Secukinumab for the treatment of SAM syndrome associated with desmoglein-1 deficiency.

Abstract

Dear Editor, Treating patients with genodermatoses is challenging because of the chronic disease course and limited available therapies. We report on the efficacy of secukinumab for the treatment of a genodermatosis caused by biallelic loss-of-function mutations in the desmoglein 1 (DSG1) gene. This syndrome comprises severe dermatitis, multiple allergies and metabolic wasting (SAM) and can manifest as ichthyosiform erythroderma at birth.1 Additional variable features include palmoplantar keratoderma, hypotrichosis, recurrent skin infections, malabsorption and failure to thrive.2 Our patient was a woman in her twenties who had been diagnosed in the neonatal period with atopic dermatitis, which continued during infancy when her weight was below the third percentile. Both parents had mild palmoplantar keratoderma that had remained undiagnosed for many years. Our patient had severe palmoplantar keratoderma and disseminated dermatitis, manifesting with erythema and lichenified plaques, accompanied by severe pruritus and multiple food allergies.3 She developed recurrent flares of erythroderma, but was otherwise in good general condition without growth retardation or metabolic wasting (body mass index 20·2 kg m−2). The molecular basis of the SAM syndrome in our patient was represented by the homozygous DSG1 mutation c.2659C > T, p.R887*, which led to the absence of desmoglein-1 in her skin.3 For a long time, cutaneous manifestations were satisfactorily treated with topical calcineurin inhibitors and intensive skincare, consisting of daily bathing with antiseptics and application of emollients at least twice a day. Palmoplantar keratoderma was alleviated with potent keratolytics and mechanical removal every 3 weeks. Our patient intermittently developed episodes of aggravation with erythroderma, cutaneous bacterial infections and severe pruritus. Therefore, hospitalizations and systemic therapy with prednisolone were required (Figure 1a). Systemic therapy with ciclosporin A (100 mg daily) was administered, leading to amelioration of cutaneous manifestations; however, pruritus did not improve. After 6 months, our patient reported an increased feeling of hunger and subsequent weight gain. After another 3 months, the patient experienced severe headaches, which ultimately led to the withdrawal of medication and deterioration of the skin condition. Immunohistochemical staining of the patient’s skin for interleukin (IL)-17A (BIN677933, Bioss Antibodies, Woburn, MA, USA) revealed increased numbers of IL-17A-positive cells, similar to skin affected by psoriasis, whereas normal skin from a healthy control did not show any IL-17A-positive cells (Figure 1c, d). Based on this finding and recent research, off-label therapy with the antibody secukinumab (Cosentyx®, Novartis, Basel, Switzerland) directed against IL-17A was initiated. After providing written informed consent, the patient received two subcutaneous injections of secukinumab (150 mg each) once per week for 5 weeks, followed by monthly administrations. The skin condition dramatically improved 3 weeks after treatment initiation; the patient continued to receive biologics at the 12-month follow-up and remained stable (Figure 1b). Importantly, the intensity of the pruritus decreased from 8–9 to 0 on a numeric scale ranging from 0 to 10. As the patient’s skin appeared almost normal without any redness, she did not require topical treatments except for emollients once daily for dryness. Even palmoplantar keratoderma became less prominent during this treatment. No clinical or laboratory adverse effects were registered. In SAM syndrome, DSG11 or desmoplakin4 mutations lead to loss of cell–cell adhesion in the upper epidermal layers and a decreased skin barrier function, ultimately facilitating the development of allergies. Available therapeutic options, such as topical corticosteroids, calcineurin inhibitors or emollients are not specific and have only limited efficacy. These therapies cannot control episodes of aggravation, and their long-term use may lead to side-effects. Novel data show an increase in proinflammatory T helper 17 expression in patients with ichthyosis, thus suggesting that blockage of IL-17A may be a promising therapeutic approach in this specific group of patients.5-7 An initial case series reporting the use of anti-IL-17 therapy in Netherton syndrome demonstrated marked cutaneous improvement, particularly in two paediatric patients with erythrodermic phenotypes.8 Detection of IL-17A-positive inflammatory cells in situ in the skin of our patient confirmed the involvement of IL-17A-producing cells, and provided a rationale for targeted therapy with an anti-IL-17A antibody. Therefore, our observation supports the repurposing of IL-17A-antibody treatment for patients with rare disorders of the epidermal barrier, such as SAM syndrome. we would like to thank the patient for her involvement and for providing consent to publish the clinical pictures. We thank Birgit Haarhaus for excellent technical assistance. Open access funding enabled and organized by Projekt DEAL. Leonie Helene Frommherz: Data curation (equal); Formal analysis (equal); Investigation (equal); Writing-original draft (equal). Christoph M Schempp: Formal analysis (equal); Methodology (equal); Supervision (equal); Validation (equal); Writing-review & editing (equal). Cristina Has: Conceptualization (equal); Formal analysis (equal); Project administration (equal); Supervision (equal); Writing-original draft (equal).