March, 2019 June, 2019 [Please see text addenda in red. Pages 3, 6, 54, 101, 106] THE MEDICAL MANAGEMENT OF FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: CURRENT TREATMENT CONSIDERATIONS From The International Clinical Council on FOP (ICC) & Consultants: Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, De Cunto C, Delai P, Diecidue R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N, Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ Corresponding Editors: Frederick S. Kaplan, M.D. Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine Co-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] Requests: [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] [Kaplan FS, et al. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP 1:1-111, 2019] 1 Contents I. ABSTRACT ................................................................................................................................................. 4 II. EXECUTIVE SUMMARY OF KEY PRACTICE POINTS ................................................................. 5 III. THE CLINICAL AND BASIC SCIENCE BACKGROUND OF FOP............................................. 10 A. INTRODUCTION ...............................................................................................................................................................10 B. CLASSIC CLINICAL FEATURES OF FOP .........................................................................................................................10 C. OTHER SKELETAL ANOMALIES OF FOP .......................................................................................................................12 D. RADIOGRAPHIC FEATURES OF FOP ..............................................................................................................................13 E. PATHOLOGY OF FOP LESIONS ......................................................................................................................................14 F. LABORATORY FINDINGS IN FOP ....................................................................................................................................15 G. ETIOLOGY & PATHOGENESIS OF FOP ...........................................................................................................................15 H. FOP VARIANTS ...............................................................................................................................................................17 I. THE IMMUNE SYSTEM & FOP ........................................................................................................................................18 J. EPIDEMIOLOGIC, GENETIC & ENVIRONMENTAL FACTORS IN FOP .............................................................................19 K. GENETIC TESTING & FOP .............................................................................................................................................19 L. ANIMAL MODELS OF FOP ..............................................................................................................................................20 M. SUPPORTIVE TREATMENT IN FOP .................................................................................................................................21 N. PROGNOSIS OF FOP ........................................................................................................................................................22 O. CHALLENGES OF THERAPEUTIC ASSESSMENT IN FOP .................................................................................................23 IV. THE PATHOLOGIC AND PATHOPHYSIOLOGIC-BASED TREATMENT OF FOP .............. 24 B. CORTICOSTEROIDS IN FOP .............................................................................................................................................24 C. CYCLO-OXYGENASE-2 (COX-2) INHIBITORS & NSAIDS IN FOP ................................................................................27 D. TOPICAL ANALGESICS IN FOP .......................................................................................................................................30 E. MAST CELL INHIBITORS IN FOP ....................................................................................................................................30 F. BISPHOSPHONATES IN FOP .............................................................................................................................................33 G. IMATINIB IN FOP ............................................................................................................................................................38 H. MUSCLE RELAXANTS IN FOP .........................................................................................................................................40 I. CHEMOTHERAPY AGENTS & RADIATION THERAPY IN FOP .........................................................................................40 J. BONE MARROW TRANSPLANTATION IN FOP ................................................................................................................41 K. MISCELLANEOUS AGENTS & APPROACHES IN FOP......................................................................................................42 L. DEFINITIVE THERAPEUTIC TARGETS IN FOP ................................................................................................................43 V. SPECIAL MEDICAL CONSIDERATIONS IN FOP .......................................................................... 46 A. INTRODUCTION ...............................................................................................................................................................46 B. INJURY PREVENTION IN FOP ..........................................................................................................................................46 C. SCALP NODULES IN FOP .................................................................................................................................................47 D. SPINAL DEFORMITY IN FOP ...........................................................................................................................................48 E. CARDIOPULMONARY FUNCTION IN FOP ........................................................................................................................49 F. RESPIRATORY HEALTH IN FOP ......................................................................................................................................52 G. IMMUNIZATIONS FOR DISEASES OTHER THAN INFLUENZA IN FOP ..............................................................................54 H. IMMUNIZATIONS FOR INFLUENZA IN FOP .....................................................................................................................59 I. ACUTE & CHRONIC PAIN MANAGEMENT IN FOP ..........................................................................................................61 J. DIFFERENTIAL DIAGNOSIS OF HIP PAIN IN FOP ............................................................................................................64 K. LIMB SWELLING IN FOP ................................................................................................................................................65 L. PRESSURE SORES IN FOP ................................................................................................................................................66 M. FRACTURES IN FOP .......................................................................................................................................................67 N. PREVENTIVE ORAL HEALTHCARE IN FOP ....................................................................................................................68 O. ORTHODONTICS & FOP .................................................................................................................................................71 P. SUBMANDIBULAR FLARE-UPS IN FOP ............................................................................................................................72 Q. DENTAL ANESTHESIA IN FOP ........................................................................................................................................74 R. GENERAL ANESTHESIA IN FOP ......................................................................................................................................76 S. ACCEPTABLE/LOW RISK PROCEDURES IN FOP .............................................................................................................79 T. NEUROLOGICAL ISSUES IN FOP .....................................................................................................................................80 2 U. HEARING IMPAIRMENT IN FOP ......................................................................................................................................81