Background/Purpose: To date, there are no head-to-head clinical trials directly comparing the effects between IL-6i and JAKi on bone destruction in RA. In recent years, a series of JAK inhibitors (JAKi) have been introduced, all of which have JAK1 inhibitory activity, and inhibition of IL-6 signaling plays an important role in their pharmacological actions. IL-6 inhibitors (IL-6i)have also been commonly used for rheumatoid arthritis (RA), and several anti-receptor antibodies are in clinical application. Recent studies have revealed the molecular basis of the immune cell-fibroblast-bone triad interactions in RA bone destruction. Therefore, to examine changes in peripheral blood gene expression after IL-6i or JAKi treatment, which inhibit a common pathway, and to estimate their respective effects on the bone immune system.

Methods: Peripheral blood gene expression changes in 38 RA patients (Tocilizumab(TCZ)=13, Tofacitinib(TOF)=15, Baricitinib (BAR)=10) were analyzed before and 3 months after the initiation of treatment using next generation sequencing. Changes in gene expression of molecules involved in bone immunity were analyzed before and after each treatment.

Results: Comparison of L-6i and JAKi showed that JAKi treatment significantly suppressed RANKL expression in peripheral blood. At the same time, significant suppression of RANK, ETS1, and IL-34 gene expression was also observed with JAKi treatment. Comparison of TOF and BAR treatment showed significant suppression of IL-4 expression in TOF and significant suppression of MMP-2 and IL-12 expression in BAR.

Conclusion: JAKi suppressed RANKL expression significantly compared to IL-6i, suggesting that JAKi is more potent than IL-6i in suppressing bone destruction. Furthermore, assuming that the promoter regions of RANK in synovial osteoclasts and ETS1 in fibroblasts are similar to those in peripheral blood, the following prediction emerges. JAKi suppresses RANK and ETS1 expression more than IL-6i, suggesting that JAKi may be favorable for preventing bone destruction in terms of (1) suppressing osteoclast differentiation and (2) suppressing tissue-destructive fibroblasts. The effect on gene expression of molecules involved in bone immunity was found to vary among each JAK inhibitor.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/common-il-6-signaling-is-inhibited-by-il-6-inhibitors-and-jak-inhibitors-but-which-is-better-at-preventing-bone-destruction-in-ra/