Journal of Allergy Clinical Immunology: In practice 2020

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

Marie-Louise Frémond, Alice Hadchouel, Laureline Berteloot, Isabelle Melki, Violaine Bresson, Laura Barnabei, Nadia Jeremiah, Alexandre Belot, Vincent Bondet, Olivier Brocq, Damien Chan, Rawane Dagher, Jean-Christophe Dubus , Darragh Duffy, Séverine Feuillet-Soummer, Mathieu Fusaro, Marco Gattorno, Antonella Insalaco, Eric Jeziorski, Naoki Kitabayashi, Mireia Lopez-Corbeto, Françoise Mazingue, Marie-Anne Morren, Gillian I Rice, Jacques G Rivière, Luis Seabra, Jérôme Sirvente, Pere Soler-Palacin, Nathalie Stremler-Le Bel, Guillaume Thouvenin, Caroline Thumerelle, Eline Van Aerde, Stefano Volpi, Sophie Willcocks, Carine Wouters, Sylvain Breton, Thierry Molina, Brigitte Bader-Meunier, Despina Moshous, Alain Fischer, Stéphane Blanche, Frédéric Rieux-Laucat, Yanick J Crow, Bénédicte Neven

Source : Journal of Allergy Clinical Immunology: In practice 2020

2020 Nov 11

Pmid : 33217613

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.

Keywords: Interstitial lung disease; JAK inhibitors; Lymphopenia; Polyarthritis; STING1; Stimulator of interferon genes; Type I interferonopathy; Vasculopathy.

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