A retrospective analysis of mepolizumab in subjects with aspirin-exacerbated respiratory disease

Tuttle, Katherine L.; Buchheit, Kathleen M.; Laidlaw, Tanya M.; Cahill, Katherine N.

doi:10.1016/j.jaip.2018.01.038

Cited by 69 publications

(45 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…After treatment with mepolizumab, there were significant reductions in total SNOT-22 score, and the individual scores for sense of smell and nasal congestion were also reduced. 55 Another humanized monoclonal antibody targeting IL-5, reslizumab, has also been studied for treatment of CRSwNP. In a randomized, double-blind, placebo-controlled study of 24 subjects, a single dose of IV reslizumab at 1 mg/kg or 3 mg/kg reduced the total nasal polyp score in half of the subjects receiving reslizumab.…”

Section: Antieil-5/ramentioning

confidence: 99%

Biologics in chronic rhinosinusitis with nasal polyposis

Laidlaw

Buchheit

2020

Annals of Allergy, Asthma & Immunology

Self Cite

View full text Add to dashboard Cite

Chronic rhinosinusitis represents a heterogenous spectrum of inflammatory diseases of the paranasal sinuses, with many patients failing current standard-of-care treatment. Type 2 cytokines, including interleukin (IL)-4, 5 and 13, have a role in eosinophilic respiratory inflammation in chronic rhinosinusitis with nasal polyps. Several cytokines, cytokine receptors, and other immunologic effector pathways are targets for currently available treatments and treatments under investigation for nasal polyposis, including IL-4Ra, IL-5, IL-5Ra, IL-33, IgE, and TSLP. Future studies focused on biomarker-based endotyping and responder analyses will allow for optimization of personalized treatment for chronic rhinosinusitis with nasal polyp patients.

show abstract

Section: Antieil-5/ramentioning

confidence: 99%

Biologics in chronic rhinosinusitis with nasal polyposis

Laidlaw

Buchheit

2020

Annals of Allergy, Asthma & Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Aspirin-exacerbated respiratory disease (AERD) is the triad of CRS with nasal polyposis, adverse reaction to aspirin, and asthma (16). A recent retrospective analysis of mepolizumab in 22 patients with AERD provided clinical evidences that IL-5 inhibition improved subject-reported upper and lower airway symptoms, but not improved forced expiratory volume in 1 second (FEV 1 ) (17). To our knowledge, no data has been reported on the benefit of mepolizumab in severe eosinophilic asthma patients with CRS.…”

Section: Introductionmentioning

confidence: 99%

Favorable clinical efficacy of mepolizumab on the upper and lower airways in severe eosinophilic asthma: a 48-week pilot study

Kurosawa¹,

Ogawa²,

Sutoh³

2019

Eur Ann Allergy Clin Immunol

View full text Add to dashboard Cite

“…44,45 A Phase 2 trial of IL-5 inhibition with mepolizumab in patients with nasal polyposis showed a therapeutic effect with a reduction in both polyp size and patient symptoms, 46 and we recently demonstrated that mepolizumab improved upper respiratory symptoms and asthma control in subjects with AERD. 47 However, another recent study of dexpramipexole, an experimental drug that depletes nearly all eosinophils from within the nasal polyp tissue, failed to show any symptomatic improvement or any reduction in nasal polyp size. 48 Taken together with our current findings, we suspect that IL-5targeting monoclonal antibodies may alter the survival and function of IL-5Rα + antibodysecreting cells, which may contribute to the mechanism of their therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

IL-5Rα marks nasal polyp IgG4 and IgE-secreting cells in aspirin-exacerbated respiratory disease

Buchheit

Dwyer

Ordovás-Montañés

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundThe cause of nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but the upstream drivers and cellular mechanisms of local antibody production in AERD remain to be investigated.ObjectiveWe sought to identify the upstream drivers and phenotypic properties of local antibody-secreting cells in nasal polyps and to understand their clinical relevance in AERD.MethodsSinus tissue was obtained from subjects with AERD, aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin-tolerant chronic rhinosinusitis without nasal polyps (CRSsNP), and healthy controls. Tissue antibody levels were quantified via ELISA and immunohistochemistry, and were correlated with clinical markers of disease severity. Tissue cytokine mRNA levels were measured with quantitative PCR (qPCR). Antibody-secreting cells were profiled with a combination of single-cell RNA-sequencing (scRNA-seq), flow cytometry and immunofluorescence.ResultsTissue IgE and IgG4 were elevated in AERD compared to controls (p<0.01 for IgE and p<0.001 for IgG4, vs. CRSwNP). Total IgG and IgG4 positively correlated with the number of polyp surgeries per subject (r=0.48, p=0.011 and r=0.58, p=0.0003, respectively). Polyp IL-10 mRNA expression was higher in AERD vs. CRSwNP (p<0.05), but there were no differences in mRNA expression of type 2 cytokines. ScRNA-seq revealed increased IL5RA, IGHG4, and IGHE in the antibody-associated cells of subjects with AERD compared to CRSwNP. Total plasma cells and IL-5Rα+ plasma cell numbers in the polyp tissue from AERD exceeded those in polyps from CRSwNP (p=0.0051 and p=0.026, respectively) by flow cytometry. With immunofluorescence, we determined that IL-5Rα and IgG4 are co-expressed in antibody-secreting cells in AERD.ConclusionsOur study identifies unique clusters of antibody-secreting cells in AERD defined by enrichment of transcripts encoding IL5RA, IGHG4 and IGHE. We confirm surface expression of IL-5Rα on these cells, and identify T cells as a unique transcriptional source of IL-5. Tissue antibody levels are elevated in AERD and correlate with disease severity. Our findings suggest a role for IL-5 in facilitating local antibody production that may drive features of severe sinus disease.Key MessagesIgG4 and IgE levels are markedly increased in nasal polyp tissue from subjects with AERD compared to aspirin-tolerant CRSwNP.Tissue IgG4 levels positively correlate with disease recurrence.IL-10 mRNA levels are significantly higher in AERD polyp tissue compared to CRSwNP tissue, but differences were not noted for type 2 cytokines or cytokines involved in class switch recombination.IL-5Rα transcript and protein surface expression is elevated in antibody-secreting cells from subjects with AERD and may play a role in facilitating class switching and/or survival of antibody-secreting cells.Capsule SummarySingle-cell RNA-sequencing (scRNA-seq) of whole nasal polyp tissue identified increased IL5RA, IGHE, and IGHG4 expression in the antibody-secreting cell compartment of subjects with aspirin-exacerbated respiratory disease (AERD) compared to aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). IgE and IgG4 levels are elevated in nasal polyp tissue from subjects with AERD compared to CRSwNP and correlate with disease recurrence.

show abstract

A retrospective analysis of mepolizumab in subjects with aspirin-exacerbated respiratory disease

Cited by 69 publications

References 11 publications

Biologics in chronic rhinosinusitis with nasal polyposis

Biologics in chronic rhinosinusitis with nasal polyposis

Favorable clinical efficacy of mepolizumab on the upper and lower airways in severe eosinophilic asthma: a 48-week pilot study

IL-5Rα marks nasal polyp IgG4 and IgE-secreting cells in aspirin-exacerbated respiratory disease

Contact Info

Product

Resources

About