Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: In the treatment of rheumatoid arthritis (RA), biologics such as IL-6 and TNF inhibitors have high therapeutic efficacy with extended duration of effect [“LITHE study” J Rheumatol. 2013; 40: 113–26, “ATTEST study” Ann Rheum Dis. 2008; 67: 1096–103]. Among RA patients treated with anti-IL-6 receptor antibody (anti-IL-6R), in particular, it is reported that 10% were able to suspend the biologic for an extended period without relapse/flare [“DREAM study” Mod Rheumatol. 2013 May 3. [Epub ahead of print] DOI:10.1007/s10165-013-0894-z]. Although not yet fully clarified, this is thought to be causally related to a sustained anti-inflammatory effect of anti-IL-6R. It was reported that levels of suppressor of cytokine signaling (SOCS)-1 and -3, well-known feedback inhibitors of the JAK/STAT pathway, are high in RA [Rheumatology (Oxford). 2007; 46: 1538–46] and should be considered when allowing a drug-holiday in RA. In this study, we investigated the efficacy of anti-IL-6R on SOCS-1 and -3 levels, using a mouse model of arthritis.
Methods: Glucose-6-phosphate isomerase (GPI)-induced arthritis was triggered in DBA/1J mice by intradermal injection of recombinant GPI. We used anti-IL-6R to inhibit IL-6. Anti-IL-6R was intraperitoneally administered once at a dose of 4 mg 5 days after immunization (Day 5). 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, SOCS-1 and -3 mRNA in the hind limbs of mice were measured by real-time PCR, and IL-6, SOCS-1 and -3 levels in blood were measured by ELISA on Days 0, 7, 14, 21, 28 and 35.
Results: The mouse model used here is a transient arthritis model: arthritis starts to develop from about Day 5 and reaches peak swelling on Day 14. Blood levels of IL-6 and SOCS-3 reached their peaks on Day 7. SOCS-1 level in blood reached the plateau level on Day 7. Expression levels of IL-6 and SOCS-3 mRNA in hind limbs reached their peaks on Day 14 in line with the arthritis score. Expression level of SOCS-1 mRNA in hind limbs reached the plateau level on Day 14. Anti-IL-6R significantly suppressed the arthritis score and SOCS-3 levels both in blood and hind limbs on Day 14. On the other hand, anti-IL-6R suppressed expression level of SOCS-1 mRNA in hind limbs on Day 14 but did not suppress SOCS-1 level in blood.
Conclusion: We demonstrated that, though each peak time was different, IL-6 and SOCS-3 changed similarly both in blood and the hind limbs, with the changes in hind limbs well associated with changes in the arthritis scores, and that anti-IL-6R inhibited both SOCS-1 and -3 in the hind limbs in line with arthritis scores and inhibited only SOCS-3 but not SOCS-1 in blood. These results suggest that a possible mechanism of the anti-arthritic effect of anti-IL-6R is a reduction in SOCS-3. However, if reduced arthritis scores were caused by an increase in SOCS-1 in blood, it would also be important to consider blood levels of SOCS-1 maintained by anti-IL-6R. Further consideration is needed to explain why SOCS-1 levels in blood and hind limbs respond differently to anti-IL-6R. Therefore, further studies for investigating the effect of anti-IL-6R on SOCS-1 and -3 may help to make a drug-holiday in RA possible.
Disclosure:
M. Suzuki,
None;
H. Yoshida,
None;
K. Tanaka,
None;
I. Matsumoto,
None;
T. Sumida,
None;
Y. Matsumoto,
None.
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