Background Iguratimod (T-614) is a novel and small molecule DMARD discovered by Toyama Chemical Co., Ltd. It was characterized by inhibitory effects on immunoglobulin production in B cells without suppression of proliferative response. Iguratimod also inhibited cytokine production by macrophages and synovial cells. Iguratimod improved the development of arthritis on adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA). In clinical trials, it was reported that the rate of 20% improvement in ACR criteria (ACR20) with iguratimod was not inferior to that with salazosulfapyridine in Japanese RA patients. Methotrexate (MTX) is widely used for the treatment of RA as an anchor DMARD. However, prescription of MTX is sometimes discontinued in RA patients because of decrease in its efficacies and increase of adverse effects like hematological disturbances. Therefore, the combination or replacement of MTX with iguratimod is expected to have the beneficial effects in the RA treatment.
Objectives Using two arthritis models, AIA and CIA, we investigated the combined effects of iguratimod and MTX by assessing arthritis swelling, bone destruction, and serum markers. In AIA, when the efficacies of MTX alone were inadequate, MTX was replaced by iguratimod, and its effects were compared with MTX alone.
Methods CIA was induced in mice (DBA/1J, male, 8-week old) by the immunization with bovine type II collagen twice on days 0 and 21. Iguratimod (10 mg/kg/day) and MTX (1 mg/kg/day) were orally administrated once daily from day 21 to day 34. Severity of arthritis was graded on a scale of 0 to 3 for each paw from day 21 to day 35. Serum levels of IL-1β, IL-6, and MMP-3 were quantitated by ELISA.
AIA was induced by the injection with M. tuberculosis into the hind paw of rats (Lewis, male, 7-week old) on day 0. Iguratimod (3 mg/kg/day) and a low dose of MTX (0.07 mg/kg/day) were orally administrated once daily from day 0 to day 24. In rat AIA with inadequate response to MTX at a low dose, MTX was switched to iguratimod from day 18 to day 24. Severity of AIA was evaluated by the measurement of paw volumes on days 0, 4, 7, 11, 14, 18, 21, and 25.
The radiographs of paws in CIA and AIA were taken on day 35 and day 25, respectively. The bone destruction was assessed by each scoring method.
Results In both animal models, the combination of iguratimod with MTX more significantly suppressed the swelling when compared with each drug alone. The bone destruction in the combined group was lower than that in each drug alone group. Serum levels of IL-1β, IL-6, and MMP-3 decreased on day 35 in the combined group in the mouse CIA.
In the rat AIA, a low dose of MTX ameliorated the arthritic scores on days 7 and 11, but not on day 18. When iguratimod was combined with the low dose of MTX from day 18, more marked inhibitions of swelling and bone destruction of paws were observed compared with MTX alone on day 25. When MTX was switched to iguratimod on day 18, the swelling was also significantly improved.
Conclusions Our results suggest that the combination of iguratimod with MTX would demonstrate beneficial effects in RA patients. The switch of MTX to iguratimod could ameliorate the disease in RA patients with inadequate response to MTX.
Disclosure of Interest M. Mikami Employee of: Toyama Chemical Co., LTD., H. Murao Employee of: Toyama Chemical Co., LTD., J. Funaki Employee of: Toyama Chemical Co., LTD., K. Tanaka Employee of: Toyama Chemical Co., LTD.
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