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Atopic dermatitis in Brazilian patients: genetic aspects, immune response and immunotherapy in mite allergic patients

Grant number: 19/26678-0
Support type:Regular Research Grants
Duration: September 01, 2020 - August 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Luisa Karla de Paula Arruda
Grantee:Luisa Karla de Paula Arruda
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Adriana Santos Moreno ; Janaina Michelle Lima Melo ; Sarah Sella Langer ; Wilson Araújo da Silva Junior

Abstract

Atopic Dermatitis (AD) is a chronic and relapsing inflammatory skin disease, characterized by intense pruritus and recurrent eczematous lesions, with prevalence varying from 0.2% to 20%. AD includes different phenotypes and endotypes, according to ethnicity, age, immune response profile, presence of loss-of-function mutation in the gene coding for filaggrin and barrier defects, infection and colonization with Staphylococcus aureus, and clinical characteristics. Most patients with AD present markers of activation of type 2 immunity, with important role of Th2 and ILC2 lymphocytes, resulting in the production of cytokines IL-4, IL-5 and IL-13, however activation of Th17 and Th22 axis may also occur. Filaggrin is a molecule with marked importance to structure, function and integrity of the stratum corneum. Loss-of-function mutations in the gene coding for filaggrin (FLG) are associated with increased severity and persistence of AD symptoms, and increased occurrence of asthma and food allergy. However, the frequency of mutations in FLG is variable in different populations, and described in up to 50% of AD patients. In Afro-descendants, mutations in the gene coding for filaggrin 2 (FLG2) have been associated to persistence and increased AD severity. Filaggrin has a central role in preventing transepidermal water loss, penetration of allergens and S. aureus colonization. In our area, reduced filaggrin expression has been demonstrated in lesional skin of adult patients with AD, and an inverse correlation was found of filaggrin expression and severity of AD. The frequency and characterization of mutations in FLG and FLG2 genes in Brazilian patients with AD is not known. Stratification in endotypes and definition of biomarkers have an importante role in development of precision medicine strategies which could improve therapeutic results. Treatment of AD includes skin hydration and emollients, topical anti-inflammatory drugs (corticosteroids, calcineurin inhibitors), systemic immunossupressants (systemic corticosteroids, cyclosporine, methotrexate), and antimicrobials. The biological agent Dupilumab, which acts preventing signaling through IL-4 and IL-13, has shown high efficacy in controlled studies, metanalysis and real life studies, however treatment costs are very high. Allergen-specific immunotherapy (IT), both by subcutaneous and sublingual routes, has been used for allergic diseased including asthma, rhinitis, reactions to insect venoms, and food allergy with high efficacy. Few studies of IT have been reported in patients with AD. Sublingual immunotherapy (SLIT) with house dust mite extract, which is the predominant allergen in our area, may be advantageous, due to easy administration, without necessity for medical supervision upon administration of the doses, and possibility to cause less adverse reactions and exacerbations of the disease. We have developed a double-blind, placebo-controlled, clinical study, registered in Clinical Trials NCT 0338886 and approved by the Ethics Committee of HC-FMRP-USP, with data inserted into the REDCap Platform, to evaluate the efficacy of SLIT with mite Dermatophagoides pteronyssinus extract in mite allergic patients with AD. Response criteria were well established, with the principal outcome measure defined as drop f 15 points in SCORAD in at least 40% of the IT group. We hope to demonstrate and increase in the regulatory response, in parallel to improvement in clinical symptoms and quality of life in our patients, and to show that SLIT could be a novel and viable form of treatment of patients with AD. Our study will also verify, for the first time in Brazilian patients with AD, the frequency of loss-of-function mutations in the genes FLG and FLG-2, and to evaluate whether presence of mutations in conjunction with clinical and immunological parameters, could help in choosing the most adequate profile of patients for treatment with SLIT. (AU)