Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation

Abstract

BackgroundNetherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by SPINK5 gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets.ObjectiveTo evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment.MethodsFour children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis.ResultsAll four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0–83.9%) and NRS (by 87.5–90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6–86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment (P = 0.029). The baseline percentage of Th2 cells (among total CD3+CD4+ T cells) was significantly higher in patients than that in healthy controls (HC) (P < 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events.ConclusionDupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.

Dupilumab in Inflammatory Skin Diseases: A Systematic Review

“…Other typical findings are ichthyosis (type linearis circumflexa) and hair abnormalities (trichorrhexis invaginata). Dupilumab treatment for patients with Netherton syndrome was reported in a total of 16 cases ( Table 6 ) [ 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 ]. All cases showed prompt resolution of itch measured by NRS and an improvement of skin lesions evaluated by EASI or BSA within 3 months.…”

“…In patients with hair abnormalities, three cases reported improved hair growth while two reported no effect. The response was sustained in 14/16 cases for various follow-up periods, while two patients experienced a relapse after 8 or 20 weeks that was not sufficiently controlled by a dose increase and led to withdrawal of dupilumab [ 195 , 202 ]. Currently, a placebo-controlled RCT is recruiting (NS-DUPI, NCT04244006).Other congenital ichthyoses can lead to skin findings similar to AD by impaired skin barrier functions.…”

Interprofessional Collaboration: Differentiating Netherton Syndrome and Atopic Dermatitis in an African American Infant

“…Netherton syndrome is a complex disorder that affects various organ systems, and it is characterized by congenital ichthyosiform erythroderma, hair shaft irregularities, and immune dysregulation [ 1 ]. While the specific pathophysiology of this condition is not fully understood, a loss-of-function mutation in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, encoding a serine protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI), is thought to contribute to progressive inflammation and skin deterioration [ 1 , 2 ]. Part of this condition's presentation involves high serum immunoglobulin E (IgE), which may present similarly to atopic dermatitis, also known as eczema [ 1 ].…”

Multidimensional response of Dupilumab in a child affected by Netherton syndrome: Improvement of trichorrhexis invaginata

“…For this reason, Dupilumab was readministrated every 2 weeks showing a rapid improvement of the skin condition (Figure 2). To our knowledge, Dupilumab administration has been reported worldwide only in seven children with NS (aged from 6 months to 14 years), [9][10][11]…”

“…It is approved for the treatment of moderate-tosevere AD in children 6 years or older and recently also in 6 months to 6-year-old children by Food and Drug Administration. 5,6 Since NS and AD share many clinical and pathogenetic features, Dupilumab has been demonstrated effective in few case reports, mostly in adult-focused 7,8 and older than 6-year-old-children-focused ones, 9,10 although three patients developed resistance to this drug. 7 Other biological treatment strategies have been showed efficacious in single case reports of pediatric patients with NS, such as anti-IL17 (Secukinumab), anti-IL12 and IL-23 (Ustekinumab), anti-TNFα (Infliximab), and anti-IL1ß (Anakinra).…”