Ellen S. Koster

Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency

Background Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (ADFLG) compared with that seen in patients with AD without these mutations (ADNON-FLG). Objectives We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with ADFLG versus patients with ADNON-FLG. We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flgft/Flgft [FlgdelAPfal] mice). Methods One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flgft/Flgft (FlgdelAPfal) mice, separated from maFlgft/maFlgft (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA. Results SC IL-1 levels were increased in patients with ADFLG; these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flgft/Flgft mice had upregulated expression of IL-1β and IL-1RA mRNA. Conclusions ADFLG is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.

FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid‐treated asthmatic children

To cite this article: Koster ES, Maitland‐van der Zee A‐H, Tavendale R, Mukhopadhyay S, Vijverberg SJH, Raaijmakers JAM, Palmer CNA. FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid‐treated asthmatic children. Allergy 2011; 66: 1546–1552.

Uncontrolled asthma at age 8: The importance of parental perception towards medication

To cite this article: Koster ES, Wijga AH, Koppelman GH, Postma DS, Brunekreef B, De Jongste JC, Smit HA, Hoekstra MO, Raaijmakers JAM, Maitland‐van der Zee A‐H. Uncontrolled asthma at age 8: The importance of parental perception towards medication. Pediatr Allergy Immunol 2011; 22: 462–468.

Inhaled corticosteroid adherence in paediatric patients: the PACMAN cohort study

Poor adherence with inhaled corticosteroids (ICSs) has been reported frequently and may be associated with uncontrolled asthma. A better understanding of factors influencing adherence may help to achieve higher adherence rates for a larger part of the population, which will eventually lead to better asthma control. The aim of this study was to investigate factors associated with adherence in paediatric ICS users.

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter‐individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti‐inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors.

Pharmacogenetics of anti-inflammatory treatment in children with asthma: rationale and design of the PACMAN cohort

AIMS To investigate the effects of genetic variation on treatment response to asthma medication in children and to identify (profiles of) SNPs that characterize response phenotypes. MATERIAL & METHODS The Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects (PACMAN) study was initiated in April 2009 as an observational retrospective pharmacy-based study, including at least 1000 children with asthma medication (aged 4-12 years). Data on respiratory symptoms and medication use behavior will be collected using a questionnaire; complete medication histories will be extracted from the pharmacy information system; additional health information will be requested from the general practitioner; quality of inhalation technique and lung function measurements will be performed and saliva samples for DNA extraction and genotyping will be collected. Two groups of patients will be defined based on questionnaire data and lung function measurements: responders and nonresponders to anti-inflammatory asthma treatment. These two groups will be compared with respect to genetic variation. Corrections will be made for potential confounding factors. RESULTS The main study end point is treatment response, including asthma control, medication use and exhaled nitric oxide as a measure of airway inflammation. Whilst our focus is on genetic factors, this study allows us to also investigate other treatment response determinants, such as inhalation technique and therapy adherence. CONCLUSION Results from the PACMAN study could eventually lead to a more individualized therapy approach. PACMAN will focus on pharmacogenetics of asthma medication in children, while knowledge will be gained of relevant interest to the treatment of the asthma population at large.

“I just forget to take it”: asthma self-management needs and preferences in adolescents

Abstract Background: Medication adherence rates often decline as children become teenagers. Effective adherence-enhancing interventions for adolescents are lacking. The objective of this study was to assess adolescent asthmatics needs and preferences regarding medication counseling and support, with focus on new media. Methods: Three focus groups including 21 asthmatic adolescents recruited from both primary and secondary care were held to explore needs and preferences regarding asthma-self management. Questions concerned adherence behavior and needs and preferences in adherence support with focus on new media (mobile technology, social media, health games). Results: Forgetting was mentioned as major reason for not using medication as prescribed. Adolescents also mentioned lack of perceived need or beneficial effects. Parents mainly play a role in reminding to take medication and collecting refills. The suggested strategies to support self-management included smartphone applications with a reminder function and easy access to online information. Participants were positive about sharing of experiences with other teenagers. Conclusion: Forgetfulness is a major reason for non-adherence in adolescents. Furthermore, our results suggest use of peer support may be helpful in promoting good medication use. Future interventions should be aimed at providing practical reminders and should be modifiable to individual preferences.

The Utrecht Pharmacy Practice network for Education and Research: a network of community and hospital pharmacies in the Netherlands

Practice-based networks can serve as effective mechanisms for the development of the profession of pharmacists, on the one hand by supporting student internships and on the other hand by collection of research data and implementation of research outcomes among public health practice settings. This paper presents the characteristics and benefits of the Utrecht Pharmacy Practice network for Education and Research, a practice based research network affiliated with the Department of Pharmaceutical Sciences of Utrecht University. Yearly, this network is used to realize approximately 600 student internships (in hospital and community pharmacies) and 20 research projects. To date, most research has been performed in community pharmacy and research questions frequently concerned prescribing behavior or adherence and subjects related to uptake of regulations in the pharmacy setting. Researchers gain access to different types of data from daily practice, pharmacists receive feedback on the functioning of their own pharmacy and students get in depth insight into pharmacy practice.

Adolescents' inhaled corticosteroid adherence: the importance of treatment perceptions and medication knowledge.

Abstract Background: Studies measuring inhaled corticosteroid (ICS) adherence frequently report adherence rates below 50%. Although asthma is common in adolescents, few studies have explored determinants of ICS adherence in adolescents. The objective of this study was to examine adherence and related factors in adolescent ICS users. Methods: Adolescent ICS users, aged 12–18 years, were randomly recruited from a sample of 94 community pharmacies belonging to the Utrecht Pharmacy Practice Network for Education and Research to complete an online questionnaire. The survey contained questions on asthma control, self-reported adherence, medication beliefs and medication knowledge. Data were collected between April and August 2013. Results: Complete questionnaire data were received from 182 adolescents of which 40% reported to be adherent. Approximately 40% of the participants perceived strong needs, whilst only 10% was highly concerned about adverse effects regarding their ICS use. Good adherence was significantly associated with asthma control (OR: 2.1, 95% CI: 1.1–4.1). Necessity beliefs and sufficient medication knowledge were associated with better adherence (p < 0.05). Conclusion: Our results suggest that by improving knowledge about asthma treatments and stimulating positive perceptions towards medicines, especially regarding the necessity of medication use, better adherence rates might be achieved.

Systems biology in pharmacogenomic research: the way to personalized prescribing?

Response to pharmacotherapy can be highly variable amongst individuals. Pharmacogenomics may explain the interindividual variability in drug response due to genetic variation. However, besides genetics, many other factors can play a role in the response to pharmacotherapy, including disease severity, co-morbidity, environmental factors, therapy adherence and co-medication use. Better understanding of these factors and inter-relationships should bring about a much more effective approach to disease management. Systems biology that studies organisms as integrated and interacting networks of genes, proteins and biochemical reactions can contribute to this. Organisms are no longer studied part by part, but in a more integral manner. Integration of the genetic data with intermediate and end point phenotypic characterization may prove essential to define the inherent nature of drug effects. Therefore, in the future, a multidisciplinary systems-based approach will be necessary to deal with the bulk of the biological data that is available and, ultimately, to reach the goal of personalized prescribing.