号转导抑制剂
阻断 ACVR1/ALK2 信号转导
目前不适用；正在进行的 II 期临床试验。
见：IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva AssociationOngoing Clinical Trials in FOP
Ongoing Clinical Trials in FOP

Ongoing Clinical Trials in FOP

Clinical trials are an integral part of drug development and are required before a medicine can be available by prescription.

IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva Association
mTOR 抑制剂
雷帕霉素（京都大学）
mTOR 抑制剂
抑制ACVR1/ALK2信号传导
目前不适用；正在进行的 II 期临床试验。
尚未确定
针对Activin A的单克隆抗体
Garetosmab（再生元）
Activin A 抗体
通过突变的 ACVR1/ALK2 阻断 Activin A 信号传导。
目前不适用；正在进行的 III 期临床试验。
见：IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva AssociationOngoing Clinical Trials in FOP
Ongoing Clinical Trials in FOP

Ongoing Clinical Trials in FOP

Clinical trials are an integral part of drug development and are required before a medicine can be available by prescription.

IFOPA - International Fibrodysplasia Ossificans Progressiva AssociationIFOPA - International Fibrodysplasia Ossificans Progressiva Association
针对 MMP-9 的单克隆抗体
安地昔单抗（Andecaliximab，āshibio）
MMP-9抗体
减少巨噬细胞和基质储存中Activin-A的释放；可能对所有HO因子具有多重作用。
目前不适用；正在进行的II/III期临床试验
见：Sandborn WJ, et al. Aliment Pharmacol Ther. 2016; 44(2): 157-69; Gossage DL, et al. Clin Ther. 2018; 40(1): 156-65; Sanborn WJ, et al. J Crohn’s Colitis. 2018; 12(9): 1021-9
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第八章. 紧急救援人员、医生和牙医的急救指南

