Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

Stefano Volpi, Antonella Insalaco, Roberta Caorsi, Elettra Santori, Virginia Messia, Oliviero Sacco, Suzanne Terheggen-Lagro, Fabio Cardinale, Alessia Scarselli, Claudia Pastorino, Gianmarco Moneta, Giuliana Cangemi, Chiara Passarelli, Margherita Ricci, Donata Girosi, Maria Derchi, Paola Bocca, Andrea Diociaiuti, May El Hachem, Caterina Cancrini & 7 others Paolo Tomà, Claudio Granata, Angelo Ravelli, Fabio Candotti, Paolo Picco, Fabrizio DeBenedetti, Marco Gattorno

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.

METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.

RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.

CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

Original languageEnglish
Pages (from-to)476-485
Number of pages10
JournalJournal of Clinical Immunology
Volume39
Issue number5
DOIs
Publication statusPublished - Jul 2019

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Janus Kinases
Therapeutics
Virus Diseases
Respiratory Tract Infections
Interferon Type I
Skin
Mutation
Interstitial Lung Diseases
Vital Capacity
Hematuria
Immunosuppressive Agents
DNA Sequence Analysis
Pulmonary Hypertension
Disease Progression
Steroids
Oxygen

Cite this

@article{25098e689b8d405ea67dc1f1fed5dbb8,
title = "Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome",
abstract = "OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.",
author = "Stefano Volpi and Antonella Insalaco and Roberta Caorsi and Elettra Santori and Virginia Messia and Oliviero Sacco and Suzanne Terheggen-Lagro and Fabio Cardinale and Alessia Scarselli and Claudia Pastorino and Gianmarco Moneta and Giuliana Cangemi and Chiara Passarelli and Margherita Ricci and Donata Girosi and Maria Derchi and Paola Bocca and Andrea Diociaiuti and {El Hachem}, May and Caterina Cancrini and Paolo Tom{\`a} and Claudio Granata and Angelo Ravelli and Fabio Candotti and Paolo Picco and Fabrizio DeBenedetti and Marco Gattorno",
year = "2019",
month = "7",
doi = "10.1007/s10875-019-00645-0",
language = "English",
volume = "39",
pages = "476--485",
journal = "Journal of Clinical Immunology",
issn = "0271-9142",
publisher = "Springer New York",
number = "5",

}

TY - JOUR

T1 - Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

AU - Volpi, Stefano

AU - Insalaco, Antonella

AU - Caorsi, Roberta

AU - Santori, Elettra

AU - Messia, Virginia

AU - Sacco, Oliviero

AU - Terheggen-Lagro, Suzanne

AU - Cardinale, Fabio

AU - Scarselli, Alessia

AU - Pastorino, Claudia

AU - Moneta, Gianmarco

AU - Cangemi, Giuliana

AU - Passarelli, Chiara

AU - Ricci, Margherita

AU - Girosi, Donata

AU - Derchi, Maria

AU - Bocca, Paola

AU - Diociaiuti, Andrea

AU - El Hachem, May

AU - Cancrini, Caterina

AU - Tomà, Paolo

AU - Granata, Claudio

AU - Ravelli, Angelo

AU - Candotti, Fabio

AU - Picco, Paolo

AU - DeBenedetti, Fabrizio

AU - Gattorno, Marco

PY - 2019/7

Y1 - 2019/7

N2 - OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

AB - OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

U2 - 10.1007/s10875-019-00645-0

DO - 10.1007/s10875-019-00645-0

M3 - Article

VL - 39

SP - 476

EP - 485

JO - Journal of Clinical Immunology

JF - Journal of Clinical Immunology

SN - 0271-9142

IS - 5

ER -