Background/Purpose: RA is characterized by poly-articular synovial inflammation, cartilage loss and erosion of subchondral bone. It is critical to diagnose and effectively treat the disease early to suppress inflammation and halt destruction of the joint. Thus, identification of the patients most likely to respond to a given intervention should be pursued for optimal benefits for both patients and payers. The objectives were i) to investigate the early changes in biomarkers of bone, cartilage, synovium and inflammation as an effect of 8mg/kg tocilizumab (TCZ) treatment, and ii) to identify profiles associated with responders and non-responders biomarker profiles.

Methods:

The prospective biomarker substudy of the LITHE trial included 626 patients. The LITHE trial (Roche WA17823) was a 2-year phase III, 3-arm randomized, double-blind, placebo-controlled, parallel group, including patients with moderate/severe active RA, and with inadequate response to DMARDs. The patients were randomized: TCZ8mg/kg (TCZ8), TCZ4mg/kg or placebo. Patients received an infusion of TCZ 8mg/kg, 4mg/kg or placebo every 4 weeks. Escape patients were defined as those who experienced <20% improvement in both swollen (SJC) and tender joint counts (TJC) at week 16 (non-responders). Current analysis only considered the TCZ8 group where serum was analyzed at baseline and 4 weeks. 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). This analysis consisted of 102 responders and 33 escape-therapies. Data is shown as geometric mean percentage change from baseline (Mann- Whitney test) and the odds ratio (OR) for response was calculated.

Results: The general inflammatory marker serum CRP was completely blocked (<10% of baseline) by TCZ8 in both the responder and non-responder group, with no significant ability to separate these groups (OR 1.6, ns). The level of serum CRPM was decreased to 72% in the responder group and only to 83% in the non-responder group (OR 4.0, 0.0014). Cartilage degradation – C2M – was reduced to 89% of baseline levels upon treatment with TCZ8 in the responder group, whereas the level of serum C2M remained unaltered or increased to 102% of baseline level in the non-responder (OR 5.8, 0.0003). The synovial turnover measure, serum C3M, was decreased to 73% of baseline in the responder group, compared to 88% in the non-responder group (OR 9.6, 0.0004).There were only minimal differences in the bone resorption and formation markers, as well as in serum MMP-3, ICTP and VICM.

Conclusion: Biomarkers of cartilage and synovial turnover were able to discriminate between responders and non-responders to anti-IL-6R intervention at an early time point, in contrast to traditional CRP and the standard bone markers. These responder and non-responder profiles may enable identification of the optimal treatment for the individual patients, so-called Il-6 super-responders. Whether these response profiles are specific for IL-6 interventions or other biological treatments or other novel interventions remain to be investigated.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-serological-biomarker-profiles-associated-with-response-to-il-6-intervention-in-rheumatoid-arthritis/