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 mutations in the STING1 gene, which encodes the stimulator of interferon genes(STING1 protein).

Rare, the exact prevalence of this rare AID - SAVI- is unknown (Frémond et al. 2021).

There are numerous sensor and adapter proteins that help cells to combat invading viruses. STING is one of them. It has been found that patients with STING-associated vasculopathy of infantile onset (SAVI) have a gain-of-function (GOF) mutation in the STING1 gene.

The encoded STING1 protein is anchored to the membrane of the ER and is indirectly activated by viral DNA and abnormal DNA from bacteria or damaged cells (Liu et al., 2021; Sun et al., 2009). After activation, STING1 migrates to the Golgi complex and perinuclear compartment, where it further interacts with several proteins, eventually leading to translocation of IRF3 to the nucleus and induction of type I IFNs (Tsuchiya et al. 2016; Zhao et al. 2016).

Although the activation mechanism varies between DNA and RNA viruses (Liu et al., 2021), SAVI-associated (GOF) mutations in the STING1 gene lead to a constitutionally activated STING1 protein, increased production of IFN-beta and autoinflammation, analogous to other interferonopathies (Ergun et al., 2019). Liu et al. 2014) showed the constitutive activation of the STING signaling pathway in peripheral blood monocytes and the upregulation of reactivity to stimulating factors in fibroblasts from patients with SAVI. In these fibroblasts, the Jak1/2 inhibitor baricitinib, which inhibits the IFN signaling pathway, shows promising results (Kim et al. 2018; Liu et al. 2014; Sanchez et al. 2018).

SAVI is an autoinflammatory syndrome (AID) with onset in early childhood with a median age of symptom onset <6 months. Only in one of 60 reported cases did the symptoms occur in adulthood (Frémond et al. 2021).

Life-threatening are severe inflammatory lung diseases that have not been observed in previously described type I interferonopathies (i.e. Mendelian autoinflammatory diseases defined by constitutive activation of the type I interferon (IFN) signaling pathway). They are clinically characterized by dyspnea, tachypnea and/or cough, with the risk of respiratory failure.

Signs of systemic inflammation are: recurrent fever; failure to thrive, arthritides or arthralgia (Frémond et al. 2021; Liu et al. 2014). In rare cases, calcifications of the basal ganglia can be detected (Cetin Gedik et al. 2022).

Skin lesions may be present at the onset of the disease or develop months later (Tang et al. 2021). As shown in a large case series by Frémond et al. (2021), 86% of patients have skin lesions. Patients usually present with an exanthema of erythematous to purple, infiltrated plaques on the toes, nose and ears, back of the hands, thighs and soles of the feet. The plaques often ulcerate. Patients also present with butterfly erythema on the face and telangiectasias on the cheeks, nose and extremities. In addition, nail dystrophies, diffuse alopecia, livedo, urticarial lesions on the upper extremities, oral aphthosis and gingivostomatitis have been described (Frémond et al. 2021; Schwartz et al. 2021; Tang et al. 2021). In severe cases (19% of patients), SAVI leads to extensive ulcers due to vascular occlusion, resulting in deformation of the ears, perforation of the nasal septum and deformation of the nose (saddle nose), anonychia and gangrene of fingers or toes (Frémond et al. 2021; Liu et al. 2014).

CRP levels and ESR are usually elevated (Liu et al., 2014). The IFN signature in the peripheral blood is also elevated, similar to CANDLE (Cetin Gedik et al. 2022). ANAs (35 of 56 patients), ANCAs (15 of 21 patients/ perinuclear ANCAs and cytoplasmic ANCAs), rheumatoid factor (17 of 30 patients) are found in >50 % of SAVI patients (Frémond et al. 2021). Leukopenia and thrombocytosis are common. IgG and IgA levels are elevated, while IgM and complement levels are within the reference range (Liu et al. 2014).

Inhibition of the Jak/STAT signaling pathway by Jak inhibitors is a promising treatment option, while treatment with glucocorticoids, conventional synthetic drugs (e.g. methotrexate, leflunomide) or biological disease-modifying drugs (e.g. etanercept, infliximab, anakinra, belimumab, rituximab, tocilizumab), hydroxychloroquine, mycophenolate motefil etanercept, infliximab, anakinra, belimumab, rituximab, tocilizumab), hydroxychloroquine, mycophenolate motefil, cyclophosphamide, intravenous immunoglobulins(IVIG), colchicine or thalidomide resulted in no or incomplete response (Cetin Gedik et al. 2022; Liu et al. 2014).

Treatment with Jak inhibitors such as ruxolitinib and baricitinib, initially in combination with systemic corticosteroids, made it possible to reduce disease symptoms (Frémond et al. 2021; Sanchez et al. 2018). Therapies with the Jak inhibitor tofacitinib were less satisfactory (Tang et al. 2020).

Pulmonary diseases are the main cause of morbidity and mortality in SAVI

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