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. 2025 Sep 3;161(11):1107–1115. doi: 10.1001/jamadermatol.2025.2972

Interleukin-17 Inhibitors and Early Major Adverse Cardiovascular Events

Maxime Raby 1,2, Frederic Balusson 1,3, Emmanuel Oger 1,3, Marion Gundelwein 1, Alain Dupuy 1,2, Florence Poizeau 1,2,✉
PMCID: PMC12409656  PMID: 40900466

Key Points

Question

On the basis of previous studies and mechanistic models, concerns have been raised about the occurrence of major adverse cardiovascular events (MACEs) following the initiation of interleukin (IL)-17(R)A inhibitors in the setting of psoriasis and psoriatic arthritis.

Findings

In a case–time-control analysis based on the French National Health Insurance database and including 34 241 individuals who received an IL-17(R)A inhibitor from 2016 to 2021, no statistically significant association was found between the initiation of IL-17(R)A inhibitors and the occurrence of MACEs in the following 6 months, using tumor necrosis factor-α inhibitors as active comparators.

Meaning

No significant association was found between MACEs and the initiation of IL-17(R)A inhibitors; however, a modest risk increase cannot be entirely ruled out.

Abstract

Importance

The cardiovascular impact of biologics used in psoriasis is not fully understood. Several studies have suggested that the inhibition of the T-helper 17 cell pathway could lead to the destabilization of atherosclerotic plaques, leading to major adverse cardiovascular events (MACEs).

Objective

To assess whether the initiation of interleukin (IL)-17(R)A inhibitors triggers MACEs.

Design, Setting, and Participants

In this case–time-control study using the French National Health Insurance database, all individuals who received IL-17(R)A inhibitors (secukinumab, ixekizumab, and brodalumab) from 2016 to 2021, were included and classified according to their cardiovascular risk level. The risk period was defined as the 6 months before the MACE, and the reference period as the 6 months before the risk period. The same design for patients who received tumor necrosis factor (TNF)–α inhibitors (adalimumab or etanercept) for similar indications (psoriasis, psoriatic arthritis, ankylosing spondylitis, or juvenile arthritis), as an active comparator. The data analysis was conducted between April 2023 and August 2024.

Exposure

The initiation of the biologic was screened in both periods.

Main Outcomes and Measures

The odds ratios (ORs) for the risk of MACEs were assessed following the initiation of IL-17(R)A inhibitors and TNF-α inhibitors independently. Subsequently, the OR for the risk of MACE associated with IL-17(R)A inhibitors was estimated using TNF-α inhibitors as the comparator.

Results

Among the 34 241 individuals who received an IL-17(R)A inhibitor, 381 MACEs were analyzed, including 176 acute coronary syndromes and 84 ischemic strokes in the main analysis. Initiation of IL-17(R)A inhibitors was not significantly associated with MACEs (OR, 1.25 [95% CI, 0.75-2.08] vs TNF-α inhibitor initiation and MACEs: OR, 0.90 [95% CI, 0.65-1.24]). Overall, the initiation of an IL-17(R)A inhibitor was not significantly associated with MACEs in the following 6 months, using TNF-α inhibitor as a comparator (OR, 1.40 [95% CI, 0.77-2.54]), regardless of the individual cardiovascular risk (P for homogeneity = .29). The definition of MACE was broadened in a first sensitivity analysis, and the risk period was shortened to 3 months in a second sensitivity analysis. The results did not change.

Conclusions

In this case–time-control study based on a national insurance database, there was no evidence of a significant association between MACEs and the initiation of IL-17(R)A inhibitors, regardless of the individual cardiovascular risk of the patient. However, a modest risk increase cannot be entirely excluded.

This case–time-control study explores whether the initiation of interleukin-17(R)A inhibitors is associated with major adverse cardiovascular events.

