STAT3 gain of function: a new aetiology of severe rheumatic disease

Giovannini‐Chami, Lisa; Vogel, Tiphanie P.; Forbes, Lisa R.; Fabre, Alexandre; Trojani, Marie-Charlotte; Leroy, Sylvie; Antunès, Ophélie; Vincent-Mefitiot, Nathalie; Hiéronimus, S.; Baqué-Juston, Marie; Roux, Christian; Tieulié, N.

doi:10.1093/rheumatology/key308

Cited by 17 publications

(26 citation statements)

References 7 publications

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“…Clinical expression phenotypes of STAT3 GOF syndrome are very diverse. Among the 42 cases (sex ratio (M/F) = 18/22 = 0.82) 1,4,6,7,[13][14][15][16][17][18]10,[19][20][21][22]11,[23][24][25] , the most frequent features were hematologic disease, failure to thrive/short stature and multi-organ autoimmune disorders.…”

Section: Clinical Aspectsmentioning

confidence: 99%

Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

Fabre

Marchal

Barlogis

et al. 2019

The Journal of Allergy and Clinical Immunology: In Practice

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158

155

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Background: STAT3 gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled. Objective:We have conducted a systematic review of published STAT3 GOF cases in order to describe clinical, diagnostic and therapeutic aspects of the disease.Methods: A systematic review including articles published before 10/10/2018 in Pubmed, WoS and CENTRAL databases was performed. We described cases of patients with STAT3 GOF germline mutations with genetic analysis and a concordant phenotype if functional analyses were not performed for the mutation. Results:The search identified 18 publications describing 42 unique patients. Twenty-eight different mutations were described. Onset of disease was very early with an average age of 3 (0.5-5) years old. The most frequent manifestations were: autoimmune cytopenias (28/42), lymphoproliferation (27/42), enteropathy (24/42), interstitial lung disease (15/42), thyroiditis (13/42), diabetes (10/42), and post-natal growth failure (15/21). Immunodeficiency was not always a predominant feature. Most patients required significant immunosuppressive therapy.Five patients received hematopoietic stem cell transplantation, 4 died from complications. Improvement of symptoms was observed for 8 out of 9 patients that received targeted biotherapies.

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Section: Clinical Aspectsmentioning

confidence: 99%

Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

Fabre

Marchal

Barlogis

et al. 2019

The Journal of Allergy and Clinical Immunology: In Practice

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158

155

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“…Retrospective analysis of published case reports and smaller case series indicated that systemic steroids only showed benefit in 3/17 patients [ 14 ]. Similarly poor treatment responses have been reported with mycophenolate mofetil (MMF) (2/5), Tacrolimus (1/4), Azathioprine (0/4) and Rituximab (1/3) [ 2 , 4 , 14 , [86] , [87] , [88] , [89] , [90] , [91] ]. However, there might be an ascertainment bias in retrospective analysis and ongoing larger cohort studies can hopefully provide more information on the use of non-targeted immunosuppressive agents in STAT3 GOF disease.…”

Section: Treating Stat3 Gof Diseasementioning

confidence: 70%

“…Tocilizumab is a monoclonal antibody against the IL6 receptor and Janus kinase inhibitors such as ruxolitinib act directly upstream of STAT3. Targeted immunosuppression with these agents has been successfully applied for the treatment of most of STAT3 GOF related symptoms including arthritis [ 4 , 86 , 91 ], interstitial lung disease [ 17 , 26 , 27 , 86 ] and enteropathy [ 22 , 27 , 92 ]. Several groups reported an additional benefit of combined treatment with tocilizumab and JAK-inhibitors in patients with severe ILD or severe enteropathy [ 27 , 86 ].…”

Section: Treating Stat3 Gof Diseasementioning

confidence: 99%

Germline STAT3 gain-of-function mutations in primary immunodeficiency: Impact on the cellular and clinical phenotype

Faletti¹,

Ehl²,

Heeg³

2021

Biomedical Journal

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Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor involved in regulation of immune cell activation and differentiation. Recent discoveries highlight the role of germline activating STAT3 mutations in inborn errors of immunity characterized by early-onset multi-organ autoimmunity and lymphoproliferation. Much progress has been made in defining the clinical spectrum of STAT3 GOF disease and unraveling the molecular and cellular mechanisms underlying this disease. In this review, we summarize our current understanding of the disease and discuss the clinical phenotype, diagnostic approach, cellular and molecular effects of STAT3 GOF mutations and therapeutic concepts for these patients.

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“…Patients with STAT3 GOF were treated with regular immunosuppressive treatments before the results of gene sequencing which always couldn't control all the clinical manifestations [10][11][12][13][14]. Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3].…”

mentioning

confidence: 99%

“…Functional analyses of STAT3 GOF mutations demonstrated increased transcriptional activity of STAT3 in unstimulated and/or stimulated cells in vitro [3]. Because IL-6 is one of the primary cytokines that utilizes STAT3 for signal transduction, IL-6 receptor (IL-6R) antagonist therapy currently have been reported to be effective in these patients [4,5,[10][11][12][13]. Here, we reviewed the clinical manifestations and immunological features of one patient with a STAT3 GOF mutation.…”

mentioning

confidence: 99%

Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation

et al. 2021

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Background We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. Results The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. Conclusions Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

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STAT3 gain of function: a new aetiology of severe rheumatic disease

Cited by 17 publications

References 7 publications

Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

Germline STAT3 gain-of-function mutations in primary immunodeficiency: Impact on the cellular and clinical phenotype

Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation

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