FRI0357 Difference in the Anti-Arthritic Effect of an IL-6 Inhibitor and A TNF Inhibitor in the Resolution Phase of Arthritis Mice

Background In rheumatoid arthritis (RA), the advent of biologics has improved treatment dramatically. The increasing number of biologics with beneficial effects makes it necessary to clarify their differences. Although the extended therapeutic efficacy of an anti-IL-6 receptor antibody (anti-IL-6R) has been reported [1, 2], the mechanism that causes this and the advantage bestows on anti-IL-6R over other biologics, particularly TNF inhibitors, are still unclear. Usually, inflammation causes anti-inflammatory response to increase, and it was reported that levels of suppressor of cytokine signaling (SOCS), a typical anti-inflammatory factor of the JAK/STAT pathway, are high in RA [3]. However, not many studies focus on anti-inflammatory factors, and there has been no claim of the effect biologics have on them. Objectives The purpose of this study was to investigate the difference in spontaneous anti-inflammatory response to IL-6 inhibition and to TNF inhibition using a mouse arthritis model. Methods Glucose-6-phosphate isomerase (GPI)-induced arthritis was triggered in DBA/1J mice by an intradermal injection of recombinant GPI. Clinical symptoms of arthritis were evaluated by observation and expressed as an arthritis score on a scale of 0–3 for each limb. Expression levels of IL-6, TNF-α, and SOCS-1 and -3 mRNA in the hind limbs of arthritis control mice were measured by real-time PCR, and IL-6, TNF-α, and SOCS-1 and -3 levels in blood were measured by ELISA on Days 0, 7, 14, 21, and 28. We i.p. administered anti-IL-6R once at a dose of 4 mg on Day 5 in one group and TNFR-Fc, as a TNF inhibitor, at doses of 1 mg three times a week from Day 5 in another. SOCS-1 levels in blood were measured by ELISA on Days 14. Results The mouse model used here is a transient arthritis model: arthritis starts to develop from about Day 7 and reaches peak swelling on about Day 14. Blood levels of IL-6, TNF-α, and SOCS-3 reached their peaks on Day 7. Expression levels of IL-6, TNF-α, and SOCS-3 mRNA in hind limbs reached their peaks on Day 14 in line with the arthritis score. Interestingly, SOCS-1 levels in blood and hind limbs increased up to Day 14 and did not decrease for two weeks after that. Furthermore, though anti-IL-6R significantly suppressed the arthritis score until about Day 15 and showed further suppression after that, TNFR-Fc significantly suppressed the arthritis score until Day 15, but not after. The SOCS-1 level in blood induced on Day 14 was inhibited by only TNFR-Fc, but not by anti-IL-6R. Conclusions We demonstrated that, though the arthritis score, IL-6, TNF-α, and SOCS-3 transiently increased, SOCS-1 was constantly induced in this model. Although both anti-IL-6R and TNFR-Fc suppressed the arthritis scores until near the peak, only anti-IL-6R continued to suppress the arthritis score after that without inhibiting SOCS-1. These results suggest that SOCS-1 is important for the anti-arthritic effect in the resolution phase. Further consideration is needed to explain what mainly induces SOCS-1; however, an anti-inflammatory factor such as SOCS-1 would be involved in the reason why anti-IL-6R has an extended therapeutic efficacy. References “LITHE study” J Rheumatol. 2013; 40: 113–26. “REACTION study” Rheumatology (Oxford). 2011; 50: 1908-15. Rheumatology (Oxford). 2007; 46: 1538–46. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1988