Introduction

People with moderate to severe psoriasis exhibit an increased risk of cardiovascular ischemic disease, both in comparison with mild psoriasis and with the general population. Moderate to severe psoriasis is associated with an increased prevalence of metabolic syndrome, including dyslipidemia, high blood pressure, diabetes, and smoking.1,2 Whether psoriasis is an independent risk factor for major adverse cardiovascular events (MACEs; ie, acute coronary syndromes or ischemic strokes) is still a matter of debate.3,4,5,6 Therefore, investigating the incremental risk of biologic use for MACEs is crucial for this population.

Over the past 2 decades, pharmaceutical companies have developed biologics targeting the inflammatory pathways involved in psoriasis, thus profoundly transforming the treatment landscape of the disease.7 These biologics inhibit either the T-helper 1 cell (Th1) or the T-helper 17 cell (Th17) inflammatory pathways, or both, and their respective impact on atherosclerosis seems to differ. The first biologics marketed were tumor necrosis factor (TNF)−α inhibitors, which inhibit the Th1 inflammatory pathway. Several studies examined the impact of these treatments on the occurrence of MACEs, generally concluding that there is no increased risk and possibly even a protective effect.8,9,10,11,12,13,14,15 Subsequently, other biologics were developed, targeting the Th17 pathway. The first were interleukin (IL)-12/23 inhibitors (briakinumab and ustekinumab), followed by IL-17(R)A inhibitors (secukinumab, ixekizumab, brodalumab, and bimekizumab), and more recently IL-23 inhibitors (mirikizumab, guselkumab, tildrakizumab, and risankizumab). A controversy regarding the cardiovascular safety of several biologics arose.16,17,18,19,20,21,22,23,24,25,26 The development of the IL-12/23 inhibitor briakinumab and the IL-23 inhibitor mirikizumab for psoriasis was discontinued after phase 3 trials reported an excess number of MACEs in the treatment groups.16,17,18,19,20 A population-based study further highlighted a potential trigger effect for MACEs within 6 months following the initiation of ustekinumab among individuals with high cardiovascular risk.27 A second large-scale epidemiological study suggested an increased risk of MACE among people receiving ustekinumab or an IL-17(R)A inhibitor, compared to those receiving TNF-α inhibitors.28

A potential immunological substratum has been hypothesized, in which the Th17 pathway produces IL-17A, a molecule thought to both promote the growth of atherosclerotic plaques and stabilize them via the synthesis of collagen fibers by the smooth muscle cells.29,30,31,32,33,34,35 Inhibiting this pathway could theoretically weaken the fibrous cap surrounding plaques, potentially destabilizing plaques and leading to MACEs.

Hence, a trigger effect for MACEs following the inhibition of the IL-17/Th17 pathway has been postulated. The present population-based study aimed to determine whether IL-17(R)A inhibitors could trigger early MACEs following treatment initiation. Patients receiving TNF-α inhibitors were analyzed alongside the main population receiving IL-17(R)A inhibitors, serving as an active comparator, as no trigger effect has been hypothesized for TNF-α inhibitors.

Methods

Data Source

This case–time-control study was conducted using the French National Health Insurance database (Système National des Données de Santé [SNDS]). This database covers 99% of the population living in France (around 66 million inhabitants), and includes pseudonymized individual sociodemographic data, exhaustive data on all reimbursements for health-related expenditures, drugs dispensed with dates of issue, any procedure (imagery, surgery, blood analysis, etc), and hospitalization discharge codes according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).36,37,38,39,40 Data from public and private practices are recorded in the same way. Rennes Hospital has permanent access to the SNDS database in accordance with the provisions of Decree 2021-848 and R. 1461-12 et seq. in the Public Health Code and the decision of the Commission Nationale de l’Informatique et des Libertés (CNIL-2016-316). Our study was approved by the Scientific and Ethics Committee of Rennes Hospital on August 1, 2022. Informed consent was not required because the data were deidentified.