  1. 避免所有肌肉内注射，除非对患者生存至关重要。这可能会导致病情加重和后续骨化。
  1. 外周静脉注射是允许的。使用尽可能小的针头，并缩短止血带的时间。避免反复使用止血带或过度充气血压袖带。
  1. 除非对患者生存必要，避免中心静脉插管。
  1. 在重大创伤情况下，立即开始口服或静脉注射等效的类固醇（泼尼松）：每日1-2 mg/kg，连续4天。
  1. 给所有骨突起垫上保护物，以防止压疮和皮肤破损。
  1. 颈椎常因FOP部分或完全强直。请勿进行操作。
  1. 下颌运动可能受到限制或功能性强直。即使活动，极易受到创伤。请勿被动操作。禁止过度拉伸和下颌阻滞，以免引发病情加重。
  1. 前颈部的病情加重可能影响呼吸和吞咽，应视为医疗紧急情况。这些下颌病灶加重需及早识别。立即给予高剂量类固醇（静脉注射索鲁美德龙（Solumedrol）80 mg或Dexamethasone15 mg）。避免因病灶操作造成额外创伤。必须进行气道监测、吸引预防、营养支持，并立即使用类固醇。
      2. Flare-ups of the anterior neck can compromise breathing and swallowing and should be considered a medical emergency. These submandibular flare-ups require early identification. Provide high dose steroids immediately (Solumedrol 80 mg iv or Dexamethasone 15 mg iv). Avoid additional trauma with lesional manipulation. Airway monitoring, aspiration precautions, nutritional support, and immediate use of corticosteroids are mandatory.
  1. 头颈部损伤常因跌倒而发生，因为肩部的强直使手臂在早期生活中变得僵硬，无法在跌倒时保护头部。
  1. 发生头部损伤时，务必固定颈部。
  1. 任何头部损伤，即使没有失去意识，均需进行头部CT扫描，以排除因未受保护的撞击导致的颅内出血。
  1. 年轻患者头部病情加重可表现为非常大的头皮肿胀，且最初可能会导致面部畸形。对于头皮病情加重应采取保守治疗，进行监测，并在必要时进行疼痛控制。头皮肿胀会随时间自愈，畸形程度极小或不存在，因为新的骨化会融入生长中的颅骨。
  1. 因头皮病情加重导致的面部肿胀在FOP患者中并不常见，但可能发生。应考虑其他面部肿胀的病因，如药物反应和海绵窦血栓。对于出现面部肿胀的FOP患者，应考虑短期使用抗组胺药物，以排除过敏反应。
  1. 对于口面部区域的肿胀或疼痛，建议进行全面的牙科检查，因为很难区分牙源性肿胀与FOP病情加重。如果牙科X光和/或牙髓测试（牙齿神经活力）未显示明显的牙源性肿胀，建议假设为FOP病情加重并开始使用泼尼松进行处理。如果无法进行牙科X光或牙髓测试，则应同时开具适当的抗生素和泼尼松，直到可以做出明确诊断。
  1. 对于“脏”或污染的伤口，使用破伤风高免疫球蛋白。除非必要，避免进行肌肉内或皮下破伤风免疫接种，因为这可能引发病情加重。
  1. FOP患者常见听力受损。说话时要大声清晰。
  1. 尽管在儿童中稳定的听力损失是FOP的常见特征，但急性听力丧失和耳痛并不常见，应像对待任何儿童一样进行评估和治疗。
  1. 牙痛是FOP患者中常见的问题，必须及时评估和治疗，但需在与FOP牙科专家充分咨询后进行。禁止过度拉伸下颌和下颌阻滞。
  1. FOP成年人中肾结石非常常见。保持良好的水分摄入。
  1. 正常及异位骨折均较常见。建议采用闭合固定、夹板和支架。除非与FOP专家充分讨论，否则不建议进行开放复位。
  1. 对于下颌强直的患者出现恶心和呕吐时，需经验性使用抗生素以预防吸入性肺炎。
  1. FOP病情加重时，四肢可能出现急性且严重的肿胀，特别是在下肢。由于强烈的炎症、血管生成和毛细血管渗漏，这种肿胀可能变得异常巨大，导致神经和组织淋巴管的血管外压迫。在排除可能的深静脉血栓后，应采用保守治疗，包括适当的疼痛控制、抬高肢体，并最终进行安全的淋巴水肿处理。尽管分腔综合征的迹象和症状可能会促使考虑紧急手术释放压力（例如，筋膜切开术），但这会加重病情加重，必须避免。如果临床怀疑分腔综合征的可能性很高，可以考虑使用甘露醇。
  1. 如果四肢肿胀引起对深静脉血栓的担忧，可能需要对静脉系统进行多普勒超声评估。
  1. 询问患者是否参与任何FOP临床试验，并与主要研究者及地区FOP专家沟通。
  1. 如果患者窒息且无法手动清除喉咙，且没有证据显示腹部有异位骨，则可进行海姆立克手法。
  1. 胸部按压可能是徒劳的。胸壁是僵硬和不动的。
  1. 插管必须由经验丰富的麻醉师通过清醒的纤维支气管镜鼻气管途径进行。
  1. 如果在前颈部有骨化的个体中需要进行紧急气管切开，可能需要使用牙钻或其他钻头来创建气道。
  1. 在紧急情况下，如果患者清除分泌物困难，可使用支气管扩张剂、化痰药和愈创木脂，且对于机械通气装置的使用阈值应降低。应通过静脉输液优化水分摄入。
  1. 避免无监测的补充氧气使用，以降低呼吸衰竭和死亡的风险。
关于FOP麻醉和气道问题的咨询：
Zvi Grunwald, MD
詹姆斯·D·温茨勒教授及麻醉学系名誉主席
托马斯·杰斐逊大学
111 South 11th Street, Suite G-8490
费城, PA 19107, USA
电话: 215-955-6161
手机: 215-206-7362
传真: 215-923-5507
电子邮件: [email protected]
关于紧急牙科护理的咨询：
Corrie Crowe, DDS
1793 Springdale Road
Cherry Hill, NJ 08003, USA
电话: 856-258-4025 (接待员: Lynn)
传真: 856-504-6179
电子邮件: [email protected]
Lisa Friedlander, DDS, PHD
口腔修复学副教授
巴黎大学
罕见口腔和牙科疾病参考中心主任
皮蒂·萨尔佩特里耶医院-查尔斯·福伊医院, 巴黎, 法国
Inserm UMR 1123, Lab Eceve
Imagine研究所
电话: 0033614395531
电子邮件: [email protected]
Clive S. Friedman, DDS, FAAPD
临床助理教授
舒立克医学院和牙科学院
Imagine Dentistry
1800 Hyde Park Road Unit # 2
伦敦, 安大略省 加拿大 N6h OK1
办公室: 519-914-2987
住宅: 519-438-1198
手机: 519-657-6014
个人电子邮件: [email protected]
关于医院牙科和牙科手术的咨询：
Robert Diecidue, MD, DMD, MBA, MPH
托马斯·杰斐逊大学
杰斐逊医学院
口腔和颌面外科系主任及教授
909 Walnut Street - Suite 300
费城, Pennsylvania 19107, USA
电话: 215-955-6215; 215-955-5131
传真: 215-923-9189
电子邮件: [email protected]
Marjolijn Gilijamse MD
颌面外科系
阿姆斯特丹大学医学中心
De Boelelaan 1117, 1081HV
阿姆斯特丹, 荷兰
电子邮件: [email protected]
原文
  1. Avoid all IM injections unless necessary for survival of the patient. They will likely cause flareups and subsequent ossification.
  1. Peripheral IVs are permissible. Use smallest needle possible with brief tourniquet time. Avoid repeated tourniquet use or over-inflation of blood pressure cuffs.
  1. Avoid central venous access unless necessary for survival of the patient.
  1. In case of major trauma, begin corticosteroids immediately (oral) or IV equivalent of oral Prednisone - 1-2 mg/kg once daily for 4 days.
  1. Pad all bony prominences to prevent pressure ulcers and skin breakdown.
  1. The cervical spine is often partially or completely ankylosed from FOP. Do not manipulate.
  1. The jaw is likely limited in movement or functionally ankylosed. Even if it is mobile, it is extremely susceptible to trauma. Do not passively manipulate. Over-stretching and mandibular blocks are forbidden as they will cause flare-ups.
  1. Flare-ups of the anterior neck can compromise breathing and swallowing and should be considered a medical emergency. These submandibular flare-ups require early identification. Provide high dose steroids immediately (Solumedrol 80 mg iv or Dexamethasone 15 mg iv). Avoid additional trauma with lesional manipulation. Airway monitoring, aspiration precautions, nutritional support, and immediate use of corticosteroids are mandatory.
  1. Head and neck injuries are common from falls as the arms are rigid from ankylosis of the shoulders early in life and cannot be used to protect the head in case of falls.
  1. With head injury, always brace the neck.
  1. With any head injury, even without loss of consciousness, a head CT is mandatory to rule out intracranial bleeding due to the high likelihood of an unprotected impact.
  1. Flare-ups of the head in younger patients can appear as very large scalp swellings and initially disfiguring. A conservative approach should be taken with scalp flare-ups, with monitoring, and pain control if necessary. Scalp flare-ups will resolve spontaneously over time and disfigurement will be minimal to none as new ossifications are incorporated into the growing skull.
