A fragment of type IV collagen released by MMP
Type IV collagen is an abundant protein of basement membranes, but is also present in the intercellular matrix of the synovial lining layer. C4M is a serologic marker of type IV collagen metabolism which reflects degradation in the extracellular matrix.
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 in patients with active rheumatoid arthritis (RA).
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.
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).
Baricitinib treatment resulted in reduced circulating biomarkers associated with joint tissue destruction as well as concomitant RA clinical improvement.
Pericellular Fibrosis Remodelling, Hepatic Fibrosis Outcome, Fibrolysis, Angiogenesis / Basement Membrane, Atherosclerotic Plaque Instability, Mucosal Damage, Mucosal Damage Resolution
Basement membrane degradation, ECM degradation
ELISA and/or on high-precision platform
Healthy reference range
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Species (Tested in)
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