Dear Editor,
Differentiating between eczema caused by atopic dermatitis (AD), allergic contact dermatitis (ACD) or irritant contact dermatitis (ICD) remains clinically challenging. Histopathology and immunophenotyping often lack specificity, while skin cytokine profiling shows promise for molecular characterization. 1 ICD results from exposure to irritants and activates the innate immunity, inducing cytokines such as IL‐1α/β, IL‐6 and tumour necrosis factor alpha (TNFα). ACD involves sensitization to allergens and triggers both innate and adaptative responses, with mixed T helper (Th)1/Th2 involvement. 2 , 3 AD, a chronic inflammatory skin disease marked by recurrent eczema and itching, is typically Th2/Th22‐driven. Although IL‐20 family cytokines have been implicated in ACD and AD models, 4 , 5 their role in ICD remains unclear. This study aimed to evaluate skin expression of Th‐associated (IFNγ, IL‐4, IL‐9, IL‐13 and IL‐17), IL‐20 family (IL‐19, IL‐20, IL‐22 and IL‐24) and inflammatory cytokines (IL‐6 and TNFα) in differentiating AD, ACD and ICD.
Forty‐two patients were included: (i) 20 with ACD confirmed by positive patch tests to nickel, fragrance mix I, and/or methylisothiazolinone; (ii) 12 patch tested with sodium lauryl sulphate (SLS) to reproduce ICD; and (iii) 10 with AD presenting with untreated acute lesions. AD patients had a median age of 35 years, were mostly male (60%), with severe disease (median SCORAD 55.0) and classical AD phenotype (90%). ACD and ICD participants had no history of atopy. Cytokine mRNA expression in lesional and non‐lesional skin was quantified using qRT‐PCR. Study methods, statistical analyses, cohort details and patch tests results (Tables S1–S3) are provided in Online Repository (available at https://zenodo.org/records/16276888). This prospective study was conducted from 2012 to 2024 in a Belgian tertiary university hospital, with ethical approval.
In non‐lesional skin, only IL22 expression was significantly increased in AD compared with ACD and ICD. Other cytokines showed no significant differences across groups (Figure 1).
FIGURE 1.
Basal level of Th‐, IL‐20‐ and inflammatory‐related cytokine expression in ICD, ACD and AD. RNA was isolated from non‐lesional skin from ICD (n = 12), ACD (n = 20) and AD patients (n = 10). Next, qPCR for the indicated cytokines and EF1 mRNA expression were performed. Each dot represents one patient, and the median is shown. Kruskal–Wallis test; *p < 0.05 and **p < 0.01.
SLS induced all cytokines, except IL4 (Figure 2; Table S4). Allergen exposure in ACD induced stronger cytokine expression than SLS in ICD, with the most notable increases in IL4, IL9 and IL22, evident as early as 24 h (Figure 2; Figure S1; Table S4). Cytokine expression was unaffected by patch test reaction severity or allergen type (Figures S2–S4).
FIGURE 2.
Induction of Th‐, IL‐20‐ and inflammatory‐related cytokine expression in ICD (n = 12), ACD (n = 20) and AD (n = 10). RNA was isolated from non‐lesional skin, patched test biopsies of ICD and ACD patients after 48 h, and lesional skin from AD. Next, qPCR for the indicated cytokines and EF1 mRNA expression were performed. Data are presented as induction compared with non‐lesional skin of the same patient. Each dot represents one patient and data are shown as mean ± SEM. Statistical analyses: Kruskal–Wallis test; *p < 0.05 and **p < 0.01.
In lesional AD skin, IL4 was the only cytokine not induced compared with non‐lesional skin (Figure 2; Table S5). IFNγ and IL9 induction was significantly higher in ACD than AD, while IL20 family cytokine expression was increased in both, with no significant differences (Figure 2; Figure S1).
IL13 and IL17 induction did not vary significantly across groups (Figure 2; Figures S1 and S4).
Our results support that ACD is characterized by strong induction of IFNγ, IL4, IL9 and IL20 family cytokines, highlighting a more complex Th response than a simple Th1/Th2 polarization. 3 IL4 and IL9 emerged as key discriminatory markers between ACD and ICD. Moreover, the weak cytokine expression observed in ICD aligns with its innate‐dominated nature.
IL‐20 family cytokines, together with Th1/Th2/Th9‐associated cytokines, play a key role in ACD inflammation, supporting previous findings. 4 , 6 , 7 In AD, IL22 was significantly increased in non‐lesional skin compared with ACD and ICD, and IL20‐related cytokines were increased in lesional AD skin. These results align with existing evidence implicating IL‐22 and IL‐24 in AD pathogenesis and support the rationale for IL‐22‐targeted therapies. 8 , 9 , 10 However, because IL20 family cytokine levels were similar in AD and ACD, only IFNγ, IL4 and IL9 could differentiate them.
In conclusion, combining IFNγ, IL4, IL9 and IL20 family cytokines enhances diagnostic precision in eczematous lesions. Th1/Th2/Th9 cytokines, particularly IL4 and IL9, help distinguish ACD from AD and ICD, while IL22 and IL24 differentiate ICD from AD. Skin cytokine analysis offers valuable diagnostic insight, but should always complement clinical evaluation, given the complexity of overlapping phenotypes in some patients.
FUNDING INFORMATION
This work was supported by grants from the Actions de Recherche Concertées UCLouvain (A.R.C. grant 19/24–098) and from the Fonds de la Recherche Scientifique (F.R.S) – FNRS (CDR numbers J.0055.23 and 1M00524F). The funders had no role in study design, data collection and analysis, interpretation or writing of the manuscript.
CONFLICT OF INTEREST STATEMENT
None to be disclosed.
ETHICAL APPROVAL
This study and data collection were conducted with the approval of the hospital and faculty institutional review board (Commission d'Ethique Biomédicale Hospitalo‐Facultaire) of Université catholique de Louvain (UCLouvain), Belgium (NCT 340320084407).
ETHICS STATEMENT
The patients in this manuscript have given written informed consent to participate and for publication of their case details.
ACKNOWLEDGEMENTS
We thank Dr. Mariana Andrade, M.D., who provided editorial assistance.
Laure Dumoutier and Marie Baeck contributed equally as senior authors.
DATA AVAILABILITY STATEMENT
Dataset generated during and/or analysed during the current study is available from the corresponding author on reasonable request.
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Associated Data
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Data Availability Statement
Dataset generated during and/or analysed during the current study is available from the corresponding author on reasonable request.