Study Population

From the SNDS database, we extracted all the data regarding individuals who had a dispensation of secukinumab, ixekizumab, or brodalumab from July 7, 2016 (date of marketing of secukinumab), to December 31, 2021. Thus, all individuals included were incident users of IL-17(R)A inhibitors. Bimekizumab was not marketed at the time of the study. From this population, we selected those who experienced a MACE (ie, the cases). As an active comparator, we also extracted those who had a dispensation of adalimumab or etanercept from January 1, 2010, to December 31, 2021, if a diagnosis of psoriasis, psoriatic arthritis, ankylosing spondylitis or juvenile arthritis (which are the indications for IL-17(R)A inhibitors) was identified, or if the individuals had a dispensation of IL-17(R)A inhibitor. Patients with a dispensation of TNF-α inhibitor in 2009 were excluded, so as to select only incident users.

MACEs

MACEs were defined as either acute coronary syndrome (ICD-10 codes I21 or I23) leading to a hospitalization in the intensive care unit (ICU), or ischemic stroke (ICD-10 codes I63, excluding I63.6), whatever the hospitalization ward, identified using the hospitalization discharge codes. Deaths caused by acute coronary syndrome or ischemic stroke occurring outside the hospital were also included. The date of admission or the date of death was used as the date of the event.

Drug Exposure

As we focused on a potential trigger effect, exposure was defined as the initiation of the treatment, that is, the first dispensation of an IL-17(R)A inhibitor. If an individual received several anti–IL-17(R)A agents in the course of the study, only the first agent received was analyzed.

Covariates

As we were seeking a differential effect between individuals predisposed and nonpredisposed to MACEs, we determined the cardiovascular risk level for each individual. Risk level was considered high in presence of at least 2 cardiovascular risk factors (including dyslipidemia, diabetes, high blood pressure, obesity, tobacco use, or being older than 50 years for men and older than 60 years for women) or a personal history of atherothrombotic disease (including ischemic heart disease, stroke, and lower limb arterial disease). Otherwise, the risk level was considered low. The indication for the treatment was identified using hospitalization discharge codes, long-term disease codes, or issues of medication. Exposure to antiplatelet, anticoagulant, antihypertensive, or lipid-lowering drugs was identified to adjust for their discontinuation, as this can lead to MACEs. The algorithms used are detailed in eTable 1 in Supplement 1.

Study Design

We performed a case–time-control study, a study design used to investigate the triggering role of different factors in acute adverse events.41 A potential trigger effect is particularly relevant for MACEs, which are known to be precipitated by several well-known transient factors (eg, respiratory infections, physical exertion, sexual activity).42,43,44 This design is based on the principle of each individual serving as his own control in a different time period. It seeks an excess of initiations in the risk period (a time period immediately preceding the MACE), as compared to a previous time period of the same duration, called the reference period. This enables time-invariant confounders to be controlled for. In other words, for each MACE included, we measured whether the individual had initiated the biologic in the risk period (defined as the 0 to 6 months before the MACE), in the reference period (the 6 to 12 months before the MACE), or in neither (Figure 1A). MACEs occurring less than 12 months after the marketing date of the biologic (July 7, 2016, for secukinumab; December 21, 2016, for ixekizumab; and October 10, 2018, for brodalumab) were excluded, to allow at least 12 months for detecting initiation of the biologic before the MACE. In addition, the validity criteria for the case–time-control design required the probability of observing initiation to be modified only by the association with a MACE (exchangeability concept). Thus, we did not include the MACE if the individual had already experienced one (or a transient ischemic attack) in the previous 2 years, since it could reduce the probability of initiation of a biologic by the physician (Figure 2).41,45,46,47,48 However, the increased prescriptions of IL-17(R)A inhibitors over time after its marketing could have increased the individual probability of initiating the biologic in the risk period compared to the reference period because the latter precedes the former, leading to a false association between initiation and outcome. To allow for this time trend, the design incorporates a group of time-controls. Time-controls are individuals receiving the same biologic but who do not experience a MACE and are matched to cases (Figure 1B). For each case, 4 time-controls of the same sex, age (±2 years), and cardiovascular risk stratum were randomly sampled among individuals receiving the same biologic. Time-controls were not compared to cases, but were used to adjust for time trends in the general prescription of biologics over time. In addition, we included an active comparator to account for time-variant confounders.46 TNF-α inhibitors were not compared with IL-17(R)A inhibitors but were used to reflect a similar degree of time-dependent confounding as IL-17(R)A inhibitors (Figure 1C). The step-by-step analysis is detailed in eTable 2 in Supplement 1.

