​SAVI – STING-associated vasculopathy with onset in infancy

Symptoms

The signs and symptoms of SAVI begin in the first months of life, and most problems are related to blood vessels (vasculopathy) and damage to the tissues that rely on these vessels for their blood supply. Affected children develop areas of severe skin lesions, especially on the face, ears, nose, fingers and toes. These lesions begin as a rash and can develop as wounds (ulcers) and dead tissue (necrosis). The skin problems, which get worse in cold weather, can lead to complications such as a tympanic membrane perforation, a hole in the tissue separating the two nostrils (nasal septum perforation) or the amputation of a finger or a toe. Individuals with SAVI also have a violet skin colour (livedo reticularis), which is caused by abnormalities in the tiny blood vessels of the skin. Affected individuals may also experience episodes of Raynaud's disease, in which the fingers and toes turn white or blue, in response to cold temperatures or stress. This effect occurs because of problems with the small vessels carrying blood to the extremities.

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In addition to problems affecting the skin, people with SAVI have recurrent low fever and swollen lymph nodes. They can also have extensive lung damage (interstitial lung disease), which can lead to the formation of scar tissue in the lungs (pulmonary fibrosis) and difficulty in breathing. These respiratory diseases can become life-threatening. Rarely, muscle inflammation (myositis) and joint stiffness can occur.

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SAVI is a rare disease with unknown prevalence. As per the articles reviewed, only 25 cases appear to have been reported so far. These patients variably manifest cutaneous lesions and inflammatory lung disease.

Diagnosis

The diagnosis is made by a genetic test. SAVI is caused by mutations in the TMEM173 gene. This gene provides instructions for the production of a protein called STING, which is involved in the function of the immune system. STING helps produce beta-interferon, which is part of a group of proteins called cytokines that promote inflammation.

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The TMEM173 mutations, which are responsible for causing SAVI, are often described as gain of function mutations because they increase the activity of the STING protein leading to overproduction of beta interferon. The unusual high levels of beta interferon cause excessive inflammation leading to tissue damage, and also to signs and symptoms of SAVI. In patients with STING mutations, interferon is active all the time. Interferons modulate innate (autoinflammatory) and adaptive (autoimmune) pathologic immune responses, in addition to the cell-intrinsic and antiviral effect.

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A diagnosis of SAVI has significant implications for patients and families, not only from the high mortality risk but also from the significant morbidity. The respiratory component of the disease may predominate, and pulmonary complications have been the cause of death.

Treatment

Unfortunately, treatment with steroids and immunosuppressive therapies apparently have shown no efficacy in avoiding progression to irreversible lung damage.  

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A new type of medication, called JAK inhibitors — tofacitinib, ruxolitinib, and baricitinib — can block the effect of the antiviral molecules, and may be useful in children with SAVI. Children with SAVI do not have significant elevations in IL-1 and IL-6, the main drivers of inflammation in most autoinflammatory diseases.  The vehicle for inflammation in patients with SAVI is interferon.