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. 2022 Dec;24(12):2422-2433.
doi: 10.1016/j.gim.2022.08.013. Epub 2022 Sep 24.

The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study

Robert J Pignolo  1 , Geneviève Baujat  2 , Matthew A Brown  3 , Carmen De Cunto  4 , Edward C Hsiao  5 , Richard Keen  6 , Mona Al Mukaddam  7 , Kim-Hanh Le Quan Sang  2 , Amy Wilson  8 , Rose Marino  8 , Andrew Strahs  8 , Frederick S Kaplan  9
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Free article

The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study

Robert J Pignolo et al. Genet Med. 2022 Dec.
Free article

Abstract

Purpose: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues.

Methods: Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months.

Results: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 103 mm3). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 103 mm3; lowest at 2 to <8 years (68.8 × 103 mm3) and increasing by age (25-65 years: 575.2 × 103 mm3). The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year).

Conclusion: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.

Keywords: Fibrodysplasia ossificans progressiva; Natural history study.

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Conflict of interest statement

Conflict of Interest R.J.P. is a research investigator at Clementia Pharmaceuticals/Ipsen and Regeneron Pharmaceuticals, Inc and is part of the advisory board as President of the International Clinical Council on Fibrodysplasia Ossificans Progressiva. G.B. is part of the advisory boards of Clementia Pharmaceuticals/Ipsen, FOP European Consortium, and International Clinical Council on FOP and is a speaker at Clementia Pharmaceuticals/Ipsen. M.A.B. is part of the advisory boards of AbbVie, Janssen, Pfizer, UCB Pharma, and Novartis; receives grant support from AbbVie; is a research investigator at AbbVie, Clementia Pharmaceuticals/Ipsen, Janssen, Novartis, Pathios Therapeutics Ltd, and Regeneron Pharmaceuticals, Inc; and is a speaker at AbbVie, United States, Janssen, Novartis, Switzerland, Pfizer, United States, Regeneron Pharmaceuticals, Inc, United States, and UCB Pharma, United Kingdom. C.D.C. is a research investigator at Clementia Pharmaceuticals/Ipsen and is a speaker at Novartis. E.C.H. is part (all voluntary) of the Fibrous Dysplasia Foundation Advisory Board, International Fibrodysplasia Ossificans Progressiva Association (IFOPA), United States Registry Medical Advisory Board, and International Clinical Council on FOP Advisory Board; receives clinical research support from Clementia Pharmaceuticals/Ipsen, France, Neurocrine Biosciences Inc, United States, and Regeneron Pharmaceuticals, Inc; and is a research investigator at Clementia Pharmaceuticals/Ipsen. R.K. is a research investigator at Clementia Pharmaceuticals/Ipsen, Kyowa Kirin, and Regeneron Pharmaceuticals, Inc and is part of the IFOPA Fibrodysplasia Ossificans Progressiva Registry Medical Advisory Board and International Clinical Council on Fibrodysplasia Ossificans Progressiva Advisory Board. M.A.M. receives research support from Clementia Pharmaceuticals/Ipsen and Regeneron Pharmaceuticals, Inc; is a non-paid consultant for BioCryst Pharmaceuticals, Inc, United States, Blueprint Medicines, Daiichi Sankyo, Incyte, and Keros Therapeutics; is part (all voluntary) of the IFOPA Registry Medical Advisory Board, Incyte Advisory Board, and International Clinical Council on FOP Advisory Board; and receives non-restricted educational fund from Excel and Catalyst sponsored by Ipsen. K.-H.L.Q.S. is a coordinator of Ipsen FOP-program and multiple osteochondromas-trial. A.W., R.M., and A.S. are employees of Ipsen. F.S.K. is a research investigator at Clementia/Ipsen and Regeneron Pharmaceuticals, Inc, is part of the IFOPA Medical Advisory Board, is a Founder and immediate past President of the International Clinical Council on FOP, and is the Chair of the Publications Committee of the International Clinical Council. In April 2019, Ipsen acquired Clementia Pharmaceuticals.

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