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Background and Importance Several systemic treatments are available for moderate-to-severe atopic dermatitis (AD). Most of these therapies have not been directly compared.Aim and Objectives To perform indirect comparisons (ICs) between innovative therapeutic alternatives using a common comparator in patients diagnosed with moderate-to-severe AD.Material and Methods A PubMed review of pivotal randomised clinical trials (RCTs) responsible for the authorisation of selected therapies (abrocitinib, baricitinib, dupilumab, lebrikizumab, tralokinumab and upadacitinib) was conducted. Inclusion criteria: phase III RCTs of treatments cited with a double-blind and placebo-controlled design, which included patients with moderate-to-severe AD. Investigator’s Global Assessment score of 0-1 (IGA 0-1, clear to almost clear skin) at 16 weeks were selected as the endpoint to estimate absolute risk reduction (ARR) for each drug. We conducted adjusted ICs using Bucher’s method. The regimen with the greatest magnitude of effect was selected as reference therapy. The maximum difference without clinical relevance (Δ) was defined as ±23% according to the average of IGA 0-1 value used in studies to calculate the sample size.Results Twelve RCTs were included. All treatments showed benefit over placebo (common comparator). Regarding upadacitinib 30 mg diary (reference therapy), ARRs were: -13.50% (95% CI, -19.98 to -7.02) vs upadacitinib 15 mg diary; -17.65% (95% CI, -25.95 to -9.35) vs abrocitinib 200 mg diary ; -22.9% (95% CI, -29.79 to -16.01) vs dupilumab 300 mg biweekly; -24.10% (95% CI, -31.22 to -16.98) vs lebrikizumab 250 mg biweekly; -32.55% (95% CI, -40.50 to -24.60) vs abrocitinib 100 mg diary; -39.85% (95% CI -46.51 to -33.19) vs baricitinib 4 mg diary: -41.50% (95% CI -47.29 to -35.71) vs tralokinumab 300 mg biweekly; and -44.15% (95% CI -50.44 to -37.86) vs baricitinib 2 mg diary. Statistically significant differences were found between upadacitinib 30 mg daily and the rest of therapies examined. Upadacitinib 30 mg only demonstrated a clinically relevant benefit versus lebrikizumab, abrocitinib 100 mg, tralokinumab, baricitinib 4 mg and 2 mg.Conclusion and Relevance Our ICs provide comparative efficacy data on therapeutic alternatives for moderate-to-severe AD in terms of IGA 0-1. Statistically significant benefit was observed between upadacitinib 30 mg with respect to all treatments, but only relevant clinical superiority over lebrikizumab, abrocitinib 100 mg , tralokinumab, baricitinib 4 mg and 2 mg.Conflict of Interest No conflict of interest