Comparative Neuropsychiatric Outcomes of JAK Inhibitors, Dupilumab, and Conventional Immunosuppressants in Atopic Dermatitis: A Real-World Cohort Study

Background: Atopic dermatitis (AD) is associated with neuropsychiatric comorbidity, yet no study has directly compared neuropsychiatric outcomes across all three major systemic treatment classes. This study examined neuropsychiatric outcomes among patients with AD receiving Janus kinase (JAK) inhibitors, dupilumab, or conventional immunosuppressants. Methods: This retrospective cohort study utilized the TriNetX global health research network. Three propensity score-matched cohorts were constructed based on demographics, comorbidities, and concomitant medications. The primary outcome was incident neuropsychiatric disorder within 24 months. Results: After matching, cohorts included 608 (JAK inhibitors vs. dupilumab), 502 (JAK inhibitors vs. conventional), and 2322 patients (dupilumab vs. conventional). In the largest cohort, conventional immunosuppressants were associated with a significantly higher incidence of neuropsychiatric disorders compared with dupilumab (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.00–1.59; p = 0.042). A similar directional trend was observed for conventional immunosuppressants compared with JAK inhibitors (HR 1.97, 95% CI 1.13–3.42; p = 0.015). The comparison between JAK inhibitors and dupilumab did not reach statistical significance (HR 0.62, 95% CI 0.37–1.03; p = 0.063). Findings regarding rare outcomes, such as autism spectrum disorders, were based on very low event counts and should be interpreted with extreme caution. Conclusions: In this large propensity-matched cohort, dupilumab was associated with significantly lower neuropsychiatric disorder incidence compared with conventional systemic immunosuppressants, with a similar directional trend observed for JAK inhibitors. These hypothesis-generating findings suggest potential neuropsychiatric outcome differences among systemic therapies for AD, warranting further investigation to establish whether the associations reflect treatment effects or residual confounding.