Genomic, transcriptomic and environmental insights into hand eczema

Hand eczema (HE) is a common inflammatory skin disease with a multifactorial pathogenesis that is not fully understood. This thesis investigates the pathogenesis of HE through genomic, transcriptomic and epidemiological studies.
Part 1 focuses on genetic factors and the transcriptome of HE in relation to atopic dermatitis (AD). A genome-wide association study (GWAS) (Chapter 2) identified locus 20q13.33 as associated with HE independent of AD and revealed large genetic overlap between the two diseases. We compared the transcriptome of palmar vesicular HE with non-palmar AD (Chapter 3) and found a largely shared immune-related pathophysiology, but with more pronounced interferon signalling in vesicular HE, indicating a stronger T-helper 1 immune response.
Part 2 focuses on environmental factors, including hair dye exposure and p-phenylenediamine (PPD) contact allergy. Two cross-sectional questionnaire-based studies (Chapters 4 and 5) showed that hair dye use is common (63.1% ever in lifetime) in the Dutch general population and frequently causes adverse skin reactions (6.8%), particularly in females who had black henna tattoos and in overweight individuals. Hair dye users with adverse skin reactions were twice as likely to report HE. A GWAS of PPD contact allergy (Chapter 6) identified six novel loci, of which three were also associated with polysensitization.
Part 3 translates our understanding of HE pathogenesis into potential treatment options. A drug repurposing study (Chapter 7), based on transcriptomic vesicular HE and our genomic HE data, identified 123 promising drug repurposing candidates, including several immunomodulators (e.g., dupilumab). Finally, Chapter 8 presents successful treatment of two severe atopic and hyperkeratotic chronic HE patients with baricitinib.