Mixed Immune Signature Identified in Chronic Hand Eczema

A recently published phase 2b randomized clinical trial provides new insight into the molecular underpinnings of chronic hand eczema (CHE) and evaluates the therapeutic impact of IL-4 receptor α (IL-4Rα) blockade with dupilumab in a broad CHE population. The findings suggest that CHE is not only clinically heterogeneous but also molecularly complex, sharing features with both atopic dermatitis (AD) and psoriasis, and that targeting type 2 signaling may have broader immunologic consequences than previously appreciated.¹

Study Overview

In this multicenter, double-blind study, 94 adults (60.6% women; mean age, 39.5 years) with long-standing CHE (mean duration, 8.7 years) were enrolled without preselection based on etiology or morphology. Occupational exposure was common, including office workers (39.4%), health care professionals, manual laborers, and food service workers. A personal history of AD was present in 68.1%, but a substantial minority had no atopic background. Allergic contact dermatitis confirmed by patch testing was identified in 27.7% of tested patients, and irritant exposures were reported in 46.8%.

Clinical presentation was diverse: fissures (68.1%) and hyperkeratosis (63.8%) predominated, followed by pulpitis and vesicles. Most patients exhibited multiple morphologic features, underscoring the limited utility of traditional classification systems. Disease severity at baseline was moderate to severe, with significant impairment in quality of life (mean Dermatology Life Quality Index [DLQI], 12.5) and work productivity.

Notably, serum eosinophil counts were within normal range across patients, whereas total IgE levels were elevated in 47.2%, reflecting an atopic subset but not a universal pattern.

Dupilumab Significantly Improves Clinical Outcomes

Participants were randomly assigned to dupilumab (n = 47) or placebo (n = 47 evaluable). At week 16, dupilumab-treated patients achieved a mean 59.8% improvement in modified Total Lesion Symptom Score compared with 15.2% in the placebo arm (P < .001). Sensitivity analyses confirmed robustness of the findings.

Importantly, clinical response was independent of AD history or baseline IgE levels. Interaction analyses did not demonstrate a modifying effect of atopic background. Approximately 53% of dupilumab-treated patients achieved Investigator Global Assessment scores of 0/1 (clear or almost clear) compared with 14.9% in the placebo group.

Symptom improvement was clinically meaningful. At week 16, reductions in pruritus, pain, and sleep disturbance were significantly greater in the dupilumab group. Quality-of-life gains were substantial, with a mean DLQI improvement of 9.3 points vs 2.5 points with placebo. A clinically meaningful DLQI improvement (≥ 4 points) occurred in 78.3% of dupilumab recipients.

Although work productivity measures did not significantly change among employed participants, overall activity impairment improved significantly. Safety findings were consistent with the known profile of dupilumab, including mild to moderate ophthalmic adverse events in approximately 23% of treated patients; none required discontinuation.

Molecular Profiling Reveals Overlapping Immune Signatures

To better define CHE biology, investigators performed whole-skin RNA sequencing and proteomic analyses. Compared with healthy controls, CHE lesions demonstrated 5465 differentially expressed genes. Dysregulated pathways involved keratinocyte differentiation, tissue remodeling, antimicrobial responses, and cytokine-mediated signaling.

Immune polarization was mixed. Markers of type 2 immunity (eg, IL-4R, IL-13, CCL17) were upregulated, as expected in AD-like inflammation. However, strong type 3 signatures (eg, IL-17A, IL-36A, IL-23A) and type 1 chemokines (CXCL9, CXCL10, CXCL11) were also present. Comparative analyses showed substantial overlap with transcriptomic signatures of both AD and psoriasis, reinforcing the concept of CHE as an immunologically blended disease rather than a single-axis disorder.

Serum proteomic analysis mirrored cutaneous findings. Patients with CHE exhibited elevated type 2 (IL-13, IL-9), type 3 (IL-17C, IL-36A), and selected type 1 markers relative to healthy controls. Compared with AD and psoriasis cohorts, CHE demonstrated an intermediate inflammatory profile—less purely type 2–skewed than AD and less strongly type 1–/type 3–dominant than psoriasis.

IL-4Rα Blockade Normalizes Immune and Barrier Programs

Among dupilumab-treated patients who underwent paired biopsies, 491 genes were significantly modulated after 16 weeks. Type 2–associated genes were suppressed, as were type 1 and type 3 mediators, including IL-17A and IL-36A. Stress keratins (KRT6, KRT16) and antimicrobial peptides were downregulated, suggesting normalization of hyperproliferative and barrier stress responses.

Gene set enrichment analyses confirmed downregulation of keratinocyte differentiation and cytokine signaling pathways. In contrast, placebo-treated patients showed no significant transcriptomic shifts.

Comparative analysis with published AD data sets indicated that dupilumab’s effects in CHE extended beyond classic type 2 suppression, with broader modulation of psoriasis-associated pathways.

Clinical Implications

This trial provides evidence that CHE is characterized by a complex, overlapping inflammatory signature bridging AD and psoriasis. Blockade of IL-4Rα with dupilumab produced significant clinical improvement and molecular normalization across immune axes, independent of atopic history.

For clinicians managing refractory CHE, these data suggest that targeting type 2 signaling may confer broader immunologic benefits than anticipated.² Larger and longer-term studies will be needed to determine the durability of response and optimal patient selection, but the findings represent an important step toward mechanism-based therapy in this challenging disease.

References

1. Gery P, Ekren R, Bérard E, et al. Integrated clinical trial and molecular profiling reveals immune drivers of chronic hand eczema. Allergy. Published online February 18, 2026. doi:10.1111/all.70263
2. Molin S, Guttman-Yassky E, Thyssen JP, Bewley A. Chronic hand eczema, real world, and patient centricity: a narrative review. Acta Derm Venereol. 2025;105:adv42596. doi:10.2340/actadv.v105.42596