256 Treatment of Netherton syndrome with dupilumab

Abstract

Netherton syndrome (NS) is a rare autosomal-recessive disease that is caused by loss-of function mutations in the SPINK 5 gene encoding for the serine protease inhibitor lympho-epithelial Kazal type inhibitor (LEKTI). LEKTI opposes the function of several epidermal serine proteases including kallikrein 5 (KLK5), kallikrein 7 (KLK7) and kallikrein 14 (KLK14). This results in an activation of the PAR2-TSLP axis and an increase of other Th2 polarizing mediators including CCL-17 and CCL-22. This presumably spurs a Th-2 response consequently leading to increased IgE levels. In NS effective treatment options are missing. In contrast, in atopic dermatitis treatment with dupilumab an antibody directed against the alpha unit of the IL-4 receptor leads to a remarkable success in controlling disease activity which is reflected in decreased IgE levels. Thus, dupilumab represents a worthwhile treatment strategy in NS. Three adult patients with genetically confirmed NS were individually treated with dupilumab 300mg injections every other week for 32 weeks. EASI scores at baseline were 30.0, 29.0 and 18.2. Clinical improvement was observed as early as at week 8 leading to continuously improved EASI scores (w32: -55.82%+/-16.69). In line, IGA scores enhanced in all three patients. DLQI clearly improved with ongoing dupilumab treatment. Serum IgE levels declined steadily (w32: -60.93%+/- 8.57). In contrast, LDH serum levels and blood eosinophil count were unchanged. Further analyses of serum cytokines are underway. Decrease of serum IgE levels clearly correlated with both EASI and DLQI reduction intra- and interindividually. Similarly, EASI improvement correlated with DLQI reduction. In summary, these data for the first time shows that dupilumab is effective in NS patients.