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.
Subject(s)
Dermatitis, Atopic , Janus Kinase Inhibitors , Neoplasms , Adult , Humans , Janus Kinase Inhibitors/therapeutic use , Dermatitis, Atopic/drug therapy , Histamine , Neoplasms/drug therapy , Janus Kinase 1/geneticsABSTRACT
We report three cases of severe thrombocytopenia during COVID-19 infection associated with either cutaneous purpura or mucosal bleeding. The initial investigations ruled out other causes of thrombocytopenia. Two of the patients were treated with intravenous immunoglobulins and eltrombopag, while the third recovered spontaneously. A good clinical and biological response was achieved in all patients leading to hospital discharge. LEARNING POINTS: Immune thrombocytopenia should be considered in COVID-19-infected patients presenting with thrombocytopenia.Coronavirus-related thrombocytopenia can be severe and life-threatening.Despite the severity of coronavirus-related immune thrombocytopenia, recovery may be spontaneous or achieved following immunoglobulin or platelet growth factor administration.
