IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti–IL-4 receptor α antagonist

Slager, Rebecca E.; Otulana, Babatunde; Hawkins, Gregory A.; Yen, Yu Ping; Peters, Stephen P.; Wenzel, Sally E.; Meyers, Deborah A.; Bleecker, Eugene R.

doi:10.1016/j.jaci.2012.03.030

Cited by 139 publications

(94 citation statements)

References 22 publications

(31 reference statements)

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“…Another mechanism predisposing to more severe or difficult-to-treat asthma may relate to pharmacogenetics, where responsiveness to asthma therapy is altered or reduced in some individuals. Asthmatics with reduced therapeutic responsiveness to controller therapies such as inhaled corticosteroids or even specific novel biological therapies could exhibit more difficult-to-control asthma and be classified as more severe [40,41].…”

Section: Genetics and Epigeneticsmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

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Section: Genetics and Epigeneticsmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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“…Polymorphisms in IL-6 [68], IL-4 [69], high-affinity IgE receptor [70], IL-4R [71], disintegrin and metalloproteinase 33 [72], and IL-13 [73] have been associated with epithelial dismantling and malfunctioning, especially in the context of asthma and chronic obstructive pulmonary disease [74,75]. In this sense, a high level of IL-13 in asthmatic patients has been involved in wall remodeling processes [76,77].…”

Section: Airway Epithelium As a Key Player In Orchestrating The Allermentioning

confidence: 99%

Airway Epithelium Plays a Leading Role in the Complex Framework Underlying Respiratory Allergy

López-Rodríguez

Benedé

Barderas

et al. 2017

J Investig Allergol Clin Immunol

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Airway epithelium is the cellular structure with the greatest surface exposed to a plethora of environmental airborne substances, including microorganisms, respiratory viruses, air pollutants, and allergens. In addition to being a protective physical barrier at the air-liquid interface, the airway epithelium acts as an effective chemical and immunological barrier that plays a crucial role in orchestrating the immune response in the lungs, by supporting the activation, recruitment, and mobilization of immune cells. Airway epithelium dysfunction has been clearly associated with various airway inflammatory diseases, such as allergic asthma. Although it is not fully understood why a person develops respiratory allergy, a growing body of evidence shows that the nature of the host's immune response is strongly determined by the state of the airway epithelium at the time of contact with the inhaled allergen. Our review highlights the physiological state of airway epithelium as a key element in the development of allergy and, particularly, in exacerbation of asthma. We review the role of physiological oxidants as signaling molecules in lung biology and allergic diseases and examine how high exposure to air pollutants (eg, cigarette smoke and diesel particles) can contribute to the increased incidence of respiratory allergy and exacerbation of the disease. Key words: Airway epithelium. Barrier dysfunction. Respiratory allergy. Redox biology. Air pollutants. ResumenEl epitelio pulmonar constituye la barrera celular más susceptible a la acción deletérea de la multitud de agentes que se encuentran en el ambiente, incluidos los alérgenos. Además de prevenir su acceso al organismo, la barrera epitelial de las vías respiratorias juega un papel inmunomodulador crucial, regulando de forma local la acción de las células del sistema inmune subyacentes. Una disfunción epitelial, provocada tanto directa como indirectamente por la acción de los aeroalérgenos, parece ser una de las causas principales de desregulación de la homeostasis pulmonar, causando una respuesta proinflamatoria descontrolada que cada vez más autores atribuyen al origen de las reacciones alérgicas. En esta revisión se quiere destacar el papel de la barrera epitelial pulmonar como regulador de la respuesta inmune en el contexto de la alergia. Las enfermedades crónicas que afectan a las vías respiratorias, tales como el asma alérgica, muestran frecuentemente una función epitelial defectuosa, apoyando así la hipótesis antes mencionada que subyace al origen de la alergia. El impacto de otros contaminantes ambientales -como virus respiratorios, bacterias, humo del tabaco y partículas diésel-sobre la integridad epitelial, así como su influencia en la biología redox pulmonar relacionada con el desarrollo de la respuesta alérgica, también se abordarán en la presente revisión.

