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The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment.

ABSTRACT: Fibrodysplasia ossificans progressiva (FOP) leads to disabling heterotopic ossification (HO) from episodic flare-ups. However, the natural history of FOP flare-ups is poorly understood. A 78-question survey on FOP flare-ups, translated into 15 languages, was sent to 685 classically-affected patients in 45 countries (six continents). Five hundred patients or knowledgeable informants responded (73%; 44% males, 56% females; ages: 1 to 71 years; median: 23 years). The most common presenting symptoms of flare-ups were swelling (93%), pain (86%), or decreased mobility (79%). Seventy-one percent experienced a flare-up within the preceding 12 months (52% spontaneous; 48% trauma-related). Twenty-five percent of those who had received an intramuscular injection reported an immediate flare-up at the injection site, 84% of whom developed HO. Axial flare-ups most frequently involved the back (41.6%), neck (26.4%), or jaw (19.4%). Flare-ups occurred more frequently in the upper limbs before 8 years of age, but more frequently in the lower limbs thereafter. Appendicular flare-ups occurred more frequently at proximal than at distal sites without preferential sidedness. Seventy percent of patients reported functional loss from a flare-up. Thirty-two percent reported complete resolution of at least one flare-up and 12% without any functional loss (mostly in the head or back). The most disabling flare-ups occurred at the shoulders or hips. Surprisingly, 47% reported progression of FOP without obvious flare-ups. Worldwide, 198 treatments were reported; anti-inflammatory agents were most common. Seventy-five percent used short-term glucocorticoids as a treatment for flare-ups at appendicular sites. Fifty-five percent reported that glucocorticoids improved symptoms occasionally whereas 31% reported that they always did. Only 12% reported complete resolution of a flare-up with glucocorticoids. Forty-three percent reported rebound symptoms within 1 to 7 days after completing a course of glucocorticoids. This study is the first comprehensive global assessment of FOP flare-ups and establishes a critical foundation for the design and evaluation of future clinical trials.

SUBMITTER: Pignolo RJ

PROVIDER: S-EPMC4829946 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment.

Pignolo Robert J RJ Bedford-Gay Christopher C Liljesthröm Moira M Durbin-Johnson Blythe P BP Shore Eileen M EM Rocke David M DM Kaplan Frederick S FS

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20151114 3

Fibrodysplasia ossificans progressiva (FOP) leads to disabling heterotopic ossification (HO) from episodic flare-ups. However, the natural history of FOP flare-ups is poorly understood. A 78-question survey on FOP flare-ups, translated into 15 languages, was sent to 685 classically-affected patients in 45 countries (six continents). Five hundred patients or knowledgeable informants responded (73%; 44% males, 56% females; ages: 1 to 71 years; median: 23 years). The most common presenting symptoms ...[more]

PMID: 27025942

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Project description:BACKGROUND:Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP. METHODS:All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed. RESULTS:Findings from 114 subjects (age range 4 to 56?years) were evaluated. While subject age was significantly (p?<?0.0001) correlated with increased CAJIS (r?=?0.66) and FOP-PFQ scores (r?=?0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47?units and 1.2%, respectively). There was also a significant (p?<?0.0001) correlation between baseline age and HO volume (r?=?0.56), with an estimated mean increase of 25,574?mm3/year. There were significant (p?<?0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r?=?0.57) and FOP-PFQ (r?=?0.52). CONCLUSIONS:Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients. TRIAL REGISTRATION:This study ( NCT02322255 ) was first posted on 23 December, 2014.

Dataset Information

The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment.

Publications

The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment.

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