Janus kinase inhibitors (JAKi) block the JAK-STAT signaling pathway, which is essential for intracellular cytokine signaling. In rheumatology, JAKi are approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. They offer responses that are comparable to, or even exceed, those of tumor necrosis factor inhibitors (TNFi), with a relatively rapid onset of action and good treatment persistence.

However, JAKi’s safety profile remains a subject of ongoing debate—particularly following the ORAL SURVEILLANCE study with tofacitinib, which revealed increased risks of major cardiovascular events, malignancies, and thromboembolic complications. These findings led to safety warnings from regulatory authorities and to nuanced restrictions in clinical use.

Current guidelines recommend the use of JAKi primarily after failure of other second-line disease-modifying therapies, with an individualized assessment of the risk–benefit ratio. Currently JAKi are recommended only when no alternatives are available, particularily—in smokers, in patients with cardiovascular risk factors, or those with known oncologic or thromboembolic risk factors.