Longitudinal and Flare-Up-Specific Biomarkers in Fibrodysplasia Ossificans Progressiva (FOP): Data from a Global Natural History Study

Introduction FOP is an ultra-rare, severely debilitating genetic disorder characterized by episodic heterotopic ossification (HO) and flare-ups. Identification of biomarkers would be useful to predict flare-ups and monitor FOP disease progression, and to identify when interventions are warranted and assess responses to these interventions. Objective: To evaluate putative serum and urine biomarkers at Baseline (BL), annually, and during the course of flare-ups in a longitudinal FOP natural history study (NHS).

Methods Individuals with FOP aged ≤65 years with a documented ACVR1R206H mutation were eligible to participate in a prospective, 36-month NHS (NCT02322255) investigating the longitudinal progression of FOP. This analysis evaluated biomarker data at BL and Month 12, and during flare-ups. Blood and urine samples were collected at BL and annual study visits, and at Days 1, 42, and 84 of imaged flare-ups to measure biomarkers of inflammation, angiogenesis, and bone/cartilage turnover. Low-dose whole-body computed tomography (WBCT, excluding the head) was performed to assess HO at Months 12, 24, and 36; flare-up HO volumes were assessed by CT at the flare-up sites. Magnetic resonance imaging (MRI) or ultrasound was used to assess flare-ups for the presence of edema. Data were analyzed using descriptive statistics.

Results BL and Month 12 assessments were completed for 99/114 participants; 93 had evaluable WBCT HO at both timepoints, of whom 37 (39.8 %) had new HO at Month 12. Overall, biomarker values did not change substantially from BL to Month 12, and mean values were similar between participants with versus those without new HO at Month 12. A total of 52 flare-ups were CT-imaged, of which 14 (26.9 %) resulted in new HO at Day 84. Out of 42 flare-ups assessed at Day 1 by MRI or ultrasound, 29 (69.0 %) had edema; of these, 10 (34.5 %) had new HO at Day 84 (versus 19 [65.5 %] with no new HO). No serum biomarker was identified that was predictive of flare-ups with BL edema or that resulted in development of new HO.

Discussion The identification of biomarkers to predict disease progression could greatly benefit the clinical management of FOP. As results from this NHS did not identify a signal for a longitudinal or flare-up-specific biomarker for FOP, potentially due to the limited panel of biomarkers tested, a narrow sampling window, and/or missing data for some participants, further research is required.

Keywords FOP, NHS,Natural history study, biomarkers

Korrespondenzadresse Robert J. Pignolo, Department of Medicine, Mayo Clinic, Rochester, MN, 200 First St. SW, 55905 Rochester, MN, USA

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Conflict of interest Research investigator: Clementia/Ipsen, Regeneron; Advisory board: President of the International Clinical Council on FOP; Chair of the Publications Committee for the IFOPA Registry Medical Advisory Board

Publication History

Article published online:
05 March 2021