Figure 1. Overview of the Case–Time-Control Design Including an Active Comparator.

Figure 1.

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A, Among individuals exposed to interleukin (IL)-17(R)A inhibitors and experiencing a major adverse cardiovascular event (MACE), biologic initiation was screened during 2 periods preceding the MACE. The number of initiations was compared between the 2 periods. B, The same scheme was applied to the time-controls (ie, individuals receiving the same biologic who did not have a MACE, matched to the cases). Therefore, the odds ratio (OR) estimating the association between the initiation of IL-17(R)A inhibitors and MACEs is adjusted for the time trend of IL-17(R)A initiations. C, The same scheme was applied to individuals receiving tumor necrosis factor (TNF) inhibitors, as TNF inhibitors are not associated with MACEs and share the same indications as IL-17(R)A inhibitors. Therefore, the OR estimating the association between the initiation of IL-17(R)A inhibitors and MACEs is adjusted for confounding factors common to both biologics.

Figure 2. Flowchart for Major Adverse Cardiovascular Events (MACEs) Among Patients Receiving Interleukin (IL)-17(R)A Inhibitors.

Figure 2.

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ICU indicates intensive care unit.

Statistical Analysis

The conditional logistic regression model was adjusted for the discontinuation of antiplatelet, anticoagulant, antihypertensive, or lipid-lowering drugs in the risk or the reference period compared to the previous 6 months, as the discontinuation of one of these medications could potentially have triggered the MACE. Finally, the odds ratio (OR) was derived from the second-order interaction term between exposure, case or time-control status, and the IL-17(R)A or TNF-α inhibitor group, introduced into the conditional logistic regression model.46 The model estimated the association between IL-17(R)A inhibitor initiation and MACEs, controlling for time trend, invariant, and variant confounders. The significance of the coefficients was assessed using a Wald test. Statistical tests were 2-tailed, with an α risk of 5%. The data management was performed using SAS Enterprise Guide Software, version 8.3 (SAS Institute, Inc), and statistical analyses were performed with R Studio, version 3.3 (R Project for Statistical Computing. The data analysis was conducted between April 2023 and August 2024.

Subgroup Analysis

A differential effect of initiation according to cardiovascular risk was anticipated, on the basis that the mechanism of atherosclerotic plaque destabilization assumes that the individual has pre-existing plaques. We stratified the analysis according to the cardiovascular risk strata (high vs low). To test for the possible interaction between the cardiovascular risk and IL-17(R)A inhibitor initiation, we evaluated homogeneity between the ORs obtained from the two cardiovascular strata, using a Wald test. Because this test is less powerful, a P value of less than .10 was considered statistically significant.

Sensitivity Analysis

We tested the robustness of our study findings in sensitivity analyses using alternative assessment criteria for the definition of the outcome and the duration of the periods. First, we extended the definition of MACEs to include acute coronary syndromes hospitalized in units other than the ICU and other acute ischemic cerebrovascular diseases (Figure 2; eTable 1 in Supplement 1). Second, we reduced the duration of the risk and the reference periods from 6 to 3 months, so as to search for a shorter triggering effect.

Results

Population Characteristics

Among the 67 million people living in France, 34 241 individuals received an IL-17(R)A inhibitor from January 2016 to December 2021. Their main characteristics are presented in the Table. Their mean (SD) age was 48.5 (13.5) years, and 45% were men. Overall, 59% had psoriasis, 17% had psoriatic arthritis, 48% had ankylosing spondylitis, 3% had juvenile arthritis, and 29% had high cardiovascular risk. Regarding the active comparator, 108 811 individuals initiated a TNF-α inhibitor from January 2010 to December 2021. Overall, 42% had psoriasis, 12% had psoriatic arthritis, 63% had ankylosing spondylitis, 8% had juvenile arthritis, and 22% had high cardiovascular risk.

