Self‐Reported Racial Group‐Associated Immune Signaling Differences in Atopic Dermatitis and Dupilumab Treatment

We read with great interest the recent publication by De Vriese et al., Geographic Differences in Dupilumab Treatment Outcomes for Atopic Dermatitis: A Systematic Review and Meta-Regression Analysis, in which they systematically reviewed atopic dermatitis (AD) manifestations and dupilumab treatment outcomes in East Asia, Northern/Central and Southern Europe. They reported that East Asians had the highest baseline AD eczema area severity index (EASI) scores and Southern Europeans exhibited the greatest EASI reduction upon dupilumab treatment [1]. However, the underlying mechanisms for these observations remain unresolved. One of the key differences in these geographic regions is the participants' self-reported racial backgrounds. Despite continuing to generate debate, self-reported racial groupings remain an essential variable in biomedical studies. There is also evidence suggesting that self-reported racial groupings are associated with corresponding genetic profiles [2], which are linked to racial differences in disease manifestations and treatment responses, as reported by us and others [3, 4]. Particularly, previous studies have also reported differences in AD prevalence across racial groups [5]. We thus endeavor to elucidate the potential implications of self-reported race in AD and dupilumab treatment responses. We hypothesized that data from individuals of diverse self-reported racial groups might shed light on these issues. For this purpose, we exhaustively surveyed the Gene Expression Omnibus (GEO) for transcriptomic datasets in the context of AD and dupilumab treatment involving individuals of diverse self-reported races. Only one study was found (GEO ID: GSE130588) [6], demonstrating the underrepresentation of racial/ancestral factors in AD research and treatment. GEO130588 analyzed the lesional and non-lesional skin biopsies from AD patients throughout a 16-week dupilumab treatment at a transcriptomic level, based on a multicenter, placebo-controlled, double-blind clinical trial (NCT1979016). It covered individuals with self-reported races of “White” (not Hispanic or Latino) versus “Asian” (Figure 1A). At baseline week 0 (W0), EASI score and SCORing Atopic Dermatitis (SCORAD) and gender profiles were similar in both groups (Figure 1B,C). They also exhibited comparable reductions in EASI and SCORAD scores as treatment responses to dupilumab (Figure 1D and Figure S1). Mechanistically, we performed Gene Set Enrichment Analysis (GSEA) on transcriptomic data from skin biopsy samples at different timepoints, comparing White and Asian groups. At W0, 134 and 117 pathways were upregulated in White versus Asian individuals in lesional and non-lesional skin areas, respectively (Figure 2A). Among the 34 pathways elevated in White participants at both lesional and non-lesional sites, “IL4 & IL13 signalling pathway” (the main target of dupilumab), and “IL10 signalling pathway” consistently featured (Figure 2B). This pattern persisted in lesional skin areas at 4-week post dupilumab treatment (W4, Figure 2C) but dissipated at the 16-week post treatment timepoint (“IL4 & IL13 signaling pathway”: p = 0.457, false discovery rate (FDR) = 1.000, normalized enrichment score (NES) = 0.99; “IL10 signaling pathway”: p = 0.557, FDR = 1.000, NES = 0.94). Collectively, this represents, to our knowledge, the first study investigating the mechanistic differences in AD and dupilumab treatment responses among individuals of different self-reported racial groups. We found that despite similar clinical manifestations, White AD patients displayed higher IL4 and IL13 signaling from baseline up to 4 weeks of dupilumab treatment. Our findings differ from those reported by De Vriese et al., who observed that East Asians had the highest EASI at baseline and that Southern Europeans demonstrated superior treatment responses to dupilumab compared to East Asians. These findings suggest that differences in self-reported racial background are unlikely to account for the observed geographic variations in AD and dupilumab treatment responses [1], although validation in larger geographically diverse cohorts is required. Comparisons across diverse racial/ancestral or geographic groups are inherently influenced by multiple confounders, including environmental and socioeconomic factors, which might partly explain the discrepancies between our findings and those reported by De Vriese et al. In this context, our analyses based solely on AD cohorts from North America may offer a more controlled comparison than the original systematic review, which integrated studies conducted across multiple continents. By design, such a systematic review might be subject to limitations related to differences in study design, patient selection, temporal and seasonal effects and healthcare system contexts. Notwithstanding these factors, as well as the controversies over the relationship between self-reported races and genetic ancestries, the self-reported racial differences we found may have implications for informing AD patient clinical stratification and personalized medicine treatment options with dupilumab, regarding dosage and duration. Ultimately, our findings also highlight the pressing need to increase racial/ancestral diversity in atopic research, promoting health equity. Study conceptualization and design: D.N. R.N. Investigation and data curation: D.N. Data analysis: D.N. Funding and resources: R.N. Manuscript preparation: D.N., R.N. All authors read, edited, and approved the final version of the manuscript. D.N. and R.N. were supported by the Norman Ernest Bequest Fund. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australasian University Librarians. This work was supported by the Norman Ernest Bequest Fund. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are openly available in Gene Expression Omnibus at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE130588, reference number GSE130588. Figure S1: Box charts for the changes in Eczema Area Severity Index (EASI, upper panels) and SCORing Atopic Dermatitis (SCORAD, lower panels) scores of AD patients from White (purple) versus Asian (cyan) groups, in Week 4 (W4) versus Week 0 (W0) (left panels) and in Week 16 (W16) versus W0 (right panels). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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