Can serum biomarkers predict the outcome of systemic immunosuppressive therapy in adult atopic dermatitis patients?

Background: Atopic dermatitis (AD or eczema) is a most common chronic skin disease. Designing personalised treatment strategies for AD based on patient stratification is of high clinical relevance, given a considerable variation in the clinical phenotype and responses to treatments among patients. It has been hypothesised that the measurement of biomarkers could help predict therapeutic responses for individual patients. Objective: We aim to assess whether serum biomarkers can predict the outcome of systemic immunosuppressive therapy in adult AD patients. Methods: We developed a statistical machine learning model using the data of an already published longitudinal study of 42 patients who received azathioprine or methotrexate for over 24 weeks. The data contained 26 serum cytokines and chemokines measured before the therapy. The model described the dynamic evolution of the latent disease severity and measurement errors to predict AD severity scores (Eczema Area and Severity Index, (o)SCORing of AD and Patient Oriented Eczema Measure) two-weeks ahead. We conducted feature selection to identify the most important biomarkers for the prediction of AD severity scores. Results: We validated our model in a forward chaining setting and confirmed that it outperformed standard time-series forecasting models. Adding biomarkers did not improve predictive performance. Conclusions: In this study, biomarkers had a negligible and non-significant effect for predicting the future AD severity scores and the outcome of the systemic therapy.

Effect of immunosuppressive treatment on biomarkers in adult atopic dermatitis patients.

BACKGROUND: Biomarkers to objectively measure disease severity and predict therapeutic responses are needed in atopic dermatitis (AD). OBJECTIVE: Primary aim: To identify biomarkers reflecting therapeutic response in patients with AD treated systemically. Secondary aims: (i) To identify a biomarker pattern predicting responsiveness to systemic treatment. (ii) To identify differences in expression of biomarker in filaggrin gene (FLG) mutation carriers vs. non-FLG mutations carriers. METHODS: Thirty-eight severe AD patients treated with methotrexate or azathioprine participated. Serum levels of a proliferation-inducing ligand, B-cell activating factor of the TNF family, thymus and activation-regulated chemokine (chemokine (C-C motif) ligand 17) (TARC (CCl-17)), interleukin-1 receptor antagonist (IL-1RA), interleukin-1 bèta, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-18, IL-31, interferon gamma, tumour necrosis factor alpha, vascular endothelial growth factor (VEGF), monokine induced by interferon gamma (chemokine (C-X-C motif) ligand 9), interferon gamma-induced protein 10 (C-X-C motif chemokine Ligand 10), monocyte chemoattractant protein-1 (chemokine (C-C Motif) ligand 2), macrophage inflammatory protein-1 beta (chemokine (C-C motif) ligand 4), regulated on activation, normal T cell expressed and secreted (chemokine (C-C motif) ligand 5), Cutaneous T-cell-attracting chemokine (chemokine (C-C motif) ligand 27) (CTACK (CCL-27)), thymic stromal lymphopoietin, IL-5, interleukin-1 alpha and granulocyte-colony stimulating factor were analysed by ELISA and Luminex. The primary outcomes were differences in mean absolute change of SCORing Atopic Dermatitis (SCORAD) between groups after 12 weeks compared with baseline. Responders to treatment were defined by a SCORAD reduction in ≥50%. Buccal mucosa swabs were collected to determine FLG genotype status. RESULTS: Thymus and activation-regulated chemokine, CTACK, IL-13 and VEGF showed a significant decrease after treatment with methotrexate or azathioprine. However, no decrease in individual cytokine levels was significantly correlated with a change in any of the outcome parameters. In addition, baseline biomarker levels were not significantly different between responders and non-responders, and FLG and non-FLG mutants showed similar biomarker profiles. CONCLUSION: Thymus and activation-regulated chemokine and CTACK were confirmed as potential biomarkers. VEGF and IL-13 have a potential value as well. Biomarkers could not be used to discriminate at baseline between responders and non-responders, or FLG genotype status.

In vivo confocal microscopy of basal cell carcinoma: a systematic review of diagnostic accuracy.

Basal cell carcinoma (BCC) is the most prevalent type of skin cancer. Histologic analysis of punch biopsy or direct excision specimen is used to confirm clinical diagnosis. In vivo reflectance confocal microscopy (RCM) is a non-invasive imaging modality that could facilitate early diagnosis and minimize unnecessary invasive procedures. We systematically reviewed diagnostic accuracy (sensitivity and specificity) of RCM in diagnosing primary BCCs to judge its usefulness. Eligible studies were reviewed for methodological quality using the QUADAS-2 tool. We used the bivariate random-effects model to calculate summary estimates of sensitivity and specificity. Six studies met the selection criteria and were included for analysis. The meta-analysis showed a summary estimate of sensitivity 0.97 (95% CI, 0.90-0.99) and specificity 0.93 (95% CI, 0.88-0.96). All but one of the QUADAS-2 items showed a high or unclear risk of bias with regards to patient selection. RCM may be a promising diagnostic tool, but the limited number of available studies and potential risk of bias of included studies do not allow us to draw firm conclusions. Future accuracy studies should take these limitations into account.

Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME).

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure.

EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference.