  1. Facial swelling due to scalp flare-ups in FOP is uncommon but may occur. Other etiologies for facial swelling should be considered, such as drug reactions and cavernous sinus thrombosis. A brief course of antihistamine should be considered to exclude allergies in FOP patients who present with facial swelling.
  1. It is always advisable to obtain a complete dental examination for swelling or pain of the oralfacial region as it can be difficult to distinguish a swelling of dental origin from a flare-up of FOP. If the dental radiographs and/or pulpal testing (vitality of the nerve of the tooth) indicates no obvious dental origin to the swelling, it is prudent to assume an FOP flare-up and initiate prednisone flare-up dosing. If it is not possible to get a dental radiograph or do pulpal testing, then prescribing an appropriate antibiotic together with prednisone is warranted until a definitive diagnosis can be made.
  1. For “dirty” or contaminated wounds use tetanus hyperimmune globulin. Avoid tetanus immunization as IM or subcutaneous immunization unless necessary, as this has a high likelihood of inciting a flare-up.
  1. Some hearing impairment is common in FOP. Speak loudly and clearly.
  1. Although stable hearing loss is a common feature of FOP in children, acute hearing loss and ear pain is not and should be evaluated and treated as in any child.
  1. Dental pain is a common issue in FOP patients and must be evaluated and treated promptly, but only after thorough consultation with an FOP dental expert. Overstretching of the jaw and mandibular blocks are forbidden.
  1. Kidney stones are very common in adults with FOP. Keep well hydrated.
  1. Fractures are common in normotopic as well as heterotopic bone. Closed immobilization with splinting and bracing are recommended. Open reduction is contraindicated unless thoroughly discussed with an FOP specialist.
  1. With nausea and vomiting in individuals with an ankylosed jaw, cover empirically with antibiotics for aspiration pneumonia.
  1. Acute and often severe limb swelling can be seen with flare-ups of FOP, especially of the lower extremities. Due to intense inflammation, angiogenesis and capillary leakage, this swelling may grow to extraordinary and alarming size and lead to extravascular compression of nerves and tissue lymphatics. After excluding a possible deep vein thrombosis, the swelling should be treated conservatively with adequate pain control, elevation, and ultimately with safe lymphedema manipulations. Although signs and symptoms of compartment syndrome may prompt consideration of emergent surgical release of pressure (e.g., fasciotomy), this will exacerbate the flare-up and MUST be avoided. If clinical suspicion of compartment syndrome is high, consider the use of mannitol.
  1. In the case of limb swelling that prompts concern for deep vein thrombosis, Doppler ultrasound evaluation of the venous system may be indicated.
  1. Ask if patient is enrolled in any FOP Clinical Trials and communicate with principal investigator and regional FOP specialist.
  1. In the case of choking and failure to clear throat manually, perform Heimlich maneuver if there is no evidence for abdominal heterotopic bone that would prevent attempts.
  1. Chest compressions will likely be futile. The chest wall is rigid and immobile.
  1. Intubation must be through an awake, fiberoptic nasotracheal approach by an experienced anesthesiologist.
  1. If an emergency tracheotomy is necessary in an individual with anterior neck ossifications, a dental or other drill may be necessary to create an airway.
  1. In emergency situations where patients have difficulty clearing secretions, use bronchodilators, mucolytics, and guaifenesin, with a low threshold for mechanical insufflation-exsufflation devices. Hydration should be optimized with intravenous fluids.
  1. Avoid unmonitored use of supplemental oxygen to minimize the chance of respiratory failure and death.
For Consultation on FOP Anesthesia & Airway Issues:
Zvi Grunwald, MD The James D. Wentzler Professor and Chairman Emeritus Department of Anesthesiology Thomas Jefferson University 111 South 11th Street, Suite G-8490 Philadelphia, PA 19107, USA Tel: 215-955-6161 Cell: 215-206-7362 Fax: 215-923-5507 Email: [email protected]
For Consultation on Emergent Dental Care:
Corrie Crowe, DDS 1793 Springdale Road Cherry Hill, NJ 08003, USA Tel: 856-258-4025 (Receptionist: Lynn) Fax: 856-504-6179 Email: [email protected]
Lisa Friedlander, DDS, PHD Associate Professor in Oral Prosthodontic Rehabilitation Université de Paris Cité Director, Reference Center for Rare Oral and Dental Diseases-Service Odontology Group Hospitalier Pitié Salpetriere-Charles Foix, Paris, France Inserm UMR 1123, Lab Eceve Institut Imagine Tel: 0033614395531 Email: [email protected]
Clive S. Friedman, DDS, FAAPD
Asst. Clinical Prof Schulich School of Medicine and Dentistry Imagine Dentistry 1800 Hyde Park Road Unit # 2 London, Ontario Canada N6h OK1 Office: 519-914-2987 Home: 519 438-1198 Cell: 519-657-6014 Personal Email: [email protected]
For Hospital Dentistry and Dental Surgery:
Robert Diecidue, MD, DMD, MBA, MPH
Thomas Jefferson University Jefferson Medical College Department of Oral and Maxillofacial Surgery Chairman and Professor 909 Walnut Street - Suite 300 Philadelphia, Pennsylvania 19107, USA Tel: 215-955-6215: 215 955 5131 Fax: 215-923-9189 Email: [email protected]
Marjolijn Gilijamse MD
Department of Maxillofacial Surgery Amsterdam University Medical Center De Boelelaan 1117, 1081HV Amsterdam, The Netherlands Email: [email protected]

