Methotrexate, TNF Inhibitors Are Safest Psoriasis Drugs for Cardiovascular Risk

While cardiovascular safety varies notably among systemic psoriasis drugs, new data suggest methotrexate (MTX) and tumor necrosis factor inhibitors (TNFi) are the most ideal for patients at elevated cardiovascular risk.1

These new findings also point to the potential of interleukin (IL)-17 inhibitors as safe alternatives for patients with psoriasis. These data resulted from a recent systematic review conducted due to inconsistencies in safety profile data regarding some of the systemic therapies that have transformed inflammatory disease management.2

Jean-Luc Perrot, MD, PhD, from the Dermatology Unit at the University Hospital of Saint-Etienne in France, led a team of investigators in authoring this review of systemic options for psoriasis.

“This systematic review aimed to (1) examine the CVE risks associated with systemic psoriasis therapies; (2) compare the CV safety profiles across different drug classes; and (3) assess the influence of study design and quality on the interpretation of CV outcomes,” Perrot and coauthors wrote.1

Systematic Review of Psoriasis Drugs

The investigative team used a set of 4 electronic databases for their structured search of available literature, including ScienceDirect, MEDLINE/PubMed, the Cochrane Library, and Wiley Online Library. They looked at data from the period from January 2013 - August 2024, using search terms which included Medical Subject Headings (MeSH) and keywords that related to psoriasis, systemic medications, and cardiovascular outcomes such as stroke, myocardial infarction, heart failure, angina, and cardiovascular mortality. In their search, they used a customized strategy for each databases, with filters being applied to restrict results to human studies which were also published in English exclusively.

Additional sources were reviewed beyond the aforementioned data, including clinical trial registries, grey literature, reference lists of articles deemed eligible, prior systematic review research, and websites of major dermatology and cardiology societies. Perrot et al's first search of available data took place in May 2023, with an updated search being carried out in September 2024 to ensure capture of all publications through August 2024.

Studies shown by the investigative team to be eligible for inclusion encompassed randomized controlled trials (RCTs), cohort studies, registry-based RCTs (rRCTs), pharmacovigilance evaluations, and systematic reviews/meta-analyses that reported on cardiovascular events in adults with psoriasis being treated with systemic drugs. The quality of these data was evaluated by the team using the Cochrane Risk of Bias tool for randomized studies and the Risk Of Bias In Non-randomized Studies – of Interventions (ROBINS-I) for observational evidence.

Findings on Cardiovascular Risk

There were 195 studies out of 14,744 records screened which Perrot and coauthors included. The findings included in the review included a total population of 1,795,823 individuals. Overall, the investigators concluded that TNFi and MTX consistently demonstrated cardiovascular protective effects on patients with psoriasis.1 Specifically, they highlighted that notable reductions in myocardial infarction, cardiovascular mortality, and stroke had been observed. The team's conclusions also supported IL-17 inhibitors as safe alternatives for psoriasis treatment, given that they were generally neutral to favorable in their cardiovascular safety profiles across both trial and observational data.

Conversely, retinoids, cyclosporine, and fumaric acid esters had been linked in these studies to cardiovascular risk increases, particularly in retrospective cohorts. The review's findings on IL-12/23 and IL-23 inhibitors were found by Perrot et al to have been heterogeneous. Specifically, they found that while short-term clinical trial data pointed to these medications' safety, some real-world and pharmacovigilance reports raised potential issues. In their sensitivity analyses, findings suggested that the conclusions remained consistent when focusing on studies with low bias risk and pre-specified cardiovascular endpoints.

“Taken together, these findings support the integration of CV risk stratification into treatment selection for patients with moderate-to-severe psoriasis,” the investigators wrote.1 “MTX and TNFi appear to offer dual benefits for disease control and CV protection, while IL-17 inhibitors may serve as safe alternatives when first-line agents are contraindicated.”

Overall, the data included in this review suggests that cardiovascular risk profiles should play a role in disease management decisions for those living with moderate-to-severe psoriasis. MTX and TNFi may provide dual benefits for individuals with heightened cardiovascular risk as well. IL-17 inhibitors may be considered a safe long-term choice when MTX or TNFi are unsuitable. Ongoing monitoring and extended real-world data were highlighted by Perrot and colleagues as crucial for assessing newer therapies, including IL-23 and JAK inhibitors.

References

1. Son MTH, Biloa YJM, Perrot JL, et al. Unravelling the Major Cardiovascular Risks of Systemic Psoriasis Medications: A Literature Systematic Review. JEADV Clinical Practice. https://doi.org/10.1002/jvc2.70134. Accessed September 4, 2025.

2. Gottlieb A, Korman NJ, Menter A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008 May;58(5):851-64. doi: 10.1016/j.jaad.2008.02.040. PMID: 18423261.