Underpinning IL-6 biology and emphasizing selective JAK blockade as the potential alternate therapeutic intervention for rheumatoid arthritis

Interleukin 6 (IL-6), a pleiotropic inflammatory cytokine, is produced transiently due to tissue damage and infections. Nonetheless, IL-6 contributes to the host regenerative defense mechanism via classical signaling at the basal physiological level. Although tightly regulated transcriptional and post-transcriptional mechanism modulates its expression, dysregulated continual production of IL-6 during inflammatory conditions negatively affects immune cells. Molecular evidence has substantiated the pernicious out-turn of IL-6 trans-signaling in developing one such autoimmune joint disorder, rheumatoid arthritis (RA). Significantly increased levels of IL-6 in RA, along with multiple growth factors mainly released by synovial-like fibroblasts (FLS) and macrophages, is crucial for clinical disease progression. Due to its pathogenicity, in mediating inflammation and context-driven signaling cassette, blockade of IL-6 could be a potent target in the therapeutic intervention of RA. The clinical trials of various humanized IL-6 and anti-IL-6 receptor antibodies have proved their efficacy. However, severe side effects like neutropenia, thrombocytopenia, and abnormal liver enzymes contributed to dysfunctional adaptive immunity. The JAK-STAT pathway has been majorly implicated in RA disease progression upon IL-6 stimulation, simultaneously paving the path for innovative therapeutic approaches. JAK inhibitors, namely Tofacitinib, Baricitinib, Decernotinib, Upadacitinib, Peficitinib, and Filgotinib, have demonstrated clinical efficacy in recent decades as an alternative therapeutic strategy to abrogate IL-6 mediated aberrant activity in RA. This approach substitutes for the side effects incurred due to the IL-6 targeted therapies. This review discusses the history of research into IL-6 biology and therapies that target the IL-6 driven JAK/STAT pathway, including the successes, challenges, and drawbacks, emphasizing RA. [Display omitted]