Defining the optimal disease duration of early diffuse systemic sclerosis for clinical trial design

Abstract

Objectives: Clinical trials in early diffuse cutaneous systemic sclerosis (SSc) using the modified Rodnan skin score (mRSS) as the primary outcome measure have most often been negative. We wanted to assess how the definition of disease onset (first SSc manifestation vs first non-Raynaud manifestation) and varying lengths of disease duration at trial entry as an inclusion criteria functioned. Our objective was to optimize trial inclusion criteria.

Methods: We used the prospective, observational University of Pittsburgh Scleroderma Cohort to identify early diffuse SSc patients first evaluated between 1980 and 2015. All had <3 years from first SSc (n = 481) or first non-Raynaud manifestation (n = 514) and three or more mRSS scores. We used descriptive, survival and group-based trajectory analyses to compare the different definitions of disease onset and disease duration as inclusion criteria for clinical trials.

Results: There was no appreciable difference between using first SSc manifestation compared with first non-Raynaud manifestation as the definition of disease onset. Compared with other disease durations, <18 months of disease had >70% of patients fitting into trajectories with worsening cutaneous disease over 6 months of follow-up. Longer disease durations demonstrated the majority of patients with trajectories showing an improvement in mRSS (regression to the mean) over 6 months.

Conclusions: Regardless of whether the first SSc or first non-Raynaud manifestation is used to define disease onset, duration of <18 months at enrolment is preferable. A longer disease duration criterion more frequently results in regression to the mean of the mRSS score, and likely contributes to negative trial outcomes.

Keywords: clinical trial design; diffuse scleroderma; scleroderma; systemic sclerosis.

Fig. 1

Kaplan–Meier curves for time to peak skin score by mutually exclusive disease duration groups mRSS: modified Rodnan skin score.

Fig. 2

Five-year mRSS trajectory plots from first SSc (A) and first non-Raynaud manifestation (B) mRSS: modified Rodnan skin score.

Fig. 3

Five-year follow-up mRSS trajectory plots for <18 and <24 months from first non-Raynaud manifestation at presentation mRSS: modified Rodnan skin score.