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Journal Articles Journal of Allergy and Clinical Immunology Year : 2023

Successful treatment of JAK1 associated inflammatory disease

Aurélien Corneau
Sébastien Viel


Background: Gain of function (GOF) variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy and eosinophilia. Objectives: To describe the clinical and immunological characteristics associated with a new GOF variant of JAK1 and report the therapeutic efficacy of JAK inhibition. Methods: We identified a family affected by JAK1 associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signalling was studied by flow and mass cytometry in patients' cells at basal state, or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with one of two JAK inhibitors; either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. Results: Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhoea, disseminated calcifying fibrous tumours and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected tested patients. Hyper-phosphorylation of STAT3 was found in 5 out of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. Conclusions: Patients with this new JAK1 GOF pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumours. The disease, that appears to be linked to STAT3 hyper-activation, was well controlled under treatment by JAK inhibitors in adult patients.
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hal-04137977 , version 1 (22-06-2023)




Antoine Fayand, Véronique Hentgen, Céline Posseme, Carole Lacout, Capucine Picard, et al.. Successful treatment of JAK1 associated inflammatory disease. Journal of Allergy and Clinical Immunology, 2023, 152 (4), pp.972-983. ⟨10.1016/j.jaci.2023.06.004⟩. ⟨hal-04137977⟩
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