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.

Diagnostic accuracy of tests for leprosy: a systematic review and meta-analysis.

OBJECTIVES: Owing to difficulties in the clinical diagnosis of leprosy, several complementary tests have been developed and used. The aim was to systematically summarize the accuracy of diagnostic tests for leprosy. METHODS: We searched for relevant articles in Embase, Medline, and Global Health databases, until June 2017. Studies evaluating the accuracy of any diagnostic techniques for differentiating between people with and without leprosy were included. Studies solely focusing on differentiating between the separate forms of leprosy were excluded. Our protocol was registered on PROSPERO (CRD42017071803). We assessed study quality using the QUADAS-2 checklist. A bivariate random effects regression model was used for the meta-analyses. RESULTS: We included 78 studies, most of those evaluating the detection of IgM antibodies against phenolic glycolipid I using ELISA. Sensitivity of the 39 studies evaluating ELISA was 63.8% (95% CI 55.0-71.8); specificity 91.0% (95% CI 86.9-93.9). The lateral flow test (nine studies) and the agglutination test (five studies) had a slightly higher sensitivity and a slightly lower specificity. Sensitivity of qPCR was (five studies) 78.5% (95% CI 61.9-89.2) and specificity 89.3% (95% CI 61.4-97.8). Sensitivity of conventional PCR was (17 studies) 75.3% (95% CI 67.9-81.5) and specificity 94.5% (95% CI 91.4-96.5). CONCLUSIONS: Although the test accuracy looks reasonable, the studies suffered from heterogeneity and low methodological quality.

How to: evaluate a diagnostic test.

BACKGROUND: The development of an in vitro diagnostic test from a good idea to a clinically relevant tool takes several steps, with more stringent requirements at every step. OBJECTIVES: This article aims to summarize the necessary questions to be asked about a test and to illustrate study designs answering these questions. We also aim to relate Regulation (EU) 2017/746 to the needs of evidence-based diagnostic testing, where applicable. SOURCES: We used literature on evidence-based diagnostics, a text book on clinical trials in the development and marketing of medical devices and the English version of Regulation 2017/746 of the European Parliament and of the Council on in vitro diagnostic medical devices. CONTENT: The combination of different test uses and different stages of development determine the required test characteristics and suitability of study designs. In an earlier stage of test development it may be crucial to know whether a test can differentiate diseased persons from healthy controls, although this tells us little about how a test will perform in practice. Later stages focus on the diagnostic accuracy of a test in a clinically relevant situation. However, a test that perfectly distinguishes between patients with and without a certain condition may still have little effect on patient outcomes. Therefore, randomized controlled trials of testing may be needed, as well as post-marketing monitoring. IMPLICATIONS: Both researchers and users of tests need to be aware of the limitations of diagnostic test accuracy and realize that accuracy is only indirectly linked to people's health status.

[Dilemma: to test or not to test for Lyme borreliosis in general practice]. / Dilemma: wel of niet testen op lymeziekte in de huisartsenpraktijk?

There is no such thing as a perfect diagnostic test and the value of a test depends on the situation in which the test is being used. Here, we discuss two options for dealing with the diagnostic process for Lyme borreliosis in general practice. One option is to manage, treat or refer according to clinical signs and symptoms, in accordance with Dutch practice guidelines. The other option is to use laboratory tests to guide further patient management (treatment or referral). The choice depends on currently unknown factors, such as the pre-test probability of Lyme disease in patients presenting to general practitioners. Furthermore, clarity is required about how to proceed after a positive or negative test result. The consequences of a false test result will depend on the patient's status, possible alternative diagnoses and treatment options. Both physician and patient should be aware of the shortcomings of diagnostic tests.

Methotrexate and azathioprine for severe atopic dermatitis: a 5-year follow-up study of a randomized controlled trial.

BACKGROUND: Systemic treatment is indicated for moderate-to-severe atopic dermatitis (AD) refractory to topical treatment. Long-term evidence, up to 5 years, of off-label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking. OBJECTIVES: To investigate long-term effectiveness, safety and drug survival of MTX and AZA. METHODS: In an open-label follow-up phase of a clinical trial, patients were seen every 3 months for 5 years. MTX and AZA doses could be increased or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator's Global Assessment (IGA) after 5 years compared with baseline. To assess safety, the type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan-Meier curves. RESULTS: Thirty-five of 43 originally included patients participated, of whom 27 completed the follow-up. At year 5, the mean relative reduction in SCORAD index was similar in the MTX and AZA groups: 53% and 54% using descriptive analysis. Twelve serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTXn = 5, AZAn = 1). CONCLUSIONS: Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate-to-severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued because of controlled AD.