Table. Baseline Characteristics of Individuals Exposed to Interleukin (IL)-17(R)A Inhibitors.

Variable No. (%)
Low cardiovascular risk (n = 24 265) High cardiovascular risk (n = 9976) Overall (N = 34 241)
Age, mean (SD), y 43.9 (11.6) 59.8 (10.8) 48.5 (13.5)
Gender
Women 14 337 (59) 4479 (45) 18 816 (55)
Men 9928 (41) 5497 (55) 15 425 (45)
Indications
Psoriasis 13 360 (55) 6903 (69) 20 263 (59)
Psoriatic arthritis 3523 (14) 2443 (24) 5966 (17)
Ankylosing spondylitis 12 599 (52) 3995 (40) 16 594 (48)
Juvenile arthritis 905 (4) 300 (3) 1205 (3)
Death during study 164 (1) 435 (4) 599 (2)
History of atherothrombotic event(s)
Lower limb arterial disease 0 258 (3) 258 (1)
Ischemic stroke 0 109 (1) 109 (0)
Hemorrhagic stroke 0 37 (0) 37 (0)
Ischemic cardiopathy 0 1452 (15) 1452 (4)
Cardiovascular risk factor(s)
High blood pressure 2005 (8) 7604 (76) 9609 (28)
Dyslipidemia 381 (2) 4796 (48) 5177 (15)
Diabetes 258 (1) 2786 (28) 3044 (9)
Tobacco use 1479 (6) 2592 (26) 4071 (12)
Obesity 1032 (4) 2807 (28) 3839 (11)
No. of risk factorsa
0 15 873 (65) 68 (1) 15 941 (47)
1 8392 (35) 146 (1) 8538 (25)
2 0 4703 (47) 4703 (14)
3 0 2912 (29) 2912 (8)
4 0 1428 (14) 1428 (4)
5 0 580 (6) 580 (2)
6 0 139 (1) 139 (0)
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a

Age was considered as a cardiovascular risk factor if older than 60 years for women and older than 50 years for men.

MACEs

From January 2016 to December 2021, 195 acute coronary syndromes and 120 ischemic strokes occurred among individuals who had previously received IL-17(R)A inhibitors, giving a crude incidence of MACEs of 3.41 per 1000 patient-years (95% CI, 3.04-3.81). The incidence was 2.11 per 1000 patient-years (95% CI, 1.82-2.43) for acute coronary syndromes, and 1.30 per 1000 patient-years (95% CI, 1.08-1.55) for ischemic strokes. After applying the exclusion criteria of the case–time-control design (Figure 2), 260 MACEs were included in the main analysis (176 acute coronary syndromes hospitalized in ICU, 84 ischemic strokes): 225 (87%) were men older than 60 years or women older than 50 years, 168 (65%) had hypertension, 132 (51%) had dyslipidemia, 64 (25%) had diabetes, 127 (49%) were smokers, and 91 (35%) had obesity.

Risk of MACE Associated With IL-17(R)A Inhibitor Initiation

Among the 34 241 individuals who received an IL-17(R)A inhibitor, 43 patients (0.1%) initiated the IL-17(R)A inhibitor in the risk period (in the 6 months prior to the MACE) and 33 (0.1%) in the reference period (in the 6- to 12-month period preceding the MACE). After adjustment for the time trend, IL-17(R)A inhibitor initiation was not significantly associated with MACEs (OR, 1.25 [95% CI, 0.75-2.08]). In contrast, among the 108 811 individuals who received a TNF-α inhibitor, 88 (0.1%) initiated the TNF-α inhibitor during the risk period, and 91 (0.1%) during the reference period. After adjustment for the time trend, the OR estimating the association between TNF-α inhibitor initiation and MACE was 0.90 (95% CI, 0.65-1.24).

