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. 2023 Nov 1;160(1):28–36. doi: 10.1001/jamadermatol.2023.4090

Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases

A Systematic Review and Meta-Analysis

Jenne P Ingrassia 1,2, Muhammad Haisum Maqsood 3, Joel M Gelfand 4, Brittany N Weber 5, Sripal Bangalore 1, Kristen I Lo Sicco 1, Michael S Garshick 1,6,✉
PMCID: PMC10620674  PMID: 37910098

This systematic review and meta-analysis assesses the risk of all-cause mortality, major adverse cardiovascular events, and venous thromboembolism (VTE) with JAK inhibitors in patients with dermatologic conditions.

Key Points

Question

Are Janus kinase (JAK) inhibitors associated with higher risk of all-cause mortality, major adverse cardiovascular events (MACE), and venous thromboembolism (VTE) when used for a dermatologic indication?

Findings

In this systematic review and meta-analysis of 35 randomized clinical trials containing over 20 000 patients with dermatologic conditions, no significant difference was found between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality or VTE.

Meaning

Short-term (<5 months) use of JAK inhibitors for a dermatologic indication likely is not associated with an increased risk of all-cause mortality, MACE, and VTE.

Abstract

Importance

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.

Introduction

Oral and topical Janus kinase (JAK) inhibitors are increasingly used to treat chronic immune-mediated inflammatory diseases (IMIDs) of the skin.1 The US Food and Drug Administration (FDA) has approved their use in atopic dermatitis (upadacitinib, abrocitinib, ruxolitinib cream), vitiligo (ruxolitinib cream), and alopecia areata (baricitinib, ritlecitinib).

JAK inhibitors are effective in the treatment of IMIDs of the skin1; however, their safety profile is concerning for an increased risk of major adverse cardiovascular events (MACE), venous thromboembolic events (VTE), serious infections, malignant neoplasm, and death. In this study, we chose to focus on the cardiovascular and thromboembolic risks of JAK inhibitors. This is especially important because many IMIDs of the skin are associated with an increased risk of MACE and VTE.2,3,4,5,6 There is a current boxed warning label for topical and oral JAK inhibitors based primarily on studies evaluating older patient populations with rheumatoid arthritis (RA) with at least 1 cardiovascular risk factor, such as the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study.7 The study enrolled patients older than 50 years with RA who were receiving methotrexate and had at least 1 cardiovascular risk factor. Over 4 years of follow-up, the study found that patients treated with the higher dose of tofacitinib (10 mg) were at increased risk of VTE (pulmonary embolism, deep vein thrombosis), and those treated at either dose (5 mg or 10 mg) were at increased risk of MACE (nonfatal myocardial infarction, stroke, death).

There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population. To our knowledge, there has not been a study specifically evaluating this risk for dermatologic indications only. Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study,7 which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.8,9,10 In this meta-analysis of phase 3 dermatology randomized clinical trials (RCTs), we sought to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors compared to placebo or active comparator in the treatment of IMIDs of the skin.

Methods

This combined systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.11 This analysis was not considered for institutional review board review because it was a trial-level meta-analysis of published clinical trial data. The study protocol was prospectively registered with PROSPERO (CRD42023439713).

Search Strategy and Selection Criteria

A time-limited search from database inception until April 1, 2023, restricted to human study participants, was conducted using PubMed. The following Medical Education Subject Headings (MeSH) terms were used for this search: “atopic dermatitis,” or “psoriasis,” or “psoriatic arthritis,” or “vitiligo,” or “alopecia areata,” and “JAK inhibitors,” or “tofacitinib,” or “abrocitinib,” or “baricitinib,” or “upadacitinib,” or “ritlecitinib,” or “delgocitinib cream,” or “ruxolitinib cream.” We also hand-searched ClinicalTrials.gov and the references of the eligible studies to identify further studies. The inclusion criteria were phase 3 RCTs of JAK inhibitors used for a dermatologic condition leading to US FDA approval or pending approval, European Union approval, or Japanese approval, such as abrocitinib, baricitinib, tofacitinib, upadacitinib, ritlecitinib, delgocitinib cream, and ruxolitinib cream. Studies without a comparison group, case reports, observational studies, and review articles were excluded.