第九章. 结论

治疗FOP患者的医生绝不可扣留任何可能真正有帮助的药物或治疗，但这些药物也必须经过科学的验证，以确定它们是否确实有效，还是仅仅出于美好的愿望。正如两千多年前罗马剧作家特伦斯所警告的：“人们容易相信他们热切希望的事物。”
在缺乏基于证据的受控临床试验的明确证据的情况下，很难热情地倡导某种特定的治疗。虽然试图在多种治疗选择中寻求安全是诱人的，但FOP的水域深邃而危险。精心设计和控制良好的临床试验可能最终是通往这些动荡水域的最安全桥梁。这种方法将需要整个FOP社区的耐心和毅力。
与此同时，负责FOP患者的医生必须不断审视不断发展的科学信息，为患者制定最安全、最富有同情心和最负责任的治疗方案，直到持久的桥梁建成并验证其安全性和有效性。
原文
A physician treating a patient with FOP must never withhold an available medication or treatment that may be truly helpful, but those medications must also be tested with scientific clarity to determine if they are, in fact, truly helpful or just simply the products of wishful thinking. As the Roman dramatist Terence warned more than two thousand years ago, “One easily believes what one earnestly hopes for.”
In the absence of clear evidence-based research from controlled clinical trials, it is difficult to advocate a particular therapy with enthusiasm. Although it is appealing to attempt to swim across multiple therapeutic currents to safety, the waters of FOP are deep and dangerous. The carefully designed and well-controlled clinical trial may ultimately be the safest bridge across these troubled waters of FOP. Such an approach will require the patience and fortitude of the entire FOP community.
In the meanwhile, the physician caring for a patient with FOP must constantly review evolving scientific information and chart the safest, most compassionate and most responsible course for the patient until the enduring bridges are built and their safety and efficacy verified.

