TY - JOUR
T1 - Natural history of fibrodysplasia ossificans progressiva
T2 - Cross-sectional analysis of annotated baseline phenotypes
AU - Pignolo, Robert J.
AU - Baujat, Geneviève
AU - Brown, Matthew A.
AU - De Cunto, Carmen
AU - Dirocco, Maja
AU - Hsiao, Edward C.
AU - Keen, Richard
AU - Al Mukaddam, Mona
AU - Sang, Kim Hanh Le Quan
AU - Wilson, Amy
AU - White, Barbara
AU - Grogan, Donna R.
AU - Kaplan, Frederick S.
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/5/3
Y1 - 2019/5/3
N2 - 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.
AB - 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.
KW - Clinical trial endpoints
KW - Cross-sectional analysis
KW - Disease progression
KW - Fibrodysplasia Ossificans Progressiva
KW - Heterotopic ossification
KW - Natural history
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U2 - 10.1186/s13023-019-1068-7
DO - 10.1186/s13023-019-1068-7
M3 - Article
C2 - 31053156
AN - SCOPUS:85065242058
SN - 1750-1172
VL - 14
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 98
ER -