The final OR for the case–time-control analysis estimating the association between IL-17(R)A inhibitor initiation and MACE, taking into account the active comparator and adjusting for the potential discontinuation of antiplatelet, anticoagulant, antihypertensive, or lipid-lowering drugs, was 1.40 (95% CI, 0.77-2.54; P = .20). The test result for heterogeneity of the ORs according to the cardiovascular risk stratum was not statistically significant (P = .29). The results of the analyses within each cardiovascular stratum are provided in the forest plot (Figure 3). The step-by-step results of the main analysis are available in eTable 2 in Supplement 1.

Figure 3. Association Between Interleukin (IL)-17(R)A Initiation and Major Adverse Cardiovascular Events (MACEs) According to Cardiovascular Risk.

Figure 3.

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The high-risk population is defined as individuals having at least 2 cardiovascular risk factors or a personal history of cardiovascular event. The low-risk population is defined as individuals under 2 cardiovascular risk factors, and no personal history of cardiovascular event. Odd ratios (ORs) estimate the association between IL-17(R)A inhibitor initiation and MACEs, adjusting for time trends in the prescription of IL-17(R)A inhibitors, the potential discontinuation of antiplatelet, anticoagulant, antihypertensive or lipid-lowering drugs, and using tumor necrosis factor (TNF)−α inhibitors as an active comparator.

Sensitivity Analysis

First, the definition of MACEs was extended: 115 acute coronary syndromes and 6 ischemic strokes were added in the sensitivity analysis, totaling 381 events. The OR was 0.97 (95% CI, 0.60-1.59) for the overall population. There was no significant differential association according to cardiovascular risk. Second, the time periods were reduced to 3 months to detect a shorter potential trigger effect of the initiation of IL-17(R)A on MACEs. The OR was 1.36 (95% CI, 0.60-3.10). Sensitivity analyses in the overall population and according to cardiovascular risk are provided in the forest plot (Figure 3).

Discussion

In this population-based case–time-control study including 34 241 individuals receiving IL-17(R)A inhibitors, we did not observe statistically significant association between treatment initiation and the occurrence of ischemic strokes and acute coronary syndromes within 6 months, whatever the baseline cardiovascular risk level of the patient (OR, 1.40 [95% CI, 0.77-2.54]; P = .20).

We chose to focus on the potential trigger effect of IL-17(R)A inhibitors for several reasons. First, several trials have shown an increased number of MACEs or arterial atherothrombotic events among patients receiving secukinumab or ixekizumab vs placebo, occurring in the first months of treatment.21,22,49 Second, a previous study demonstrated a trigger effect for MACEs associated with the initiation of ustekinumab.27 Lastly, several basic research studies support a stabilizing role of the Th17 pathway on atherosclerotic plaques, which would imply that inhibiting this pathway could suddenly trigger MACEs.31,32,33,34,35,50,51 Therefore, we chose a design specifically suited to detecting a triggering effect. Indeed, longitudinal cohorts evaluating long exposure to a biologic cannot detect a risk of early MACEs because they assume that the risk of MACE remains constant over time during the biologic treatment. However, the risk could be transient and disappear with continued treatment. For example, isotretinoin can trigger acne fulminans shortly after initiation, yet it ultimately resolves acne over time. Similarly, IL-17(R)A inhibitors could plausibly induce a short-term cardiovascular risk, while having neutral or even beneficial cardiovascular effects in the longer term. That is why the long-term postmarketing surveillance data used to conclude the safety of IL-17(R)A inhibitors are not sufficient to be reassuring and should not preclude the investigation of short-term risks.25,49,52,53,54 In addition, individuals who remain on the biologic are those who tolerate it: this phenomenon is called the depletion of susceptibles. Therefore, exploring a longer duration of exposure to the biologic can yield falsely reassuring results.55 The case-crossover design is a reference standard for studying a sudden and transient effect that triggers an acute event.56 In the case of prolonged exposures, such as biologics, if the effect persists, a case-crossover design may yield biased estimates. To address this, we used a case–time-control design, which incorporates a control group to correct for this potential bias. This approach has been validated in simulation studies.57 Although our use of this design departs from its traditional application, we believe it is appropriate to test the specific hypothesis of a transient increase in cardiovascular risk following biologic initiation.

