Successful treatment of JAK1-associated inflammatory disease
Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:152 |
|---|---|
| Enthalten in: |
The Journal of allergy and clinical immunology - 152(2023), 4 vom: 10. Okt., Seite 972-983 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 24.10.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jaci.2023.06.004 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM358453054 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM358453054 | ||
| 003 | DE-627 | ||
| 005 | 20231226074755.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jaci.2023.06.004 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1194.xml |
| 035 | |a (DE-627)NLM358453054 | ||
| 035 | |a (NLM)37343845 | ||
| 035 | |a (PII)S0091-6749(23)00799-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Fayand, Antoine |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Successful treatment of JAK1-associated inflammatory disease |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.10.2023 | ||
| 500 | |a Date Revised 24.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a JAK 1 | |
| 650 | 4 | |a JAK inhibitors | |
| 650 | 4 | |a allergy | |
| 650 | 4 | |a atopic dermatitis | |
| 650 | 4 | |a inborn errors of immunity | |
| 650 | 7 | |a baricitinib |2 NLM | |
| 650 | 7 | |a ISP4442I3Y |2 NLM | |
| 650 | 7 | |a Janus Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Histamine |2 NLM | |
| 650 | 7 | |a 820484N8I3 |2 NLM | |
| 650 | 7 | |a JAK1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Janus Kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 700 | 1 | |a Hentgen, Véronique |e verfasserin |4 aut | |
| 700 | 1 | |a Posseme, Céline |e verfasserin |4 aut | |
| 700 | 1 | |a Lacout, Carole |e verfasserin |4 aut | |
| 700 | 1 | |a Picard, Capucine |e verfasserin |4 aut | |
| 700 | 1 | |a Moguelet, Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Cescato, Margaux |e verfasserin |4 aut | |
| 700 | 1 | |a Sbeih, Nabiha |e verfasserin |4 aut | |
| 700 | 1 | |a Moreau, Thomas R J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Yixiang Y J |e verfasserin |4 aut | |
| 700 | 1 | |a Charuel, Jean-Luc |e verfasserin |4 aut | |
| 700 | 1 | |a Corneau, Aurélien |e verfasserin |4 aut | |
| 700 | 1 | |a Deibener-Kaminsky, Joelle |e verfasserin |4 aut | |
| 700 | 1 | |a Dupuy, Stéphanie |e verfasserin |4 aut | |
| 700 | 1 | |a Fusaro, Mathieu |e verfasserin |4 aut | |
| 700 | 1 | |a Hoareau, Benedicte |e verfasserin |4 aut | |
| 700 | 1 | |a Hovnanian, Alain |e verfasserin |4 aut | |
| 700 | 1 | |a Langlois, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Le Corre, Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Maciel, Thiago T |e verfasserin |4 aut | |
| 700 | 1 | |a Miskinyte, Snaigune |e verfasserin |4 aut | |
| 700 | 1 | |a Miyara, Makoto |e verfasserin |4 aut | |
| 700 | 1 | |a Moulinet, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Perret, Magali |e verfasserin |4 aut | |
| 700 | 1 | |a Schuhmacher, Marie Hélène |e verfasserin |4 aut | |
| 700 | 1 | |a Rignault-Bricard, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Viel, Sébastien |e verfasserin |4 aut | |
| 700 | 1 | |a Vinit, Angélique |e verfasserin |4 aut | |
| 700 | 1 | |a Soria, Angèle |e verfasserin |4 aut | |
| 700 | 1 | |a Duffy, Darragh |e verfasserin |4 aut | |
| 700 | 1 | |a Launay, Jean-Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Callebert, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Herbeuval, Jean Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Rodero, Mathieu P |e verfasserin |4 aut | |
| 700 | 1 | |a Georgin-Lavialle, Sophie |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of allergy and clinical immunology |d 1971 |g 152(2023), 4 vom: 10. Okt., Seite 972-983 |w (DE-627)NLM000018449 |x 1097-6825 |7 nnns |
| 773 | 1 | 8 | |g volume:152 |g year:2023 |g number:4 |g day:10 |g month:10 |g pages:972-983 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jaci.2023.06.004 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 152 |j 2023 |e 4 |b 10 |c 10 |h 972-983 | ||