Comparative assessment of selective Janus Kinase inhibitors in rheumatoid arthritis mouse model: Insights into immune modulation and therapeutic implications

Janus kinase inhibitors (JAKi) are a class of orally available drugs for treating rheumatoid arthritis (RA). With a focus on enhancing safety profiles and therapeutic efficacy, the development of JAKi has transitioned from first-generation non-selective inhibitors to second-generation selective inhibitors. To better understand the roles of distinct JAK isoforms in the pathogenesis and progression of RA, we employed the Collagen-Induced Arthritis (CIA) mouse model to evaluate the effects of four selective JAK inhibitors: Upadacitinib (JAK1 inhibitor), CEP-33779 (JAK2 inhibitor), Ritlecitinib (JAK3 inhibitor), and Deucravacitinib (TYK2 inhibitor).

All four JAK inhibitors showed varying degrees of alleviation in paw swelling and histological severity. We utilized flow cytometry to characterize the lymphoid and myeloid compartments within the spleen and Olink technology to analyze cytokines in the plasma.

Our findings suggested that JAK1 and JAK3 play an important role in the differentiation and proliferation of T cells, while JAK2 is crucial in the development of myeloid cells. Notably, the TYK2 inhibitor exhibited significant effect in suppressing the expression of inflammatory cytokines.

In summary, this study represents a comprehensive comparison of four selective JAKi in the CIA mouse model, offering valuable insights into immune modulation and potential implications for optimizing the benefit-risk profile of selective JAK inhibitors in the treatment of RA.