FOP is an autosomal-dominant genetic disorder characterized by progressive and cumulative heterotopic ossification (HO) of select skeletal muscles, ligaments, and tendons, resulting in the fixation of joints, progressive immobility, and premature death. Some HO events are preceded by episodes of significant local tissue inflammation called flare-ups. While it is recognized that FOP may sometimes progress in the absence of flare-ups (Pignolo 2016), the extent to which progression of HO occurs independently of flare-up is unknown. 18F-NaF PET has been used to visualize actively-forming heterotopic bone in both human and mouse FOP and to discriminate growing lesions from ones that are quiescent (Botman 2019, Upadhyay 2017). Furthermore, in FOP mice, 18F-NaF PET has been a useful biomarker of disease activity that showed the effect of REGN2477, an anti-Activin A monoclonal antibody on halting ongoing HO (Hatsell 2015).
We describe the prevalence, multiplicity, and flare-up correlates of active HO in FOP by analyzing baseline 18F-NaF PET/CT imaging data from LUMINA-1, a multi-center safety and efficacy study of REGN2477 (NCT03188666). Adult patients with genetically confirmed FOP were enrolled and assessed at baseline for demographics (age, sex, ethnicity, mutation), CAJIS score (Kaplan 2017), physical examination and static whole-body 18F-NaF PET/CT.
44/44 (100%) of patients displayed heterotopic, high-intensity lesions indicative of metabolically-active HO. Metabolically-active lesions were observed in patients with both classical and non-classical mutations. Although 100% of patients showed ≥2 active lesions on baseline 18F-NaF PET/CT, only 3 of 44 patients demonstrated flare-up within 7 days of the baseline. Moreover, in 3 of these patients, the site of metabolically-active lesions indicative of HO was not coincidental with the site of clinically diagnosed flare-up.
This systematic investigation, using new and sensitive methodology, indicates that HO is usually active, multifocal and disassociated from clinically diagnosed flare-ups. The high prevalence of such lesions implies that therapeutic interventions should be directed towards continuous pathology, in addition to episodic (such as flare-up) pathology. While these cross-sectional data represent significant new insights into the natural history of FOP, we await longitudinal results to further evaluate the natural history and imaging correlates of HO as well as its response to monoclonal antibody therapy directed at Activin A.