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.