Update on reslizumab for eosinophilic asthma.
Ontology highlight
ABSTRACT:
SUBMITTER: Cardet JC
PROVIDER: S-EPMC5161345 | biostudies-other | 2015
REPOSITORIES: biostudies-other
Publications
Update on reslizumab for eosinophilic asthma.
Cardet Juan Carlos JC Israel Elliot E
Expert opinion on biological therapy 20150101 10
<h4>Introduction</h4>Patients with severe eosinophilic asthma have an unmet need for novel and efficacious treatments. Reslizumab is one of the three monoclonal antibodies targeting the IL-5 pathway and has been found in Phase IIIb clinical trials to reduce asthma exacerbations, control asthma-related symptoms and improve pulmonary function in patients with eosinophilic asthma.<h4>Areas covered</h4>In this article, we discuss the results of asthma clinical trials using reslizumab, beginning with ...[more]
Similar Datasets
Project description:Background: Eosinophilic esophagitis (EoE) was first described in the 1990s, showing an increasing incidence and prevalence since then, being the leading cause of food impaction and the major cause of dysphagia. Probably, in a few years, EoE may no longer be considered a rare disease. Methods: This article discusses new aspects of the pathogenesis, symptoms, diagnosis, and treatment of EoE according to the last published guidelines. Results: The epidemiological studies indicate a multifactorial origin for EoE, where environmental and genetic factors take part. EoE affects both children and adults and it is frequently associated with atopic disease and IgE-mediated food allergies. In patients undergoing oral immunotherapy for desensitization from IgE-mediated food allergy the risk of developing EoE is 2.72%. Barrier dysfunction and T-helper 2 inflammation is considered to be pathogenetically important factors. There are different patterns of clinical presentation varying with age and can be masked by adaptation habits. Besides, symptoms do not usually correlate with histologic disease activity. The diagnostic criteria for EoE has evolved but mainly requires symptoms of esophageal dysfunction with histologic evidence of a peak value of at least 15 eosinophils per high-power field. Endoscopies have to be repeated in order to diagnose, monitor, and treat EoE. Treatment of EoE can be started either by drugs (PPIs and topical corticosteroids) or elimination diets. The multistage step-up elimination diet management approach of EoE is promising. Endoscopic dilation is used for patients with severe dysphagia/food impaction with inadequate response to anti-inflammatory treatment. Conclusions: Research in recent years has contributed to a better understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization in assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. However, several unmet needs are to be solved urgently, as finding a non-invasive disease-monitoring methods and biomarkers for routine practice, the development or new therapies, novel food allergy testing to detect triggering foods, drug, and doses required for initial therapy and safety issues with long-term maintenance therapy, amongst others. Besides, multidisciplinary management units of EoE, involving gastroenterologists, pediatricians, allergists, pathologists, dietitians, and ENT specialists are needed.
| S-EPMC6192373 | biostudies-literature
Project description:Morphea, also known as localized scleroderma, encompasses a group of idiopathic sclerotic skin diseases. The spectrum ranges from relatively mild phenotypes, which generally cause few problems besides local discomfort and visible disfigurement, to subtypes with severe complications such as joint contractures and limb length discrepancies. Eosinophilic fasciitis (EF, Shulman syndrome) is often regarded as belonging to the severe end of the morphea spectrum. The exact driving mechanisms behind morphea and EF pathogenesis remain to be elucidated. However, extensive extracellular matrix formation and autoimmune dysfunction are thought to be key pathogenic processes. Likewise, these processes are considered essential in systemic sclerosis (SSc) pathogenesis. In addition, similarities in clinical presentation between morphea and SSc have led to many theories about their relatedness. Importantly, morphea may be differentiated from SSc based on absence of sclerodactyly, Raynaud's phenomenon, and nailfold capillary changes. The diagnosis of morphea is often based on characteristic clinical findings. Histopathological evaluation of skin biopsies and laboratory tests are not necessary in the majority of morphea cases. However, full-thickness skin biopsies, containing fascia and muscle tissue, are required for the diagnosis of EF. Monitoring of disease activity and damage, especially of subcutaneous involvement, is one of the most challenging aspects of morphea care. Therefore, data harmonization is crucial for optimizing standard care and for comparability of study results. Recently, the localized scleroderma cutaneous assessment tool (LoSCAT) has been developed and validated for morphea. The LoSCAT is currently the most widely reported outcome measure for morphea. Care providers should take disease subtype, degree of activity, depth of involvement, and quality-of-life impairments into account when initiating treatment. In most patients with circumscribed superficial subtypes, treatment with topical therapies suffices. In more widespread disease, UVA1 phototherapy or systemic treatment with methotrexate (MTX), with or without a systemic corticosteroid combination, should be initiated. Disappointingly, few alternatives for MTX have been described and additional research is still needed to optimize treatment for these debilitating conditions. In this review, we present a state-of-the-art flow chart that guides care providers in the treatment of morphea and EF.
