Adult-Onset ANCA-Associated Vasculitis in SAVI: Extension of the Phenotypic Spectrum, Case Report and Review of the Literature

Lay Title: A report of adult-onset STING-associated vasculopathy and a literature review describing other adult-onset cases and a wide range of symptoms at presentation

Date of publication:

12/5/26

Author:

Roger Brooks

Category:

SAVI Clinical

Article body content:

Plain Language

This paper describes a family affected by a rare inherited inflammatory disease called SAVI (STING-associated vasculopathy with onset in infancy). SAVI is usually diagnosed in babies or young children, but in this report one young man first became ill at age 19 with kidney inflammation and eye disease linked to ANCA-associated vasculitis.

Genetic testing showed that both he and his father carried a mutation in the STING1 gene. His father had severe lung disease and kidney failure and died young from breathing complications. The study also reviewed 56 known SAVI patients from the medical literature and showed that SAVI can appear in many different ways, including later in life than previously recognised.

The authors highlight that SAVI may sometimes look like autoimmune diseases such as lupus or ANCA vasculitis, which can delay diagnosis.

Why it Matters

This study significantly broadened the recognised clinical spectrum of SAVI. Prior to this report, SAVI was primarily considered a disease of infancy with severe skin and lung involvement. This paper demonstrated that:

· SAVI can present in adulthood,

· disease expression may vary greatly even within families,

· and isolated ANCA-associated vasculitis can be a presenting feature.

The findings are clinically important because patients with unexplained vasculitis, pulmonary fibrosis, or autoimmune serology may have an underlying monogenic interferonopathy. Earlier genetic diagnosis could improve treatment selection and family counselling.

The review also highlighted the severe burden of disease, including high mortality and progressive pulmonary fibrosis.

Hope for the Future

The paper supports growing awareness that SAVI exists along a broad clinical spectrum and may be under-recognised in adults with inflammatory or autoimmune disease.

The authors suggest that improved recognition of interferonopathies may lead to:

· earlier diagnosis,

· more targeted treatments,

· better monitoring for lung and kidney complications,

· and future development of precision therapies aimed at interferon/STING signalling pathways.

Although treatment responses remain variable, the growing use of JAK inhibitors and interferon-targeted therapies offers hope for more effective disease control in the future.

Read More:

Background

SAVI is an autosomal dominant type I interferonopathy caused by gain-of-function mutations in STING1/TMEM173, which encodes the stimulator of interferon genes (STING) protein. Constitutive STING activation drives chronic innate immune activation and excessive interferon signalling, leading to systemic inflammation and vasculopathy.

SAVI was originally described as a severe infantile vasculopathy characterised by:

· cutaneous vasculitis,

· interstitial lung disease (ILD),

· pulmonary fibrosis, and

· systemic inflammation.

However, accumulating evidence suggests broader phenotypic heterogeneity. In this report, the authors describe a family carrying a heterozygous p.V155M STING1

mutation, in which the proband presented with isolated adult-onset anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis affecting the kidneys and eyes.

The study additionally reviewed 56 genetically confirmed SAVI cases to better define:

· age of onset,

· organ involvement,

· mortality,

· genotype-phenotype relationships, and

· treatment responses.

What the Study Found

The 19-year-old proband presented with:

· exertional dyspnoea,

· severe microcytic anaemia,

· iritis,

· myeloperoxidase (MPO)-positive ANCA,

· proteinuria,

· haematuria and

· pauci-immune crescentic necrotizing glomerulonephritis on renal biopsy.

Family history was significant:

· the patient’s father had childhood-onset pulmonary fibrosis and ANCA-associated vasculitis leading to respiratory failure and death at age 30,

· and a sibling died in utero with renal vein thrombosis.

Whole-exome sequencing identified a pathogenic STING1 c.463G>A (p.V155M) mutation. Interferon-stimulated gene expression was markedly elevated, confirming interferon pathway activation.

The literature review of 56 SAVI patients demonstrated:

· disease onset usually occurred early in life, but adult-onset disease was possible,

· mortality was high (18%), mainly due to respiratory complications,

· pulmonary involvement occurred in nearly 70% of patients, often progressing to fibrosis,

· cutaneous vasculopathy was common, including chilblains, telangiectasia, livedo reticularis, and digital ischemia,

· renal disease was rare but included glomerulonephritis and focal segmental glomerulosclerosis,

· many patients had positive autoantibodies including anti-nuclear (ANA)A and ANCA, sometimes leading to misdiagnosis as lupus or ANCA vasculitis.

The paper also noted that conventional immunosuppressive therapies often had limited efficacy. JAK inhibitors showed variable benefit in some patients. In the reported patient, rituximab, glucocorticoids, and azathioprine achieved remission of ocular disease and partial renal improvement.

Citation Staels et al., 2020 Front. Immunol. 11:575219.

Authors

Staels F, Betrains A, Doubel P, Willemsen M, Cleemput V, Vanderschueren S,

Corveleyn A, Meyts I, Sprangers B, Crow YJ, Humblet-Baron S, Liston A,

Schrijvers R

Date of publication 29/9/2020 Link 10.3389/fimmu.2020.575219