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Inhibitors of JAK for the treatment of rheumatoid arthritis: rationale and clinical data

Charles J Malemud

The JAK/ STAT signal transduction pathway is primarily involved in regulating STAT-target gene transcription. Many of the STAT-target genes are those responsible for the synthesis of proinflammatory cytokines, proteins that regulate apoptosis and/or cell survival and genes that control determination of cell fate. The aberrant over production of proinflammatory cytokines, the imbalance between cell survival and apoptosis skewed towards survival and the abnormal proliferation of cells of the immune system and synoviocytes are several hallmark characteristics of the pathophysiology of human rheumatoid arthritis (RA). Several of the disease-modifying antirheumatic biological drugs, including TNF-α antagonists and IL-6-receptor neutralizing monoclonal antibodies retard the clinical and radiographic progression of RA and also inhibit JAK/STAT pathway activation. The long-term goal of developing JAK-specific small-molecule inhibitors through medicinal chemistry strategies may ultimately be to reduce the dependency on the use of biologics by directly inhibiting activation of JAK/STAT signaling. A few of these small-molecule inhibitors have been proven to have efficacy by ameliorating the severity of arthritis in rodent models of inflammatory arthritis. Several of these small-molecule JAK inhibitors are now being evaluated in human RA clinical trials where the preliminary evidence indicates that JAK inhibitors are safe and well-tolerated and produce positive RA clinical responses, as measured by the American College of Rheumatology response criteria.