Major adverse cardiovascular events in patients with atopic dermatitis treated with oral Janus kinase inhibitors: a systematic review and meta-analysis

Abstract

Background: On the basis of safety data for patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors (JAKi) has been linked to the occurrence of major adverse cardiovascular events (MACE). However, these inflammatory diseases are proatherogenic; in contrast, patients with atopic dermatitis (AD) do not usually have a high cardiovascular (CV) comorbidity burden.

Objectives: To perform a systematic review and meta-analysis of MACE in patients with AD treated with JAKi.

Methods: We systematically searched PubMed, Embase, Cochrane Library and Google Scholar from their inception to 2 September 2022. Cohort studies, randomized controlled trials and pooled safety analyses providing CV safety data on patients taking JAKi for AD were selected. We included patients aged ≥ 12 years. We built a 'controlled-period' cohort (n = 9309; 6000 exposed to JAKi and 3309 exposed to comparators) and an 'all-JAKi' cohort (n = 9118 patients exposed to a JAKi in any of the included studies). The primary outcome was a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death. The broader secondary MACE outcome encompassed ACS, stroke (whether ischaemic or haemorrhagic), transient ischaemic attack and CV death. The frequency of primary and secondary MACE was assessed in both cohorts. A fixed-effects meta-analysis using the Peto method was used to calculate the odds ratio (OR) for MACE in the 'controlled-period' cohort. Evaluation of the risk of bias was done using the Cochrane risk-of-bias tool (version 2). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Results: Eight per cent of the records identified initially met the selection criteria, corresponding to 23 records included in the 'all-JAKi' cohort. Patients had been exposed to baricitinib, upadacitinib, abrocitinib, ivarmacitinib, placebo or dupilumab. Four primary events (three with JAKi and one with placebo) and five secondary events (four with JAKi and one with placebo) occurred among 9309 patients in the 'controlled-period' cohort (MACE frequency 0.04% and 0.05%, respectively). Eight primary events and 13 secondary events occurred among 9118 patients in the 'all-JAKi' cohort (MACE frequency 0.08% and 0.14%, respectively). The OR for primary MACE in patients with AD treated with JAKi vs. placebo or dupilumab was 1.35 (95% confidence interval 0.15-12.21; I2 = 12%, very low certainty of evidence).

Conclusions: Our review highlights rare cases of MACE among JAKi users for AD. JAKi may have little-to-no effect on the occurrence of MACE in patients with AD vs. comparators, but the evidence is uncertain. Real-life long-term population-level safety studies are needed.