BACKGROUND: Demonstration of adequate reliability and validity is sufficient for concluding that an instrument is applicable for descriptive and predictive purposes, but before we can confidently use an outcome measure in clinical trials, the responsiveness (synonymous with sensitivity to change) and minimal clinically important difference (MCID) should be known. With this study, we aimed to assess responsiveness and MCID of four outcome measures used in atopic eczema: the Severity Scoring of Atopic Dermatitis (SCORAD), the objective SCORAD, Eczema Area and Severity Index (EASI), and the Patient-Oriented Eczema Measure (POEM). METHODS: Data of three randomized controlled trials were used. To demonstrate responsiveness, we plotted receiver operating characteristic (ROC) curves. MCID was estimated using mean change scores of patients that showed a relevant improvement. Bland and Altman methods were used to quantify the limits of agreement. RESULTS: Area under the ROC curve for the SCORAD was 0.70 [95% confidence interval (CI): 0.61-0.78], for the objective SCORAD, 0.73 (95% CI: 0.70-0.77), for the EASI, 0.67 (95% CI: 0.60-0.76), and for the POEM, 0.67 (95% CI: 0.59-0.75). Scores above 0.70 represent a fair responsiveness. The MCID was 8.7 points for the SCORAD, 8.2 for the objective SCORAD, 6.6 for the EASI, and 3.4 for the POEM. CONCLUSION: The objective SCORAD and SCORAD showed a fair responsiveness. The MCIDs are an important prerequisite for the interpretation of published eczema trials and for the planning/sample size estimation of future trials.

Is there a rural/urban gradient in the prevalence of eczema? A systematic review.

BACKGROUND: Eczema affects approximately 10% of all schoolchildren in the western world and has shown an increase over the past decades in 'developing' countries. Numerous factors have been suggested that might contribute to the increasing prevalence of eczema. A plausible explanation is the role of environmental factors. As part of the 'hygiene hypothesis' it has been thought that eczema is more common in urban than in rural communities, but such a notion has never been assessed systematically. OBJECTIVE: Our aim was to assess whether there is a rural/urban gradient for the prevalence of eczema and, if so, to what extent. METHODS: All data sources were identified through a search in MEDLINE and EMBASE. All primary studies comparing the prevalence rate of eczema between urban and rural populations were assessed for eligibility. Included articles were reviewed for methodological quality and a relative risk was calculated to indicate the risk of eczema in urban over rural areas. Results Twenty-six articles were included for analysis. Nineteen showed a higher risk for eczema in an urbanized area, of which 11 were significant. Six studies showed a lower risk of eczema in an urbanized area, of which one was statistically significant. One study had a relative risk of 1.00. RESULTS: were more homogeneous among studies of good methodological quality. A pooled relative risk could have been calculated but was not because of heterogeneity. CONCLUSION: There is some evidence of a higher risk for eczema in urban compared with rural areas, suggesting that place of residence may have a role in the pathogenesis of eczema. Future reviews on environmental circumstances should be carried out to reveal the factors associated with a higher prevalence of eczema in urban areas and the association with other allergic diseases.

Dermatologists are essential for quality of care in the general practice of medicine.

Dermatology is an increasingly growing specialty with several subspecialties that frequently overlap with other disciplines. Dedication to specific areas varies widely between countries, even within the European Union. The lack of uniform criteria that regulate the practice of dermatology and its subspecialties has a negative impact on the distribution of resources. Consequently, this may impair adequate patient care as access to dermatologists, who are the best trained physicians to recognize and treat skin disorders, may be delayed or unavailable. Not uncommonly, especially in the hospital setting, many specialists are consulted for a skin condition before a referral is made to a dermatologist. In this article, through a case series from daily practice, we illustrate the need for dermatologists to be recognized as the most suitable specialists to diagnose and treat skin diseases. A prompt referral is probably more cost-effective than any other measure, reducing patient morbidity and, in some instances, it can also be life-saving. Another issue that merits consideration is the reimbursement of selected, non-medicated pharmaceuticals, that are medically indicated for some patients with serious dermatological disorders.

Diagnostic criteria for atopic dermatitis: a systematic review.

BACKGROUND: Atopic dermatitis (AD) has a wide spectrum of dermatological manifestations and despite various validated sets of diagnostic criteria that have been developed over the past decades, there is disagreement about its definition. Nevertheless, clinical studies require valid diagnostic criteria for reliable and reproducible results. OBJECTIVE: To summarize the evidence concerning the validity of diagnostic criteria for AD. METHODS: All data sources were identified through searches on Medline, Embase and Cochrane databases. The Quality Assessment of Diagnostic Accuracy tool (QUADAS) was used. Results are presented in a receiver operating characteristic (ROC) plot. RESULTS: Out of the 20 articles that met the criteria, 27 validation studies were identified. In two studies concerning Hanifin and Rajka diagnostic criteria sensitivity and specificity ranged from 87.9% to 96.0% and from 77.6% to 93.8%, respectively. Nineteen validation studies of the U.K. diagnostic criteria showed sensitivity and specificity ranging from 10% to 100% and 89.3% to 99.1%, respectively. Three validation studies concerning the Schultz-Larsen criteria showed sensitivity from 88% to 94.4% and specificity from 77.6% to 95.9%. In one article concerning the criteria of Diepgen, the sensitivity ranged from 83.0% to 87.7% and the specificity from 83.9% to 87.0%. One article studied the Kang and Tian criteria and reported 95.5% sensitivity and 100% specificity. One article validating the International Study of Asthma and Allergies in Childhood (ISAAC) criteria showed a positive and negative predictive value of 48.8% and 91.1%, respectively. CONCLUSION: With this systematic review of the existing sets of diagnostic criteria for AD a varying number of validation studies with varying methodological quality was found. The U.K. diagnostic criteria are the most extensively validated. However, improvement of methodological design for validation studies and uniformity in well-validated and applicable diagnostic criteria are needed to improve future intervention studies and to compare study results.