We used PICO (Population, Intervention, Comparison, and Outcome) criteria for study selection.12 Population of interest was IMIDs of skin; intervention: JAK inhibitors; comparison: placebo or active comparator; and outcomes: primary safety outcomes were a composite of MACE (defined as stroke, nonfatal myocardial infarction, cardiovascular death) and all-cause mortality, and VTE (defined as deep vein thrombosis, pulmonary embolism, or retinal vein thrombosis).

Data Analysis

Data Extraction and Quality Assessment

The studies were screened, data abstracted, and quality assessed by 2 independent authors (M.S.G. and J.P.I.). Nonrelevant studies were excluded based on review of the abstract. Full-text studies were then screened for final selection based on the abovementioned, prespecified inclusion criteria. The methodological quality of included trials was assessed using the Cochrane Risk of Bias Tool, which assessed selection, allocation, performance, detection, attrition, and reporting bias (eTable in Supplement 1).13

Statistical Analysis

Continuous variables were reported as mean with standard deviation and categorical variables were expressed as frequency/percentage. Adverse events using odds ratio (ORs) and 95% CIs were calculated using a random-effects model and the DerSimonian-Laird method.14 Heterogeneity between studies was assessed using I2 statistic.15 An I2 value less than 25%, 25% to 50%, 50% to 75%, and greater than 75% indicated low, moderate, high, and extreme heterogeneity, respectively. Primary analysis included atopic dermatitis, alopecia areata, psoriasis, and vitiligo as IMIDs of the skin for each of the abovementioned outcomes. Secondary analysis included additional psoriatic arthritis RCTs to determine if the psoriatic arthritis phenotype was associated with the level of risk for VTE and MACE. Two subgroup analyses were conducted based on oral vs topical JAK inhibitors and various dermatologic conditions. A sensitivity analysis was done by including trials with adult populations (excluding pediatric trials). A funnel plot was used to assess publication bias. A P value less than .05 was considered statistically significant. Risk estimates and effect sizes, sensitivity analyses, and cumulative meta-analyses were calculated using Stata, version 18.0 (StataCorp LLC).

Results

Literature Search

The initial search yielded 1027 reports in PubMed and 9 trials in ClinicalTrials.gov, which were screened by reviewing the abstract. A total of 35 RCTs (6 abrocitinib, 8 baricitinib, 2 delgocitinib cream, 4 ruxolitinib cream, 7 tofacitinib, 1 ritlecitinib, and 7 upadacitinib) were included in the final meta-analysis (eFigure 1 in Supplement 1).16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44

Baseline Characteristics

The trials enrolled a total of 20 651 patients (13 597 randomized to JAK inhibitors and 7054 to placebo/active comparator) with atopic dermatitis (21 trials), alopecia areata (3 trials), psoriasis (including psoriatic arthritis) (9 trials), and vitiligo (2 trials), with a mean (SD) follow-up of 4.9 (2.68) months. The 35 included trials were published between 2015 and 2023 with an almost equal proportion of female and male participants (male, 54%); mean (SD) age was 38.5 (10.1) years. The baseline characteristics of the study populations are provided in the Table.16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44

Table. Baseline Characteristics of Included Randomized Clinical Trials.