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“…In a dose-ranging study of pitrakinra, a significant dose-response in asthmatics with a specific IL4RA variant genotype (GG of rs8832, nearly one-third of the cohort) was noted while no dose response was observed in subjects with the remaining genotypes (AG or AA at allele rs8832) [20,21]. This clinical trial was an example of how a pharmacogenetic biomarker can identify a subgroup of responders embedded within an overall cohort that were which was unresponsive to a drug.…”

Section: Pharmacogenomics In Respiratory Disease -Asthmamentioning

confidence: 99%

“…A molecular inhibitor of the IL-4α receptor subunit, pitrakinra, and a monoclonal antibody, dupilumab, have been shown to be effective in preventing loss of symptom control in asthma subpopulations, characterized by increased blood or sputum eosinophils. Both biologic drugs block the IL-4α receptor subunit (encoded by IL4RA), resulting in dual inhibition of a shared IL-4 and IL-13 pro-inflammatory pathway.In a dose-ranging study of pitrakinra, a significant dose-response in asthmatics with a specific IL4RA variant genotype (GG of rs8832, nearly one-third of the cohort) was noted while no dose response was observed in subjects with the remaining genotypes (AG or AA at allele rs8832) [20,21]. This clinical trial was an example of how a pharmacogenetic biomarker can identify a subgroup of responders embedded within an overall cohort that were which was unresponsive to a drug.…”

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confidence: 99%

Pharmacogenomics: The Scientific Basis of Rational Drug Development and Prescribing

Abraham¹,

Jethwa²

2017

Clin Pharmacol Biopharm

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Abstract"It is more important to know what sort of a patient has a disease than what sort of a disease a patient has" (Hippocrates 460 BC-370 BC).The holy grail of drug discovery is to ensure that an individual responds positively to an investigational drug with minimal or no adverse events. This could then translate to newly discovered drugs being licenced for prescribing as safe and effective therapeutics. Pharmacogenomics may herald the technology for this aspiration to become reality.Uniting the disciplines of pharmacology and genomics, pharmacogenomics provides a mechanism to understand and predict the response of an individual to a drug or group of drugs. This is based on the premise that an individual's genotype affects the pharmacokinetics, pharmacodynamics and, ultimately, the individual's their response to a drug. This review will begin by reviewing the history of drug development and then proceed to discuss the use of pharmacogenomics in drug development through case studies in oncology, respiratory and vaccinology. It will then go on to discuss how pharmacogenomics presently influences prescribing practices and how this technology may have the potential to enhance patient safety when medicines are administered. KeywordsPharmacology; Genomics; Pharmacokinetics; Pharmacodynamics Historical Perspective of Drug Development and PharmacogenomicsThe observation that individuals react differently to exogenous agents dates back to Ancient Greece 510 BC, where Pythagorus observed the differential effects of Fava bean consumption on individuals [1]. It was, however, not until 1956 that glucose-6-phosphate enzyme deficiency was recognised as the culprit for "Favism" and, additionally, the sensitivity to drugs such as primaquine [2]. Also in the 1950s, a German physician, Friedrich Vogel, first coined the term "pharmacogenetics". This initially concentrated on explaining the unexpected response to drugs related in relation to an individual's genetic makeup, (which usually relates to metabolism) and explored the genetic variation in a population or variations specific to a disease. It applies genomic technologies to help develop new therapeutics and potentially categorise existing therapeutics [3]. Thereafter, the completion and publication of the human genome opened the possibilities for a new era of drug discovery and personalised prescribing [4,5]. Pharmacogemonic Approaches to Drug Development and Clinical TrialsThe human genome consists of approximately 3.3 billion base-pairs and the difference between any two individuals in terms of DNA sequence is just 0.1%; it is this difference that influences disease susceptibility, progression of disease and response to drug intervention [6,7]. A solid platform for a rationalised drug discovery programme emerged with the completion of the human genome project and rapidly advancing technology.The pharmaceutical industry applies the principles of pharmacogenomics in the drug discovery programmes they oversee; it also undertakes in-depth evaluation of target gene sequences...

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IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti–IL-4 receptor α antagonist

Cited by 139 publications

References 22 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Airway Epithelium Plays a Leading Role in the Complex Framework Underlying Respiratory Allergy

Pharmacogenomics: The Scientific Basis of Rational Drug Development and Prescribing

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