Treatment of Netherton syndrome with spesolimab

Netherton syndrome (NS) is an autosomal recessive disorder characterized by the triad of congenital ichthyosiform erythroderma or ichthyosis linearis circumflexa, hair shaft abnormalities and high serum IgE levels with atopic manifestations. Therapeutic options for NS are limited, often failing to elicit a satisfactory response in patients. Multiomic analyses revealed an IL-36 signature to be a hallmark of NS.1 In this report, we present a case of NS successfully treated with spesolimab, an interleukin (IL)-36R inhibitor. A 5-year-old girl with a prior diagnosis of NS (due to compound heterozygous c.80A>G and c.710delT mutations in the SPINK5 gene) was referred for treatment. She presented with generalized erythema, scaling and severe pruritus. She had a history of erythroderma and scaling at birth, alongside signs of delayed growth. The patient was the first child of non-consanguineous parents. Physical examination revealed sparse, brittle hair and eyebrows, superficial scaling, facial redness and widespread serpiginous and polycyclic erythematous plaques with double-edged peripheral scaling on her trunk and extremities (Figure 1). Trichoscopy showed hair shaft invagination consistent with trichorrhexis invaginate (bamboo hair). Laboratory investigations demonstrated significantly elevated serum total IgE level exceeding 5000 KU/L (normal range: 0~100 KU/L). White blood count was 20.92 × 10E9/L (normal range: 4.0~12.0 × 10E9/L). Her treatment history included topical emollients, corticosteroids, calcineurin inhibitors and oral antihistamines. However, improvement was not significant. Treatment with dupilumab at 300 mg every 4 weeks was attempted but discontinued after 8 weeks due to ineffectiveness. After obtaining parental consent, treatment with spesolimab was initiated at a monthly dose of 450 mg thereafter. The Pruritus Numeric Rating Scale (NRS), Netherton Area Severity Assessment (NASA) and Ichthyosis Area and Severity Index (IASI) were evaluated at baseline and at 4, 8 and 12 weeks post-treatment. Remarkable improvement (Figure 2) was noted with NRS for pruritus from 9 at baseline to 4; IASI and NASA scores decreased from 29 and 45 to 7.8 and 16.4, respectively. NS is diagnosed by mutations in the SPINK5 gene, encoding the lymphoepithelial Kazal-type-related inhibitor, a novel serine protease inhibitor crucial for skin barrier formation and immunity. There is currently no established treatment for NS, and existing literature primarily consists of individual case reports. Traditional therapeutic approaches have shown only limited effectiveness in addressing this condition. Several case reports have proven the efficacy of various biotherapies targeting IL-17A, IL-12/IL-23, IL-4Rα, TNF-α and IL-1β in paediatric NS patients.2, 3 However, our patient exhibited treatment failure with dupilumab, an IL-4Rα inhibitor. Recent research has underscored the potential of targeting the interleukin-36-driven inflammatory pathway as an effective treatment strategy for NS.4 Multiomic studies showed the IL-17/IL-36 pathway to be significantly upregulated in NS, with IL-36-driven immune responses evident in both skin and peripheral blood.1 Increased expression of IL-36α and IL-36γ cytokines in NS skin correlates with disease severity.4 NS patients are at an increased risk of Staphylococcus aureus infections, which also activates the IL-36 axis, thereby exacerbating skin inflammation.5 Spesolimab is a human antagonistic monoclonal IgG1 antibody that blocks IL36α, IL36β and Il36γ-induced activation of IL36R. In our patient, after 12 weeks of spesolimab treatment, both the patient's pruritus, scaling, generalized serpiginous and polycyclic erythematous plaques and erythema showed remarkable improvement. Thus, spesolimab emerges as a promising novel therapeutic strategy for NS. Currently, a registered clinical trial is underway, and its outcomes are eagerly anticipated. The views expressed in this manuscript are those of the author and do not necessarily reflect the official policy or position of any institution, organization, employer or funding source. No potential conflicts of interest relevant to this article have been reported. The patient's parents in this manuscript have given written informed consent to the publication of their case details. The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.