2. Academic Validation
  3. Successful treatment of JAK1-associated inflammatory disease

Successful treatment of JAK1-associated inflammatory disease

  • J Allergy Clin Immunol. 2023 Oct;152(4):972-983. doi: 10.1016/j.jaci.2023.06.004.
Antoine Fayand 1,  Véronique Hentgen 2,  Céline Posseme 3,  Carole Lacout 4,  Capucine Picard 5,  Philippe Moguelet 6,  Margaux Cescato 7,  Nabiha Sbeih 8,  Thomas R J Moreau 7,  Yixiang Y J Zhu 7,  Jean-Luc Charuel 9,  Aurélien Corneau 10,  Joelle Deibener-Kaminsky 11,  Stéphanie Dupuy 12,  Mathieu Fusaro 5,  Benedicte Hoareau 10,  Alain Hovnanian 13,  Vincent Langlois 14,  Laurent Le Corre 15,  Thiago T Maciel 8,  Snaigune Miskinyte 16,  Makoto Miyara 17,  Thomas Moulinet 11,  Magali Perret 18,  Marie Hélène Schuhmacher 19,  Rachel Rignault-Bricard 8,  Sébastien Viel 20,  Angélique Vinit 10,  Angèle Soria 21,  Darragh Duffy 3,  Jean-Marie Launay 22,  Jacques Callebert 22,  Jean Philippe Herbeuval 7,  Mathieu P Rodero 7,  Sophie Georgin-Lavialle 23
Affiliations

Affiliations

  • 1 Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Centre National de la Recherche Scientifique (CNRS), Paris, France; Department of Internal Medicine, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France.
  • 2 Pediatric Infectious Disease Group, Créteil, France; Department General Pediatrics, Centre Hospitalier de Versailles, Le Chesnay, France.
  • 3 Translational Immunology Unit, Institut Pasteur, Université de Paris Cité, Paris, France.
  • 4 Genetic Laboratory, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France; Department of Internal Medicine, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France.
  • 5 Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (APHP), Université de Paris Cité, Paris, France.
  • 6 Department of Pathology, Sorbonne Université, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 7 Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Centre National de la Recherche Scientifique (CNRS), Paris, France.
  • 8 Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Université de Paris Cité, Paris, France.
  • 9 Département of Immunology, Groupement Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 10 Production et Analyse de données en Sciences de la vie et en Santé (PASS), Plateforme de Cytométrie de la Pitié-Salpêtrière, Unité Mixte de Service (UMS) 037, Sorbonne Université, Paris, France.
  • 11 Department of Internal Medicine and Clinical Immunology, Nancy University Hospital, University of Lorraine, Nancy, France; Molecular Engineering and Articular Physiopathology, Unité Mixte de Recherche 7365, Centre national de la recherche scientifique (CNRS), University of Lorraine, Nancy, France.
  • 12 BioMedTech Facilities, Institut national de la santé et de la recherche médicale (INSERM) Unité mixte de services (US) 36, Centre national de la recherche scientifique (CNRS) Unité d'appui et de recherche (UAR) 2009, Université de Paris Cité, Paris, France.
  • 13 Laboratory of Genetic Skin Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Imagine Institute, Université de Paris Cité, Paris, France; Department of Genomics Medicine of Rare Diseases, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 14 Department of Internal Medicine, Jacques Monod Hospital, Le Havre, France.
  • 15 Macromolecular Modeling Platform, Laboratoire de Chimie et Biochimie, Pharmacologiques et Toxicologiques, Centre national de la recherche scientifique (CNRS), Unité Mixte de Recherche (UMR) 8601, Université de Paris Cité, Paris, France.
  • 16 Laboratory of Genetic Skin Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Imagine Institute, Université de Paris Cité, Paris, France.
  • 17 Département of Immunology, Groupement Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France; Centre d'Immunologie et des Maladies Infectieuses, Institut national de la santé et de la recherche médicale (INSERM) U1135, Hôpital Pitié-Salpêtrière AP-HP, Sorbonne Université, Paris, France.
  • 18 Immunology Laboratory, Lyon Sud Hospital, Hospices Civils de Lyon, University of Claude Bernard-Lyon 1, Lyon, France.
  • 19 Department of Internal Medicine, Emile Durkheim Hospital, Épinal, France.
  • 20 Department of Genomics Medicine of Rare Diseases, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 21 Dermatology-Allergology Department, Sorbonne Université, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 22 Service of Biochemistry and Molecular Biology, Institut national de la santé et de la recherche médicale (INSERM) U942, Hospital Lariboisière, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 23 Department of Internal Medicine, Tenon Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France. Electronic address: [email protected].
PMID: 37343845 DOI: 10.1016/j.jaci.2023.06.004
Abstract

Background: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.

Objectives: This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition.

Methods: The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling 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 1 of 2 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 diarrhea, disseminated calcifying fibrous tumors, 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 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 gain-of-function 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 tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.

Keywords

JAK 1; JAK inhibitors; allergy; atopic dermatitis; inborn errors of immunity.

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