JAK-STAT Inhibition in Rheumatoid Arthritis

The pathophysiology of rheumatoid arthritis is complex, involving the interaction of numerous cell types and multiple mediators of inflammation. The JAK/STAT pathway mediates downstream transduction into the nucleus of the signals from multiple cytokines critical to the pathogenesis of rheumatoid arthritis. Cytokine receptors share a distinct intracellular signaling pathway mediated by JAKs. When a cytokine engages its cell surface receptor, JAKs become activated, and these activated kinases phosphorylate each other, and the intracellular portion of the receptors. These phosphorylation sites provide docking sites for STATs, which are associated with the cytoplasmic domain of the cytokine receptor. The STATs are phosphorylated and activated, allowing them to dimerize. The activated STAT dimers then translocate into the nucleus where they interact with gene promoters to induce the transcription of target genes encoding for proinflammatory cytokines that are then produced at high levels. We now have a class of drugs called JAK inhibitors, including tofacitinib, baricitinib, and upadacitinib, which specifically inhibit the phosphorylation and activation of JAKs, ultimately inhibiting proinflammatory cytokine production. This then leads to reduction of associated inflammation.