Pharmacoepidemiologist Regeneron Pharmaceuticals, Inc., United States
Background: Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant rare disease characterized by progressive episodic multi-focal heterotopic ossification (HO) of skeletal muscle, ligaments, tendons, and fascia. The population characteristics and natural disease history of FOP are currently ill defined.
Objectives: A systematic literature review (SLR) assessed the current knowledge of FOP, including mortality, comorbidities, and current clinical care management recommendations including medication use. HO formation frequency and patterns in the pediatric population were also assessed.
Methods: We searched Pubmed, Embase, the Cochrane central register of controlled trials, the Trip database and NICE documents to retrieve relevant studies reporting an outcome of interest in the FOP population, restricted to humans but not by language. Studies were kept if they reported at least 1 of the following outcomes: mortality, comorbidity, medication-use pattern, standard of care, or HO in pediatric population. Clinical trials solely aiming to assess a treatment for FOP were excluded to avoid potential disease-modifying effects. Two independent reviewers conducted the study selection. Data extraction was conducted by 1 investigator and was reviewed and confirmed by the second. Quality assessment was conducted using the appropriate tools by study design. The SLR was registered on Prospero (CRD42022366914).
Results: Thirty-nine studies were selected. Publications were on a global geographical scale with wide age groups. Study duration varied from 1 day to 33 years. Sample size ranged from 3 to 299 patients. Eight studies reported on mortality; out of 62 reported deaths with a recorded cause, 25 were due to cardiovascular or cardiorespiratory failure. Twenty-five publications included information on comorbidities, with 8 studies reporting deafness as a comorbidity, followed by chronic pain in 5 publications. The 3 most affected systems by order of magnitude were cardiovascular, respiratory, and skeletal. Twelve studies provided standard-of-care recommendations and medication use. Eight studies had extractable data on pediatric HO formation.
Conclusions: Despite the number of studies included in this SLR, there were important limitations (eg, several studies used the same group of patients; lack of clear definition, outcomes, or follow-up periods). Re-use of the same patient pool meant that duplicate data could not be ruled out, which inhibited data aggregation and the estimation of background rates. Our SLR highlights the need for detailed information provided in published studies to allow for critical evaluation and summarization of studies in SLRs, especially in rare diseases.
