Successful treatment of JAK1 associated inflammatory disease

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

1 CHU Tenon [AP-HP]
2 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
3 GPIP - Groupe de Pathologie Infectieuse Pédiatrique [Paris]
4 CHV - Centre Hospitalier de Versailles André Mignot
5 Immunologie Translationnelle - Translational Immunology lab
6 CHU Trousseau [APHP]
7 SU - Sorbonne Université
8 Hôpital Necker - Enfants Malades [AP-HP]
9 UPCité - Université Paris Cité
10 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
11 CHU Pitié-Salpêtrière [AP-HP]
12 PASS-CYPS - Cytométrie Pitié-Salpêtrière
13 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
14 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
15 UMS 2009 / US36 - Biomedtech Facilities
16 GHH - Groupe Hospitalier du Havre Hôpital Jacques Monod (MONTIVILLIERS)
17 CIMI - Centre d'Immunologie et des Maladies Infectieuses
18 UCBL - Université Claude Bernard Lyon 1
19 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
20 CH Epinal / CHED - Centre Hospitalier Emile Durkheim [Epinal]
21 MASCOT (UMR_S_942 / U942) - Marqueurs cardiovasculaires en situation de stress
22 Hôpital Lariboisière-Fernand-Widal [APHP]

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.

Mots clés: JAK 1; JAK inhibitors; allergy; atopic dermatitis; inborn errors of immunity

Domaines: Sciences du Vivant [q-bio]

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⟩