STING-associated vasculopathy with onset in infancy

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome Abstract Objectives Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. Methods We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. Results We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. Conclusions We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

STING-associated vasculopathy with onset in infancy 
 Description
STING-associated vasculopathy with onset in infancy (SAVI) is a disorder involving abnormal inflammation throughout the body, especially in the skin, blood vessels, and lungs. Inflammation normally occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and help with tissue repair. Excessive inflammation damages the body's own cells and tissues. Disorders such as SAVI that result from abnormally increased inflammation are known as autoinflammatory diseases.

The signs and symptoms of SAVI begin in the first few months of life, and most are related to problems with blood vessels (vasculopathy) and damage to the tissues that rely on these vessels for their blood supply. Affected infants develop areas of severely damaged skin (lesions), particularly on the face, ears, nose, fingers, and toes. These lesions begin as rashes and can progress to become wounds (ulcers) and dead tissue (necrosis). The skin problems, which worsen in cold weather, can lead to complications such as scarred ears, a hole in the tissue that separates the two nostrils (nasal septum perforation), or fingers or toes that require amputation. Individuals with SAVI also have a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin. Affected individuals may also experience episodes of Raynaud phenomenon, in which the fingers and toes turn white or blue in response to cold temperature or other stresses. This effect occurs because of problems with the small vessels that carry blood to the extremities.

In addition to problems affecting the skin, people with SAVI have recurrent low-grade fevers and swollen lymph nodes. They may also develop widespread lung damage (interstitial lung disease) that can lead to the formation of scar tissue in the lungs (pulmonary fibrosis) and difficulty breathing; these respiratory complications can become life-threatening. Rarely, muscle inflammation (myositis) and joint stiffness also occur.

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 Frequency
The prevalence of this condition is unknown. Only a few affected individuals have been described in the medical literature.

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 Causes
SAVI is caused by mutations in the TMEM173 gene. This gene provides instructions for making a protein called STING, which is involved in immune system function. STING helps produce beta-interferon, a member of a class of proteins called cytokines that promote inflammation.

The TMEM173 gene mutations that cause SAVI are described as "gain-of-function" mutations because they enhance the activity of the STING protein, leading to overproduction of beta-interferon. Abnormally high beta-interferon levels cause excessive inflammation that results in tissue damage, leading to the signs and symptoms of SAVI.

 Learn more about the gene associated with SAVI
TMEM173
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 Inheritance Pattern
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, this condition likely results from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

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 Diagnosis & Management Links
 Genetic Testing Information (2 links)
What is genetic testing?
Genetic Testing Registry: Sting-associated vasculopathy, infantile-onset
 Research Studies from ClinicalTrials.gov (1 link)
ClinicalTrials.gov
 Other Diagnosis and Management Resources (3 links)
Beth Israel Deaconess Medical Center: Autoinflammatory Disease Center
Eurofever Project
University College London: Vasculitis and Autoinflammation Research Group
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 Other Names for This Condition
SAVI
STING-associated vasculopathy, infantile onset
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 Additional Information & Resources
 Health Information from MedlinePlus (3 links)
Health Topic: Autoimmune Diseases
Health Topic: Fever
Health Topic: Interstitial Lung Diseases
 Genetic and Rare Diseases Information Center (1 link)
STING-associated vasculopathy with onset in infancy
 Additional NIH Resources (3 links)
National Institute of Arthritis and Musculoskeletal and Skin Diseases: Autoinflammatory Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases: Raynaud's Phenomenon
NIH News: NIH Scientists Identify Gene Linked to Fatal Inflammatory Disease in Children
 Educational Resources (3 links)
International Patient Organisation for Primary Immunodeficiences: Autoimmunity and Autoinflammation (PDF)
MalaCards: sting-associated vasculopathy with onset in infancy
Orphanet: STING-associated vasculopathy with onset in infancy
 Patient Support and Advocacy Resources (1 link)
Autoinflammatory Alliance
 Scientific Articles on PubMed (1 link)
PubMed
 Catalog of Genes and Diseases from OMIM (1 link)
STING-ASSOCIATED VASCULOPATHY, INFANTILE-ONSET
 Medical Genetics Database from MedGen (1 link)
Sting-associated vasculopathy, infantile-onset
 Sources for This Page
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