Overview of STING-associated vasculopathy with onset in infancy (SAVI) among 21 patients.

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 SAVI patients. Methods Assessment of clinical, radiological, and immunologic data from 21 patients (17 families). Results Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most patients were symptomatic from infancy but late onset in adulthood occurred in one 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 one infant mimicked a combined immune deficiency. Extended features reminiscent of other interferonopathies were also found e.g. intracranial calcification, glaucoma, 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 benefice of ruxolitinib in SAVI unless the treatment is started early in the course of the disease underlying the need for early diagnosis. Tolerance was reasonably good. Conclusion This largest worldwide cohort of SAVI patients precise core features and extends the clinical and immunological phenotype of the disease, displaying overlap with other monogenic interferonopathies.