Trial name Reference JAKI No. PBO/AC No. Total Disease condition JAKI Approval Mean age, y Male, % Follow-up, mo PBO, AC, or both AC
JADE MONO-1 Simpson et al,16 2020 310 77 387 Atopic dermatitis Abrocitinib FDA and EU 54.8 32.5 3 PBO NA
JADE-MONO-2 Silverberg et al,17 2020 313 78 391 Atopic dermatitis Abrocitinib FDA and EU 35.1 58.6 3 PBO NA
JADE Teen Eichenfield et al,18 2021 96 189 285 Atopic dermatitis Abrocitinib FDA and EU 15.0 50.9 12 PBO NA
JADE DARE Riech et al,19 2022 365 362 727 Atopic dermatitis Abrocitinib FDA and EU 36.6 53.0 6.5 Both Dupilumab
JADE REGIMEN Blauvelt et al,20 2021 531 267 798 Atopic dermatitis Abrocitinib FDA and EU 28.7 55.0 3 PBO NA
JADE Compare Bieber et al,21 2021 464 374 838 Atopic dermatitis Abrocitinib FDA and EU 37.9 50.4 4 Both Dupilumab
Heads Up Blauvelt et al,22 2021 348 344 692 Atopic dermatitis Upadacitinib FDA and EU 36.7 54.5 4 AC Dupilumab
Measure Up 1 Guttman-Yassky et al,23 2021 566 281 847 Atopic dermatitis Upadacitinib FDA and EU 34.0 54.0 4 PBO NA
Measure Up 2 Guttman-Yassky et al,23 2021 558 278 836 Atopic dermatitis Upadacitinib FDA and EU 33.6 56.0 4 PBO NA
AD Up Reich et al,24 2021 597 304 901 Atopic dermatitis Upadacitinib FDA and EU 34.0 62.0 4 PBO NA
Rising Up Katoh et al,25 2023 182 90 272 Atopic dermatitis Upadacitinib FDA and EU 35.6 75.8 6 PBO NA
BREEZE-AD1 Simpson et al,26 2020 375 249 624 Atopic dermatitis Baricitinib EU 35.8 62.7 4 PBO NA
BREEZE-AD2 Simpson et al,26 2020 370 244 614 Atopic dermatitis Baricitinib EU 34.5 62.0 4 PBO NA
BREEZE-AD4 Bieber et al,27 2022 370 93 463 Atopic dermatitis Baricitinib EU 38.4 62.5 4 PBO NA
BREEZE AD5 Simpson et al,28 2021 292 146 438 Atopic dermatitis Baricitinib EU 40.0 49.0 4 PBO NA
BREEZE-AD7 Reich et al,43 2020 220 108 328 Atopic dermatitis Baricitinib EU 33.8 66.0 4 PBO NA
BREEZE-AD-PEDS Torrelo et al,29 2023 361 122 483 Atopic dermatitis Baricitinib EU 12.0 50.7 4 PBO NA
TRuE-AD1 Papp et al,30 2021 505 126 631 Atopic dermatitis Ruxolitinib cream FDA 32.0 38.0 2 PBO NA
TRuE-AD2 Papp et al,30 2021 494 124 618 Atopic dermatitis Ruxolitinib cream FDA 33.0 38.5 2 PBO NA
BRAVE-AA1 King et al,31 2022 465 189 654 Alopecia areata Baricitinib FDA and EU 37.0 39.3 9 PBO NA
BRAVE-AA2 King et al,31 2022 390 156 546 Alopecia areata Baricitinib FDA and EU 37.0 39.3 9 PBO NA
NA Bachelez et al,44 2015 659 442 1101 Psoriasis Tofacitinib EU 44.3 71.1 3 Both Etanercept
OPT Pivotal 1 Papp et al,32 2015 723 177 900 Psoriasis Tofacitinib EU 45.8 71.4 4 PBO NA
OPT Pivotal 2 Papp et al,32 2015 763 196 959 Psoriasis Tofacitinib EU 45.4 67.6 4 PBO NA
NA Zhang et al,33 2017 178 88 266 Psoriasis Tofacitinib EU 41.1 72.9 12 PBO NA
SELECT-PSA 1 McInnes et al,34 2021 852 852 1704 Psoriatic arthritis Upadacitinib FDA and EU 50.6 46.3 3 Both Adalimumab
SELECT-PSA 2 Mease et al,35 2021 429 212 641 Psoriatic arthritis Upadacitinib FDA and EU 53.4 54.3 6 PBO NA
Opal Broaden Mease et al,36 2017 211 211 422 Psoriatic arthritis Tofacitinib EU 48.0 44.6 12 Both Adalimumab
OPAL Beyond Gladman et al,37 2017 263 131 394 Psoriatic arthritis Tofacitinib EU 49.9 44.7 6 PBO NA
NA Leng et al,38 2023 136 68 204 Psoriatic arthritis Tofacitinib EU 44.8 59.3 6 PBO NA
TRuE-V1 Rosmarin et al,39 2022 221 109 330 Vitiligo Ruxolitinib cream FDA and EU 40.2 43.5 6 PBO NA
TRuE-V2 Rosmarin et al,39 2022 228 115 344 Vitiligo Ruxolitinib cream FDA and EU 38.9 49.9 6 PBO NA
ALLEGRO-2b/3 King et al,42 2023 587 131 718 Alopecia areata Ritlecitinib FDA and Japan 33.8 37.9 12 PBO NA
Peds: Part 1 Nakagawa et al,40 2021 69 68 137 Atopic dermatitis Delgocitinib cream Japan 8.3 51.1 4 PBO NA
Adults: QBA4-1 Nakagawa et al,41 2020 106 52 158 Atopic dermatitis Delgocitinib cream Japan 31.7 62.0 4 PBO NA
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Abbreviations: AC, active comparator; EU, European Union; FDA, US Food and Drug Administration; JAKI, Janus kinase inhibitor; NA, not applicable; PBO, placebo.

