The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

Abstract

Background: Tissue released blood-based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo-controlled study of baricitinib in patients with active rheumatoid arthritis (RA). Methods: Serum biomarkers associated with synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), bone resorption (CTX-I), and bone formation (osteocalcin) were analyzed at baseline, and weeks 4 and 12, from a subgroup of patients (n = 240) randomized to placebo or 2-mg or 4-mg baricitinib (RA-BUILD, NCT01721057). Mixed-model repeated measure was used to identify biomarkers altered by baricitinib. The relationship between changes in biomarkers and clinical measures was evaluated using correlation analysis. Results: Treatment arms were well balanced for baseline biomarkers, demographics, and disease activity. At week 4, baricitinib 4-mg significantly reduced C1M from baseline by 21% compared to placebo (p < 0.01); suppression was sustained at week 12 (27%, p < 0.001). Baricitinib 4-mg reduced C3M and C4M at week 4 by 14% and 12% compared to placebo, respectively (p < 0.001); they remained reduced by 16% and 11% at week 12 (p < 0.001). In a pooled analysis including all treatment arms, patients with the largest reduction (upper 25% quartile) in C1M, C3M, and C4M by week 12 had significantly greater clinical improvement in the Simplified Disease Activity Index at week 12 compared to patients with the smallest reduction (lowest 25% quartile). Conclusion: Baricitinib treatment resulted in reduced circulating biomarkers associated with joint tissue destruction as well as concomitant RA clinical improvement. Trial registration: ClinicalTrials.gov NCT01721057; date of registration: November 1, 2012.