Strengths and Limitations

Our study has several strengths. First, our design avoids all time-invariant confounders by using within-participant comparisons. To address residual time-variant confounders, we used controls for the time trend, an active comparator, and adjusted for the discontinuation of treatments for cardiovascular risk factors. Second, we used one of the largest and exhaustive insurance databases. By selecting all people who had received at least 1 dispensation of an IL-17(R)A inhibitor in France, we strongly limited selection bias. The SNDS database avoids attrition bias because all the reimbursements and hospitalizations of an individual living in France are recorded up to their death. Finally, we believe that almost all MACEs are correctly reported in this database (except those that did not result in hospitalization or an out-of-hospital death), and we used 2 definitions of MACEs (for the main and sensitivity analyses) that were more or less restrictive regarding the sudden and severe nature of the events being investigated. Third, we conducted 2 sensitivity analyses, the results of which are consistent with those of our main analysis.

Some limitations of this study also need to be discussed. First, we considered drug dispensations as a proxy for actual intake, a common approach in pharmacoepidemiologic research.58 Second, incomplete clinical data on cardiovascular risk factors could have introduced a misclassification bias between the high and low cardiovascular risk strata. Tobacco use and obesity are often underreported in hospital discharge coding. No data were available regarding diet or physical activity. Moreover, dyslipidemia was identified only through dispensations of statins or fibrates, potentially missing untreated individuals with elevated risk. Nevertheless, we believe our risk stratification approach successfully distinguished 2 meaningful cardiovascular risk subpopulations. Third, the choice of 6-month periods is questionable and somewhat arbitrary. We reduced these periods to 3 months in a sensitivity analysis, without altering the results. Last but not least, a lack of power can be suspected. With 381 MACEs, the study had 80% power to detect an OR of 1.63. While a small trigger effect cannot be excluded, a larger risk increase appears unlikely.

Other current evidence regarding IL-17(R)A inhibitors supports a rather neutral effect on cardiovascular risk associated with their use. Indeed, several meta-analyses of randomized placebo-controlled trials have not identified an increased risk of MACE.59,60 Furthermore, the VIP-S trial failed to demonstrate a reduction in aortic vascular inflammation in patients receiving secukinumab compared to placebo.61 Similarly, 1 year of treatment with secukinumab or ixekizumab did not improve traditional cardiovascular risk factors, although secukinumab appeared to reduce high-sensitivity C-reactive protein and the neutrophil-lymphocyte ratio.62,63,64

Conclusions

In this case–time-control study, we did not find any trigger effect of the initiation of IL-17(R)A inhibitors for MACEs. While this result provides some reassurance for prescribers and patients, a modest risk cannot be definitively ruled out. Other issues remain: for example, is a detrimental effect or, conversely, a beneficial effect expected with the long-term use of IL-17(R)A inhibitors? What can be said about the cardiovascular safety of IL-23 inhibitors? Further studies are still required to explore the cardiovascular effect of biologics in immune-mediated diseases.

Supplement 1.

eTable 1. Algorithms used to identify events, indications, comorbidities and other treatments of interest

eTable 2. Step-by-step analysis of the case–time-control design assessing the association between Major Adverse Cardiovascular Events (MACEs) and the initiation of IL-17(R)A inhibitor, using TNF-α inhibitors as an active comparator

jamadermatol-e252972-s001.pdf (308.8KB, pdf)
Supplement 2.

Data sharing statement

jamadermatol-e252972-s002.pdf (15.9KB, 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 1. Algorithms used to identify events, indications, comorbidities and other treatments of interest

eTable 2. Step-by-step analysis of the case–time-control design assessing the association between Major Adverse Cardiovascular Events (MACEs) and the initiation of IL-17(R)A inhibitor, using TNF-α inhibitors as an active comparator

jamadermatol-e252972-s001.pdf (308.8KB, pdf)
Supplement 2.

Data sharing statement

jamadermatol-e252972-s002.pdf (15.9KB, pdf)

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