Primary Analysis

Composite MACE and All-Cause Mortality

There was no significant difference in composite MACE and all-cause mortality between JAK inhibitors and placebo/active comparator using a random-effects DerSimonian-Laird method in the primary analysis (OR, 0.83; 95% CI, 0.44-1.57; I2 = 0%; 30 trials) (Figure 1). Subgroup analyses based on oral vs topical JAK inhibitors (heterogeneity P = .84) showed a similar association without significant heterogeneity (supporting data in Figure 1) or evidence of publication bias (eFigure 2A in Supplement 1). Sensitivity analysis by exclusion of pediatric trials (mean age <18 years) showed nonsignificant outcomes (OR, 0.83; 95% CI, 0.43-1.61; I2 = 0%; 27 trials) (eFigure 2B-C in Supplement 1). Subgroup analyses (of the sensitivity analysis) based on oral vs topical JAK inhibitors (heterogeneity P = .80) and dermatologic conditions (heterogeneity P = .93) showed a similar association without significant heterogeneity (supporting data in eFigure 2B-C in Supplement 1).

Figure 1. Primary Analysis: Composite of Major Adverse Cardiac Events (MACE) and All-Cause Mortality With Janus Kinase (JAK) Inhibitors Excluding Psoriatic Arthritis Trials.

Figure 1.

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OR indicates odds ratio.

There was no significant difference in composite MACE and all-cause mortality between JAK inhibitors and placebo/active comparator when including trials with psoriatic arthritis (OR, 0.74; 95% CI, 0.42-1.31; I2 = 0%; 35 trials) (eFigure 6A in Supplement 1). Subgroup analyses based on IMID conditions (heterogeneity P = .87) showed a similar association without significant heterogeneity (supporting data in eFigure 6A in Supplement 1). There was no evidence of publication bias assessed by funnel plot (eFigure 4 in Supplement 1).

Venous Thromboembolism

There was no significant difference in VTE between JAK inhibitors and placebo/active comparator (OR, 0.52; 95% CI, 0.26-1.04; I2 = 0%; 30 trials) (Figure 2). Subgroup analyses based on oral vs topical JAK inhibitors (heterogeneity P = .83) showed similar association without significant heterogeneity (supporting data in Figure 2). There was no evidence of publication bias assessed by funnel plot (eFigure 3A in Supplement 1).

Figure 2. Primary Analysis: Composite of Venous Thromboembolism (VTE) With Janus Kinase (JAK) Inhibitors Excluding Psoriatic Arthritis Trials.

Figure 2.

Open in a new tab

OR indicates odds ratio.

Sensitivity Analysis

Sensitivity analysis by the exclusion of pediatric trials (mean age <18 years) showed nonsignificant outcomes (OR, 0.38; 95% CI, 0.07-2.19; I2 = 0%; 27 trials) (eFigure 3B-C in Supplement 1). Subgroup analyses (of the sensitivity analysis) based on oral vs topical JAK inhibitors (heterogeneity P = .75) and dermatologic conditions (heterogeneity P = .99) showed a similar association without significant heterogeneity (supporting data in eFigure 3B-C in Supplement 1).

There was no significant difference in VTE between JAK inhibitors and placebo/active comparator when including trials with psoriatic arthritis (OR, 0.54; 95% CI, 0.29-1.02; I2 = 0%; 35 trials) (eFigure 6B in Supplement 1). Subgroup analyses based on dermatologic conditions (heterogeneity P = .99) showed a similar association without significant heterogeneity (supporting data in eFigure 6B in Supplement 1). There was no evidence of publication bias assessed by funnel plot (eFigure 5 in Supplement 1).

