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Cardiovascular and Venous Thromboembolic Risk Associated With JAK Inhibitor Use in Patients With Immune-Mediated Inflammatory Skin Diseases
TAKE-HOME MESSAGE
- This meta-analysis of 35 clinical trials with a mean follow-up duration of 4.9 months aimed to assess the risk of all-cause mortality, major adverse cardiovascular events (MACE), and venous thromboembolism (VTE) in patients with dermatologic conditions using JAK inhibitors. There was no significant difference between patients receiving JAK inhibitors and those receiving placebo/active comparator in terms of composite MACE, VTE, and all-cause mortality. Subgroup analysis of oral versus topical JAK inhibitors also did not find significant differences between patients who were exposed to JAK inhibitors and those who were not.
- Short-term use of JAK inhibitors for dermatologic indications may not increase the risk of all-cause mortality, MACE, or VTE; however, long-term trials are needed to fully evaluate safety risks.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
Janus kinase (JAK) inhibitors are an effective treatment option for patients with certain skin-related conditions, such as atopic dermatitis, alopecia areata, and vitiligo, but there is a current US Food and Drug Administration (FDA) boxed warning label for oral and topical JAK inhibitors regarding increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), serious infections, malignant neoplasm, and death. However, this boxed warning was precipitated by results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study, which only included patients with rheumatoid arthritis, and the same association may not be observed in dermatologic conditions.
OBJECTIVE
To determine the risk of all-cause mortality, MACE, and VTE with JAK inhibitors in patients with dermatologic conditions.
DATA SOURCES
PubMed and ClinicalTrials.gov were searched from database inception to April 1, 2023.
STUDY SELECTION
This review included phase 3 randomized clinical trials with a placebo/active comparator group of JAK inhibitors used for a dermatologic indication with FDA approval or pending approval or with European Union or Japanese approval. Studies without a comparison group, case reports, observational studies, and review articles were excluded.
DATA EXTRACTION AND SYNTHESIS
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Adverse events using odds ratios (ORs) and 95% CIs were calculated using a random-effects model and the DerSimonian-Laird method. Studies were screened, data abstracted, and quality assessed by 2 independent authors. The protocol was prospectively registered with PROSPERO.
MAIN OUTCOMES AND MEASURES
Primary outcomes were a composite of adjudicated MACE and all-cause mortality, and VTE.
RESULTS
The analysis included 35 randomized clinical trials with 20 651 patients (mean [SD] age, 38.5 [10.1] years; male, 54%) and a mean (SD) follow-up time of 4.9 (2.68) months. Findings did not show a significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (OR, 0.83; 95% CI, 0.44-1.57) or VTE (OR, 0.52; 95% CI, 0.26-1.04).
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, use of JAK inhibitors was not associated with increased risk of all-cause mortality, MACE, and VTE compared to the placebo/active comparator groups. Additional trials with long-term follow-up are needed to better understand the safety risks of JAK inhibitors used for dermatologic indications.
Additional Info
Disclosure statements are available on the authors' profiles:
Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases: A Systematic Review and Meta-Analysis
JAMA Dermatol 2023 Nov 01;[EPub Ahead of Print], JP Ingrassia, MH Maqsood, JM Gelfand, BN Weber, S Bangalore, KI Lo Sicco, MS GarshickFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Janus Kinase (JAK) inhibitors have emerged as an advanced treatment for challenging chronic immune-mediated inflammatory disorders, such as atopic dermatitis, vitiligo, and alopecia areata.
Despite their proven efficacy, healthcare providers remain hesitant to prescribe the JAK inhibitors due to concerns for potentially serious side effects. The FDA issued a boxed warning for oral and topical JAK inhibitors regarding the increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignant neoplasms, serious infections, and death.
The current boxed warning label was primarily based on the Oral Rheumatoid Arthritis Trial (ORAL) evaluating patients with rheumatoid arthritis (RA) treated with oral tofacitinib. Patients enrolled in this study were older patients with RA and at least one cardiovascular risk factor. Significantly, the enrolled patients with RA were more than 50 years old and were receiving methotrexate. The boxed warning impacted FDA approved JAK inhibitors for atopic dermatitis (upadacitinib, abrocitinib, ruxolitinib cream), vitiligo (ruxolitinib cream), and alopecia areata (baricitinib, ritlecitinib).
But, are the cardiovascular and embolic risks higher with the new JAK inhibitors used for dermatologic conditions? In an important pivotal study, a systematic review and meta-analysis of 35 randomized clinical trials containing more than 20,000 patients with dermatologic conditions was performed. There was no significant difference between JAK inhibitors and placebo/active comparator in composite MACE, VTE, and all-cause mortality. This was the first comprehensive meta-analysis with JAK inhibitors for primary dermatologic conditions.
The authors point out important differences between the patients in the ORAL study with RA and the meta-analysis of those with dermatologic conditions. Patients with dermatologic conditions were younger (mean age 38.5 years) compared with those with RA (mean 61 years). The patients with RA in the ORAL study also experienced higher cardiovascular risk factors and were on methotrexate. Study duration was 4 years in the ORAL study and only 4.9 months in the dermatologic meta-analysis.
The bottom line is that there does not appear to be an elevated all-cause mortality, MACE, or VTE in patients with dermatologic conditions treated with short-term oral or topical JAK inhibitors for inflammatory skin conditions. Dermatologists should carefully assess baseline cardiovascular risk factors when considering JAK inhibitors and during the therapy duration. Long-term safety during follow-up studies are needed. It is unclear whether the cardiovascular risks of JAK inhibitors are due to the patient level of cardiovascular risk factors or drug mediation.