Abstract The main conventional systemic treatments for atopic eczema are methotrexate (MTX) and ciclosporin (CIC). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomized controlled trials or real-world studies comparing these agents directly. The aim of this study was to compare the real-world clinical effectiveness and safety of CIC, dupilumab and MTX in atopic eczema. We compared the treatment effectiveness and safety of these systemic agents in a prospective cohort study of adult and paediatric patients recruited into the UK-Irish Atopic Eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children’s DLQI (cDLQI). The minimum duration of treatment was 28 days, and follow-up was 12 months. Adjusted Cox regression was used to compare the hazards of achieving EASI 50, EASI 75 and EASI 90 (≥ 50%, ≥ 75 and ≥ 90% improvement from baseline) over time, and linear mixed-effects models were used to estimate changes in effectiveness scores. Treatment safety was assessed by examining adverse events at follow-up visits. In total, 488 patients were included: 282 on dupilumab, 149 on MTX and 57 on CIC. CIC and MTX were primarily used first line, while dupilumab was mainly used second line. EASI 50, EASI 75 and EASI 90 were achieved more rapidly in the dupilumab and CIC groups compared with MTX (Table). After adjustment for previous severity, the reductions in EASI, POEM, PP-NRS and DLQI were greater for patients treated with dupilumab compared with MTX. In patients with severe disease the reductions in EASI, POEM and PP-NRS were even greater with CIC. Seven of 13 serious adverse events (SAEs) occurred in 7 of 282 (2%) patients on dupilumab, including 1 event that was considered treatment related: a herpes simplex infection. There were 6 of 13 SAEs reported in 6 of 149 (4%) patients on MTX, including 2 events that were considered treatment related: one herpes simplex infection and 1 joint effusion. There were no SAEs reported in the 57 patients on CIC. This real-world comparison of CIC, dupilumab and MTX in atopic eczema suggests that dupilumab is consistently more effective than MTX, and that CIC is most effective in very severe disease within one follow-up year.TableHazard ratios and 95% confidence intervals between treatment groups of patients achieving EASI 50, EASI 75 and EASI 90ComparisonEASI 50EASI 75EASI 90Dupilumab – methotrexate1.31 (0.93–1.85), P = 0.121.55 (1.02–2.36), P = 0.043.04 (1.53–6.04), P = 0.002Ciclosporin – methotrexate2.22 (1.42–3.47), P < 0.0011.97 (1.11–3.50), P = 0.024.24 (1.86–9.62), P < 0.001Ciclosporin – dupilumab1.69 (1.12–2.57), P = 0.011.27 (0.75–2.17), P = 0.381.39 (0.71–2.73), P = 0.33