Short-term risks of major adverse cardiovascular events associated with Janus kinase inhibitors in patients with atopic dermatitis: A systematic review and meta-analysis
Journal
Journal of the European Academy of Dermatology and Venereology : JEADV
Date Issued
2023-04-05
Author(s)
Chen, Y T
Abstract
Atopic dermatitis (AD) affects up to 20% and 16% of children and adults, respectively.1 Janus kinase inhibitors (JAKi) have become a promising treatment option for AD. However, the US Food and Drug Administration has recently added a new warning label about an increased risk of serious cardiovascular-related events such as heart attack or stroke, for JAKi used to treat rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis and ulcerative colitis.2 A multicenter, randomized, open-label trial3 reported a 1.33-fold increased risk of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, associated with tofacitinib in comparison to a tumour necrosis factor blocker among RA patients who are 50 years or older and had at least one additional cardiovascular risk factor. Nevertheless, the risks of MACE among patients with AD receiving JAKi remain unclear. We, therefore, performed a systematic review and meta-analysis to evaluate the association between patients with AD receiving treatment with JAKi and risk of MACE. The review protocol was registered in PROSPERO (CRD42022367521) and reported based on the PRISMA guidelines. A literature search was conducted using Pubmed, MEDLINE, Cochrane Library and Web of Science from inception to 31 October 2022. Search terms were: ‘(atopic dermatitis or atopic eczema) AND (Janus Kinase Inhibitors)’. Phase II and phase III randomized controlled trials (RCTs) reporting the safety of JAKi for AD patients with a control group receiving placebo or dupilumab were included. Data were independently screened and extracted by two authors (Y.T.C. and H.Y.C.), and discrepancies were resolved by a third independent researcher (T.S.W.). Review Manager, version 5.4.1 was used to conduct meta-analysis with generic inverse variance methods assuming a random effects model. We used absolute risk differences to measure the risk of MACE in patients receiving different JAKi compared with placebo or dupilumab. The search identified 1549 articles. Of these, 136 full-text articles were assessed for eligibility. Twenty RCTs with a total of 10,107 participants were included in the meta-analysis. Table 1 summarized the characteristics of the included studies. The participants in the included RCTs investigating 4 JAKi (abrocitinib, baricitinib, upadacitinib and SHR0302) across multiple countries were primarily adults (9187 [91%]) and adolescents (920 [9%]). Overall, 5 of 6531 patients (0.08%) with AD receiving JAKi had MACE compared with 0 of 3576 (0.00%) participants receiving placebo or dupilumab. One patient in her 70s with a history of aortic valve sclerosis and untreated hypertension had a sudden cardiac death 3 weeks after discontinuation of the 100-mg dose of abrocitinib. Another two patients with 15-mg of upadacitinib had cerebellar haemorrhage (Rising Up study). One patient with hypertension received 200-mg abrocitinib died from intracranial haemorrhage (JADE DARE). One patient in the baricitinib 2-mg treatment group had an acute myocardial infarction (BREEZE-AD4). The meta-analysis found no significant difference in the risk of MACE between participants with AD receiving JAKi and those receiving placebo or dupilumab (risk difference, 0; 95% CI, 0–0; I2 = 0%; Figure 1). The funnel plot symmetry indicated no significant publication bias. This review suggests that the evidence to date from RCTs is insufficient to support MACE being associated with JAKi in treating AD patients, which was congruous with previous meta-analyses of JAKi regarding multiple indications.4, 5 The limitations of this study include the too-short duration of included RCTs to detect rare or long-term MACE. Due to unavailable individual patient-level data, we could not stratify the risks by preexisting cardiovascular risk factors and age. Additional research is necessary to confirm the longer-term safety in the real world. We thank Dr. Ting-Shun Wang for assistance with resolving discrepancies in data extraction between the two authors. We thank the staff of Department of Medical Research, National Taiwan University Hospital Hsin-Chu Branch for their assistance in study design, statistical analysis and for providing careful review and insightful comments regarding the articles. This work was funded in part by grants from National Taiwan University Hospital, Hsin-Chu Branch (111-HCH004, 111-HCH108) and Taiwan Ministry of Science and Technology (MOST 111-2314-B-002-244). The funders had no role in the study design, data collection and analysis, interpretation of findings, manuscript writing or target journal selection. All authors have completed the ICMJE uniform disclosure form available at www.icmje.org/coi_disclosure.pdf and declare the following: H. Y. Chiu received speaking fees from AbbVie, Novartis Pharmaceuticals Corporation, Janssen-Cilag Pharmaceutica, Eli-Lilly, Kyowa Hakko Kirin Taiwan and Pfizer Limited and conducted clinical trials for Eli-Lilly, AbbVie and Sanofi Pharmaceuticals. Y. T. Chen has no conflicts of interest to declare. The data that support the findings of this study are available from the corresponding author upon reasonable request.
SDGs
Publisher
WILEY
Type
letter