A Novel Biallelic STING1 Gene Variant Causing SAVI in Two Siblings

Alghamdi, Malak; Mulla, Jaazeel; Sharif-Askari, Narjes Saheb; Guzmán‐Vega, Francisco J.; Arold, Stefan T.; Abd-Alwahed, Mervat; Alharbi, Nasser; Kashour, Tarek; Halwani, Rabih

doi:10.3389/fimmu.2020.599564

Cited by 13 publications

(19 citation statements)

References 25 publications

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“…A positive effect was noted in patients, including on the lung status, as ground glass opacities decreased and pulmonary function tests improved. Several other reports reported global improvement under JAK1/2 inhibitors (ruxolitinib or baracitinib) in SAVI [83,[94][95][96]. This was also confirmed in our longer-term follow-up cohort of eight patients treated with ruxolitinib, in which five patients improved their pulmonary radiological and functional parameters [58].…”

Section: Jak Inhibitorssupporting

confidence: 88%

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

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Section: Jak Inhibitorssupporting

confidence: 88%

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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“…Six case reports (34)(35)(36)(37)(38)(39) and seven case series (40)(41)(42)(43)(44)(45)(46) reporting on SAVI could be identified (full text n = 9, conference abstracts n = 1, letters n = 3). Additional two articles (24,33) reported on the same study population (patients with SAVI, CANDLE, other interferonopathies).…”

Section: Evidence On Effectiveness and Safety For Sting Associated Va...mentioning

confidence: 99%

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

et al. 2022

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IntroductionAutoinflammatory diseases (AID) are rare diseases presenting with episodes of sterile inflammation. These involve multiple organs and can cause both acute organ damage and serious long-term effects, like amyloidosis. Disease-specific anti-inflammatory therapeutic strategies are established for some AID. However, their clinical course frequently includes relapsing, uncontrolled conditions. Therefore, new therapeutic approaches are needed. Janus Kinase inhibitors (JAKi) block key cytokines of AID pathogenesis and can be a potential option.MethodsA systematic review of the literature in accordance with the PRISMA guidelines was conducted. Three databases (MEDLINE, Embase and Cochrane Central Register of Controlled Trials) were searched for publications regarding the use of JAKi for AID. Data from the included publications was extracted and a narrative synthesis was performed. Criteria for defining treatment response were defined and applied.ResultsWe report data from 38 publications with a total of 101 patients describing the effects of JAKi in AID. Data on Type I Interferonopathies, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Familial Mediterranean Fever (FMF), and Behçet's Syndrome (BS) was identified. From a total of 52 patients with type I interferonopathies, in seven patients (7/52, 13.5%) a complete response was achieved, most (35/52, 67.3%) showed a partial response and a minority (10/52, 19.2%) showed no treatment response. For AOSD, a complete or a partial response was achieved by eleven (11/26, 42.3%) patients each. Two sJIA patients achieved complete response (2/4, 50%) and in two cases (2/4, 50%) a partial response was reported. Half of FMF patients showed a complete response and the other half had a partial one (3/6, 50.0%). Amongst BS patients most achieved a partial response (8/13, 61.5%). Five patients showed no response to therapy (5/13, 38.5%). Overall, the most frequent AEs were upper respiratory tract infections (17), pneumonia (10), BK virus viremia (10) and viruria (4), herpes zoster infection (5), viral gastroenteritis (2) and other infections (4).ConclusionThe results from this systematic review show that JAKi can be beneficial in certain AID. The risk of AEs, especially viral infections, should be considered. To accurately assess the risk benefit ratio of JAKi for AID, clinical trials should be conducted.

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“…STING-associated vasculopathy with onset in infancy (SAVI) was described in 2014 and is related to GOF mutation in STING1 (65,66). Most patients harbor heterozygous mutations, but few patients with homozygous GOF mutation have been recently described (67,68). STING is a central component in DNA sensing that leads to induction of type I IFNs, which in turn drives the expression of ISG.…”

Section: Savimentioning

confidence: 99%

Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity

2021

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Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.

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A Novel Biallelic STING1 Gene Variant Causing SAVI in Two Siblings

Cited by 13 publications

References 25 publications

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity

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