PA03 Should patients with atopic dermatitis be screened for genes associated with hyper-IgE syndrome?
Authors: Poh Jane Yi Jen , Murphy Ruth 
Published: June 2024

Abstract
Individuals with severe atopic dermatitis (AD) may present with very high serum IgE levels (&gt; 10 000 IU mL−1). Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES), a rare immunosuppressive disorder, shares pathogenic similarities with AD, involving dysregulation in the STAT3 signalling pathway and clinical, genetic and serological features similar to AD. Despite these parallels, patients with AD with very high IgE levels are not routinely tested for genetic overlap with STAT3-HIES. This might be relevant in therapeutic intervention. We reviewed the literature to identify individuals with possible overlap of both conditions to help identify a novel mixed phenotype (AD/STAT3-HIES). Intervention with Janus kinase (JAK) inhibitors in this subgroup might be beneficial given their shared dysregulation in STAT3 signalling pathways. This review investigates the identification of the AD/STAT3-HIES phenotype and its response to Janus kinase (JAK) inhibitors. A literature review was undertaken on PubMed, Scopus, Ovid and Google Scholar. Search terms included ‘atopic dermatitis’, ‘hyper-IgE syndrome’, ‘HIES’, ‘Job syndrome’, ‘STAT3’, ‘JAK/STAT pathway’ and ‘Janus kinase inhibitors’. Inclusion criteria were studies published in English between January 2005 and December 2023 relevant to the clinical features, treatment, pathogenesis and genetics of AD or STAT3-HIES. Out of 152 studies identified during the search, 29 met the inclusion criteria. The Table outlines the features of AD, STAT3-HIES and areas of overlap (AD/STAT3-HIES). Clinically, AD and STAT3-HIES share characteristics including eczematous lesions and staphylococcal skin infections. STAT3-HIES is distinguished from AD by the presence of immunoparesis and extracutaneous manifestations. Both diseases commonly exhibit elevated IgE levels. In severe AD, studies reported IgE levels ranging from 356 to 2379 IU mL−1, while patients with STAT3-HIES demonstrated levels between 1000 and 46 850 IU mL−1. Genetically, both diseases are associated with the STAT3 and IL6 genes. JAK inhibitors proved effective in treating AD in multiple studies. To date, only one ex vivo study suggested a potential treatment utility of JAK inhibitors in dominant negative STAT3 mutation. We postulate that patients with AD with elevated IgE levels beyond the typical range may benefit from further genotyping (STAT3 and IL6 gene mutations) to identify the AD/STAT3-HIES phenotype. Future clinical trials could assess the potential benefits of targeted intervention with JAK inhibitors in this subgroup and/or in patients with AD with very high serum IgE.ADAD/STAT3-HIESSTAT3-HIESClinicalPruritic eczematous lesionsPruritic eczematous lesionsPruritic eczematous lesionsStaphylococcal skin infectionsStaphylococcal skin infectionsStaphylococcal skin infectionsCold staphylococcal abscessRecurrent pneumoniaSkeletal and dental abnormalitiesConnective tissue abnormalitiesSerologyElevated IgEElevated IgEElevated IgEGenetic associationsSTAT3STAT3STAT3IL6RIL6RIL6RFLGIL6STIL2/IL21ZNF341IL7RTYK2IL15RA/IL2RAImmunologicalElevated interleukin-4Elevated interleukin-4Elevated interleukin-4Elevated interleukin-13Elevated interleukin-13Elevated interleukin-13