Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

Zimmerman, Ofer; Rösler, Berenice; Zerbe, Christa S.; Rosen, Lindsey B.; Hsu, Amy P.; Uzel, Gülbû; Freeman, Alexandra F.; Sampaio, Elizabeth P.; Rosenzweig, Sergio D.; Kuehn, Hye Sun; Kim, Tiffany; Brooks, Kristina M; Kumar, Parag; Wang, Xiaowen; Netea, Mihai G.; Veerdonk, Frank L. van de; Holland, Steven M.

doi:10.1093/ofid/ofx202

Cited by 57 publications

(51 citation statements)

References 18 publications

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“…Interestingly, other STAT1 GOF related disorders, such as alopecia and enteropathy have also shown considerable improvement with JAK1/2 inhibitors . In contrast to these reports, two adult patients with severe dermatophytosis and disseminated coccidioidomycosis due to STAT1 GOF mutation were recently reported to fail to respond to ruxolitinib . In our study, one of the patients was treated with ruxolitinib, 10 mg twice daily, due to aortic calcification which is believed to be driven by IFN .…”

Section: Discussionmentioning

confidence: 58%

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

et al. 2019

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STAT1 gain‐of‐function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1‐dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN‐α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN‐α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon‐stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon‐related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

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Section: Discussionmentioning

confidence: 58%

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

et al. 2019

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“…However, major adverse effects, such as infection and a cytokine rebound effect, have been reported in patients treated with ruxolitinib for STAT1 GOF mutations and other conditions (126)(127)(128). Recently, an international retrospective study on a cohort of 15 patients with STAT1 GOF mutations who received HSCT showed poor overall survival (40%) and poor event-free survival (10%) (129).…”

Section: Stat1mentioning

confidence: 99%

Lessons learned from the study of human inborn errors of innate immunity

Bucciol

Moens

Bosch

et al. 2019

Journal of Allergy and Clinical Immunology

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Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors.

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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%

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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Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

Cited by 57 publications

References 18 publications

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

Lessons learned from the study of human inborn errors of innate immunity

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

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