JAK inhibitors and adverse cardiovascular events: Class effect or molecule-specific risk?

Janus kinase inhibitors (JAKis) have established themselves as a valuable treatment option in treating rheumatoid arthritis and other immune-mediated inflammatory diseases, providing rapid and effective disease control across multiple refractory populations. However, their cardiovascular safety has come under intense scrutiny following the ORAL Surveillance trial, which showed an increased risk of major adverse cardiovascular events (MACE; a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) with tofacitinib compared with tumor necrosis factor inhibitors in patients with elevated baseline cardiovascular risk. Randomized trials, observational studies, and pharmacovigilance analyses involving tofacitinib, baricitinib, upadacitinib, and filgotinib have produced heterogeneous findings, with no consistent replication of a uniform class-wide cardiovascular signal. This divergence has generated ongoing debate about whether the observed risk reflects a true JAK inhibitor class effect or is driven by molecule-specific properties, patient selection, and study design. Mechanistic plausibility exists for both hypotheses through shared JAK-STAT pathway effects on vascular inflammation and thrombosis. This narrative review synthesizes current evidence from clinical trials, real-world data, and regulatory perspectives to critically assess the available evidence regarding whether cardiovascular risk represents a class effect or a molecule-specific phenomenon.