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

Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis—a comprehensive review

“…Consistent with the results of preclinical studies, a recent analysis of serum biomarkers in blood samples from 240 patients participating in RA-BUILD showed that treatment with baricitinib 4 mg once daily significantly reduced serum biomarkers of joint synovial inflammation and tissue destruction [42]. At week 4, serum levels of three different biomarkers of synovial inflammation (C1M, C3M and C4M) had decreased by 12-21%, depending on the biomarker (p < 0.01), and these reductions were maintained at week 12 (reductions of 11-27%; p < 0.001).…”

Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments

“…The excellent clinical results and bone-erosion-reducing effects with BAR have been reported [ 198 ]. Thudium et al [ 169 ] conducted a subgroup analysis of the RA-BUILD study and have reported changes in bone metabolism markers in 240 subjects. After 12 weeks of the BAR treatment, osteogenic markers did not change significantly, whereas bone resorption markers were significantly reduced.…”

Association between disease‐modifying antirheumatic drugs and bone turnover biomarkers

“…It was discovered that treatment with baricitinib reduced the circulating biomarkers linked with the destruction of joint tissue, which led to a simultaneous improvement in clinical symptoms of RA. 73 It was discovered by Farr and colleagues that a JAKi inhibited the production of the pro-inflammatory secretome by senescent cells. Studies conducted in vitro demonstrated that senescent cell-conditioned medium led to increased osteoclastogenesis by inhibiting osteoblast mineralization and enhancing osteoclast progenitor survival.…”

“…Within the context of a placebo‐controlled, randomized phase 3 trial of baricitinib in active RA patients, Tudium et al evaluated the related biomarkers with the turnover of joint tissue. It was discovered that treatment with baricitinib reduced the circulating biomarkers linked with the destruction of joint tissue, which led to a simultaneous improvement in clinical symptoms of RA 73 . It was discovered by Farr and colleagues that a JAKi inhibited the production of the pro‐inflammatory secretome by senescent cells.…”