Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 ( STAT1 )

Meesilpavikkai, Kornvalee; Dik, Willem A.; Schrijver, Benjamin; Nagtzaam, Nicole M. A.; Sluijs, Sandra J. Posthumus-van; Hagen, P. Martin van; Dalm, Virgil A.S.H.

doi:10.1016/j.jaci.2018.02.045

Cited by 35 publications

(31 citation statements)

References 11 publications

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“…JAK/STAT activation is present in various autoimmune diseases, and treatment with specific JAK inhibitors in immune‐mediated diseases has been increasingly reported . Recently, the oral JAK1/2 inhibitor baricitinib was approved for the treatment of active rheumatoid arthritis and was also found to be effective in the treatment of a patient with a STAT1 gain‐of‐function mutation . In this report, we describe an AGS patient treated with baricitinib and demonstrate its potential clinical applications for the treatment of type I interferonopathies.…”

mentioning

confidence: 83%

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Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi‐Goutières Syndrome, a Type I Interferonopathy

Meesilpavikkai

Dik

Schrijver

et al. 2019

Arthritis & Rheumatology

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mentioning

confidence: 83%

“…Furthermore, we measured total STAT1 and phosphorylated STAT1 in peripheral blood T lymphocytes by flow cytometry . Before and during treatment, T lymphocytes from the patient expressed higher levels of total STAT1 than those observed in 2 age‐, sex‐, and race‐matched healthy controls (Figure C).…”

mentioning

confidence: 96%

Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi‐Goutières Syndrome, a Type I Interferonopathy

Meesilpavikkai

Dik

Schrijver

et al. 2019

Arthritis & Rheumatology

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“…In STAT1 and STAT3 ‐GOF, treatment with JAK inhibitors (i.e., ruxolitinib, tofacitinib, and baricitinib) may reduce the burden of autoimmune disease (e.g., immune cytopenias) and IL‐6 R antagonists (i.e., tocilizumab) used alone or in combination with JAK inhibitors in STAT3 ‐GOF reduces the burden of autoimmune disease, lymphoproliferation, and hyperinflammation . Increased risk of invasive fungal infections needs to be considered when considering addition of JAK inhibitors for the management of immune dysregulation …”

Section: Primary Immune Regulatory Disorders Spectrum: Alps‐like/ipexmentioning

confidence: 99%

“…In STAT1 and STAT3-GOF, treatment with JAK inhibitors (i.e., ruxolitinib, tofacitinib, and baricitinib) [48][49][50] may reduce the burden of autoimmune disease (e.g., immune cytopenias) and IL-6 R antagonists…”

Section: Jakinibs and Il-6 R Antagonistsmentioning

confidence: 99%

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

Chandrakasan

Chandra

Saldaña

et al. 2019

Pediatric Blood & Cancer

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An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS‐like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) and IPEX‐like disorders, common variable immunodeficiency (CVID), CVID‐like, and late‐onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case‐based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.

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“…We here show a partial effect of G-CSF resulting in a clinical benefit. Increasing evidence is accumulating that Jak inhibitors are successful in resolving candidiasis in STAT1 GOF patients (18–20), but this is not entirely risk-free (21). Unfortunately, we have not yet been able to obtain compassionate access to Jak inhibitors for our patient, and as he does not experience adverse effects of G-CSF therapy this therapy is still continued.…”

Section: Discussionmentioning

confidence: 99%

Impaired STAT3-Dependent Upregulation of IL2Rα in B Cells of a Patient With a STAT1 Gain-of-Function Mutation

et al. 2019

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Heterozygous STAT1 gain-of-function (GOF) mutations form the most common genetic cause of chronic mucocutaneous candidiasis (CMC). In such patients, increased STAT1 function leads to impaired STAT3-dependent activation of IL-17A and IL-17F in T cells, thereby causing impaired Th17 responses to Candida . In spite of the critical role of STAT3 in IL-21 signaling in B cells, nearly all STAT1 GOF patients have normal or high serum IgG. We here present a 44 year-old male with childhood onset of CMC and antibody deficiency since early adulthood. Sequence analysis of STAT1 revealed a heterozygous missense mutation in the coiled-coil domain (p.D168E), which resulted in increased STAT1 phosphorylation of B-cells activated with IFNα and IFNγ. IL-21 induced STAT3 phosphorylation and nuclear localization were normal, but resulted in impaired upregulation of IL2Rα. This newly identified B-cell intrinsic impairment of STAT3 function could underlie the progressive development of hypogammaglobulinemia. Considering the high risk of bronchiectasis and irreversible organ damage, this case illustrates the need for monitoring of IgG levels and/or function in adult patients with STAT1 GOF mutations.

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Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 ( STAT1 )

Cited by 35 publications

References 11 publications

Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi‐Goutières Syndrome, a Type I Interferonopathy

Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi‐Goutières Syndrome, a Type I Interferonopathy

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

Impaired STAT3-Dependent Upregulation of IL2Rα in B Cells of a Patient With a STAT1 Gain-of-Function Mutation

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