Judith L. Thijs

Biomarkers for atopic dermatitis: a systematic review and meta-analysis.

Purpose of reviewA large number of studies investigating the correlation between severity of atopic dermatitis and various biomarkers have been published over the past decades. The aim of this review was to identify, evaluate and synthesize the evidence examining the correlation of biomarkers with disease severity in atopic dermatitis patients, something that has not been performed previously. Recent findingsThree electronic databases were systematically searched and relevant studies were selected for inclusion. A total of 222 articles, reporting on 115 different biomarkers in 30 063 patients, were critically appraised. Studies were divided into two main groups. The first group consisted of longitudinal randomized controlled trials and cohort studies, which reported measurements at multiple time points. The second contained cross-sectional studies that reported only one measurement per patient. Out of 222 articles, 108 articles reported sufficient data for meta-analysis. Only four biomarkers were eligible for meta-analysis in the longitudinal group, and nine in the cross-sectional group. SummarySerum thymus and activation-regulated chemokine (TARC) was found to be the most reliable biomarker studied, showing pooled correlation coefficients of 0.60 (95% CI 0.48–0.70) and 0.64 (95% CI 0.57–0.70) in longitudinal and cross-sectional studies, respectively. Additional biomarkers that could prove useful but require additional research include serum cutaneous T-cell attracting chemokine (CTACK), sE-selectin, macrophage-derived chemokine (MDC), lactate dehydrogenase (LDH) and interleukin (IL)-18.

A panel of biomarkers for disease severity in atopic dermatitis

A panel of biomarkers for disease severity in atopic dermatitis J. L. Thijs, S. Nierkens, A. Herath , C. A. F. Bruijnzeel-Koomen, E. F. Knol, B. Giovannone, M. S. de Bruin-Weller and D. Hijnen Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht, The Netherlands, U-DAIR and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands, MedImmune Biotech, Cambridge, UK and Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis

Background Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. Objective We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. Methods Sera from 193 adult patients with moderate‐to‐severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3‐23.3] and 39.1 [95% CI, 37.5‐40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen‐specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k‐means cluster analysis of the principal components. Results Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty‐seven principal components described approximately 90% of the variance. Unsupervised k‐means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation‐regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN‐&agr;, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN‐&bgr;, IL‐1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL‐1, IL‐4, IL‐13, and thymic stromal lymphopoietin. Conclusion AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.

New Developments in Biomarkers for Atopic Dermatitis.

The application of biomarkers in medicine is evolving. Biomarkers do not only give us a better understanding of pathogenesis, but also increase treatment efficacy and safety, further enabling more precise clinical care. This paper focuses on the current use of biomarkers in atopic dermatitis, new developments and future perspectives. Biomarkers can be used for many different purposes, including the objective determination of disease severity, confirmation of clinical diagnosis, and to predict response to treatment. In atopic dermatitis, many biomarkers have been investigated as a marker for disease severity. Currently serum thymus and activation-regulated chemokine (TARC) is the superior biomarker for assessing disease severity. However, we have recently shown that the use of a panel of serum biomarkers is more suitable for assessing disease severity than an individual biomarker. In this overview, we will discuss alternative sources for biomarkers, such as saliva and capillary blood, which can increase the user friendliness of biomarkers in atopic dermatitis (AD). Both methods offer simple, non-invasive and cost effective alternatives to venous blood. This provides great translational and clinical potential. Biomarkers will play an increasingly important role in AD research and personalized medicine. The use of biomarkers will enhance the efficacy of AD treatment by facilitating the individualization of therapy targeting the patients’ specific biological signature and also by providing tools for predicting and monitoring of therapeutic response.

Current and Future Biomarkers in Atopic Dermatitis

Atopic dermatitis (AD) is a heterogeneous disease and many attempts have been made to define subsets of patients based on clinical characteristics. However, the current characterization of patients with AD might not adequately reflect the pathophysiologic diversity within patients with AD. This article reviews current biomarkers for AD and future perspectives. In the future, patients with AD will be stratified based on biomarker expression levels in body fluids and tissue, genetic variants, or combined biomarker expression patterns. With new targeted therapies for AD currently investigated in clinical trials this will lead to better identification of patients that can benefit from these highly specific, but expensive new treatments.

Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Abstract Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage.

Dupilumab in atopic dermatitis: rationale, latest evidence and place in therapy

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The prevalence of AD is increasing and is currently estimated at 10–20% in adults worldwide. In the majority of patients, AD can be adequately controlled with topical treatment or ultraviolet light therapy, but there is a high unmet need for effective and safe therapeutics in patients with more severe or difficult to treat AD. During the past decade, new advances in the understanding of the underlying immune pathogenesis of AD have led to the development of new, more targeted therapies. Dupilumab, a fully human monoclonal antibody targeting the interleukin (IL)-4 receptor α, thereby blocking the IL-4 and IL-13 pathway, is one of the first biologics that has been developed for AD. Dupilumab has shown promising results in phase III trials and has recently been approved by the US Food and Drug Administration and the European Commission for the treatment of moderate to severe AD. With the approval of dupilumab, we are entering a new era of biological therapeutics in AD management. The place of dupilumab should be established in the current treatment standards. Based on current treatment guidelines and experts’ opinions in the management of AD, we have built a proposal for a treatment algorithm for systemic treatment of AD in European countries.

EASI p-EASI: predicting disease severity in atopic dermatitis patients treated with Cyclosporin A

not shown). In summary, the present study showed exposure to MNP induced intestinal epithelial barrier dysfunction and facilitated the development of intestinal allergy, which was abolished by administration of caspase inhibitors. The results suggest that the environmental pollution may contribute to the development of allergic diseases, which may be prevented by administration with caspase inhibitors.