1. Successful treatment of JAK1 associated inflammatory disease
- Author
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Fayand, Antoine, Hentgen, Véronique, Posseme, Céline, Lacout, Carole, Picard, Capucine, Moguelet, Philippe, Cescato, Margaux, Sbeih, Nabiha, Moreau, Thomas R.J., Zhu, Yixiang Yj., Charuel, Jean-Luc, Corneau, Aurélien, Deibener-Kaminsky, Joelle, Dupuy, Stéphanie, Fusaro, Mathieu, Hoareau, Benedicte, Hovnanian, Alain, Langlois, Vincent, Le Corre, Laurent, Maciel, Thiago, Miskinyte, Snaigune, Miyara, Makoto, Moulinet, Thomas, Perret, Magali, Schuhmacher, Marie Hélène, Rignault-Bricard, Rachel, Viel, Sébastien, Vinit, Angélique, Soria, Angèle, Duffy, Darragh, Launay, Jean-Marie, Callebert, Jacques, Herbeuval, Jean Philippe, Rodero, Mathieu P, Georgin-Lavialle, Sophie, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Groupe de Pathologie Infectieuse Pédiatrique [Paris] (GPIP), Société Française de Pédiatrie (SFP), Centre Hospitalier de Versailles André Mignot (CHV), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Biomedtech Facilities (UMS 2009 / US36), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Groupe Hospitalier du Havre Hôpital Jacques Monod (MONTIVILLIERS) (GHH), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Emile Durkheim [Epinal] (CH Epinal / CHED), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, and Hôpital Lariboisière-Fernand-Widal [APHP]
- Subjects
JAK 1 ,JAK inhibitors ,atopic dermatitis ,inborn errors of immunity ,[SDV]Life Sciences [q-bio] ,allergy - Abstract
International audience; 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.
- Published
- 2023