| S-EPMC5506513 | biostudies-literature
Project description:Asthma is a prevalent chronic non-communicable disease, affecting approximately 300 million people worldwide. It is characterized by significant airway inflammation, hyperresponsiveness, obstruction, and remodeling. Eosinophilic asthma, a subtype of asthma, involves the accumulation of eosinophils in the airways. These eosinophils release mediators and cytokines, contributing to severe airway inflammation and tissue damage. Emerging evidence suggests that targeting eosinophils could reduce airway remodeling and slow the progression of asthma. To achieve this, it is essential to understand the immunopathology of asthma, identify specific eosinophil-associated biomarkers, and categorize patients more accurately based on the clinical characteristics (phenotypes) and underlying pathobiological mechanisms (endotypes). This review delves into the role of eosinophils in exacerbating severe asthma, exploring various phenotypes and endotypes, as well as biomarkers. It also examines the current and emerging biological agents that target eosinophils in eosinophilic asthma. By focusing on these aspects, both researchers and clinicians can advance the development of targeted therapies to combat eosinophilic pathology in severe asthma.
| S-EPMC10931088 | biostudies-literature
Project description:BackgroundMost studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK).MethodsWe conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016-20. All centres studied children and adolescents (age range 8-20 years), except the UK centre which involved 26-27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum.ResultsOf 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37-2.94) with lower odds in the LMICs: Brazil (0.73, 0.42-1.27), Ecuador (0.40, 0.24-0.66) and Uganda (0.62, 0.37-1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda.ConclusionsThis is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.
| S-EPMC10114118 | biostudies-literature
Project description:Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations.We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum.Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma.Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)
| S-EPMC3992367 | biostudies-literature
Project description:Eosinophilic diseases of the gastrointestinal tract, including eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), are rare chronic pathologies of the digestive system, with an immuno-mediated pathogenesis. Recent data suggest that, together with the "classic" IgE-response to allergens, also a delayed hypersensitivity mechanism could be involved in the development of eosinophilic disorders. EoE and EGE were studied only in the latest decades and as a consequence accurate data are not yet available, concerning not only pathogenesis, but also epidemiology, treatment and outcomes. The diagnosis of EoE is centered on endoscopic findings but the certainty is obtained by histological examination from biopsy samples, that has a sensitivity of 100% when based on five samples. The currently available treatments include topical corticosteroids, specific diets and endoscopic treatment. Concerning EGE, three subtypes (mucosal, muscular, and serosal) were identified. The diagnosis is based, as for EoE, on endoscopic and histological assessment, and the treatment includes pharmacological and dietetic approaches. Further studies are warranted in order to better define the etiology and pathogenesis of eosinophilic diseases of the gastrointestinal tract, and thus to develop more appropriate and specific therapies.
| S-EPMC5131414 | biostudies-literature
Project description:IntroductionAsthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome-wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma-associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs and asthma-associated traits and assess expression quantitative trait locus (e-QTLs) to reveal their downstream functional effects and find drug targets.MethodsAssociation analyses between 128 asthma SNPs and associated traits (blood eosinophil numbers, atopy, airway obstruction, airway hyperresponsiveness) were conducted using regression modelling in population-based studies (Lifelines N = 32,817/Vlagtwedde-Vlaardingen N = 1554) and an asthma cohort (Dutch Asthma genome-wide association study N = 917). Functional enrichment and pathway analysis were performed with genes linked to the significant SNPs by e-QTL analysis. Genes were investigated to generate novel drug targets.ResultsWe identified 69 asthma SNPs that were associated with at least one trait, with 20 SNPs being associated with multiple traits. The SNP annotated to SMAD3 was the most pleiotropic. In total, 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy. We identified genetically driven pathways regulating eosinophilia. The largest network of eosinophilia contained two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma. Several novel targets were identified such as IL-18, CCR4, and calcineurin.ConclusionMany asthma SNPs are associated with blood eosinophil counts and genetically driven molecular pathways of asthma-associated traits were identified.
