Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis

Steinfeld, Jonathan; Bradford, Eric; Brown, Judith C.; Mallett, Stephen; Yancey, Steven W.; Akuthota, Praveen; Cid, María C.; Gleich, Gerald J.; Jayne, David; Khoury, Paneez; Langford, Carol A.; Merkel, Peter A.; Moosig, Frank; Specks, Ulrich; Weller, Peter F.; Wechsler, Michael E.

doi:10.1016/j.jaci.2018.11.041

Cited by 101 publications

(62 citation statements)

References 20 publications

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“…Eosinophils are generally believed to play important roles in the pathogenesis of certain allergic or inflammatory disorders. For example, anti-interleukin (IL)-5 treatments that selectively attenuate the number and functional status of eosinophils dramatically improve disease control of severe bronchial asthma with eosinophilia or eosinophilic granulomatosis with polyangiitis [1,2]. In a murine model of asthma, a lack of eosinophils is sufficient to abolish airway remodeling [3].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of eosinophilic inflammation

Nagata

Nakagome

Soma

2020

Asia Pacific Allergy

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Eosinophils play roles in the pathogenesis of various diseases. In order to accumulate within sites of inflammation, eosinophils must adhere to, and migrate across the microvasculature. These processes are largely controlled by type 2-immune responses; interleukin (IL)-4 and IL-13 induce the expression of endothelial adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), a representative adhesive ligand for eosinophils, while also stimulating generations of CC chemokines from structural cells, including epithelial cells. VCAM-1 and CC chemokines synergistically induce transmigration of eosinophils to the tissue inflammation site. Another type 2 cytokine, IL-5, prolongs survival, and enhances the effector functions of eosinophils. Recently, accumulating evidence has established that corticosteroid-resistant group 2 innate lymphoid cells are cellular sources for IL-5. Another immunological mechanism that may be contributing to eosinophilic inflammation involves type 1 immune system-associated molecules such as interferons and IP-10. In addition to these immune pathways, lipid mediators, such as cysteinyl leukotrienes, directly provoke the infiltration and activation of eosinophils. Extracellular matrix proteins including periostin also induce the adhesion and activation of eosinophils. Finally, activated neutrophils can also induce eosinophil transmigration. In summary, various mechanisms are involved within eosinophilic inflammation, and effective therapeutic strategies targeting these pathways should be established.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of eosinophilic inflammation

Nagata

Nakagome

Soma

2020

Asia Pacific Allergy

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“…Akin to eotaxin‐1, a serum to lesional gradient is present for IL‐5 that together may explain the highly localized and destructive cellular infiltrates formed in BP . Immunotherapies directed at neutralizing IL‐5 have been trialed in several hypereosinophilic diseases, and mepolizumab, an anti‐IL5 antibody, is currently FDA approved for asthma and eosinophilic granulomatosis with polyangiitis . Its efficacy in BP is currently under investigation in a phase II, randomized, placebo‐controlled, double‐blind study (NCT01705795).…”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Kridin

Kowalski

Kneiber

et al. 2019

Acad Dermatol Venereol

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Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B‐cell depletion, T‐regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases.

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“…In a recent article Steinfeld et al 1 reported the results of post hoc assessment of clinical benefit of mepolizumab, an mAb that targets IL-5, in patients with relapsing/refractory eosinophilic granulomatosis with polyangiitis (EGPA) using data from a randomized, placebo-controlled, double-blind, parallel-group trial Mepolizumab In Relapsing or Refractory EGPA (MIRRA). Organ-threatening EGPA and life-threatening EGPA (eg, with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage, and severe cardiac disease) were exclusion criteria.…”

Section: To the Editormentioning

confidence: 99%