INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

Clinical Immunology and Primary Immunodeficiencies Unit Pediatric Allergy and Clinical Immunology Department Hospital Sant Joan de Déu Barcelona Spain

Clinical Immunology Program Hospital Sant Joan de Déu Hospital Clínic Barcelona Barcelona Spain

Departamento de Farmacología Pediatría y Radiología Facultad de Medicina Universidad de Sevilla Seville Spain

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatrics 1st Faculty of Medicine Charles University Prague Thomayer University Hospital Prague Czech Republic

Department of Pediatrics Hospital Universitari Son Espases Palma Spain

Division of Immunology and Allergy Dept of Pediatrics Ribeirão Preto Medical School University of São Paulo Ribeirão Preto Brazil

Human Immunopathology Research Laboratory Institut d'Investigació Sanitària de Les Illes Balears Palma Spain

Immunology Department Hospital Universitari Son Espases Palma Spain

Inborn Errors of Immunity Group Laboratory 205 Instituto de Biomedicina de Sevilla Seville Spain

Infection in Immunocompromised Pediatric Patients Research Group Vall d'Hebron Institut de Recerca Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Catalonia Spain

Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies Barcelona Spain

Laboratorio de Alteraciones Congénitas de La Inmunidad Instituto de Biomedicina de Sevilla Laboratorio 205 Seville Spain

Multidisciplinary Group for Research in Peadiatrics Hospital Universitari Son Espases Balearic Islands Health Research Institute Palma Spain

Pediatric Infectious Diseases and Immunodeficiencies Unit Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Catalonia Spain

Pediatric Infectious Diseases Rheumatology and Immunology Unit Hospital Universitario Virgen del Rocio Sevilla Spain

Pediatric Rheumatology Unit Rheumatology Department Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Catalonia Spain

Study Group for Immune Dysfunction Diseases in Children Institut de Recerca Sant Joan de Déu Barcelona Spain

Universitat de Barcelona Barcelona Spain

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Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition

Immunoprofiling of monocytes in STAT1 gain-of-function chronic mucocutaneous candidiasis