Successful treatment of JAK1-associated inflammatory disease.
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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 Y J, Charuel Jean-Luc, Corneau Aurélien, Deibener-Kaminsky Joelle, Dupuy Stéphanie, Fusaro Mathieu, Hoareau Benedicte, Hovnanian Alain, Langlois Vincent, Le Corre Laurent, Maciel Thiago T, 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
Аннотация
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.