STING Associated Vasculopathy with Onset in Infancy

STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function variants in STING1 (TMEM173). It causes cold induced vasculopathy with skin ulceration and interstitial lung disease from infancy.

Pathophysiology. Gain-of-function variants make STING signal without its ligand, driving constant interferon beta and interferon stimulated gene activity and vascular injury. Endothelial and lung cells are damaged, and T cells and lymphocytes are lost.

It is very rare. Variants are usually de novo, and dominant inheritance occurs in a few families.

Lung disease determines survival in many patients.

• Violaceous, painful rash on cheeks, nose, ears, fingers and toes, worse in the cold, from the first weeks to months of life
• Acral ulceration, necrosis and loss of digits
• Nasal septal perforation
• Interstitial lung disease with cough, tachypnoea, hypoxaemia and failure to thrive
• Recurrent fever and recurrent infection
• Lung fibrosis and pulmonary hypertension
• Arthritis, myositis and autoimmune features (positive autoantibodies)

• Genetic testing of STING1 (TMEM173), with parental testing.
• Interferon signature: raised interferon stimulated gene expression in blood, and raised interferon induced chemokines.
• Inflammatory markers: CRP, ESR and immunoglobulins.
• Autoantibodies: antinuclear antibody, ANCA, antiphospholipid antibodies, rheumatoid factor.
• Lung assessment: high resolution CT, lung function and oxygen saturation (overnight oximetry), echocardiogram for pulmonary hypertension.
• Skin biopsy: vasculopathy with capillary thrombosis, and inflammation.
• Exclusion of infection and other interferonopathies.

Differential diagnosis.

• Aicardi-Goutières syndrome, COPA syndrome and other type I interferonopathies
• Chilblain lupus and familial chilblain lupus (TREX1)
• Granulomatosis with polyangiitis and other vasculitis
• Systemic lupus erythematosus
• Antiphospholipid syndrome and cold agglutinin disease
• Primary immunodeficiency with interstitial lung disease

• JAK inhibitor (reduces interferon signalling) in specialist care: baricitinib 4 mg orally once daily in adults (children 2 to 4 mg daily by weight), or ruxolitinib 5 to 20 mg orally twice daily in adults (children by weight), or tofacitinib 5 mg orally twice daily. Titrate to response and tolerance.
• Infection prophylaxis on JAK inhibitor: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly), and inactivated vaccines before starting.
• Adjuncts: prednisolone 0.5 to 1 mg/kg orally daily (maximum 60 mg) for flares, with limited effect on lung disease.
• Skin and vascular care: protect from cold, keep warm, avoid smoking, treat ulcers with wound care, and consider vasodilators (for example nifedipine) for acral ischaemia.
• Lung disease: oxygen, treat infections promptly, monitor pulmonary hypertension, and consider lung transplant in end stage disease.
• Screen before JAK inhibitor therapy: blood count, liver enzymes, lipids, hepatitis B and C, HIV, and tuberculosis, with monitoring thereafter.
• Genetic counselling: most variants are de novo, but recurrence risk exists with germline mosaicism.

Special groups.

• Infants: dose by weight, growth monitoring, and close respiratory review.
• Patients with end stage lung disease: early transplant assessment.

Monitoring. Full blood count, liver enzymes, creatinine and lipids every 1 to 3 months on a JAK inhibitor. Lung function, oximetry and high resolution CT every 6 to 12 months. Echocardiogram yearly. Skin and digit review at each visit.

Referral and escalation. Refer to paediatric immunology, rheumatology and respiratory medicine. Urgent for new hypoxaemia, fever, digital necrosis or infection. Emergency for respiratory failure.