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Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients

Marie-Louise Frémond 1, 2 Alice Hadchouel 3, 4 Laureline Berteloot 5 Isabelle Melki 1, 2, 6 Violaine Bresson 7 Laura Barnabei 1 Nadia Jeremiah 8 Alexandre Belot 9, 10 Vincent Bondet 11, 12 Olivier Brocq 13 Damien Chan 14 Rawane Dagher 15 Jean-Christophe Dubus 16 Darragh Duffy 11, 12 Séverine Feuillet-Soummer 17 Mathieu Fusaro 1, 18 Marco Gattorno 19 Antonella Insalaco 20 Eric Jeziorski 21, 22 Naoki Kitabayashi 1 Mireia Lopez-Corbeto 23 Françoise Mazingue 24 Marie-Anne Morren 25, 26 Gillian Rice 27 Jacques Rivière 23, 28 Luis Seabra 1 Jérôme Sirvente 21 Pere Soler-Palacin 23, 28, 29 Nathalie Stremler-Le Bel 16 Guillaume Thouvenin 30 Caroline Thumerelle 24 Eline van Aerde 25 Stefano Volpi 19 Sophie Willcocks 31 Carine Wouters 2, 25, 32 Sylvain Breton 5 Thierry Molina 33 Brigitte Bader-Meunier 1, 2 Despina Moshous 1, 2 Alain Fischer 1, 2, 34 Stéphane Blanche 2 Frédéric Rieux-Laucat 1 yanick Crow 1, 35 Bénédicte Neven 1, 2 
Abstract : Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD). Objective: To describe a cohort of patients with SAVI. Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out. Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good. Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
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Soumis le : mardi 18 mai 2021 - 13:44:31
Dernière modification le : jeudi 12 mai 2022 - 09:04:07

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Marie-Louise Frémond, Alice Hadchouel, Laureline Berteloot, Isabelle Melki, Violaine Bresson, et al.. Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients. Journal of Allergy and Clinical Immunology: In Practice, Elsevier, 2021, 9 (2), pp.803-818.e11. ⟨10.1016/j.jaip.2020.11.007⟩. ⟨hal-03228789⟩



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