Cumulatively, the active targets in this study suggest that JAK inhibitors may have a beneficial effect on cardiovascular risk, and therefore do not support a hypothesis that the risk of thrombosis is related to an off-target drug effect (in the framework of the macromolecular targets investigated in this study). Nevertheless, we note that recent USbased cohort studies that have identified no difference in thrombosis risk between tofacitinib and TNF-inhibitors, thereby suggesting much of the observed risk seen in pharmacovigilance studies(6,5) may be due to underlying risk factors rather than a drug effect. For example, standardized incidence rates (IR) of venous thromboembolism The risk of thrombosis can be further increased in RA patients with high disease activity, cardiovascular risk factors (e.g., obesity), immobility, and hormonal replacement therapy. Patients using JAK inhibitors frequently have high disease activity with non-or inadequate-response to csDMARDs and bDMARDs and multiple chronic conditions (e.g., cardiovascular disorders and depression), which can make the attribution of thrombotic events in patients treated with JAK inhibitors even more intricate.