MEFV variants contribute to eosinophil-dominant refractory atopic dermatitis and enhance the therapeutic response to JAK inhibitors

Summary: Atopic dermatitis (AD) is an inflammatory skin disorder influenced by genetic and environmental factors. To explore genetic factors contributing to refractory AD, we performed whole-exome sequencing on 13 patients with moderate-to-severe AD. Five harbored <i>MEFV</i> variants (rs150819742, rs201766654, rs190705322, rs11466023, rs11466024, rs11466018), with three heterozygous and two compound heterozygous cases. <i>MEFV</i> encodes pyrin, crucial for innate immunity, and its mutations cause familial Mediterranean fever (FMF) and PFAPA syndrome. Eight patients received upadacitinib (JAKi), including four with <i>MEFV</i> variants. Baseline characteristics and treatment responses were compared. Despite no significant differences in age, sex, disease severity, or prior treatments, patients with <i>MEFV</i> variants had significantly higher eosinophil counts (1913 vs. 454.6 cells/μL, P = 0.0228, unpaired t-test). After 3 months of JAKi, eosinophil counts significantly decreased in patients with <i>MEFV</i> variants (mean reduction: -1623 cells/μL, 95% CI: -2701 to -545.4, P < 0.01, two-way ANOVA with Bonferroni posttests), whereas no significant reduction was seen in those without variants (-96.57 cells/μL, P > 0.05). Two of four patients without <i>MEFV</i> variants developed MSSA infections, including impetigo, erysipelas, and abscesses within 3 months, whereas none occurred in those with variants except for one pre-existing folliculitis case. <i>MEFV</i> encodes pyrin, expressed in neutrophils, eosinophils, and monocytes. Pyrin inflammasomes activate IL-1 and IL-18, and IL-18 is essential for eosinophil maturation, like IL-5. Our findings suggest that <i>MEFV</i> variants contribute to eosinophil-dominant refractory AD and may enhance JAK inhibitor response by modifying immune activation. Emi Sato¹, Naoko Obonai¹, Hiroko Imayoshi¹, Yuki Tsutsui¹, Shinichi Imafuku¹ 1. Dermatology, Fukuoka University Faculty of Medicine, Fukuoka, Japan. Innate Immunity, Microbiology, and Microbiome