Development of the Fibrodysplasia Ossificans Progressiva FLare EXperience Revised (FOP-FLEX-R©) Questionnaire: A Patient-Reported Outcome Measure

Robert J Pignolo; Edward C Hsiao; Mona Al Mukaddam; Monica Brova; Daniella Olonilua; Alan L Shields; Timothy P LaBranche; Cori Ann Sherwin; Elaine A Boing; Negar Karimian; Oyinkan Solanke; Frederick S Kaplan

doi:10.1016/j.bone.2026.117982

Development of the Fibrodysplasia Ossificans Progressiva FLare EXperience Revised (FOP-FLEX-R©) Questionnaire: A Patient-Reported Outcome Measure

Bone. 2026 Jun 18:212:117982. doi: 10.1016/j.bone.2026.117982. Online ahead of print.

Authors

Affiliations

¹ Department of Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address: pignolo.robert@mayo.edu.
² Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, the Eli and Edyth Broad Institute for Regeneration Medicine, and the Institute of Human Genetics, Department of Medicine, and the UCSF Program in Craniofacial Biology, University of California San Francisco, San Francisco, CA, USA.
³ Departments of Orthopaedic Surgery and Medicine, Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Adelphi Values, Boston, MA, USA.
⁵ Blueprint Medicines, Cambridge, MA, USA.
⁶ Ipsen, Cambridge, MA, USA.
⁷ Ipsen, Montreal, Canada.
⁸ Ipsen, London, UK.

PMID: 42314957
DOI: 10.1016/j.bone.2026.117982

Abstract

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, genetic disorder mainly characterized by progressive heterotopic ossification (HO). Flare-ups in FOP, involving soft tissue swelling, pain, warmth, and stiffness, often precede HO. We report development of the FOP-FLEX-R© questionnaire (Ipsen, 2026), providing clinical researchers with a comprehensive tool to assess patient experiences during flare-ups, and address the limitations of existing patient-reported outcome measures (PROMs).

Methods: The FOP-FLEX questionnaire was developed through: a targeted literature review to identify signs, symptoms, and impacts of FOP; concept selection and questionnaire development activities; validation of content and readability in expert consultations and patient interviews; revisions to create the FOP-FLEX-R© questionnaire.

Results: The literature review identified 42 'sign and symptom' and 28 'impact' concepts. Ten concepts were selected for inclusion in the initial FOP-FLEX: swelling, pain, skin warmth, stiffness, skin redness, impaired daily activities, frustration, bother, fatigue/tiredness, and appetite loss. Consultations with clinical experts (n = 5) and interviews with patients (n = 12) affirmed these concepts. Cognitive debriefing with the same patients indicated the FOP-FLEX was understandable and easy to complete, though some revisions were made, including those to enable the assessment to be completed by younger patients and to remove non-flare-up items.

Conclusions: The FOP-FLEX-R© questionnaire offers a comprehensive, content-validated PROM for use in clinical trials, to understand the lived experience of flare-ups in FOP and evaluate the benefit of new therapies.

Keywords: Fibrodysplasia ossificans progressiva; Flare-ups; Patient-reported outcome measure.