Immune Overlap Between AA and AD Fuels New Treatment Approaches

For decades, clinicians treated alopecia areata and atopic dermatitis as immunologically unrelated conditions, but a growing body of evidence suggests the 2 diseases share far more in common than previously recognized, with implications for how patients with both conditions may be treated.

A narrative review published in the Journal of Inflammation Research synthesized current understanding of the shared immunopathogenesis of alopecia areata (AA) and atopic dermatitis (AD), cataloguing approved and investigational therapies with potential dual-disease relevance.¹ The authors, affiliated with the Icahn School of Medicine at Mount Sinai and collaborating institutions, argued that convergent inflammatory mechanisms—particularly Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway dysregulation and regulatory T cell (Treg) insufficiency—provide a rationale for mechanistically targeted treatments that may benefit patients living with either or both conditions.²

A Growing Case for Treating AA and AD Through a Shared Lens

Up to 40% of patients with AA have atopic comorbidities, and comorbid AD has been identified as a poor prognostic factor for AA treatment response and a predictor of relapse.¹ Several epidemiologic and translational studies published over the past decade have reinforced the association, with population-based analyses showing patients with AA experience disproportionately high rates of AD and other atopic conditions compared with the general population.

These findings have supported the concept that at least a subset of AA exists within a broader atopic disease spectrum characterized by overlapping immune dysregulation. Despite this clinical overlap, treatment strategies have historically been developed in parallel rather than in concert. The authors of the present study noted that therapies effective for one condition have often shown limited or no efficacy in the other—IL-13 inhibitor monotherapy, for example, is approved for AD but has not demonstrated efficacy in AA. This therapeutic disconnect highlighted the need for a systematic examination of shared pathogenic mechanisms.

Immune Profiling Reveals Overlapping Inflammatory Signatures

The review described how both AA and AD involve dysregulation across multiple cytokine axes, including T helper 1 (Th1), Th2, and Th22 pathways, with JAK-STAT–dependent signaling serving as a common downstream mediator. Key shared biomarkers included elevated IL-4, IL-13, and immunoglobulin E (IgE), alongside dysregulated interferon-gamma (IFN-γ) and IL-15 signaling.

The authors also highlighted the OX40/OX40 ligand costimulatory pathway as a convergent mechanism, with OX40-positive T cells and OX40L-positive antigen-presenting cells enriched in lesional skin in AD and perifollicular tissue in AA. Transcriptomic studies demonstrated robust upregulation of Th1 and Th2-associated products in AA scalp, with OX40 signaling playing a particularly prominent role in AA comorbid with atopy.

Existing Therapies Already Show Signs of Dual Utility

JAK inhibitors emerged as the class with the broadest validated overlap. Baricitinib, a JAK1/JAK2 inhibitor, became the first FDA-approved treatment for severe AA in adults in 2022. In the BRAVE-AA1 trial, 38.8% of patients receiving baricitinib 4 mg achieved a Severity of Alopecia Tool (SALT) score of 20 or lower at week 36, compared with 6.2% on placebo. Upadacitinib and abrocitinib—both JAK1-selective—are approved for moderate to severe AD, with upadacitinib demonstrating an EASI-75 response in 72.4% of patients vs 62.6% for dupilumab in a head-to-head trial.

Dupilumab, an IL-4 receptor α antagonist, demonstrated benefit in a subset of AA patients with concurrent atopic disease or elevated serum IgE in a phase 2a trial, though its effect was more modest than in AD. Responders were more likely to have a personal or familial atopic history, suggesting that patient endotype influences treatment response.

As the authors wrote, “Endotype-stratified approaches, selecting therapies based on atopic background, serum IgE, and transcriptomic immune signatures, represent the most promising path toward personalized, potentially disease-modifying interventions for both AA and AD.”

Emerging Agents Test the Limits of Shared Pathway Targeting

Several pipeline agents showed promise across both conditions. Rezpegaldesleukin, a Treg-selective IL-2 receptor agonist, achieved a mean 28.2% to 30.3% SALT reduction vs 11.2% on placebo over 36 weeks in a phase 2b AA trial, while also meeting primary end points in a phase 2b AD study. Bempikibart, an IL-7 receptor α antagonist, produced a 16% SALT reduction vs 2% on placebo in AA but failed to meet its primary end point in a phase 2a AD trial. Amlitelimab, an anti-OX40L monoclonal antibody, met all primary end points in a phase 3 AD trial and is currently in phase 2 trials for severe AA.

Evidence Gaps Highlight the Need for Interventional Studies

The authors acknowledged several important constraints. Much of the mechanistic evidence supporting shared pathways derives from transcriptomic data rather than interventional studies. Additionally, the shared mechanism framework appeared most applicable to the atopic-associated AA endotype, in which Th2 dysregulation is prominent, and less so for non-atopic AA, which is characterized by predominantly Th1-skewed inflammation. The authors also noted that agents effective in one disease may not adequately address the full pathogenic architecture of the other.

References

1. Tang A, Rachko G, Margiotta FM, Levine J, Del Duca E, Ungar B. Alopecia areata and atopic dermatitis: common mechanisms and emerging therapeutics. J Inflamm Res. Published online April 7, 2026. doi:10.2147/JIR.S549496
2. Lensing M, Jabbari A. An overview of JAK/STAT pathways and JAK inhibition in alopecia areata. Front Immunol. 2022;13:955035. doi:10.3389/fimmu.2022.955035