Successful treatment of JAK1 associated inflammatory disease - Archive ouverte HAL
Journal Articles Journal of Allergy and Clinical Immunology Year : 2023

Successful treatment of JAK1 associated inflammatory disease

Aurélien Corneau
Sébastien Viel

Abstract

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.
Fichier principal
Vignette du fichier
Fayand et al, JAK1.pdf (8.06 Mo) Télécharger le fichier
Origin Files produced by the author(s)
Licence

Dates and versions

hal-04137977 , version 1 (22-06-2023)

Licence

Identifiers

Cite

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⟩
902 View
169 Download

Altmetric

Share

More