Safety and Efficacy of Non‐Steroidal Topical Aryl Hydrocarbon Receptor Agonists for the Treatment of Atopic Dermatitis: A Systematic Review and Meta‐Analysis of Randomised Controlled Trials

ABSTRACT Background Current first‐line topical treatments for atopic dermatitis (AD) are often limited by concerns related to age, systemic absorption, especially when applied to large body surface areas or under maximal usage conditions and undesirable adverse events (AEs), highlighting the need for alternative therapies. Methods We performed a systematic review and meta‐analysis of seven randomised controlled trials (RCT) comparing topical aryl hydrocarbon receptor agonists (TAHRA), including tapinarof and benvitimod cream, to vehicle at different concentrations and application frequencies in patients with AD, which evaluated outcomes such as Investigator Global Assessment (IGA) scores/Validated Investigator's Global Assessment (vIGA), the Eczema Area and Severity Index (EASI‐75), change from baseline in body surface area (BSA) and pruritus score (PS) and safety profiles. Results A total of 1631 patients, 1086 received TAHRA, while 545 received vehicle. Overall, TAHRA led to a significant improvement in the IGA/vIGA scores (RR 2.38; 95% CI 1.68 to 3.37; p < 0.0001), EASI‐75 (RR 2.94; 95% CI 2.07 to 4.17; p < 0.00001). Similar findings were observed for mean change from baseline in BSA% (MD −6.08; 95% CI −8.00 to −4.16; p < 0.00001), and PS (Std MD −0.90; 95% CI −1.41 to −0.39; p = 0.0006). The incidence of AE was significantly higher in the TAHRA group (RR 1.48; 95% CI: 1.19–1.85; p = 0.0005). We found no significant difference in the incidence of serious adverse events (SAEs) (RR of 1.51; 95% CI: 0.34–6.64; p = 0.59). Treatment‐emergent adverse events (TEAEs), such as folliculitis, were more frequent in the TAHRA group (RR 8.06; 95% CI: 2.75–23.60; p = 0.0001). Conclusion Our findings support the efficacy of TAHRA among different metrics with minimal and tolerable AEs and its use as a valuable new non‐steroidal option for the treatment of AD.