IL-23 Inhibitors Associated With Lower 3-Year Risk of Psoriatic Arthritis Compared With TNF, IL-17s

For rheumatologists managing patients with psoriasis who carry risk factors for psoriatic arthritis (PsA), biologic selection may carry implications beyond skin clearance. A retrospective database study published in Baylor University Medical Center Proceedings found that IL-23 inhibitors — risankizumab, guselkumab, and ustekinumab — were consistently associated with a lower 3-year risk of PsA development compared with TNF-alpha inhibitors and IL-17 inhibitors across propensity score–matched cohorts.¹

The study, authored by Madelyn Schmidt, a medical student at University of Texas and colleagues at the University of Texas Medical Branch, used the TriNetX Research Network to identify psoriasis patients treated with one of 10 immunomodulators between January 2012 and January 2023: adalimumab, infliximab, ixekizumab, secukinumab, tildrakizumab, certolizumab pegol, risankizumab, etanercept, guselkumab, and ustekinumab. Patients with a prior PsA diagnosis or use of a second immunomodulator during the study period were excluded. Cohorts were 1:1 propensity score matched using a greedy nearest-neighbor algorithm, with matching variables including demographics, socioeconomic factors, obesity, inflammatory bowel disease, gout, diabetes mellitus, hypertension, hyperlipidemia, tobacco use, and alcohol-related disorders. Cox proportional-hazards models with 95% CIs were used to estimate 3-year PsA risk across pairwise comparisons.¹

The balanced cohorts were predominantly between 40 and 60 years of age (mean age 50), with an even gender distribution and mostly non-Hispanic/Latino ethnicity. Incident PsA occurred in 5% to 13% of patients across cohorts during the follow-up period.¹

Risankizumab demonstrated the strongest protective signal in pairwise comparisons. Patients treated with adalimumab had a significantly increased 3-year PsA risk compared with risankizumab (HR, 2.46; 95% CI, 1.97–3.08), and a similar pattern was observed for infliximab vs risankizumab (HR, 2.23; 95% CI, 1.57–3.16), ixekizumab vs risankizumab (HR, 2.06; 95% CI, 1.54–2.76), secukinumab vs risankizumab (HR, 2.39; 95% CI, 1.86–3.06), certolizumab pegol vs risankizumab (HR, 3.92; 95% CI, 2.28–6.77), and etanercept vs risankizumab (HR, 0.33; 95% CI, 0.26–0.42, favoring risankizumab). Risankizumab also showed a significantly lower risk compared with guselkumab (HR, 0.64; 95% CI, 0.47–0.87).¹

Guselkumab and ustekinumab similarly outperformed TNF-alpha inhibitors. Adalimumab was associated with increased PsA risk compared with guselkumab (HR, 1.42; 95% CI, 1.10–1.83) and ustekinumab (HR, 1.72; 95% CI, 1.45–2.05). Etanercept showed increased risk compared with both guselkumab (HR, 1.76; 95% CI, 1.35–2.29) and ustekinumab (HR, 1.96; 95% CI, 1.62–2.37). Certolizumab pegol carried increased risk compared with guselkumab (HR, 2.19; 95% CI, 1.37–3.49) and ustekinumab (HR, 1.98; 95% CI, 1.27–3.09).¹

Among IL-17 inhibitors, ixekizumab showed a significantly increased PsA risk compared with ustekinumab (HR, 1.60; 95% CI, 1.23–2.07), and secukinumab similarly showed increased risk compared with guselkumab (HR, 1.55; 95% CI, 1.19–2.00) and ustekinumab (HR, 1.87; 95% CI, 1.52–2.29). Ixekizumab showed a decreased risk compared with certolizumab pegol (HR, 0.50; 95% CI, 0.31–0.81). Kaplan-Meier analysis showed consistently higher PsA-free survival for IL-23 inhibitors compared with TNF-alpha and IL-17 agents across pairwise comparisons.¹

The findings add to a growing body of real-world evidence suggesting a class-level protective effect for IL-23 inhibition in psoriatic disease progression. A 2025 analysis by Gisondi and colleagues in Annals of Rheumatic Diseases similarly reported that psoriasis patients initiating different biologic classes had differential PsA incidence rates, with IL-23 inhibitors associated with reduced risk relative to other classes.²

The authors propose that IL-23 inhibitors may more broadly suppress both innate and adaptive immune responses involved in entheseal inflammation and joint remodeling — pathways thought to underlie PsA pathogenesis — leading to a more sustained protective effect than agents targeting downstream cytokines such as IL-17 or TNF-alpha.¹

Several limitations warrant caution in interpreting these findings. The TriNetX platform did not capture treatment duration or dosage for individual patients, precluding any dose-response analysis; the authors note that longer biologic exposure may confer greater protection. Certain cohorts — particularly those involving tildrakizumab and certolizumab pegol — had small sample sizes, limiting the precision and reliability of those pairwise estimates. The large number of drug-exposure comparisons raises the risk of false-positive findings. Residual confounding from unmeasured variables such as baseline psoriasis severity and disease duration is also possible despite propensity matching. Uncoded PsA at baseline could have introduced misclassification, and the retrospective design precludes causal inference.¹

References

1. Schmidt M, Dowdle TS, Golovko G, Munoz A. Comparative risk of psoriatic arthritis in psoriasis patients on immunomodulators. Proc (Bayl Univ Med Cent). 2026;39(2):310–314. doi:10.1080/08998280.2025.2596529

2. Gisondi P, Bellinato F, Galeone C, et al. Risk of developing psoriatic arthritis in patients with psoriasis initiating treatment with different classes of biologics. Ann Rheum Dis. 2025;84(3):435–441. doi:10.1016/j.ard.2025.01.006