第十章. 致谢

作者感谢Karen Kirchoff女士在整理《辅助工具与适应措施》部分方面的宝贵协助，以及Kamlesh Rai女士在本文件的准备和修订中所提供的勤勉帮助和广泛支持。
本项工作部分得到了以下机构的支持：Ian Cali基金、Whitney Weldon基金、国际FOP协会、FOP及相关疾病研究中心、Isaac & Rose Nassau骨科分子医学教授席、Cali-Weldon FOP研究教授席、Robert & Arlene Kogod教授席，以及全球FOP患者的朋友和家人。
作者感谢Radiant Hope基金会和宾夕法尼亚大学FOP及相关疾病研究中心对国际FOP临床委员会（ICC）的支持。
原文
The authors thank Mrs. Karen Kirchoff for her invaluable assistance in assembling the section on Aids, Assistive Devices & Adaptations, and Mrs. Kamlesh Rai for her diligent help and extensive support in the preparation and revision of this document.
This work was supported in part by The Ian Cali Endowment, The Whitney Weldon Endowment, The International FOP Association, The Center for Research in FOP and Related Disorders, The Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine, The Cali-Weldon Professorship of FOP Research, The Robert & Arlene Kogod Professorship, and the Friends and Families of FOP patients worldwide.
The authors thank The Radiant Hope Foundation and the Center for Research in FOP & Related Disorders at the University of Pennsylvania for supporting the International Clinical Council for FOP (ICC).

第十一章. 披露事项

FSK 是Ashibio、Incyte、Ipsen和Regeneron的临床试验研究员；是美国专利（待审）共同发明人，该专利涉及宾夕法尼亚大学对MMP-9抑制剂用于异位骨化的使用，以及国际FOP协会（IFOPA）医学登记顾问委员会的成员。
MAK 是Ashibio、Incyte、Ipsen和Regeneron的临床试验研究员。
GB 是Ipsen、Regeneron和BioMarin的顾问，获得FOP France、BioMarin和Ipsen的研究资助和会议支持，是BioMarin和Inozyme顾问委员会的成员，负责Ipsen、Inozyme、BioMarin、QED、Ascendis、Alexion和Inozyme的临床试验，是Ipsen、Inozyme、Alexion、BioMarin和Ascendis临床试验的首席研究员，并且是FOP France董事会的成员。
AHB 是Incyte、Ipsen和Regeneron的临床试验研究员。
MB 是Incyte、Ipsen和Regeneron的临床试验研究员。
AC - 无
T-JC 是Incyte和Ipsen的临床试验研究员。
CC - 无
CLDC 是Incyte和Ipsen的临床试验研究员，并且是IFOPA医学登记顾问委员会的成员。
PD 是Ipsen的顾问，Incyte、Ipsen和Regeneron的临床试验研究员，还是Tin Soldiers Global和瑞士Noi Ci Siamo协会的董事会成员。
RJD - 无
MDR 曾是Regeneron的临床试验研究员。
EMWHE 是STOPFOP、Regeneron、Ipsen和Incyte的临床试验研究员，是IFOPA医学登记顾问委员会、阿姆斯特丹骨科中心指导委员会、罕见骨病欧洲参考网络的成员，还是欧洲FOP联盟的代表，NVE BoNe董事会成员，并且是阿姆斯特丹UMC罕见骨病中心的主席。
LF - 无
CF 是Ipsen的顾问，特殊奥林匹克组织的临床主任，Tin Soldiers Global董事会成员，并因一次演讲获得Springer的酬金。
ZG 是Axdev Group的顾问。
NH 曾是Ipsen的临床研究员。
ECH 是临床试验研究员，并通过其机构获得来自Clementia（Ipsen公司）、Ipsen、Ascendis和Ashibio的临床试验支持，之前获得Regeneron和Ultragenyx的支持，是IFOPA医学登记顾问委员会的成员，也是FD/MAS联盟医学顾问委员会的成员。
RK 是Ipsen、Alexion、Kyowa Kirin、UCB、Amgen和Richter的顾问，Alexion、Kyowa Kirin、Theramex的顾问委员会成员，Alexion、Kyowa Kirin、Incyte、Ipsen和Regeneron的临床研究员，还是脆骨症协会和英国国家健康服务体系（NHS）的顾问委员会成员。
JK - 无
CL - 无
VM - 无
RM 是Ipsen的顾问。
JCN - 无
CS 是Ipsen的顾问，曾是Ipsen和Regeneron的临床试验研究员。
EMS - 无
MAZ 曾是Clementia/Ipsen数据安全监测委员会（DSMB）成员，参与Palovarotene临床试验，目前在Incyte的DSMB中。
KZ 是Incyte、Ipsen和Regeneron的临床试验研究员。
RJP 是Ashibio、Incyte、Ipsen和Regeneron的临床试验研究员，是美国专利（待审）共同发明人，该专利涉及宾夕法尼亚大学对MMP-9抑制剂用于异位骨化的使用，是IFOPA医学登记顾问委员会的成员，也是Incyte、Ipsen和Regeneron的顾问。
原文
FSK is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron; a co-inventor of U.S. Patent (Pending) to the Trustees of the University of Pennsylvania on the Use of MMP-9 Inhibitors for Heterotopic Ossification and a member of the Medical Registry Advisory Board of the IFOPA.
MAK is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron.
GB is a consultant for Ipsen, Regeneron and BioMarin, has research grants and conference support from FOP France, BioMarin and Ipsen, is a member of the Advisory Boards of BioMarin and Inozyme, conducts clinical trials for Ipsen, Inozyme, BioMarin, QED, Ascendis, Alexion and Inozyme, is the PI on clinical trials for Ipsen, Inozyme, Alexion, BioMarin, Ascendis and is a member of the Board of FOP France.
AHB is a clinical trial investigator for Incyte, Ipsen, and Regeneron. MB is a clinical trial investigator for Incyte, Ipsen and Regeneron.
AC- None T-JC is a clinical trial investigator for Incyte and Ipsen.
CC - None CLDC is a clinical trial investigator for Incyte and Ipsen and a member of the Medical Registry Advisory Board of the IFOPA.
PD is a consultant for Ipsen, a clinical trial investigator for Incyte, Ipsen, and Regeneron and a member of the Board of Directors of Tin Soldiers Global and the Noi Ci Siamo Association in Switzerland.
RJD - None MDR was a clinical trial investigator for Regeneron.
EMWHE is a clinical trial investigator for STOPFOP, Regeneron, Ipsen, and Incyte, a member of the Medical Registry Advisory Board of the IFOPA, of the steering committee of the Amsterdam Bone Center, of the European Reference Network on rare bone diseases, a representative to the European FOP consortium, a board member NVE BoNe, and is Chair of the Rare Bone Disease Center Amsterdam UMC.
LF - None CF is a consultant for Ipsen, Clinical Director for The Special Olympics, a member of the Board of Directors of Tin Soldiers Global and has received an honorarium from Springer for a presentation.
ZG is a consultant for the Axdev Group.
NH was a clinical investigator for Ipsen.
ECH is a clinical trial investigator and receives clinical trial support through his institution from Clementia (an Ipsen Company), Ipsen, Ascendis, and Ashibio, previously received support from Regeneron and Ultragenyx, is a member Medical Registry Advisory Board of the IFOPA, and a member of the FD/MAS Alliance Medical Advisory Board.
RK is a consultant for Ipsen, Alexion, Kyowa Kirin, UCB, Amgen and Richter, a member of the Advisory Board of Alexion, Kyowa Kirin, Theramex, a clinical investigator for Alexion, Kyowa Kirin, Incyte, Ipsen, and Regeneron, and a member of the Advisory Board of The Brittle Bone Society and the National Health Service (NHS) of England.
JK - None CL - None
VM - None RM is a consultant for Ipsen.
JCN - None CS is a consultant for Ipsen and was a previous clinical trial investigator for Ipsen and Regeneron.
EMS - None MAZ was a member of the Clementia/Ipsen Data Safety Monitoring Board (DSMB) during the Palovarotene clinical trials, and is currently on the Incyte DSMB
KZ is a clinical trial investigator for Incyte, Ipsen, and Regeneron.
RJP is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron, a co-inventor of U.S. Patent (Pending) to the Trustees of the University of Pennsylvania on the Use of MMP-9 Inhibitors for Heterotopic Ossification, a member of the Medical Registry Advisory Board of the IFOPA, and a consultant for Incyte, Ipsen and Regeneron.

