Targeted therapy in atopic dermatitis: Endotype heterogeneity, treatment sequencing, and lessons from a contracting pipeline: A narrative review

Atopic dermatitis is the most prevalent chronic inflammatory skin disease worldwide, and seven targeted systemic agents have been approved for moderate-to-severe disease since 2017. This narrative review addresses a question that the expanding evidence base has made urgent but has not resolved: given several agents of broadly comparable efficacy, how should a clinician choose between them, and what should be done when the first choice fails? We summarize the current understanding of disease mechanisms, focusing on endotype heterogeneity—intrinsic disease, T helper 17 and 22 contributions, and molecular variation across ancestral and age groups—that the dominant type 2 paradigm does not fully capture. Furthermore, we evaluated the approved biologics and oral Janus kinase inhibitors and compared the speed of response, magnitude of benefit, safety, and monitoring burden to develop an explicit framework for first-line selection, treatment sequencing after inadequate response, and long-term maintenance, including dose interval extension. We also examined a development that reframes prevailing expectations; during 2026, both agents targeting the OX40–OX40L axis were withdrawn from development in atopic dermatitis, including one that was withdrawn after a malignancy signal. Together with earlier failures of alarmin blockade, this narrows the near-term pipeline and highlights the need for better use of existing therapies. Validated predictive biomarkers remain the principal unmet need.