Highlight
– Initiation of IL-17(R)A inhibitors does not significantly increase the risk of early major adverse cardiovascular events (MACEs).
– This finding is consistent across patients with varying baseline cardiovascular risk.
– Tumor necrosis factor (TNF)-α inhibitors used as active comparators show similar cardiovascular safety profiles.
– Sensitivity analyses confirm stability of findings despite varying definitions and risk windows.
Study Background and Disease Burden
Psoriasis is a chronic inflammatory skin disease frequently requiring systemic therapy for moderate to severe cases. Biological therapies targeting specific immune pathways have transformed management, with interleukin-17 receptor A (IL-17(R)A) inhibitors emerging as effective options. However, psoriasis is associated with increased cardiovascular disease (CVD) risk, linked to systemic inflammation and shared risk factors. There is clinical concern that modulation of inflammatory pathways, especially inhibition of the T-helper 17 (Th17) cell axis, might influence cardiovascular outcomes, possibly by affecting atherosclerotic plaque stability.
Major adverse cardiovascular events (MACEs), including acute coronary syndromes and ischemic strokes, represent critical clinical endpoints. Prior studies have shown conflicting signals regarding the cardiovascular safety of IL-17 inhibitors, necessitating rigorous population-based evaluation to inform clinical decision-making and patient safety.
Study Design
This retrospective case–time-control study utilized the French National Health Insurance database, a comprehensive nationwide health claims repository. The study period covered 2016 to 2021, encompassing patients treated with IL-17(R)A inhibitors (secukinumab, ixekizumab, and brodalumab). Patients with indications including psoriasis, psoriatic arthritis, ankylosing spondylitis, or juvenile arthritis were included and categorized by cardiovascular risk profile.
A risk period was defined as the 6 months immediately before the occurrence of a MACE, with a preceding 6-month reference period. The timing of biologic initiation was evaluated within these intervals. An active comparator group was established comprising patients initiating tumor necrosis factor (TNF)-α inhibitors (adalimumab or etanercept) for analogous indications, aiding adjustment for confounding by indication and temporal factors.
The primary exposure was initiation of either IL-17(R)A or TNF-α inhibitors. The primary outcome was the odds ratio (OR) for MACEs associated with biologic initiation, assessed independently for IL-17(R)A and TNF-α inhibitors, and comparatively for IL-17(R)A versus TNF-α inhibitors.
Data analysis was conducted from April 2023 through August 2024, employing conditional logistic regression within the case–time-control design to mitigate confounding by fixed individual characteristics.
Key Findings
The cohort included 34,241 patients treated with IL-17(R)A inhibitors who experienced 381 MACEs, specifically 176 acute coronary syndromes and 84 ischemic strokes analyzed in the main analysis.
Initiation of IL-17(R)A inhibitors was not significantly associated with occurrence of MACEs in the 6-month risk period compared with the reference period (OR 1.25; 95% confidence interval [CI] 0.75–2.08). Similarly, initiation of TNF-α inhibitors was not associated with increased MACE risk (OR, 0.90; 95% CI, 0.65–1.24).
When directly comparing IL-17(R)A to TNF-α inhibitors, the OR for MACEs within 6 months was 1.40 (95% CI, 0.77–2.54), indicating no statistically significant difference in cardiovascular risk between these biologics. Importantly, this association was consistent across subgroups stratified by cardiovascular risk levels (P for homogeneity = 0.29).
Sensitivity analyses further supported robustness of results: broadening the MACE definition and shortening the risk window to 3 months did not materially alter risk estimates.
These findings suggest that initiation of IL-17(R)A inhibitors does not confer a significant early increase in major cardiovascular events when compared to TNF-α inhibitors, even in patients with higher baseline cardiovascular risk.
Expert Commentary
The study by Raby et al. significantly contributes to the evolving understanding of cardiovascular safety associated with IL-17 pathway inhibition. The case–time-control design effectively controls for time-invariant confounders and leverages real-world data from a large national cohort.
Mechanistically, IL-17 has complex roles in atherosclerosis and vascular inflammation, with preclinical data suggesting both proatherogenic and potentially protective effects depending on context. These clinical findings temper concerns about destabilization of plaques following IL-17 inhibition, at least in the short term.
However, limitations merit consideration. The study’s observational nature cannot fully exclude residual confounding. The modest elevation of OR (1.25 to 1.40) with wide confidence intervals indicates insufficient power to definitively exclude a small increased risk. Longer-term cardiovascular outcomes beyond 6 months remain unexplored in this study. Additionally, granular clinical data such as disease severity, lifestyle factors, and detailed cardiovascular biomarkers were unavailable.
Current guidelines acknowledge the importance of cardiovascular risk assessment in patients with psoriasis but do not contraindicate IL-17 inhibitor use due to cardiovascular concerns. This study reinforces that stance, emphasizing individualized clinical evaluation.
Future prospective studies and registries with prolonged follow-up and detailed phenotyping are needed to further elucidate cardiovascular safety of IL-17 inhibition.
Conclusion
In this extensive case–time-control study utilizing nationwide insurance claims data, initiation of IL-17(R)A inhibitors was not associated with a statistically significant increase in early major adverse cardiovascular events compared with initiation of TNF-α inhibitors. This finding persisted across varying cardiovascular risk profiles and with sensitivity analyses.
Clinicians can be cautiously reassured about the cardiovascular safety of IL-17(R)A inhibitors in the early post-initiation period. Nonetheless, continued vigilance for potential modest risk increases is warranted. Personalized cardiovascular risk management remains essential in patients receiving biologic therapies for psoriasis and related inflammatory diseases.
References
1. Raby M, Balusson F, Oger E, Gundelwein M, Dupuy A, Poizeau F. Interleukin-17 Inhibitors and Early Major Adverse Cardiovascular Events. JAMA Dermatol. Published online September 03, 2025. doi:10.1001/jamadermatol.2025.2972
2. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80(4):1073-1113. doi:10.1016/j.jaad.2018.11.058
3. Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011 Oct;124(8):775.e1-6. doi:10.1016/j.amjmed.2011.03.026
4. Buono R, Scavello I, Morra M, et al. The role of IL-17 in cardiovascular disease. Int J Mol Sci. 2021;22(2):766. doi:10.3390/ijms22020766
5. Gisondi P, Cazzaniga S, Chimenti S, Girolomoni G. Cardiovascular risk in psoriasis: clinical evidence and emerging mechanisms. Curr Pharm Des. 2017;23(21):3166-3174. doi:10.2174/1381612823666170517122752
