Precision Dermatology: Aligning Immune Pathways with Therapy

Over the past decade and a half, dermatology has experienced a profound shift driven by advances in molecular biology and immunology. Improved understanding of immune signaling pathways has enabled the development of highly targeted biologic and small-molecule therapies that have transformed the management of inflammatory skin diseases. Despite these advances, variability in treatment response remains a persistent challenge.¹ Recent research proposes that precision medicine, defined by molecular characterization of disease rather than reliance on clinical morphology alone, may provide a solution. The review summarizes recent findings supporting immune pathway–based classification of inflammatory dermatoses and discusses their implications for diagnosis and treatment selection.²

Immune Pathways Underlying Inflammatory Skin Disease

Key immune pathways implicated in dermatologic inflammation largely correspond to T helper (Th) cell differentiation programs. The Th17 axis, driven by interleukin (IL)-23 and IL-17A, plays a central role in psoriasis. Th2-mediated inflammation, characterized by IL-4, IL-5, and IL-13, underlies atopic dermatitis, while Th1 responses dominated by interferon-γ (IFN-γ) are associated with lichen planus. Beyond adaptive immunity, innate immune mechanisms contribute substantially to disease pathogenesis. Type I interferons (IFN-α/β) are strongly linked to lupus erythematosus, neutrophilic and IL-1/IL-36–driven pathways define several neutrophilic dermatoses, and eosinophil-driven inflammation characterizes conditions such as Wells syndrome.

The clinical relevance of these immune axes is underscored by the success of pathway-specific therapies. However, clinical practice demonstrates that not all patients respond predictably, even when diagnosis appears straightforward. This observation has prompted increasing interest in molecular profiling approaches capable of identifying the dominant immune pathway in individual patients.

MORE ON PATHWAY-SPECIFIC THERAPIES: Immune Signatures Outperform Clinical Appearance in Treatment Guidance

Development of Immune Module Cartography

Traditional efforts to define immune pathways have focused on detecting effector cytokines, which are often expressed at low levels and may lack discriminatory power across diseases. To overcome this limitation, recent research has employed transcriptomic profiling of skin biopsies from reference diseases with well-established therapeutic responses. By identifying genes differentially expressed in each disease relative to others, investigators derived composite gene signatures—termed immune modules—representing Th17, Th2, Th1, type I interferon/IFN-stimulated genes (ISG), neutrophilic, macrophagic, and eosinophilic pathways.

These immune modules include not only canonical cytokines but also upstream chemokines and downstream response genes, providing a more robust representation of pathway activity. Using an 80-gene Nanostring panel, unsupervised clustering achieved clear separation of reference diseases, outperforming larger immune gene panels and whole-transcriptome approaches. Importantly, independent validation samples clustered with high sensitivity and specificity, supporting the reproducibility of this modular framework.

Molecular Classification of Inflammatory Dermatoses

Application of immune module cartography reveals that some skin diseases are defined by a single dominant pathway, while others reflect combinations of immune modules. Psoriasis, atopic dermatitis, lupus erythematosus, lichen planus, neutrophilic dermatoses, and Wells syndrome each show a dominant module consistent with established pathophysiology. In contrast, bullous pemphigoid demonstrates co-dominant Th2 and eosinophilic/macrophagic signatures, while drug eruptions display a combination of ISG, Th2, and macrophagic activity with variable Th1 involvement. Morphea is characterized by Th1 and myeloid signatures with subdominant interferon activity.

This modular approach suggests that inflammatory skin diseases can be systematically classified by combinations of known immune pathways rather than requiring the identification of novel mechanisms for each condition.

Clinical Translation and Diagnostic Utility

To facilitate clinical implementation, a digital platform has been developed that projects transcriptomic data from patient biopsies onto the immune cartography. The platform generates heatmaps, UMAP visualizations, and quantitative outputs indicating dominant immune modules, enabling clinicians to compare patient samples with reference disease cohorts. Cross-center validation has demonstrated reproducibility, and the platform is accessible through the Skin Science Foundation.

The diagnostic value of this approach is most apparent in clinically ambiguous conditions. Erythroderma, which encompasses a broad differential diagnosis, can be molecularly classified with greater precision than clinical or histopathologic evaluation alone. Similarly, palmoplantar dermatoses, often difficult to distinguish clinically, can be stratified into distinct molecular groups. Reported clinical misclassification rates of up to 63% in these settings highlight the limitations of traditional diagnostic paradigms.

Opportunities for Therapeutic Repurposing

Immune module mapping also supports rational drug repurposing. Th2 dominance in bullous pemphigoid provides a mechanistic basis for IL-4 receptor inhibition, while interferon and Th1 signatures in conditions such as toxic epidermal necrolysis and morphea suggest potential responsiveness to JAK inhibition. Conversely, identification of Th17 dominance in Darier’s disease supports targeted cytokine blockade, though compensatory mechanisms may influence individual responses.

Conclusions and Future Directions

Collectively, these findings support a shift toward molecularly defined diagnosis and treatment in dermatology. Immune module cartography provides a unifying framework that integrates disease classification, therapeutic selection, and interpretation of treatment failure. While further prospective, multicenter studies are required to validate clinical benefit, this precision medicine approach represents a significant conceptual advance. By aligning diagnosis and therapy with individual immune profiles, dermatology may move closer to truly personalized care for patients with inflammatory skin disease.

References

1. Gniadecki R. A decade of progress and innovation in dermatology. Front Med (Lausanne). 2025 Jan 22;11:1546471. doi: 10.3389/fmed.2024.1546471.
2. Di Domizio J, Girardin A, Conrad C, Seremet T, Gilliet M. Dermatology 2.0: Precision medicine for inflammatory skin diseases. J Eur Acad Dermatol Venereol. Published online December 26, 2025. doi:10.1111/jdv.70251