Upadacitinib and Cardiovascular Events in AD

A recent review examined whether upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor approved for atopic dermatitis (AD) and other chronic inflammatory diseases, may—despite a boxed warning to the contrary—confer cardioprotective and thromboprotective effects.¹ By comparing background rates of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) in AD populations with long-term incidence rates from clinical trials, the authors found that upadacitinib-treated patients experienced lower rates of both MACE and VTE than expected.¹ While these findings raise the possibility of cardiovascular benefit, they remain hypothesis-generating and must be interpreted in light of the broader JAK inhibitor safety concerns highlighted by the ORAL Surveillance trial of tofacitinib.²

Background and Study Results

AD is increasingly recognized as a systemic inflammatory disease, with patients demonstrating higher risk of cardiovascular disease and thromboembolic complications.¹ Chronic inflammation contributes to atherosclerosis, elevating risk for myocardial infarction and stroke.¹

Upadacitinib (UPA), a selective JAK1 inhibitor, is highly effective for moderate-to-severe AD and other immune-mediated diseases.¹ Given that systemic inflammation is a driver of cardiovascular pathology, its inhibition could theoretically reduce cardiovascular risk.

In this review, the authors compared real-world incidence rates of MACE and VTE in AD patients with those reported in long-term clinical trials of upadacitinib.¹

Background rates in AD populations: MACE ranged from 0.3 to 1.2 per 100 patient-years; VTE ranged from 0.1 to 0.3 per 100 patient-years.

Upadacitinib trials (up to 5 years):

MACE: 0.2 (15 mg) and < 0.1 (30 mg) per 100 patient-years

VTE: 0.1 per 100 patient-years for both doses

These findings suggest that UPA-treated patients experience fewer cardiovascular and thrombotic events compared with untreated background AD cohorts. From a biological standpoint, upadacitinib reduces C-reactive protein and pro-inflammatory cytokines such as IL-6, which are implicated in atherosclerosis and thrombosis.¹

However, interpretation of these results must be cautious. Clinical trial participants may differ systematically from real-world AD patients, and close monitoring in trials may reduce event detection bias.¹

Comments and Clinical Implications

While the safety of JAK inhibitors remains under scrutiny, this review suggests that upadacitinib may not share the same cardiovascular risk profile as tofacitinib. The ORAL Surveillance trial demonstrated increased risk of MACE, malignancy, and VTE in older rheumatoid arthritis patients with cardiovascular risk factors treated with tofacitinib compared with tumor necrosis factor inhibitors.² These results prompted the US Food and Drug Administration to apply a boxed warning across the entire JAK inhibitor class.³

Subsequent analyses and expert commentary, including the review “Oral Surveillance and JAK Inhibitor Safety: The Theory of Relativity,” emphasize the importance of context: Patient age, baseline cardiovascular risk, disease type, and JAK inhibitor selectivity may all influence safety outcomes.³ Upadacitinib, which is more JAK1-selective than tofacitinib, has not shown the same safety signals in younger, healthier AD populations.

For dermatologists, these findings are cautiously reassuring. Upadacitinib appears safe from a cardiovascular perspective in AD patients without high baseline risk and may even reduce systemic inflammation in ways that could benefit long-term cardiovascular outcomes. Nonetheless, dedicated cardiovascular outcome trials are needed before confirming any cardioprotective role.¹ 

The authors report no relevant financial disclosures. 

References

1. Alani O, et al. Is upadacitinib cardioprotective in chronic inflammatory diseases? A review of major adverse cardiovascular events and venous thromboembolism in atopic dermatitis. J Drugs Dermatol. 2025;24(5). doi:10.36849/JDD.9049

2. Curtis JR, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2023;82(3):331–343. doi:10.1136/ard-2022-222543

3. Winthrop KL, Cohen SB. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18(5):301–304. doi:10.1038/s41584-022-00767-7