Tofacitinib: Current Considerations in the Management of Immune Inflammatory Disorders

Abstract

INVITED REVIEWTofacitinib, the first member of targeted-synthetic disease-modifying antirheumatic drugs, is an oral inhibitor of Janus kinases (JAKs), preferentially JAK-1 and 3. It is an analog of adenosine triphosphate and inhibits several pro-inflammatory cytokines and pathways. Tofacitinib is rapidly absorbed and eliminated mainly via the liver. The efficacy of tofacitinib has been studied extensively in patients with RA patients with different clinical scenarios. Now, tofacitinib is approved in several countries with the indications of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular and systemic juvenile idiopathic arthritis, and ulcerative colitis. Also, studies to assess the efficacy of tofacitinib in patients with several different indications are under consideration. Neutropenia, anemia, elevation of transaminase levels, hyperlipidemia, and increased risk of infections with several causes are well-known side effects. However, recent data from the ORAL Surveillance study shed light on the risk of cardiovascular events and malignancy. In that study, patients with RA over 50 years with at least 1 cardiovascular risk factor were randomized to anti-tumor necrosis factors or tofacitinib; revealing and increased cardiovascular event risk and malignancy (especially lung cancer and lymphoma) in the tofacitinib arm. Although post hoc analysis of the data set suggested a possible link between the history of cardiovascular disease and both cardiovascular and malignancy end-points, FDA, and EMA announced black-box warnings for all JAK inhibitors covering all indications. Obviously, JAK inhibitors, the game changers of the last decade, need further evaluation, especially regarding safety issues.