Background/Purpose Rheumatoid arthritis (RA) patients develop bone and joint damage due to chronic inflammation mediated by critical cytokines, eg, IL-6. Pre-clinical studies have implicated IL-6 signaling in regulation of osteoclasts and fibroblast-like synoviocytes (FLS) to increase levels of bone resorptive molecules like receptor activated NF kB ligand (RANKL) and joint destructive proteins, such as matrix metalloproteinases (MMPs). Blockade of IL-6R signaling by sarilumab significantly reduced structural damage in RA patients, as measured by the modified van der Heijde total Sharp Score, including the erosion score and joint space narrowing components in the Phase 3 part of the MOBILITY study (NCT01061736). Most common TEAEs included infections and injection site reactions. A higher incidence of serious infections was observed with sarilumab. Lab abnormalities included decreases in neutrophils and increases in transaminases and lipids. To elucidate mechanisms of clinical reduction of bone and joint damage by sarilumab, we evaluated a panel of serum markers associated with bone resorption (RANKL and osteoprotegerin [OPG]), bone turnover (CTX-1 and C1M), osteoblast formation (osteocalcin [OC]), synovium (MMP-3 and C3M) and cartilage degradation (C2M) in patients enrolled in MOBILITY B.

Methods Sera were analyzed from 128 patients treated with placebo (Pbo) + methotrexate (MTX), and 131 patients receiving subcutaneous 200 mg sarilumab every other week (q2w) + MTX. Serum biomarkers levels were measured by ELISA. All biomarkers were analyzed at baseline, and post-treatment at Wks 2 and 24, with the exceptions of CTX-1 and OC, which were analyzed at baseline, Wks 24 and 52 post-treatment. A mixed effect model with repeated measures on % change from baseline (after rank transformation) was performed for all biomarkers (ANOVA-type method). Treatments were compared at each visit. For samples above the limit of quantitation (LOQ), the LOQ was used in analyses, for samples below the LOQ, half the LOQ was used.

Results Sarilumab + MTX treatment significantly reduced levels of MMP-3 and MMP generated fragments of collagen type 1 and type 3 (C1M and C3M) compared to Pbo + MTX at all timepoints analyzed (Table). RANKL levels were also reduced at Wk 24 in the sarilumab + MTX group, however approximately 15% of values were above the LOQ. In contrast, OC increased from baseline in the sarilumab 200 mg q2w + MTX group compared to Pbo + MTX but did not reach significance (Wk 52, p=0.0571).

Conclusion Sarilumab reduced bone resorption and joint damage markers, and increased OC, a marker of bone formation, in RA patients. This is the first report that IL-6 inhibition leads to RANKL reduction in RA patients. This data supports a mechanism whereby increased IL-6 signaling promotes structural damage through osteoclasts and FLS and by reducing osteoblast bone formation.