Background: The circadian rhythm is a universal biological process regulated by the Earth’s rotation and solar cycles. It affects various bodily functions and symptom of disease, such as Rheumatoid arthritis (RA). The clinical symptoms of RA show an earlier circadian rhythm. Not coincidentally, several classical DMARDs such as triptolide, brucine and methotrexate have shown different efficacy or toxicity in the treatment of RA varies with different administration times. It is not clear whether the effect of iguratimod, a highly effective and safe novel DMARDs used in China and Japan, in treating RA also has similar characteristics.

Objectives: Here we aimed to investigate the chronoefficacy and chronotoxicity of iguratimod against collagen-induced arthritis (CIA) in rats.

Methods: CIA model was induced in Wistar rats and then treated with iguratimod (6 mg/kg/day, gavage.) at different circadian time points ZT8 or ZT20. Arhtirits index, paw thickness, weight were measured. Serum inflammatory factors were assessed using enzyme-linked immunosorbent assay. Related pathological tests were evaluated by hematoxylin-eosin staining. Sreum factors associated with liver damage were assessed using colorimetry assay. Expression of clock genes in joints were detected by immunohistochemical method.

Results: CIA rats oral administration with iguratimode at ZT20 had lower levels of foot swelling, Cartilage and bone destruction, inflammatory cell infiltration, key inflammatory factors (IL-6, TNF-α and IL-17A) than at ZT8. On the other hand, iguratimode significantly decreaed the weight of rat increased the level of Histamine, AST and ALT compared with control rats, but without different between ZT20-treatment and ZT8-treatment. Furthermore, the levels of Bmal1 and CLOCK were markedly decreased by iguratimodedosing at ZT20 only.

Conclusion: These results indicated that iguratimode dosed at ZT20 was more effective in protecting against CIA than drug dosed at ZT8. While the hepatotoxicity of iguratimode didn’t seem to have a time pattern. The chronoefficacy of iguratimode might be related to the regulation of clock genes. Our work is of great importance. The therapeutic effects of existing drugs cannot meet the treatment needs of patients. Therefore, new drugs or treatment options have always been under development. It would be very encouraging if a reasonable drug regimen which is developed based on our results can improve the therapeutic effect. And, this improvement is very cost-effective and fast.

REFERENCES: NIL.

Acknowledgements: This study was supported by National Natural Science Foundation of China Youth Fund (81873301, 81903883).

Disclosure of Interests: None declared.