Comparative efficacy and safety of systemic therapies for moderate-to-severe atopic dermatitis in adults: a systematic review of randomized controlled trials

Background Atopic dermatitis (AD) is a common, chronic inflammatory skin condition, and patients with moderate-to-severe disease often require systemic therapy. Since 2017, targeted systemic agents, biologics and Janus kinase (JAK) inhibitors, have expanded treatment options available, but comparative evidence remains limited by heterogeneous trial design, outcome reporting, and follow-up duration. Objective To systematically review the efficacy and safety of European Medicines Agency (EMA)-approved systemic therapies for moderate-to-severe AD in adults. Methods Following PRISMA 2020 guidelines, we searched PubMed/MEDLINE, Embase and Web of Science for randomized controlled trials evaluating EMA-approved biologics (dupilumab, tralokinumab, lebrikizumab, nemolizumab) and JAK inhibitors (upadacitinib, abrocitinib, baricitinib) at recommended adult doses. The primary outcome was the proportion of patients achieving EASI-75 at the primary trial endpoint (12–16 weeks). Due to substantial clinical and methodological heterogeneity, a structured narrative synthesis was conducted rather than a meta-analysis. Results Twenty-five RCTs met inclusion criteria. At EMA-recommended doses, EASI-75 responses ranged from 44% to 69% for dupilumab, 60.6% for lebrikizumab, 25-64% for tralokinumab, and 49.1% for nemolizumab (combination-therapy data only). Among JAK inhibitors, upadacitinib showed the highest observed response rate (73.0% at 16 weeks), followed by abrocitinib (64.6% at 12 weeks) and baricitinib (17.9-48.0%). Placebo response rates ranged from 6% to 36% and were consistently higher in combination-therapy trials. Any adverse event occurred in 45.2% (abrocitinib 100 mg) to 82.46% (nemolizumab) of patients, with serious adverse events generally low across therapies. Conclusion EMA-approved systemic therapies for moderate-to-severe AD demonstrate meaningful short-term efficacy and acceptable safety. However, treatment selection should remain individualized given cross-trial heterogeneity and the current absence of long-term comparative data. Further head-to-head trials and real-world evidence are needed to optimize treatment sequencing. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251102911