• Inflammatory Disorders
• Rheumatoid Arthritis Clinical Trials

Proteolytic enzymes, such as matrix metalloproteinase (MMP), are unregulated in inflamed tissue. The protein fragments that are generated from MMP-mediated protein destruction are known as neoepitopes, which serve as biomarkers of inflammation in patients with rheumatoid arthritis (RA). The aim of this study, presented by Anne C. Bay-Jensen, MS, PhD, Nordic Bioscience, Harlev, Denmark, was to identify biomarker profiles that are associated with early response to tocilizumab in patients with RA, using neoepitope markers.

The Randomized, Double-Blind Study of Safety and Prevention of Structural Joint Damage During Treatment With Tocilizumab Versus Placebo, in Combination With Methotrexate, in Patients With Moderate to Severe Rheumatoid Arthritis study [LITHE; NCT00106535] examined the efficacy of tocilizumab in a Phase 3, 3-arm, randomized, parallel-group study of 1196 patients with moderate or severe active RA who had inadequate response to methotrexate. This analysis included a subset of patients from the tocilizumab 8 mg/kg plus methotrexate arm (TCZ8; n=206) and from the placebo plus methotrexate arm (n=211). Nonresponders were escape patients from the TCZ8 arm, defined as <20% improvement in both swollen joint count (SJC) and tender joint count (TJC) at Week 16.

The effect of TCZ8 (n=168) versus placebo (n=112) on serum biomarkers was monitored from baseline to Week 52. Patients who were receiving rescue treatment were excluded. An early-response profile was determined by subdividing TCZ8-treated patients into responders (n=91) and nonresponders (n=29). Serum biomarkers were measured, including the inflammation markers' total C-reactive protein (CRP), the neoepitope MMP-degraded CRP (CRPM), and citrullinated and MMP-generated vimentin fragments (VICM); the cartilage degradation and synovium turnover markers MMP3 and the MMP-degraded type II and III collagen (C2M and C3M, respectively); and the bone turnover markers osteocalcin, cathepsin K-mediated type 1 collagen degradation (CTX-I), and MMP-degraded type I collagen (ICTP).

In response to TCZ8, CRP was significantly blocked whereas CRPM continued to decrease over time (p<0.0001 for both at Weeks 4 and 52). TCZ8 significantly inhibited C2M (p<0.001 at Week 4; p<0.01 at Week 52) and C3M (p<0.0001 at Weeks 4 and 52) levels compared with baseline. From baseline, the mean % change in CRPM (responders, about −24% vs nonresponders, about −60%; OR, 4.0; 95% CI, 1.7 to 9.4; p=0.0014), but not in CRP (responders, about −64% vs nonresponders, about −14%; OR, 1.6; p=0.18), at 4 weeks was predictive of TCZ8 response. The mean % change from baseline in C2M (responders, about −10% vs nonresponders, about +10%; OR, 5.8; 95% CI, 2.2 to 15; p=0.0003) and in C3M (responders, about −23% vs nonresponders, about −10%; OR, 9.6; 95% CI, 2.8 to 33; p=0.0004) was highly predictive of TCZ8 response.

TCZ8 strongly inhibited markers of cartilage degradation (C2M) and inflammation-mediated tissue turnover (C3M, CRPM), which may explain, in part, the beneficial effect of TCZ on the joints. In contrast to traditional CRP and the other markers that were measured, the novel neoepitope biomarkers of cartilage and synovial turnover discriminated between early TCZ8 responders and nonresponders. These neoepitope markers may reflect the same predictive effect with other doses of TCZ or other biologic interventions.

• © 2012 MD Conference Express®