第十二章. 作者联系信息

（标*号为ICC成员）
*Mona Al Mukaddam, 医学博士, 理学硕士, CCD（临床骨密度学认证）
临床医学副教授
内分泌、糖尿病和代谢学科
Ian Cali FOP临床学者，骨科外科系
宾夕法尼亚大学佩雷尔曼医学院
宾州医学大学城
市场街3737号，三楼
美国宾夕法尼亚州费城，邮政编码19104
电话：215-294-9702
传真：215-243-4664
电子邮件：[email protected]
*Genevieve Baujat, 医学博士
骨骼疾病参考中心
遗传学系
尼克医院儿童病房
法国巴黎
电话（秘书处）：003344495153
办公室电话：003371196418
电子邮件：[email protected]
*Alberto Hidalgo Bravo, 医学博士, 哲学博士
教授
医学科学研究员
国家康复研究所，
基因组医学系
墨西哥城，
卡尔萨达墨西哥-索西米尔科289号
电话和传真：+525559991000 分机 19401
电子邮件：[email protected]
*Matthew Brown, 医学学士, 医学博士, 澳大利亚和新西兰皇家内科医学院的院士, 澳大利亚科学院院士 (名誉)
医学教授
伦敦国王学院
盖伊医院，第七层塔翼
大迷宫池，伦敦SE1 9RT，英国
首席科学官
英国基因组学公司
加拿大广场1号
伦敦，E14 5AB，英国
手机：+44 7468 351 337
电子邮件：[email protected]
Amanda Cali (名誉职)
电子邮件：[email protected]
*Tae-Joon Cho, 医学博士
教授
儿科骨科系
首尔国立大学儿童医院
大汉路101号，钟路区
首尔110-744，韩国
电话：+82-2-2072-2878
传真：+82-2-6072-5303
电子邮件：[email protected]; [email protected]
Corrie Crowe, 牙医学士
春谷路1793号
美国新泽西州樱桃山，邮政编码08003
电话：856-258-4025（接待员：Lynn）
传真：856-504-6179
电子邮件：[email protected]
*Carmen L. De Cunto, 医学博士
教授及主任
阿根廷FOP临床顾问
儿科风湿病学科
儿科系
布宜诺斯艾利斯意大利医院
加斯孔450号，1181
阿根廷布宜诺斯艾利斯自治市
电话：+5411-4959-0578
传真：+5411-4959-0577
电子邮件：[email protected]
*Patricia L.R. Delai, 医学博士
阿尔伯特·爱因斯坦以色列医院
教学与研究所
办公室：佩德罗·德·托莱多街129号，cj 121-维拉·克莱门蒂诺
邮政编码04039-001
巴西圣保罗-SP
电话：+55-11-99394-5848
+55-11-99658-8816
电子邮件：[email protected]; [email protected]
*Robert J. Diecidue, 牙医学博士, 医学博士, 工商管理硕士, 公共卫生硕士, 哲学博士
牙科生物科学科的Cohen Reichlin教授
口腔颌面外科教授及主任
西德尼·基梅尔医学院
托马斯·杰斐逊大学
核桃街909号，三层
美国宾夕法尼亚州费城，邮政编码19107
电话：215-955-6215；215-955-5131
传真：215-923-9189
电子邮件：[email protected]
Maja DiRocco, 医学博士 (名誉)
罕见疾病科
儿科系
IRCCS贾尼娜·加斯利尼研究所
杰罗拉莫·加斯利尼街5号
意大利热那亚16147
电话：+39-010-563-6794
传真：+39-010-563-6211
电子邮件：[email protected]
*Elisabeth Marelise W. Eekhoff, 医学博士, 哲学博士
教授
阿姆斯特丹大学医学中心（Amsterdam UMC）
内科/内分泌与代谢系
德博尔兰街1117号
荷兰阿姆斯特丹1081HV
电话：+31-20-4440588 或 +31-622959618
电子邮件：[email protected]
Dr. Lisa Friedlander, 牙外科学博士, 哲学博士
口腔修复学副教授
巴黎大学城市
罕见口腔与牙科疾病参考中心主任
皮提·萨尔佩特里医院-查尔斯·福伊克，巴黎，法国
Inserm UMR 1123, Lab Eceve
想象研究所
电话：0033614395531
电子邮件：[email protected]
*Clive S. Friedman, 牙外科学学士 (美国儿童牙科协会认证)
临床助理教授
舒立赫医学院与牙科学院
想象牙科
海德公园路1800号，单元2
加拿大安大略省伦敦，邮政编码N6H OK1
办公室电话：519-9142987
家庭电话：519-438-1198
手机：519-657-6014
电子邮件：[email protected]
*Zvi Grunwald, 医学博士
詹姆斯·D·温茨勒教授及名誉主席
麻醉学系
托马斯·杰斐逊大学
南11街111号，G-8490室
美国宾夕法尼亚州费城，邮政编码19107
电话：215-955-6161；手机：215-206-7362
传真：215-923-5507
电子邮件：[email protected]
*Nobuhiko Haga, 医学博士
院长
国家残疾人康复中心
名木4-1，所泽市
埼玉县359-8555，日本
电话：+81-4-2995-3100
传真：+81-4-2995-3102
电子邮件：[email protected]
*Edward Hsiao, 医学博士, 哲学博士
内分泌与代谢科
医学系
加利福尼亚大学旧金山分校
帕纳苏斯大道400号，5楼A550
UCSF邮政信箱1222
美国加利福尼亚州旧金山94143-1222
电话：415-353-2350；研究相关问题专用办公室电话：415-476-9732
电子邮件：[email protected]
*Frederick S. Kaplan, 医学博士
骨科分子医学的艾萨克与罗斯·纳萨尔教授
FOP及相关疾病研究中心共同主任
宾夕法尼亚大学佩雷尔曼医学院
骨科手术系
市场街3737号 - 六楼
美国宾夕法尼亚州费城19104
电话：（办公室）215-294-9145
传真：215-222-8854
电子邮件：[email protected]
*Dr. Richard Keen, 科学学士, 哲学博士, 皇家内科医师学院会员
风湿病学家及代谢骨病荣誉高级讲师
皇家国家骨科医院
斯坦莫尔，米德尔塞克斯HA7 4LP
英国
电话：+44 (0)20 3947 0056（选项3 - 秘书）
传真：+44 (0)20 8420 7487
电子邮件：[email protected]
Richard Keen的额外联系方式：
代谢骨病中心
皇家国家骨科医院
布罗克利山，斯坦莫尔，米德尔塞克斯HA7 4LP，英国
电话：+44(0)20 3947 0056
电子邮件：[email protected]
Joseph A. Kitterman, 医学博士
名誉教授
儿科及心血管研究所
U-503, 邮政信箱0734
加利福尼亚大学旧金山分校
美国加利福尼亚州旧金山94143-0734
电子邮件：[email protected]
Charles Levy, 医学博士
物理治疗系兼职副教授
医学艺术中心研究学者
佛罗里达大学
西南43街426号
美国佛罗里达州盖恩斯维尔32607
电子邮件：[email protected]
*Dr. Vrisha Madhuri
骨科教授，干细胞研究中心兼职科学家
儿科骨科系
临床研究艾达·斯卡德尔主席
基督教医学院医院
印度维洛尔632004
备用地址：
干细胞研究中心实验室4
基督教医学院
印度维洛尔632002
电子邮件：
[email protected]
[email protected]
[email protected]
*Rolf Morhart, 医学博士
儿科系
加米施-帕滕基兴医院
阿亨街6号
德国加米施-帕滕基兴82467
电话：+49-(0)8821-58889
传真：+49-(0)8821-77-1351
电子邮件：[email protected]
*J. Coen Netelenbos, 医学博士, 哲学博士
名誉教授 内分泌学
阿姆斯特丹大学医学中心（Amsterdam UMC）
VU大学医学中心（VUMC）阿姆斯特丹
内科/内分泌学科
自由大学医院
德博尔兰街1117号，1081HV阿姆斯特丹，荷兰
电话：+31-20-444-0530
手机：+31 62-128-2918
电子邮件：[email protected]
*Robert J. Pignolo, 医学博士, 哲学博士
老年医学与老年病学科主任
老年医学的罗伯特与阿琳·科戈德教授
梅奥诊所医学院
西第一街200号，SW
美国明尼苏达州罗切斯特55905
电话：507-293-0813
传真：507-293-3853
电子邮件：[email protected]
*Christiaan Scott, 医学学士和外科医学学士, 南非儿科医师学院会员 (SA), 西澳大学儿科风湿病学研究生证书(UWA)
儿科风湿病学家
皮肤科与风湿病学系
儿科系教授
渥太华大学
CHEO | 401 Chemin Smyth Road, Ottawa (ON) K1H 8L1
电话：（613）737-7600 分机1015 |
传真：（613）738-4297
电子邮件：[email protected]
Eileen M. Shore, 哲学博士
FOP研究的卡利-维尔登教授
宾夕法尼亚大学
骨科系
斯特梅勒大厅309A
汉密尔顿步道3450号
美国宾夕法尼亚州费城19104-6081
电话：215-898-2331；
传真：215-573-2133
电子邮件：[email protected]
*Michael Zasloff, 医学博士, 哲学博士
兼职教授
骨科手术与遗传学系
FOP及相关疾病研究中心
宾夕法尼亚大学医学院
及
外科与儿科系教授
外科免疫学主任
乔治城大学
医学/牙科NW 210
美国华盛顿特区20007
电话：202-687-5707（办公室）或
家庭电话：610-617-3488
手机：484-433-7807
传真：202-687-0992
电子邮件：[email protected] 或 [email protected]
*张克勤, 医学博士, 哲学博士
内分泌科主任
同济医院
上海同济大学
新村路389号
中国上海200065
电子邮件：[email protected]
 
