Subsets of Patients With Lupus Identified by Gene Expression Profiles Exhibit Differential Clinical Responsiveness to Baricitinib.

Abstract

Baricitinib is a JAK1 inhibitor that showed efficacy in patients with systemic lupus erythematosus (SLE) in a phase 2 study but failed to meet the primary endpoint in phase 3 trials. To understand this discrepancy and identify patients with SLE who are responsive to baricitinib, we conducted baseline and longitudinal transcriptomic analysis in patients enrolled in the phase 2 trial. Whole-blood samples from 272 patients with SLE were analyzed. Clinical response was assessed using SLE Responder Index-4 after 24 weeks of placebo or baricitinib (2 or 4 mg daily). Gene expression profiling was conducted using Gene Set Variation Analysis (GSVA) of 32 immune-related gene modules. Eight distinct molecular endotypes (A-H) were identified from baseline GSVA scores, with progressively increasing immune disturbances. Baseline demographics were similar across endotypes, with modest but significant differences in anti-double-stranded DNA and complement levels but no SLE Disease Activity Index differences. Significant clinical responses to baricitinib were confined to endotypes D and G (P = 0.004 and 0.048 vs placebo, with effect sizes of 41.54% and 31.89%, respectively). Importantly, patient clustering based on clinical features failed to identify treatment-responsive subsets. Endotype G demonstrated the most pronounced treatment-related transcriptional modulation, with dose-dependent suppression of interferon, JAK1/JAK2/TYK2 signaling, immunoproteasome, and inflammatory pathways evident as early as week 2 and sustained through week 24. Transcriptional changes in response to baricitinib were largely confined to clinical responders in endotype G. Feature importance analysis identified the interferon and Treg cell signatures as major predictors of response. Transcriptomic analysis identified subsets of patients with SLE responsive to baricitinib.