The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis.

BACKGROUND: Interpretation of serological assays in Lyme borreliosis requires an understanding of the clinical indications and the limitations of the currently available tests. We therefore systematically reviewed the accuracy of serological tests for the diagnosis of Lyme borreliosis in Europe. METHODS: We searched EMBASE en MEDLINE and contacted experts. Studies evaluating the diagnostic accuracy of serological assays for Lyme borreliosis in Europe were eligible. Study selection and data-extraction were done by two authors independently. We assessed study quality using the QUADAS-2 checklist. We used a hierarchical summary ROC meta-regression method for the meta-analyses. Potential sources of heterogeneity were test-type, commercial or in-house, Ig-type, antigen type and study quality. These were added as covariates to the model, to assess their effect on test accuracy. RESULTS: Seventy-eight studies evaluating an Enzyme-Linked ImmunoSorbent assay (ELISA) or an immunoblot assay against a reference standard of clinical criteria were included. None of the studies had low risk of bias for all QUADAS-2 domains. Sensitivity was highly heterogeneous, with summary estimates: erythema migrans 50% (95% CI 40% to 61%); neuroborreliosis 77% (95% CI 67% to 85%); acrodermatitis chronica atrophicans 97% (95% CI 94% to 99%); unspecified Lyme borreliosis 73% (95% CI 53% to 87%). Specificity was around 95% in studies with healthy controls, but around 80% in cross-sectional studies. Two-tiered algorithms or antibody indices did not outperform single test approaches. CONCLUSIONS: The observed heterogeneity and risk of bias complicate the extrapolation of our results to clinical practice. The usefulness of the serological tests for Lyme disease depends on the pre-test probability and subsequent predictive values in the setting where the tests are being used. Future diagnostic accuracy studies should be prospectively planned cross-sectional studies, done in settings where the test will be used in practice.

Molecular tools for diagnosis of visceral leishmaniasis: systematic review and meta-analysis of diagnostic test accuracy.

Molecular methods have been proposed as highly sensitive tools for the detection of Leishmania parasites in visceral leishmaniasis (VL) patients. Here, we evaluate the diagnostic accuracy of these tools in a meta-analysis of the published literature. The selection criteria were original studies that evaluate the sensitivities and specificities of molecular tests for diagnosis of VL, adequate classification of study participants, and the absolute numbers of true positives and negatives derivable from the data presented. Forty studies met the selection criteria, including PCR, real-time PCR, nucleic acid sequence-based amplification (NASBA), and loop-mediated isothermal amplification (LAMP). The sensitivities of the individual studies ranged from 29 to 100%, and the specificities ranged from 25 to 100%. The pooled sensitivity of PCR in whole blood was 93.1% (95% confidence interval [CI], 90.0 to 95.2), and the specificity was 95.6% (95% CI, 87.0 to 98.6). The specificity was significantly lower in consecutive studies, at 63.3% (95% CI, 53.9 to 71.8), due either to true-positive patients not being identified by parasitological methods or to the number of asymptomatic carriers in areas of endemicity. PCR for patients with HIV-VL coinfection showed high diagnostic accuracy in buffy coat and bone marrow, ranging from 93.1 to 96.9%. Molecular tools are highly sensitive assays for Leishmania detection and may contribute as an additional test in the algorithm, together with a clear clinical case definition. We observed wide variety in reference standards and study designs and now recommend consecutively designed studies.

Systematic reviews and meta-analyses of diagnostic test accuracy.

Systematic reviews of diagnostic test accuracy summarize the accuracy, e.g. the sensitivity and specificity, of diagnostic tests in a systematic and transparent way. The aim of such a review is to investigate whether a test is sufficiently specific or sensitive to fit its role in practice, to compare the accuracy of two or more diagnostic tests, or to investigate where existing variation in results comes from. The search strategy should be broad and preferably fully reported, to enable readers to assess the completeness of it. Included studies usually have a cross-sectional design in which the tests of interest, ideally both the index test and its comparator, are evaluated against the reference standard. They should be a reflection of the situation that the review question refers to. The quality of included studies is assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 checklist, containing items such as a consecutive and all-inclusive patient selection process, blinding of index test and reference standard assessment, a valid reference standard, and complete verification of all included participants. Studies recruiting cases separately from (healthy) controls are regarded as bearing a high risk of bias. For meta-analysis, the bivariate model or the hierarchical summary receiver operating characteristic model is used. These models take into account potential threshold effects and the correlation between sensitivity and specificity. They also allow addition of covariates for investigatation of potential sources of heterogeneity. Finally, the results from the meta-analyses should be explained and interpreted for the reader, to be well understood.

The prevalence of thyroid disease in patients with vitiligo: a systematic review.

