Background/Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by poly-articular inflammation, cartilage loss, synovial inflammation, subchondral bone erosion, and joint space narrowing. In this analysis, we investigated the effect of tocilizumab (TCZ; anti-IL-6R mAb) in combination with methotrexate (MTX) on serum biomarkers of bone, cartilage, and synovium turn over in patients with moderate to severe RA enrolled in the LITHE study.

Methods: The LITHE study (Roche WA17823) was a 2-year phase III, 3-arm randomized (1:1:1), double-blind, placebo-controlled, parallel group study of TCZ in moderate to severely active RA with inadequate response to MTX. 1196 patients were randomized to receive stable doses of MTX (10 – 25 mg / week) plus placebo, TCZ at 4 mg/kg (TCZ4), or TCZ at 8 mg/kg (TCZ8) every 4 weeks for 52 weeks. Patients who experienced less than 20% improvement in both swollen (SJC)/tender joint counts (TJC) at week 16 were given escape therapy. Serum samples were collected at baseline and week 2, 4, 16, 24, and 52. Following biomarkers were measured: C2M (cartilage degradation), C3M (synovial inflammation), MMP3, total CRP, CRPM (MMP-degraded CRP), VICM (Citrullinated and MMP degraded Vimentin), ICTP (MMP destroyed type I collagen), osteocalcin (bone formation) and CTX-I (Bone resorption). Analysis of dose- and time-dependent effect of TCZ on the release of biomarkers compared to placebo both including and excluding the escape patients was done by two-way ANOVA.

Results: In the TCZ8 group, the cartilage degradation marker C2M was rapidly reduced as compared to placebo (week 2: -12%) and remained low through weeks 4, 16, 24, and 52 (-13 to -16%, p<0.001). A similar pattern was observed for C3M, VICM, and CRPM, which were reduced at week 4 by -28, -50, and -30% (p<0.0001), respectively. The levels of these 4 markers were not affected in the TCZ4 group or in the placebo group. In contrast, MMP3 levels were strongly reduced in both TCZ4 and TCZ8 groups. The circulating level of total CRP was completely inhibited by TCZ8, but only inhibited by 50% in the TCZ4 group. Osteocalcin and CTX-I were both increased in response to TCZ8, but only osteocalcin was increased in response to TCZ4. No change in ICTP was observed. There was a significant difference (p<0.001) in the biomarker profiles between escape patients, non-responders and responders.

Conclusion: TCZ8 strongly inhibited serum markers of cartilage degradation, synovial inflammation, and inflammation mediated tissue turnover suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. TCZ4, on the other hand, had limited effect on the release of the markers. This might indicate that TCZ8 had a more beneficial effect on the joint health as compared to TCZ4. Furthermore, the difference in the biomarkers profiles of responders and non-responders were markedly different indicating that predictive profiles for responders and non-responders may exist.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-effect-of-4-and-8-mgkg-tocilizumab-in-combination-with-methotrexate-on-serum-biomarkers-of-cartilage-connective-tissue-and-bone-turnover/