Treatment of STAT3-deficient hyper–immunoglobulin E syndrome with monoclonal antibodies targeting allergic inflammation

James, Alyssa; West, Laura; Schloss, Katheryn; Nataraj, Pavan; Urban, Amanda; Hirsch, Aleksandra; Krausz, Máté; Kumar, Shashi; Raasch, Jason; Risma, Kimberly A.; Church, Joseph A.; Grimbacher, Bodo; Bergerson, Jenna; Chong, Hey; Freeman, Alexandra F.

doi:10.1016/j.jaip.2022.01.011

Cited by 10 publications

(8 citation statements)

References 7 publications

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“… 17 Off‐label use of dupilumab, an IL‐4a receptor antagonist that disrupts the unbalanced IL‐4 signaling and the allergic type 2 cytokine signature in HIES, has demonstrated efficacy for atopic dermatitis in HIES, as well as other HIES manifestations including asthma and allergic bronchopulmonary aspergillosis. 1 , 18 This case report adds to the existing literature in demonstrating sustained clearance of atypical skin manifestations, including eosinophilic folliculitis and recurrent cutaneous infections. Though further studies are warranted, dupilumab demonstrates potential as an option for long‐term management of the cutaneous spectrum of HIES due to its targeted mechanism of action.…”

Section: Discussionmentioning

confidence: 62%

“…Prophylactic antibiotics targeted against S. aureus , bleach baths, chlorhexidine washes, and immune globulin replacement are efficacious for prevention of infection 17 . Off‐label use of dupilumab, an IL‐4a receptor antagonist that disrupts the unbalanced IL‐4 signaling and the allergic type 2 cytokine signature in HIES, has demonstrated efficacy for atopic dermatitis in HIES, as well as other HIES manifestations including asthma and allergic bronchopulmonary aspergillosis 1,18 . This case report adds to the existing literature in demonstrating sustained clearance of atypical skin manifestations, including eosinophilic folliculitis and recurrent cutaneous infections.…”

Section: Discussionmentioning

confidence: 77%

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Clearance of atypical cutaneous manifestations of hyper‐IgE syndrome with dupilumab

Nihal

Comstock

Holland

et al. 2022

Pediatric Dermatology

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Hyper-IgE syndromes (HIES) are a heterogeneous group of rare primary immunodeficiency diseases classically characterized by the triad of atopic dermatitis, and recurrent cutaneous and pulmonary infections. Autosomal dominant, loss-of-function STAT3 pathogenic variants are the most common genetic cause, which lead to deficiency of Th17 lymphocytes, impaired interferon gamma production, and IL-10 signal transduction, and an unbalanced IL-4 state. Dupilumab, a monoclonal antibody to the IL-4a receptor, inhibits both IL-4 and IL-13, and has been shown to improve atopic dermatitis and other manifestations of HIES including asthma and allergic bronchopulmonary aspergillosis. We present a pediatric patient with HIES who presented predominantly with eosinophilic folliculitis, recurrent cutaneous infections, and other non-eczematous findings and achieved sustained clearance with dupilumab.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 77%

Clearance of atypical cutaneous manifestations of hyper‐IgE syndrome with dupilumab

Nihal

Comstock

Holland

et al. 2022

Pediatric Dermatology

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“…68 This therapeutic approach generally resulted in a dramatic decrease in levels of serum IgE and striking improvement in cutaneous manifestations such as atopic dermatitis, pruritis, asthma, and allergy. 138,[240][241][242][243][244] Furthermore, it was recently reported that dupilumab alleviated clinical features in three patients with STAT6 GOF, including atopy/eczema, eosinophilia, and skin inflammation. 146 These improvements were accompanied by a reduction in the need for corticosteroids as well as a reduction in a Th2 gene signature.…”

Section: Contributi On Of B -Cell E X Trin S I C Fac Tor S To Hyper I...mentioning

confidence: 99%

“…These findings have led to at least three major outcomes. First, they provided proof of concept for the treatment of STAT3 DN, 240–243 ZNF341‐deficient 244 and IL6ST DN 138 patients with the biological inhibitor dupilumab, a mAb against IL‐4R that concomitantly blocks the stimulatory effect of IL‐4 and IL‐13 68 . This therapeutic approach generally resulted in a dramatic decrease in levels of serum IgE and striking improvement in cutaneous manifestations such as atopic dermatitis, pruritis, asthma, and allergy 138,240–244 .…”

Section: Contribution Of B‐cell Extrinsic Factors To Hyper Ige and At...mentioning

confidence: 99%

“…First, they provided proof of concept for the treatment of STAT3 DN, 240–243 ZNF341‐deficient 244 and IL6ST DN 138 patients with the biological inhibitor dupilumab, a mAb against IL‐4R that concomitantly blocks the stimulatory effect of IL‐4 and IL‐13 68 . This therapeutic approach generally resulted in a dramatic decrease in levels of serum IgE and striking improvement in cutaneous manifestations such as atopic dermatitis, pruritis, asthma, and allergy 138,240–244 . Furthermore, it was recently reported that dupilumab alleviated clinical features in three patients with STAT6 GOF, including atopy/eczema, eosinophilia, and skin inflammation 146 .…”

Section: Contribution Of B‐cell Extrinsic Factors To Hyper Ige and At...mentioning

confidence: 99%

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The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

Tangye,

Mackie,

Pathmanandavel

et al. 2023

Immunological Reviews

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SummaryThe essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)‐secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high‐affinity Ag‐specific Abs of different classes, enabling effective pathogen neutralization and long‐lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non‐redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B‐cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses.

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ERBIN and phosphoglucomutase 3 deficiency

Milner

2023

Current Opinion in Immunology

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Treatment of STAT3-deficient hyper–immunoglobulin E syndrome with monoclonal antibodies targeting allergic inflammation

Cited by 10 publications

References 7 publications

Clearance of atypical cutaneous manifestations of hyper‐IgE syndrome with dupilumab

Clearance of atypical cutaneous manifestations of hyper‐IgE syndrome with dupilumab

The trajectory of human B‐cell function, immune deficiency, and allergy revealed by inborn errors of immunity

ERBIN and phosphoglucomutase 3 deficiency

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