Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis

Abstract

IntroductionSystemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.MethodsAdult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30 % post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.ResultsTen subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud’s symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71 %) randomized to abatacept and one out of three patients (33 %) randomized to placebo experienced ≥30 % improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (−8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (−2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate −9.8, 95 % confidence interval −16.7 to −3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (−13.5 ± 3.1 vs. −4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.ConclusionsClinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.Trial registrationClinicalTrials.gov NCT00442611. Registered 1 March 2007.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0669-3) contains supplementary material, which is available to authorized users.

Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity

“…A growing body of evidence supports the use of skin, lung, and peripheral blood transcriptomes as SSc biomarkers to quantify interpatient heterogeneity, to identify dysregulated molecular pathways underlying disease, and to identify appropriate patients for specific SSc therapies (6)(7)(8)(9). These studies have identified remarkable homogeneity in skin biopsies obtained from the same patient such that transcriptomic profiles of clinically unaffected back and clinically affected forearm biopsies are nearly identical (10)(11)(12).…”

Biological Therapy in Systemic Sclerosis

“…Adverse events were similar in both groups, with one serious adverse event in the treatment group (supraventricular tachycardia), considered to be unrelated to the study drug and the patient completed the study. Patients who improved with abatacept mapped to the inflammatory intrinsic subset of skin gene expression at baseline and showed decreased gene expression after treatment, mainly in genes related to CD28 T-cell co-stimulation, whereas non-improvers and the placebo group showed stable or reverse inflammatory gene expression [51].…”

“…Improvement in mRSS was defined as ≥30% from baseline; skin biopsies were obtained for differential gene expression and intrinsic gene expression subset assignment (inflammatory signature, fibroproliferative signature and normal-like signature). This included biopsies from four healthy controls [51].…”

A functional genomic meta-analysis of clinical trials in systemic sclerosis: towards precision medicine and combination therapy

“…First, since SSc is a rare disease, clinical trials tend to have small sample sizes. Thus, few differentially expressed genes (DEGs) can be detected after multiple hypothesis testing correction (Chakravarty et al, 2015;Gordon et al, 2015).…”

“…To gain mechanistic insight into the action of experimental therapies, clinical trials in SSc have collected genome-wide gene expression data from skin biopsies pre-and post-treatment (Chakravarty et al, 2015;Gordon et al, 2015;Rice et al, 2015a;Hinchcliff et al, 2013;Chung et al, 2009) (Martyanov et al Submitted). However, these studies in clinical trials face limitations.…”