Tofacitinib relieves symptoms of stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173

Seo, Jieun; Kang, Jung Ah; Suh, Dong In; Park, Eun Byeol; Lee, Cho Rong; Choi, Sun Ah; Kim, Soo Yeon; Kim, Yeji; Park, Sang Heon; Ye, Michael; Kwon, Soonhak; Park, June Dong; Lim, Byung Chan; Lee, Dong Hun; Kang, Sang-Won; Choi, Murim; Park, Sung‐Gyoo; Chae, Jong Hee

doi:10.1016/j.jaci.2016.10.030

Cited by 72 publications

(51 citation statements)

References 16 publications

(24 reference statements)

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“…Interferonopathies represent a collection of both acquired and inherited disorders characterized by overproduction of IFNs. Genetic disorders included among the interferonopathies have been treated with jakinibs with positive results . However, higher doses are required to control symptoms in these patients and treatment has been associated with BK viremia, presumably related to over‐immunosuppression .…”

Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

“…Genetic disorders included among the interferonopathies have been treated with jakinibs with positive results. [110][111][112][113] However, higher doses are required to control symptoms in these patients and treatment has been associated with BK viremia, presumably related to overimmunosuppression. 111,113,114 Of interest, it has been proposed that Down syndrome should be classified as an interferonopathy, and jakinibs have been suggested as a possible therapy.…”

Section: Polycythemia Vera and Myelofibrosismentioning

confidence: 99%

“…[110][111][112][113] However, higher doses are required to control symptoms in these patients and treatment has been associated with BK viremia, presumably related to overimmunosuppression. 111,113,114 Of interest, it has been proposed that Down syndrome should be classified as an interferonopathy, and jakinibs have been suggested as a possible therapy. 115 Other genetic disorders that directly involve STATs include STAT1 GOF-driven, chronic mucocutaneous candidiasis and STAT3 GOF-associated autoimmunity; jakinibs are being tested in these disorders.…”

Section: Polycythemia Vera and Myelofibrosismentioning

confidence: 99%

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Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

129

100

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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Section: A Brief Survey Of Approved and Late Phase Jakinibsmentioning

confidence: 99%

Section: Polycythemia Vera and Myelofibrosismentioning

confidence: 99%

Section: Polycythemia Vera and Myelofibrosismentioning

confidence: 99%

See 1 more Smart Citation

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

129

100

View full text Add to dashboard Cite

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“…In addition, evidence indicates that inflammatory disease can be caused by germline missense mutations in the coding region of the STING gene itself (V147L/M, N154S, V155M, C206Y, R281Q, R284G, and S102P/F279L), which exert a gain-of-func-tion phenotype referred to as STING-associated vasculopathy with onset in infancy (SAVI) (Clarke et al, 2016; Fre´mond et al, 2016; Jeremiah et al, 2014; Liu et al, 2014; Melki et al, 2017;Picard et al, 2016; Seo et al, 2017). This disease causes skin lesions, rashes, and interstitial lung disease in children.…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

et al. 2018

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The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial orself-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of auto- inflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate cytokine production. Our findings add to the growing list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease.

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“…Ex vivo treatment with any of three JAK inhibitors blocked the constitutive phosphorylation of STAT1 in a patient's B and CD4+ T cells 46 . Recently two papers reported the clinical efficacy of JAK inhibitors in SAVI 52,56 , with reduction in febrile episodes and almost complete resolution of dermatologic lesions. Early genetic diagnosis and treatment may prevent the eventual need for surgical amputations and the irreversible pulmonary damage of SAVI.…”

Section: Type I Interferonopathiesmentioning

confidence: 99%

Genomics, Biology, and Human Illness

Oda

Kastner

2017

Rheumatic Disease Clinics of North America

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SYNOPSIS The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically-determined recurrent sterile inflammation, and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines such as IL-1 and TNF and intracellular cytokine signaling pathways have proven effective in many cases. Emerging next generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. In this review we will cover several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.

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Tofacitinib relieves symptoms of stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173

Abstract: IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens.

Cited by 72 publications

References 16 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

Genomics, Biology, and Human Illness

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