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

Abstract

The efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic gene expression subset would show the most significant clinical improvement. 84 participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-seq was performed on 233 skin paired biopsies at baseline, 3-and 6-months. Improvement was defined as a 5 point or >20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subset (inflammatory, fibroproliferative, or normal-like). In the abatacept arm, change in mRSS was most pronounced for the inflammatory (p<0.001) and normal-like (p=0.03) subsets relative to placebo. Participants on placebo remained in their molecular subset while inflammatory participants treated with abatacept moved toward normal-like. The CD28 costimulation pathway decreased in patients that improved on abatacept (FDR=5.88x10 -4 ) and was specific to the inflammatory subset (FDR=0%). Patients in the inflammatory subset had elevation of the CD28 costimulation pathway at baseline relative to fibroproliferative (p = 0.0026) and normal-like (p=0.0001) participants. There was a correlation between improved ΔmRSS and baseline expression of the CD28 costimulation pathway (R=-0.62, p=0.02). This study provides an example of precision medicine in SSc clinical trials.

Scleromyositis: A distinct novel entity within the systemic sclerosis and autoimmune myositis spectrum. Implications for care and pathogenesis

“…A randomized control trial failed to demonstrate efficacy of abatacept on skin thickening in patients with SSc ( 189 ), although recent analysis by intrinsic gene expression signatures seemed to show an effect in patients in the inflammatory subset ( 190 ). Preliminary results of a recent randomized control trial indicate efficacy of abatacept in a subgroup of patients with IMNM ( 191 ).…”

Enrichment strategies for clinical trials targeting skin fibrosis and interstitial lung disease in systemic sclerosis

“…These may depend on the drug being tested. For example, further analysis of data from the abatacept trial [31 ▪ ] has shown that expression of the costimulation of the CD28 Family Reactome Pathway was increased in patients in the ‘inflammatory’ subset and that expression decreased with abatacept, suggesting that high baseline expression might predict treatment response. A posthoc analysis of the DesiReS trial [32 ▪ ] comparing rituximab to placebo (noting that this was not a study specifically of early dcSSc [33]), concluded that high CD19-positive cell counts were associated with improvement in mRSS with rituximab.…”