Discussion

We performed a meta-analysis of 35 RCTs with over 20 000 patients to determine the cardiovascular and VTE risk of JAK inhibitors used for atopic dermatitis, alopecia areata, psoriasis (including psoriatic arthritis), and vitiligo. In our primary analysis, we did not find a significant difference in composite MACE and all-cause mortality or in VTE between JAK inhibitors and the placebo/active comparator. In our secondary analysis, which included additional psoriatic arthritis RCTs, we similarly found no significant differences between the treatment and placebo/active comparator groups. Subgroup analysis of oral vs topical JAK inhibitors and a sensitivity analysis excluding pediatric trials failed to demonstrate significant differences between those exposed to JAK inhibitors and those not exposed.

This study addresses an important literature gap and, to our knowledge, is the first comprehensive meta-analysis specifically evaluating the risk of all-cause mortality, VTE, and MACE with JAK inhibitors used for a primary dermatologic indication. A previous meta-analysis specifically explored the association between VTE (but not MACE or all-cause mortality) and JAK inhibitors in atopic dermatitis and did not find an increased risk of VTE with their use (hazard ratio, 0.95; 95% CI, 0.62-1.45).45 JAK inhibitors have demonstrated high efficacy in treating inflammatory skin diseases, owing to their ability to target multiple cytokines simultaneously. IMIDs of the skin may be recalcitrant to traditional therapies, and JAK inhibitor therapy increases the treatment options for these patients.46,47 Fewer than half of patients treated with dupilumab, an approved first-line biologic for moderate to severe atopic dermatitis, achieved clear or nearly clear skin after 16 weeks of therapy.22 Furthermore, some patients may experience a reduction in their response over time.48 In patients with severe alopecia areata, baricitinib and the newly approved JAK inhibitor ritlecitinib are the only FDA-approved therapies.

With the use of JAK inhibitors rising, understanding their safety profile in the target population is important. JAK inhibitors are less specific than biologics due to the inherent redundancy of the JAK/STAT pathway and therefore may display an increase in off-target effects, which may be related to the association of increased MACE and VTE observed in patients with RA.1 The ORAL Surveillance study7 highlighted safety concerns of JAK inhibitors and found an increased risk of MACE, VTE, all-cause mortality, serious infections, and malignant neoplasm with their use. However, this study only included patients with RA with at least 1 cardiovascular risk factor, and it is well established that RA, similar to psoriasis, independently increases the risk of MACE and VTE.49,50,51 The mechanism by which JAK inhibitors increased the risk of VTE and MACE is unclear and highlights the need for a future mechanistic study.

There are key differences between the dermatology RCTs included in our meta-analysis and the ORAL Surveillance study.7 The patients with dermatologic conditions were younger (mean age, 38.5 years) than the patients with RA (mean age, 61 years), which could explain the low overall incidence of MACE, all-cause mortality, and VTE among patients included in dermatology clinical trials. Additionally, the patients in ORAL Surveillance had higher cardiovascular risk than the patients with dermatologic conditions, as the study only enrolled patients with RA with at least 1 cardiovascular risk factor. Also, the patients with RA studied were receiving concomitant methotrexate and some were also receiving systemic corticosteroids, unlike the patients included in dermatology clinical trials, who were receiving JAK inhibitor monotherapy. Another difference between studies was the study duration, which was 4 years in ORAL Surveillance vs 4.9 months on average in this meta-analysis. Also, the majority of JAK inhibitors tested in dermatology clinical trials are selective for JAK1/2, which differs from the selectivity of tofacitinib, which predominantly inhibits JAK1/3. Finally, the control group in ORAL Surveillance consisted of patients with RA receiving tumor necrosis factor inhibitors. The majority of RCTs in this study had a placebo group rather than an active comparator group. In summary, the different IMIDs studied, age of participants, number of cardiovascular risk factors, concomitant immunosuppressive therapy, differential JAK selectivity, and study durations are critical differences between the dermatologic RCTs and ORAL Surveillance and may help to explain our dissimilar findings.

Our results differ from those found in a recent, expanded meta-analysis52 of 66 RCTs of JAK inhibitors across IMIDs. The study found a numerically higher rate of VTE with JAK inhibitors compared to active comparator groups, but not the placebo group, and a nonsignificant, numerically higher rate of MACE in those treated with JAK inhibitors compared to the placebo/active comparator groups. The majority of patients included in this study were being treated for a rheumatologic rather than a dermatologic condition. Only 16 of 66 trials (not including psoriatic arthritis) included in the meta-analysis were for dermatologic indications. In contrast, our study focused only on dermatologic conditions and included 30 dermatology-specific RCTs. This meta-analysis52 also found that the risk of MACE and VTE may occur in a time-dependent manner (≥12 months of drug exposure). Similarly, ORAL Surveillance7 included 4 years of safety data in its analysis. While both of these studies primarily focused on the rheumatology cohort, the results of our study may not be generalizable to patients receiving JAK inhibitor therapy for dermatologic conditions for extended time periods. We only analyzed short-term safety data because we chose to include RCTs with an active comparator or placebo group, and many of the extension trials had a crossover design without a comparator arm. Whether an association between JAK inhibitor use and MACE and/or VTE would be observed with longer-term safety data in the population with dermatologic conditions is not known.

