Playing it Safe with RA? JAK vs. TNF Debate Save

The ORAL surveillance trial raised safety concerns that the janus kinase inhibitor (JAKi) tofacitinib was associated with an increased incidence of cancer and major adverse cardiovascular events (MACE), compared to tumor necrosis factor inhibitors (TNFi), in the treatment of rheumatoid arthritis (RA) patients. Based on results of this trial, the Food & Drug Administration implemented black box warnings for cardiovascular safety and cancer risk extended to all JAKi (including upadacitinib and baricitinib). The reported safety signals, at odds with the efficacy of these medications, have left rheumatology clinicians in a difficult position when considering when during a patient’s treatment course and in which patients, specifically, JAKi should be used.

Two abstracts from ACR convergence 2024 further contribute to our understanding of this potential risk profile.

Gibson et al. explored malignancy risk via a Bayesian systemic meta-analysis, identifying 196 randomized control trials (and long-term extensions) of JAK and TNF inhibitors in adult RA, psoriasis, psoriatic arthritis, axial spondyloarthritis, and inflammatory bowel disease patients (Abstract 0989). While the risk of all cancers, excluding non-melanoma skin cancer (NMSC), were lower with TNFi compared to JAKi (likelihood log rate ratio = -0.60), the risk of malignancy was similar between JAKi and placebo. Interestingly, rates of all cancers, excluding NMSC, were actually lower with TNFi compared to placebo – this apparent protective effect likely powered the difference between TNFi and JAKi, given the latter’s non-difference with placebo. Rates of hematologic cancers were lower with JAK inhibitors (and TNF inhibitors) compared to placebo. The group reported that malignancy risk was lowest with filgotinib and highest with baricitinib but did not report individual risk with tofacitinib or upadacitinib, which would be elucidating given the more prominent use of these two agents in the United States.

A Spanish group used a national registry to retrospectively review over 3000 patients with RA taking JAKi or TNFi and found no significant difference in malignancy or MACE incidence rate ratios between the treatments (Abstract 2275). The incidence of general cardiac adverse events was higher in the JAKi group, compared to TNFi user, but the specific meaning of this term was not defined.

Using large-scale analysis and real-world experience, these studies provide some reassurance regarding the safety of JAKi use, particularly as it relates to malignancy risk. Questions remain whether each particular JAKi may carry unique risk profiles, based on the specific mechanism of action.