LAUSR

OBJECTIVE Clinical trials in early diffuse systemic sclerosis (SSc) have consistently shown a placebo group response with a declining modified Rodnan skin score (mRSS), with negative outcomes. Our objective was to identify strategies using clinical characteristics or laboratory values to improve trial design. METHODS We identified early diffuse SSc patients first seen at the University of Pittsburgh from 1980-2015. Eligible patients had ≥3 visits, with at least two mRSS scores within the first year of follow-up. We performed Kaplan-Meier analyses, group-based trajectory analysis of mRSS scores, followed by multivariable regression analysis and classification tree analysis. We applied the results to the abatacept in early diffuse SSc (ASSET) trial outcome data. RESULTS We identified 403 patients with <18 months, and 514 of < 36 months disease duration. The median number of mRSS follow-up scores was 14 (IQR 8, 25). All methodologic approaches identified skin thickness progression rate, RNA polymerase III (RNAP3) antibody positivity and presence of tendon friction rubs (TFR) as predictors of mRSS trajectory over 5 years of follow-up; thereby potential enrichment variables. When applied to the ASSET data, both adjustment for RNAP3 and TFR demonstrated reduction of the placebo mRSS response, particularly at 6 months. A significant difference in the ACR CRISS score was found with adjustment by RNAP3 at 6, and TFR or RNAP3 at 12 months. CONCLUSION Adjustment for both RNAP3 and TFR predicts mRSS trajectory and diminished the mRSS decline in ASSET placebo group, and identified significant differences in CRISS. RNAP3, particularly, is a stratification or enrichment approach to improve early diffuse SSc trial design.