Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis

Abstract

Objective: To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials.

Methods: Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture.

Results: The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = -0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty-three percent of patients with "early" disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty-one percent of patients with "late" disease (disease duration ≥ 18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome.

Conclusion: Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

Copyright © 2012 by the American College of Rheumatology.

Figures

Figure 1

Skin Scores at Baseline and Change During Clinical Trials 1a. MRSS at Baseline (all subjects) 1b. Change in Individual Skin Scores Over Time 1c. Distribution of Change in MRSS From Baseline to 6 Months

Figure 2

HAQ Scores at Baseline and Change During Clinical Trials 2a. HAQ at Baseline (all subjects) 2b. Change in Individual HAQ Scores Over Time 2c. Distribution of Change in HAQ From Baseline to 6 Months

Figure 3

Relationships Between MRSS or HAQ and Disease Duration 3a. Correlation Between Baseline MRSS and Baseline Disease Duration (at 6 Months) 3b. Correlation Between Baseline HAQ and Baseline Disease Duration 3c. Correlation Between Change in MRSS and Baseline Disease Duration 3d. Correlation Between Change in HAQ (at 6 Months) and Baseline Disease Duration