原文
(*Member of the ICC)
*Mona Al Mukaddam, MD, MS, CCD
Associate Professor of Clinical Medicine
Division of Endocrinology, Diabetes and Metabolism;
Ian Cali Clinical Scholar in FOP, Department of Orthopaedic Surgery,
The Perelman School of Medicine - The University of Pennsylvania
Penn Medicine University City
3737 Market Street, 3rd floor
Philadelphia, PA 19104, USA
Tel: 215-294-9702
Fax: 215-243-4664
Email: [email protected]
*Genevieve Baujat, MD
Centre de Référence Maladies Osseuses Constitutionnelles
Departement de Génétique
Hôpital Necker-Enfants Malades
Paris, France
Tel: (secretariat): 003344495153
Office: 003371196418
Email: [email protected]
*Alberto Hidalgo Bravo, MD, PhD
Profesor
Investigador en Ciencias Médicas
Instituto Nacional de Rehabilitación,
Department of Genomic Medicine.
Calzada México-Xochimilco 289.
  1. Mexico City, Mexico.
Telephone and fax: +525559991000 Ext. 19401
Email: [email protected]
Matthew Brown, MBBS, MD, FRACP, FAA (Emeritus)
Professor of Medicine
King’s College London
Guy’s Hospital, 7th Floor Tower Wing
Great Maze Pond, London SE1 9RT, U.K.
Chief Scientific Officer
Genomics England
1 Canada Square
Canary Wharf, London, E14 5AB, U.K.
Mobile: +44 7468 351 337
Email: [email protected]
Amanda Cali (Ex officio, Emeritus)
Email: [email protected]
*Tae-Joon Cho, MD
Professor
Division of Pediatric Orthopaedics
Seoul National University Children’s Hospital
101 Daehang-ro Jongno-gu
Seoul 110-744, Republic of Korea
Tel: +82-2-2072-2878
Fax: +82-2-6072-5303
Email: [email protected]; [email protected]
Corrie Crowe, DDS
1793 Springdale Road
Cherry Hill, NJ 08003, USA
Tel: 856-258-4025 (Receptionist: Lynn)
Fax: 856-504-6179
Email: [email protected]
*Carmen L. De Cunto, MD
Professor and Chief
FOP Clinical Advisor, Argentina
Pediatric Rheumatology Section
Department of Pediatrics
Hospital Italiano de Buenos Aires
Gascón 450, 1181
Ciudad Autónoma de Buenos Aires, Argentina
Tel: +5411-4959-0578
Fax: +5411-4959-0577
Email: [email protected]
*Patricia L.R. Delai, MD
Hospital Israelita Albert Einstein
Instituto de Ensino e Pesquisa
Office: Rua Pedro de Toledo 129 cj 121- Vila Clementino
Cep-04039-001
São Paulo-SP, Brazil
Tel: +55-11-99394-5848
+55-11-99658-8816
Email: [email protected]; [email protected]
*Robert J. Diecidue, DMD, MD, MBA, MPH, PhD
Cohen Reichlin Professor of Dental Biosciences
Professor and Chair OMFS
Sidney Kimmel Medical College
Thomas Jefferson University
909 Walnut Street – Floor 3,
Philadelphia, PA 19107, USA
Tel: 215-955-6215; 215 955 5131
Fax: 215-923-9189
Email: [email protected]
Maja DiRocco, MD (Emeritus)
Unit of Rare Diseases
Department of Pediatrics
IRCCS Giannina Gaslini Institute
Via Gerolamo Gaslini 5
16147 Genoa, Italy
Tel: +39-010-563-6794
Fax: +39-010-563-6211
Email: [email protected]
*Elisabeth Marelise W. Eekhoff, MD, PhD
Professor
Amsterdam University Medical Center (Amsterdam UMC)
Department of Internal Medicine/Endocrinology & Metabolism
De Boelelaan 1117
1081HV Amsterdam, The Netherlands
Tel: +31-20-4440588 or +31-622959618
Email: [email protected]
Dr Lisa Friedlander, DDS, PHD
Associate Professor in Oral Prosthodontic Rehabilitation
Université de Paris Cité
Director, Reference Center for Rare Oral and Dental Diseases-Service Odontology Group
Hospitalier Pitié Salpetriere-Charles Foix, Paris, France
Inserm UMR 1123, Lab Eceve
Institut Imagine
Tel: 0033614395531
Email: [email protected]
*Clive S. Friedman, BDS (Diplomate AAPD)
Asst. Clinical Prof Schulich School of Medicine and Dentistry Imagine Dentistry
1800 Hyde Park Road Unit # 2
London, Ontario
Canada N6h OK1
Office: 519-9142987
Home: 519 438-1198
Cell: 519-657-6014
Email: [email protected]
*Zvi Grunwald, MD
The James D. Wentzler Professor and Chairman Emeritus
Department of Anesthesiology
Thomas Jefferson University
111 South 11th Street, Suite G-8490
Philadelphia, PA 19107, USA
Tel: 215-955-6161: Cell: 215-206-7362
Fax: 215-923-5507
Email: [email protected]
*Nobuhiko Haga, MD
President
National Rehabilitation Center for Persons with Disabilities
4-1 Namiki, Tokorozawa City,
Saitama Pref. 359-8555, Japan
Tel: +81-4-2995-3100,
Fax: +81-4-2995-3102
Email: [email protected]
*Edward Hsiao, MD, PhD
