Review

Issue 1 - 2026

Small-molecule therapies in paediatric atopic dermatitis: current landscape and future perspectives

Authors

Federica Minguzzi , Lorenza Parini , Arianna Giannetti

Key words: atopic dermatitis, small molecules, PDE4 inhibitors, JAK inhibitors, AhR modulators, S1PR modulators, histamine H4 receptor antagonists
DOI: 10.53151/2531-3916/2026-2226
Publication Date: 2026-03-27

Abstract

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by complex immune dysregulation, barrier dysfunction, and intense pruritus. While biologic therapies targeting type 2 cytokines have significantly improved outcomes in moderate-to-severe disease, small molecule agents have emerged as a complementary and increasingly sophisticated therapeutic strategy. These compounds act predominantly at the intracellular level, modulating key signaling pathways involved in immune activation and epidermal homeostasis.
This review provides an updated overview of currently approved and investigational small molecules for pediatric AD, including phosphodiesterase 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, aryl hydrocarbon receptor (AhR) modulators, sphingosine-1-phosphate receptor (S1PR) modulators, histamine H4 receptor antagonists, and emerging transcriptional regulators such as STAT6 inhibitors and degraders. PDE4 inhibitors represent the first successful class of intracellular immunomodulators in dermatology, offering steroid-sparing options particularly in mild-to-moderate disease. JAK inhibitors provide rapid and robust clinical responses in moderate-to-severe AD, though safety considerations require careful patient selection. Novel approaches targeting upstream T-cell signaling (e.g., ITK inhibition), dual kinase pathways, or transcriptional hubs such as STAT6 reflect a shift toward more precise modulation of type 2 inflammation. In contrast, S1PR modulators and H4 receptor antagonists have thus far shown limited clinical efficacy in AD despite strong biological rationale.
Collectively, small molecules are reshaping the therapeutic landscape of AD by expanding options beyond extracellular cytokine blockade. Future positioning will depend on balancing efficacy, selectivity, long-term safety, and patient phenotype, with the potential for increasingly personalized, mechanism-driven treatment strategies.

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Federica Minguzzi - U.O. Pediatria, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

Lorenza Parini - U.O Pediatria, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

Arianna Giannetti - U.O. Pediatria, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy

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Copyright (c) 2026 Italian Journal of Pediatric Allergy and Immunology

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Minguzzi, F., Parini, L., & Giannetti, A. (2026). Small-molecule therapies in paediatric atopic dermatitis: current landscape and future perspectives. Italian Journal of Pediatric Allergy and Immunology, 40(1), 2–24. https://doi.org/10.53151/2531-3916/2026-2226
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