TREAT-Brazil: a national registry for pheno-endotypic characterization and detection of endotypic biomarker profiles predictive of severity in Atopic Dermatites

• Grant number: 24/08975-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2025
• End date: March 31, 2030
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Valeria Aoki
• Grantee: Valeria Aoki
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Mírian Nacagami Sotto
• Associated researchers: Anna Julia Pietrobon ; Carsten Flohr ; Maria Notomi Sato ; Marina Passos Torrealba ; Mario Cezar Pires ; Naiura Vieira Pereira ; Nátalli Zanete Pereira ; Raquel Leão Orfali ; Yasmim Álefe Leuzzi Ramos

Abstract

Atopic dermatitis (AD), a chronic, multifactorial, pruritic inflammatory dermatosis, has aspects that still need to be elucidated, especially in Latin America. The prevalence of AD varies between 5% and 20% in the pediatric population, and 2% to 10% in adults. An international multicenter study found that Brazil has the highest prevalence of AD in all age groups among Latin American countries (20.1%). The TREAT-Brazil research project aims to create an up-to-date prospective cohort of patients with moderate to severe AD, generating data on medical care, response to treatment, and the detection of phenotype-endotypic biomarkers, unpublished in the Brazilian population. Four subprojects (SP) are part of this thematic project: SP1, a non-interventional, multicenter registry aimed at long-term observation of 1,000 patients with moderate to severe AD, with an emphasis on treatment efficacy and adequacy, psychosocial impact and epidemiology, risk factors for disease progression, associated comorbidities and ethnic-racial characteristics. Registration data and biological samples will be collected at 23 participating centers in all regions of Brazil. All samples will be received, processed, stored and analyzed anonymously at the Dermatology Research Laboratory-LIM-56, Department of Dermatology, HC-FMUSP, the Study Coordinating Center. The subprojects (SP2-4) will be based on pheno-endotypic biomarkers, which will be analyzed in an anonymous manner. The sub-projects (SP2-4) will be based on pheno-endotypic biomarkers, which will help to stratify predictive factors of worse prognosis and response to target-specific therapy in AD. SP2 will analyze whole blood samples from 150/1000 patients included in SP1, aged > 12 years, to evaluate pheno-endotypic biomarkers associated with AD severity, with endotyping based on the serum profile of 40 cytokines/chemokines, analyzed by the Luminex platform, and detailed endotyping of clinical, ethnic or demographic groups. In SP3, we will analyze the relevance of the neuroimmune system in the pathogenesis of pruritus in AD and in nodular prurigo-like lesions (NP), since 15% of AD patients can present concomitant skin lesions of AD and NP, with pruritus and the inflammatory process being the common denominator between the two. In this stage, AD skin samples will be obtained by tape stripping (25 AD and 25 AD+NP, patients from the HC-FMUSP AD outpatient clinic), and by biopsy (AD and AD+NP), where we will evaluate the genes of the components linked to pruritus/neuroimmune axis in AD, including innate cell populations (mast cells and nerve endings) by single cell transcriptomic analysis, immunohistochemistry (IHQ) and immunofluorescence (IF). Whole blood samples will be collected to assess PD1, TIM3, HLA-DR and CD38 depletion molecules (ex vivo) and after stimulation with SEA and SEB (in vitro) by flow cytometry, with dosage of proinflammatory cytokines in culture supernatants by ELISA. SP4 will evaluate the crosstalk between the Th2-type inflammatory response (IL-4, IFN-g), antiviral factors (IFN-g, IFN-a, IFN-l, TBK-1, STING), plasmacytoid dendritic cells and IFN-g-producing TCD4+ and TCD8+ cells by transcript analysis, IF and IHQ in lesions of patients with the DA endotype and eczema herpeticum (DAEH+), in skin samples (10 DA and 10 DAEH+, patients from HC-FMUSP). HS is a complication that affects 3% of patients with AD, associated with herpes simplex virus (HSV) 1 and 2, with HSV-specific TCD8+ cells located at the dermal-epidermal junction close to the peripheral sensory nerve endings. This study could provide data on biosafety, drug-economics and psychosocial aspects of the disease; and will be relevant for characterizing the phenotype-endotype profile related to the severity of AD, with the detection of biomarkers in a Brazilian population, generating unprecedented data that will help in precision medicine. (AU)