Division of Endocrinology and Metabolism
Department of Medicine
University of California-San Francisco
400 Parnassus Ave., 5th Floor A550
UCSF Box 1222
San Francisco, CA 94143-1222, USA
Tel: 415-353-2350: Office phone (for research-related questions only): 415- 476-9732
Email: [email protected]
*Frederick S. Kaplan, MD
Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine
Co-Director, Center for Research in FOP & Related Disorders
The Perelman School of Medicine at The University of Pennsylvania
Department of Orthopaedic Surgery
3737 Market Street – Sixth Floor
Philadelphia, PA 19104, USA
Tel: (office) 215-294-9145
Fax: 215-222-8854
Email: [email protected]
*Dr. Richard Keen, BS, PhD, FRCP
Rheumatologist & Honorary Senior Lecturer in Metabolic Bone Disease
The Royal National Orthopaedic Hospital
Stanmore, Middlesex HA7 4LP
United Kingdom
Tel: +44 (0)20 3947 0056 (option 3 - Secretaries)
Fax: +44 (0)20 8420 7487
Email: [email protected]
Additional contact for Dr. Richard Keen:
Centre for Metabolic Bone Disease
Royal National Orthopaedic Hospital
Brockley Hill, Stanmore, Middlesex HA7 4LP, United Kingdom
Tel: +44(0)20 3947 0056
Email: [email protected]
Joseph A. Kitterman, MD
Professor Emeritus
Department of Pediatrics and Cardiovascular Research Institute
U-503, Box 0734
University of California San Francisco
San Francisco, CA 94143-0734, USA
Email: [email protected]
Charles Levy, MD
Adjunct Associate Professor, Department of Physical Therapy
Research Scholar, Center for Arts in Medicine
University of Florida
426 SW 43 rd Terrace
Gainesville, Florida 32607, USA
Email: [email protected]
*Dr. Vrisha Madhuri
Professor Orthopaedics, Adjunct Scientist Center for Stem Cell Research
Department Paediatric Orthopaedics
Ida Scudder Chair for Clinical Research
Christian Medical College Hospital
Vellore 632004, India
The alternative address is:
Lab 4, Centre for Stem Cell Research
Christian Medical College
Vellore 632002, India
Email:
[email protected]
[email protected]
[email protected]
*Rolf Morhart, MD
Department of Pediatrics
Klinikum Garmisch- Partenkirchen
Auenstr.6
D- 82467 Garmisch- Partenkirchen, Germany
Tel: +49-(0)8821-58889
Fax: +49-(0)8821-77-1351
Email: [email protected]
*J. Coen Netelenbos, MD, PhD
Professor Emeritus Endocrinology
Amsterdam University Medical Center (Amsterdam UMC)
Location VU University Medical Center (VUMC) Amsterdam
Department of Internal Medicine/ Section Endocrinology
University Hospital Vrije Universiteit
De Boelelaan 1117, 1081HV Amsterdam, The Netherlands
Tel: +31-20-444-0530
Cell: +31 62-128-2918
E-mail: [email protected]
*Robert J. Pignolo, MD, PhD
Chair, Division of Geriatric Medicine & Gerontology
Robert and Arlene Kogod Professor of Geriatric Medicine
Mayo Clinic College of Medicine
200 First Street, SW
Rochester, MN 55905, USA
Tel: 507-293-0813
Fax: 507-293-3853
Email: [email protected]
*Christiaan Scott, MBChB, FCPaed (SA), Grad Cert Paed Rheum(UWA)
Paediatric Rheumatologist
Division of Dermatology and Rheumatology
Professor, Department of Pediatrics
University of Ottawa
CHEO | 401 Chemin Smyth Road, Ottawa (ON) K1H 8L1
Tel: (613) 737-7600 x 1015 |
Fax: (613) 738-4297
Email: [email protected]
Eileen M. Shore, PhD
Cali-Weldon Professor of FOP Research
University of Pennsylvania
Department of Orthopaedics
309A Stemmler Hall
3450 Hamilton Walk
Philadelphia, PA 19104-6081, USA
Phone: 215-898-2331;
Fax: 215-573-2133
Email: [email protected]
*Michael Zasloff, MD, PhD
Adjunct Professor
Departments of Orthopaedic Surgery and Genetics
The Center for Research in FOP & Related Disorders
The University of Pennsylvania School of Medicine
and
Professor, Departments of Surgery and Pediatrics
Director, Surgical Immunology
Georgetown University
Med/Dent NW 210
Washington, DC 20007, USA
Tel: 202-687-5707 (office) or
Home: 610-617-3488
Cell: 484-433-7807
Fax: 202-687-0992
Email: [email protected] or [email protected]
*Keqin Zhang, MD, PhD
Director, Department of Endocrinology
Tongji Hospital
Shanghai Tongji University
389. Xin Cun Road
Shanghai 200065, P.R. China
Email: [email protected]

图1. FOP的靶点与潜在疗法

notion image
原图
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