Predictors of Treatment Failure with JAK Inhibitors in Alopecia Areata: T-Cell Dynamics and Clinical Determinants of Inadequate Response

ABSTRACT: The Janus kinase (JAK) inhibitors have been the first targeted treatments to be approved for Alopecia areata (AA), an autoimmune disease that affects T cells and results in non-scarring hair loss. Although baricitinib (2022), ritlecitinib (2023), and deuruxolitinib (2024) have been recently approved, there is still an important percentage of patients not achieving enough or any response (30-55% depending on the agent and endpoint). This review analyses in detail immunological and clinical factors that are involved in treatment failure in AA with JAK inhibitors, with a special emphasis on the dynamics of T cells, Treg dysfunction, Th2 skewing, AA phenotype and baseline disease burden. Mechanistic studies, real-world cohorts and phase 3 studies all support a multifactorial model of non-response, in which disease duration, alopecia totalis/alopecia universalis subtype, baseline atopy, high baseline Severity of Alopecia Tool (SALT) scores >75, and low Treg compartment size are all independent risk factors for failure. Single-cell transcriptomic evidence of emerging data indicates hyperactivation of CD8⁺ effector memory T cells and JAK-STAT pathway redundancy as cellular substrates of resistance. The need for clinical translation to a biomarker-stratification framework is pressing. This review summarises the existing data and suggests further research in personalised JAK inhibitor treatment of AA. Keywords: Alopecia areata; JAK inhibitors; treatment failure; T-cell dynamics; regulatory T cells; baricitinib; ritlecitinib; biomarkers; SALT score; immune resistance.