Safety Profile of Upadacitinib for Treatment of Patients With RA at High Risk for Cardiovascular Events

Rates of serious infection were greater among patients with RA at high risk for cardiovascular events treated with upadacitinib vs adalimumab or MTX.

Patients with rheumatoid arthritis (RA) predisposed to cardiovascular events may be at increased risk for major adverse cardiovascular events (MACE), certain malignancies, and venous thromboembolism (VTE), though rates are comparable when stratified by treatment with upadacitinib vs adalimumab or methotrexate (MTX), according to results of a post hoc analysis published in Annals of the Rheumatic Diseases.

Previously published research has revealed differences in the safety profiles of the Janus kinase (JAK) inhibitor tofacitinib vs tumor necrosis factor inhibitors for treatment of RA. Whether the increased occurrence of adverse events (AEs) is present in patients treated with any JAK inhibitor remains unknown. Investigators assessed the risk for AEs among patients with RA at increased risk for cardiovascular events treated with upadacitinib vs adalimumab or MTX monotherapy.

Data were taken from 6 phase 3 trials assessing AEs among patients with RA. Patients received upadacitinib 15 mg once daily (with or without concomitant synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant MTX, or 20 mg/wk MTX monotherapy.

AEs were evaluated in the overall trial population and in patients aged 50 years or more at greater risk for cardiovascular events. Additionally, patients at greater risk for cardiovascular events included in the SELECT-COMPARE trial (a head-to-head study of upadacitinib vs adalimumab) were assessed in parallel. 

These findings in patients with RA at risk of potential [cardiovascular] events may help to clinically contextualise the overall risk profile of upadacitinib.

A total of 4102 patients were included in the analysis, with 3209 patients receiving upadacitinib, 579 receiving adalimumab, and 314 receiving MTX monotherapy.

Median exposure duration for upadacitinib, adalimumab, and MTX were 3.7 years, 2.2 years, and 2.6 years, respectively. In each treatment group, more than half of the patients from the overall population were considered at high risk for cardiovascular events (upadacitinib, n=1717; adalimumab, n=320; MTX, n=162). A similar trend was noted among patients in the SELECT-COMPARE study (upadacitinib, n=649; adalimumab, n=177). The most common comorbidities placing patients in the higher-risk category included low high-density lipoprotein-cholesterol levels (~11%), smoking (~37%), and hypertension (~40%).

Among the higher-risk population, the rate of serious infections was greater with upadacitinib (exposure adjusted incidence rate [EAIR], 3.0/100 person years [PY]) vs adalimumab (EAIR, 2.8/100 PY) and MTX monotherapy (EAIR, 1.3/100 PY).

In all populations, the risk for herpes zoster (HZ) and nonmelanoma skin cancer (NMSC) was greater with upadacitinib (EAIR HZ, 2.9/100 PY; EAIR NMSC, 0.4/100 PY) vs adalimumab (EAIR HZ, 1.0/100 PY; EAIR NMSC, <0.1/100 PY) or MTX (EAIR HZ, 0.9/100 PY; EAIR NMSC, 0/100 PY), respectively.

Patients aged at least 65 years in the SELECT-COMPARE higher-risk population had a numerically greater risk for serious infection associated with upadacitinib vs adalimumab (hazard ratio [HR], 1.53; 95% CI, 0.46-5.06). Similarly, this population had a greater risk for HZ (HR, 3.07; 95% CI, 0.96-9.88) and NMSC (HR, 0.37; 95% CI, 0.14-0.97) associated with upadacitinib vs adalimumab.

Though the higher-risk population had slightly greater rates of MACE, malignancy (excluding NMSC), VTE, and mortality vs the overall population, rates were comparable between therapies. Reports of COVID-19-related mortality (15 patients) were only noted in patients treated with upadacitinib.

This study was limited by its post hoc nature and small sample size. Additionally, data pooling across trials of differing phases may have impacted results.

“These findings in patients with RA at risk of potential [cardiovascular] events may help to clinically contextualise the overall risk profile of upadacitinib,” the researchers concluded.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Fleischmann R, Curtis JR, Charles-Schoeman C, et al. Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme. Ann Rheum Dis. Published online June 12, 2023. doi:10.1136/ard-2023-223916