An evolving area of research is trying to understand how systemic inflammatory conditions are associated with cardiovascular risk factors. IMIDs, including those of the skin, have been associated with an increased risk of cardiovascular disease.5 Post hoc analyses of ORAL Surveillance found that rates of MACE with JAK inhibitors primarily occurred in patients with preexisting atherosclerotic cardiovascular disease and that the risk of VTE and MACE was higher for those with active RA.53,54 Another study55 found that the incidence rates of MACE and VTE with JAK inhibitors were lower for patients with fewer cardiovascular risk factors across conditions, including RA. It is likely that the patients included in the dermatology RCTs had fewer cardiovascular comorbidities than the patients enrolled in the rheumatology RCTs. The risks of MACE and VTE with JAK inhibitors likely increase in patients with elevated cardiovascular comorbidities. Therefore, the results of our study may not be translatable to patients with dermatologic conditions at higher cardiovascular risk. An individualized approach to cardiovascular risk management in patients who may benefit from JAK inhibitor therapy is likely appropriate.56

Limitations

This study should be interpreted in light of several limitations. First, we did not have access to patient-level data. Second, the duration of follow-up time varied from short-term to long-term follow-up; the majority of studies only included short-term follow-up. Also, most of the trials consisted of small RTCs limited to specific geographical areas, so the extent of generalizability and trends in different populations are uncertain. Furthermore, the mean age was 38.5 years; therefore, the incidence of MACE, VTE, and all-cause mortality would be low and has limited generalizability in an older patient population. In this study, we chose to focus on 3 of the 5 boxed warnings for JAK inhibitors, and the risks of serious infections and malignant neoplasm warrant further investigation in patients with dermatologic conditions. Finally, the mean follow-up time was 4.9 months, so the association of long-term use of JAK inhibitors is unknown.

Conclusions

In this systematic review and meta-analysis of phase 3 dermatology RCTs, we did not find an elevated risk of adjudicated composite all-cause mortality and MACE or VTE in patients treated with short-term oral or topical JAK inhibitor therapy for IMIDs of the skin. It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient-level cardiovascular risk factors or are drug mediated. Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment. Additional RCTs with long-term safety follow-up are needed to better understand the risks of all-cause mortality, MACE, and VTE, and even cancer and infection, with JAK inhibitors used for a dermatologic indication.

Supplement 1.

eTable. Cochrane risk of assessment bias

eFigure 1. PRISMA flow

eFigure 2. Effect of JAK inhibitors on composite of MACE and all-cause mortality (primary analysis)

eFigure 3. Effect of JAK inhibitors on VTE (primary analysis)

eFigure 4. Funnel plot: effect of JAK inhibitors on composite of MACE and all-cause mortality (secondary analysis)

eFigure 5. Funnel plot: effect of JAK inhibitors on VTE (secondary analysis)

eFigure 6. Secondary analysis

eAppendix. PRISMA checklist

Click here for additional data file. (1.6MB, pdf)
Supplement 2.

Data Sharing Statement

Click here for additional data file. (16.3KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable. Cochrane risk of assessment bias

eFigure 1. PRISMA flow

eFigure 2. Effect of JAK inhibitors on composite of MACE and all-cause mortality (primary analysis)

eFigure 3. Effect of JAK inhibitors on VTE (primary analysis)

eFigure 4. Funnel plot: effect of JAK inhibitors on composite of MACE and all-cause mortality (secondary analysis)

eFigure 5. Funnel plot: effect of JAK inhibitors on VTE (secondary analysis)

eFigure 6. Secondary analysis

eAppendix. PRISMA checklist

Click here for additional data file. (1.6MB, pdf)
Supplement 2.

Data Sharing Statement

Click here for additional data file. (16.3KB, pdf)

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