Machine-learning classification identifies patients with early systemic sclerosis as abatacept responders via CD28 pathway modulation

Here, the efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic subset would show the most significant clinical improvement. Eighty-four participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-Seq was performed on 233 skin paired biopsies at baseline and at 3 and 6 months. Improvement was defined as a 5-point or more than 20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subsets (inflammatory, fibroproliferative, or normal-like subsets). In the abatacept arm, change in mRSS was most pronounced for the inflammatory and normal -like subsets relative to the placebo subset. Gene expression for participants on placebo remained in the original molecular subset, whereas inflammatory participants treated with abatacept had gene expression that moved toward the normal-like subset. The Costimulation of the CD28 Family Reactome Pathway decreased in patients who improved on abatacept and was specific to the inflammatory subset. Patients in the inflammatory subset had elevation of the Costimulation of the CD28 Family pathway at baseline relative to that of participants in the fibroproliferative and normal-like subsets. There was a correlation between improved Delta mRSS and baseline expression of the Costimulation of the CD28 Family pathway. This study provides an example of precision medicine in systemic sclerosis clinical trials.

Automated summary

This study analyzed the efficacy of abatacept in patients with early diffuse systemic sclerosis and found that patients in the inflammatory intrinsic subset showed the most significant clinical improvement. Gene expression analysis revealed that patients treated with abatacept had improved gene expression moving toward the normal-like subset. The study provides an example of precision medicine in systemic sclerosis clinical trials.