Duality of Netherton syndrome manifestations and response to ixekizumab

To the Editor: Netherton syndrome (NS) is a rare autosomal recessive ichthyosis due to loss-of-function mutations in SPINK5 encoding LEKTI.1Chavanas S. Bodemer C. Rochat A. et al.Mutations SPINK5, serine protease inhibitor, cause syndrome.Nat Genet. 2000; 25: 141-142Crossref PubMed Scopus (659) Google Scholar Patients with NS typically present linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE) associated trichorrhexis invaginata and severe atopic manifestations high serum immunoglobulin E levels.2Hovnanian syndrome: skin inflammation allergy by loss of inhibition.Cell Tissue Res. 2013; 351: 289-300Crossref (123) Current treatment only symptomatic. Recent studies showed that patients display prevailing T helper (Th) type 17 immune response,3Paller A.S. Renert-Yuval Y. Suprun M. al.An IL-17-dominant profile shared across major orphan forms ichthyosis.J Allergy Clin Immunol. 2017; 139: 152-165Abstract Full Text PDF (62) Scholar,4Czarnowicki T. He H. Leonard al.The are characterized systemic T-cell activation Th-17/Tc-17/Th-22/Tc-22 polarization blood.J Invest Dermatol. 2018; 138: 2157-2167Abstract (17) suggesting blocking Th17 axis could be therapeutic strategy. We report compassionate use ixekizumab, humanized anti–interleukin (IL) 17A/F antibody 3 per dosing regimen used for plaque psoriasis.5Langley R.G. Kimball A.B. Nak al.Long-term safety ixekizumab moderate-to-severe psoriasis: an integrated analysis from 11 clinical trials.J Eur Acad Dermatol Venereol. 2019; 33: 333-339Crossref (39) 1 had NS-ILC, patient 2 presented NS-SE (Fig Supplemental Table I; available via Mendeley at https://doi.org/10.17632/3b25453w6y.1), each displaying form did not respond symptomatic treatment. All psoriasiform epidermal hyperplasia 2). Immunostaining lesional increased neutrophils stratum corneum papillary dermis mast cell infiltrates 2. Serum cytokine profiling enhanced levels inflammation-, allergy- chemotaxis-related chemokines, particular CCL20/MIP-3? CXCL13/BCA-1, which IL-17–induced chemokines (Supplemental II; https://doi.org/10.17632/3b25453w6y.1).Fig 2Lesional histopathologic features showing and/or neutrophil before after ixekizumab. A, Ixekizumab initiation. Hematoxylin-eosin-safranin (HES) coloration (upper panel) hyperplasia, reduced absent granular layer, detachment. The enlargement shows subcorneal collection 1. tryptase (green) identified predominant (middle panel). MPO (red) dermal (lower initiation B, Week 24 HES slight reduction detachment Mast stained now predominate panel), significant seen weeks Enlargements pictures show parakeratosis; absent, apparent layer; collection. (Original magnification: ×40.) DAPI, 4?,6-diamidino-2-phenylindole; MPO, myeloperoxidase; NS, syndrome.View Large Image Figure ViewerDownload Hi-res image Download (PPT) During induction phase, cutaneous improvement was observed, especially NS-ILC. Flares oozing disappeared, pruritus scaling decreased, their topical corticosteroids. After months therapy, all scores except Ichthyosis Area Severity Index - Erythema (IASI-E), statistically 1). maintenance benefits were largely maintained NS-ILC contrast NS-SE. At 6 treatment, Dermatology Life Quality remained decreased whereas almost returned baseline values IASI-E unchanged during this period. For these reasons, stopped temporarily discontinued 1, continued monthly injections. replaced cells 3. Of 8 cytokines above 2-fold baseline, (CXCL13/BCA-1) subnormal values; (CCL26/eotaxin-3, CXCL11/I-TAC, CCL17/TARC, CCL22/MDC, CCL21/6Ckine, CCL19/MIP-3?), (CCL20/MIP-3?) upon III; https://doi.org/10.17632/3b25453w6y.1). persistence elevated Th2-associated CCL26/eotaxin-3, CCL13/MCP-4 play part infiltration decrease CCL3/MIP-1? IL-8/CXCL8, chemoattractants, contribute marked Importantly, discrepancy course CCL20/MIP-3?, together markers, including tumor necrosis factor ? interferon ?, suggest other pathways overlapping IL-17A inflammation. In conclusion, anti–IL-17A/F therapy well tolerated brought substantial improvement, phase Clinical benefit partially sustained longer improve efficacy additional inflammatory allergic biological cascades should targeted. would like acknowledge Professor Hervé Bachelez helpful discussions valuable advice. thankful French National Research Agency (ANR-17-CE14-0025-03 Tfh Atopy ANR-19-CE17-0017-01TARGET-NS) Imagine Institute (Imagine Cross-Laboratory Project) support.