Background/Purpose: Activator protein-1 (AP-1) is an important transcription factor for cytokine production and joint destruction in rheumatoid arthritis (RA), and a potential target for the treatment of RA. We previously reported the preventive and therapeutic effects of T-5224, a small molecule inhibitor of c-Fos/AP-1, on type II collagen-induced arthritis (CIA) in mice. The purpose of this study was to investigate the effect of T-5224 in combination with or with add-on to methotrexate (MTX) on the development of arthritis and joint destruction in mice with CIA.

Methods: CIA was induced in DBA/1J mice by the immunization with bovine type II collagen twice on days 0 and 21. In a combination study, T-5224 (3 mg/kg/day) and/or MTX (0.5–5 mg/kg/day) were orally administered once daily from the day of the 2nd immunization (day 21) to day 34. In an add-on study, MTX (0.5 mg/kg/day) was administered from day 21 to day 49. The add-on treatment of T-5224 (3 mg/kg/day) to MTX (0.5 mg/kg/day) or MTX at a dose increased to 5 mg/kg/day started from day 27. In both studies, anti-rheumatic efficacy was determined by arthritis score, X-ray examination, and serum interleukin-1β (IL-1β) on days 35 and 50, respectively.

Results: In a combination study, MTX alone showed dose dependent reduction in arthritis scores by 15% to 58% at 0.5 to 5 mg/kg/day. T-5224 at 3 mg/kg/day in combination with MTX at 0.5 and 1.5 mg/kg/day decreased the arthritis scores by 57% and 62%, respectively, which was similar to that achieved by MTX alone at 5 mg/kg/day (58%). The joint destruction was suppressed by 78% and 90%, respectively, in combination of T-5224 and MTX at 0.5 and 1.5 mg/kg/day, which was more potentiated than MTX alone at 5 mg/kg/day. Elevated IL-1β level in the serum reduced by combined treatment of T-5224 and MTX, whereas MTX alone at 0.5 and 1.5 mg/kg was without effects.

Add-on treatment of T-5224 (3 mg/kg/day) with MTX (0.5 mg/kg/day) decreased the arthritis scores by 70%, which was more marked than MTX alone at a dose escalated from 0.5 to 5 mg/kg/day (29%), when started dosing from day 27 after the onset of arthritis. Add-on treatment of T-5224 with MTX reduced the joint destruction scores by 81%, while MTX alone did by 46%. Serum level of IL-1β decreased only in mice treated with T-5224 added-on to MTX.

Conclusion: These results indicate that either combined or add-on use of T-5224 and MTX with a different mode of anti-arthritic actions is expected to augment anti-rheumatic and anti-joint destructive effects in the therapy of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/combined-effects-of-a-c-fosap-1-inhibitor-t-5224-and-methotrexate-on-collagen-induced-arthritis-in-mice/