Background: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects.

Objectives: We systematically synthesized the benefits and harms of AD prescription topical treatments.

Methods: For the 2023 AAAAI/ACAAI JTFPP AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT to September 5, 2022 for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-quality of life, flares, and harms. The GRADE approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using seven classes-group 1 being most potent. OSF: https://osf.io/q5m6s.

Results: 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty, pimecrolimus improved six of seven outcomes-among the best for two; high-dose tacrolimus (0.1%) improved five-among the best for two; low-dose tacrolimus (0.03%) improved five-among the best for one. With moderate-to-high certainty, group 5 TCS improved six-among the best for three; group 4 TCS and delgocitinib improved four-among the best for two; ruxolitinib improved four-among the best for one; group 1 TCS improved three-among the best for two. These interventions did not increase harms. Crisaborole and difamilast were intermediately effective, but uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus.

Conclusions: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.