The First Russian Experience of Using Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva: Two Case Reports

Background. Fibrodysplasia ossificans progressiva (FOP) — is an extremely rare genetic disorder with an autosomal dominant type of inheritance. FOP is associated with a genetically determined disorder caused by the presence of a specific mutation in the ACVR1/ALK2 gene encoding the bone morphogenetic protein receptor. FOP is clinically manifested by the unrestrained formation of heterotopic ossifications, leading to a gradual progression of disability up to complete immobility of the patient. At an early age, the disease can be recognized by the presence of characteristic phenotypic stigmas, mainly the characteristic malformation of the thumbs, confirming the diagnosis by molecular genetic analysis. Early diagnosis of FOP avoids unnecessary iatrogenic manipulations and slows down the progression of the disease. Up until recently, there was no therapy that had a pathogenetic effect, preventing the development of ossifications. The first and only drug that has proven its effectiveness as a result of clinical trials and is registered for use in patients with FOP in a number of countries is palovarotene.

Case reports: The publication presents the first Russian experience of using palovarotene with a description of two clinical observations of patients with a genetically confirmed diagnosis of FOP. The clinical picture, the difficult path to diagnosis, and the encouraging experience of treating patients, including anti-inflammatory therapy using Janus kinase inhibitors (tofacitinib) and pathogenetic therapy with palovarotene, are described.

Conclusion. The aggressive nature of the course of FOP, which inevitably leads to severe disability of patients, necessitates the widespread attention of practitioners to the early diagnosis of FOP, an in-depth study of the factors determining progression, and new opportunities for pathogenetic therapy allow us to count on improving the prognosis of this extremely serious disease.

1. Kaplan FS, Chakkalakal SA, Shore EM. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech. 2012;5(6):756–762. doi: https://doi.org/10.1242/dmm.010280.

2. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011;6:80. doi: https://doi.org/10.1186/1750-1172-6-80

3. Anwar S, Yokota T. Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers. Genes (Basel). 2023;14(12):2162. doi: https://doi.org/10.3390/genes14122162

4. Liljesthröm M, Pignolo RJ, Kaplan FS. Epidemiology of the Global Fibrodysplasia Ossificans Progressiva (FOP) Community. J Rare Dis Res Treat. 2020;5(2):31–36. doi: https://doi.org/10.29245/2572-9411/2020/2.1196.

5. 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. 2017;12(1):123. doi: https://doi.org/10.1186/s13023-017-0674-5

6. P ignolo RJ, Baujat G, Brown MA, et al. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019;14(1):98. doi: https://doi.org/10.1186/s13023-019-1068-7

7. Kaplan FS, Xu M, Seemann P, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30(3):379–390. doi: https://doi.org/10.1002/humu.20868

8. Kaplan FS, Al Mukaddam M, Baujat G, et al. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2024;3:1–159.

9. Antelava ОA, Nikishina IP, Guseva IA, et al. Progressive ossifying fibrodysplasia. RMJ. 2015;(7):415–420 (In Russ).

10. Connor JM, Skirton H, Lunt PW. A three generation family with fibrodysplasia ossificans progressiva. J Med Genet. 1993;30(8):687–689. doi: https://doi.org/10.1136/jmg.30.8.687

11. Towler OW, Peck SH, Kaplan FS, et al. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol. 2021;470:136–146. doi: https://doi.org/10.1016/j.ydbio.2020.11.004

12. Nikishina IP, Arsenyeva SV, Matkava VG, et al. Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva. Pediatr Rheumatol Online J. 2023;21(1):92. doi: https://doi.org/10.1186/s12969-023-00856-1

13. Pignolo RJ, Baujat G, Hsiao EC, et al. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial. J Bone Miner Res. 2022;37(10):1891–1902. doi: https://doi.org/10.1002/jbmr.4655

14. Pignolo RJ, Hsiao EC, Al Mukaddam M, et al. 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. 2023;38(3):381–394. doi: https://doi.org/10.1002/jbmr.4762

15. Nikishina I, Matkava V, Arsenyeva S, et al. Combination therapy with palovarotene and tofacitinib in patients with fibrodysplasia ossificans progressiva: hopeful promising for a hopeless disease. Pediatr Rheumatol. 2024;22(Suppl 2):83. doi: https://doi.org/10.1186/s12969-024-01005-y

16. Diolintzi A, Pervin MS, Hsiao EC. Immunologic Aspects in Fibrodysplasia Ossificans Progressiva. Biomolecules. 2024;14(3):357. doi: https://doi.org/10.3390/biom14030357