JAK Inhibitor Safety in Rheumatology: Navigating the ORAL Surveillance Aftermath

ORAL Surveillance: What the Data Actually Showed

The ORAL Surveillance trial compared tofacitinib to TNF inhibitors in RA patients aged 50 or older with at least one cardiovascular risk factor. Tofacitinib was associated with higher rates of MACE (HR 1.33, 95% CI 0.91-1.94) and malignancy (HR 1.48, 95% CI 1.04-2.09) compared to TNF inhibitors. These results led to FDA black box warnings for all JAK inhibitors.

Risk Stratification: Who Can Safely Receive JAK Inhibitors

The key insight from ORAL Surveillance is that the excess risk was concentrated in patients with pre-existing cardiovascular risk factors. For patients under 50 without cardiovascular risk factors or malignancy history, the absolute risk increase is likely small. Current ACR guidelines recommend JAK inhibitors after failure of at least one biologic DMARD for patients with cardiovascular risk factors, but allow earlier use in lower-risk patients.

Comparing JAK Inhibitors: Tofacitinib, Baricitinib, Upadacitinib

The three FDA-approved JAK inhibitors for RA differ in selectivity: tofacitinib (JAK1/JAK3), baricitinib (JAK1/JAK2), and upadacitinib (JAK1-selective). SELECT-COMPARE demonstrated upadacitinib superiority to adalimumab for ACR50 response, while head-to-head data between JAK inhibitors remain limited.