International physician survey on management of FOP: a modified Delphi study

Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a rare and disabling genetic condition of progressive heterotopic ossification with a point prevalence of approximately 1 per 2 million. No ethnic, racial, gender or geographic predisposition has been reported [1, 2]. FOP results from mutations in the intracellular domain of the bone morphogenetic protein (BMP) type I receptor, ACVR1, which drive extraskeletal bone formation [3‐5]. Mutant (mt) ACVR1 exhibits mild basal hyperactivity and hyper-responsiveness to canonical and non-canonical ligands [6‐8].

Classic FOP, seen in ~97% of patients worldwide is characterized by two clinical features: malformations of the great toes and progressive heterotopic endochondral ossification (HEO), and by a single missense activating mutation in ACVR1 (c.617G > A;R206H) [1‐4]. Misdiagnosis is common [9]. Clinical and genetic variants have been described [2, 4]. Malformations of the great toe are noted at birth; neck stiffness due to orthotopic fusion of cervical vertebra is a common early finding. Other skeletal anomalies associated with FOP include short malformed thumbs, clinodactyly, short broad femoral necks, hip dysplasia and proximal medial tibial osteochondromas [4].

Most individuals with classic FOP experience episodes of painful inflammation of soft tissues (flare-up), followed by heterotopic ossification of skeletal muscle, fascia, tendons, aponeuroses, and ligaments beginning in the first decade of life. Progressive joint dysfunction without flare-up can also occur, with or without HEO. Extraskeletal bone formation is permanent and leads to progressive immobility and need for assistance in performing activities of daily living [10]. Finally, progressive restrictive chest wall disease and secondary cardiac failure lead to death, commonly in the fifth decade [11]. At present, no definitive treatment is available; symptomatic management prevails but varies widely [12]. Basic and clinical research is identifying robust targets for clinical development [1, 7, 8, 13‐16].

In order to better understand if there is worldwide consensus among clinicians in FOP patient care, an expert panel of physicians directly involved in patient management was convened at an international FOP patient meeting to address this issue.

The consensus process incorporated a five-step modified Delphi method, which took place between January and June 2016 [17]. First, a thorough review of the literature and FOP Treatment Guidelines was performed by the principal investigator (PI; MDR). Second, an e-mail questionnaire, with a comprehensive list of statements related to four main topics (diagnosis, prevention of flare-ups, patient and family-centered care and general clinical management issues) was established by the PI. Third, a panel of ten international experts was convened by the PI based on physician participation at the annual FOP patient and family meeting of FOP Italia in Livorno, Italy in April, 2016. The panel included physicians from ten countries (Argentina, Australia, Brazil, France, Germany, Italy, Japan, Netherlands, United Kingdom and the United States) and from five continents (North America, South America, Europe, Asia and Australia). Fourth, the expert panel was asked to rank, revise and order statements for consideration. Finally, the panel was asked to indicate agreement, partial agreement or disagreement with specific statements agreed upon for assessment.

Twenty statements considered by the expert panel received at least consensus approval and are reported in Table 1.

There was broad consensus on most of the statements considered by the panel (Table 1). However, there were some notable exceptions including – but not limited to – the chronic use of non-steroidal anti-inflammatory medications to prevent HEO. The expert panel agreed to disagree on this contentious issue but reached consensus on the need for additional evidence-based data.

There are many issues regarding the management of FOP that were not addressed in this research study. The exclusion of management issues related to FOP should not be construed as a failure to reach consensus. Many topics were beyond the scope of this ad hoc study.

First, the panel of experts assembled was limited to those attending the FOP Italia Patient and Family Meeting in Livorno, Italy in 2016 and did not necessarily reflect the totality of global expertise in this field. Second, the generation of topics for consideration focused primarily on prevention and purposely circumvented controversial topics of symptomatic management such as palliative medications. Third, the FOP Treatment Guidelines, a consensus document published by clinical experts worldwide, and whose revision is anticipated in 2018, will comprehensibly address the central management issues in FOP as it has in the past [12]. Nevertheless, this survey will assist physicians in the contemporary clinical management of FOP patients, circumscribe critical areas of preventive management, and inform future consensus guidelines. Finally, the consensus statements reported in this study are not intended to substitute for the independent professional judgment of treating physicians as they cannot account for regional heterogeneity of access to clinical care or the best advice and guidance for individual FOP patients and families.