| S-EPMC10119226 | biostudies-literature
Project description:Asthma is characterized by episodic, reversible airflow obstruction associated with variable levels of inflammation. Over the past several decades, there has been an increasing appreciation that the clinical presentation of asthma comprises a diverse set of underlying pathologies. Rather than being viewed as a single disease entity, asthma is now thought of as a clinical syndrome with the involvement of multiple pathological mechanisms. While it is appreciated that eosinophilia is present in only a subset of patients, it remains a key feature of asthma and other eosinophilic disorders such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Eosinophils are bone marrow-derived leukocytes present in low numbers in health; however, during disease the type 2 cytokines [interleukins (IL)-4, -5, and -13] can induce rapid eosinophilopoiesis, prolonged eosinophil survival, and trafficking to the site of injury. In diseases such as allergic asthma there is an aberrant inflammatory response leading to eosinophilia, tissue damage, and airway pathology. IL-13 is a pleiotropic type 2 cytokine that has been shown to be integral in the pathogenesis of asthma and other eosinophilic disorders. IL-13 levels are elevated in animal models of eosinophilic inflammation and in the blood and tissue of patients diagnosed with eosinophilic disorders. IL-13 signaling elicits many pathogenic mechanisms including the promotion of eosinophil survival, activation, and trafficking. Data from preclinical models and clinical trials of IL-13 inhibitors in patients have revealed mechanistic insights into the role of this cytokine in driving eosinophilia. Promising results from clinical trials further support a key mechanistic role of IL-13 in asthma and other eosinophilic disorders. Here, we provide a perspective on the role of IL-13 in asthma and other eosinophilic disorders and describe ongoing clinical trials targeting this pathway in patients with significant unmet medical needs.
| S-EPMC5627038 | biostudies-literature
Project description:Asthma is a chronic inflammatory disorder of the airways with variable clinical severity from very mild and occasional symptoms to recurrent critical exacerbations, at risk of fatal or near-fatal outcome, in a small percentage of patients. Within the different inflammatory cascades involved in asthma, eosinophils play a central role in the pathogenesis and largely influence disease severity. Interleukin-5 (IL-5) is the main cytokine controlling eosinophil activity and proliferation at the site of inflammation. Mepolizumab was the first biological humanized anti-IL-5 monoclonal antibody tested in randomized clinical trials on eosinophilic asthma and other eosinophilic diseases. On the basis of several positive clinical efficacy data, it has recently been approved by the US Food and Drug Administration for the treatment of severe eosinophilic asthma. Unfortunately, high costs are at present a critical issue. Future studies will probably help in the correct selection of a potential "responder phenotype", allowing the prescription of this promising therapy to appropriate patients and best define cost-effectiveness issues.
| S-EPMC4907717 | biostudies-literature
Project description:Asthma is a chronic eosinophilic inflammatory disease with an increasing prevalence worldwide. Endocannabinoids are known to have immunomodulatory biological effects. However, the contribution of oleoylethanolamide (OEA) to airway inflammation remains to be elucidated. To investigate the effect of OEA, the expression of proinflammatory cytokines was measured by RT-qPCR and ELISA in airway epithelial (A549) cells. The numbers of airway inflammatory cells and cytokine levels in bronchoalveolar lavage fluid, airway hyperresponsiveness, and type 2 innate lymphoid cells (ILC2s) were examined in BALB/c mice after 4 days of OEA treatment. Furthermore, eosinophil activation after OEA treatment was evaluated by measuring cellular CD69 levels in eosinophils from human peripheral eosinophils using flow cytometry. OEA induced type 2 inflammatory responses in vitro and in vivo. OEA increased the levels of proinflammatory cytokines, such as IL-6, IL-8, and IL-33, in A549 cells. In addition, it also induced eosinophilic inflammation, the production of IL-4, IL-5, IL-13, and IL-33 in bronchoalveolar lavage fluid, and airway hyperresponsiveness. OEA increased the numbers of IL-5- or IL-13-producing ILC2s in a mouse model. Finally, we confirmed that OEA increased CD69 expression (an eosinophil activation marker) on purified eosinophils from patients with asthma compared to those from healthy controls. OEA may play a role in the pathogenesis of asthma by activating ILC2s and eosinophils.
| S-EPMC8257664 | biostudies-literature