BACKGROUND: Thyroid disease has been suggested to be associated with vitiligo. However, the outcomes of prevalence studies on thyroid disease in vitiligo vary widely. OBJECTIVES: To summarize and critically appraise current evidence of the prevalence of thyroid diseases in vitiligo. METHODS: A systematic review was performed searching the electronic databases OVID MEDLINE, OVID EMBASE and PubMed. Guidelines for the critical appraisal of studies on prevalence of a health problem were adapted to evaluate the methodological quality of the included studies. Results were analysed in a meta-analysis with a risk ratio (RR). RESULTS: Forty-eight studies published between 1968 and 2012 met the inclusion criteria. Most of the studies (50%) were of fair methodological quality, whereas 18 studies (38%) were of poor quality and six studies (12%) were of good quality. Thyroid disease, autoimmune thyroid disease and presence of thyroid-specific autoantibodies showed a mean prevalence of, respectively, 15·1%, 14·3% and 20·8% in patients with vitiligo and an RR of, respectively, 1·9, 2·5 and 5·2 (all statistically significant). This review shows an increased prevalence and an increased risk of (autoimmune) thyroid disease in patients with vitiligo compared with nonvitiligo. This risk seems to increase with age. CONCLUSIONS: Clinicians should be aware of this increased risk in patients with vitiligo and should be attentive for symptoms of thyroid disease. To make recommendations on screening for thyroid disease in patients with vitiligo future research of good methodological quality, including differentiation of vitiligo types and the use of standardized outcome measures, is needed.

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.

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.

Accuracy of body mass index in predicting pre-eclampsia: bivariate meta-analysis.

OBJECTIVE: The objective of this study was to determine the accuracy of body mass index (BMI) (pre-pregnancy or at booking) in predicting pre-eclampsia and to explore its potential for clinical application. DESIGN: Systematic review and bivariate meta-analysis. SETTING: Medline, Embase, Cochrane Library, MEDION, manual searching of reference lists of review articles and eligible primary articles, and contact with experts. POPULATION: Pregnant women at any level of risk in any healthcare setting. METHODS: Reviewers independently selected studies and extracted data on study characteristics, quality, and accuracy. No language restrictions. MAIN OUTCOME MEASURES: Pooled sensitivities and specificities (95% CI), a summary receiver operating characteristic curve, and corresponding likelihood ratios (LRs). The potential value of BMI was assessed by combining its predictive capacity for different prevalences of pre-eclampsia and the therapeutic effectiveness (relative risk 0.90) of aspirin. RESULTS: A total of 36 studies, testing 1,699,073 pregnant women (60,584 women with pre-eclampsia), met the selection criteria. The median incidence of pre-eclampsia was 3.9% (interquartile range 1.4-6.8). The area under the curve was 0.64 with 93% of heterogeneity explained by threshold differences. Pooled estimates (95% CI) for all studies with a BMI > or = 25 were 47% (33-61) for sensitivity and 73% (64-83) for specificity; and 21% (12-31) and 92% (89-95) for a BMI > or = 35. Corresponding LRs (95% CI) were 1.7 (0.3-11.9) for BMI > or = 25 and 0.73 (0.22-2.45) for BMI < 25, and 2.7 (1.0-7.3) for BMI > or = 35 and 0.86 (0.68-1.07) for BMI < 35. The number needed to treat with aspirin to prevent one case of pre-eclampsia ranges from 714 (no testing, low-risk women) to 37 (BMI > or = 35, high-risk women). CONCLUSIONS: BMI appears to be a fairly weak predictor for pre-eclampsia. Although BMI is virtually free of cost, noninvasive, and ubiquitously available, its usefulness as a stand-alone test for risk stratification must await formal cost-utility analysis. The findings of this review may serve as input for such analyses.

Accuracy of fibronectin tests for the prediction of pre-eclampsia: a systematic review.

The purpose of this study was to review systematically all studies that assessed the accuracy of maternal plasma fibronectin as a serum marker for early prediction of pre-eclampsia. We therefore assessed studies that reported on fibronectin as serum marker for pre-eclampsia before the 25th gestational week. For the selected studies, sensitivity and specificity were calculated and plotted in ROC-space. We included 12 studies, of which only 5 studies reported sufficient data to calculate accuracy estimates, such as sensitivity and specificity. These five studies reported on 573 pregnant women of whom 109 developed pre-eclampsia. At a sensitivity of at least 50%, specificities ranged between 72 and 96% for cellular fibronectin. For total fibronectin, these numbers were 42-94%. Fibronectin seems to be a promising marker for the prediction of pre-eclampsia, however, further studies are needed to determine whether the accuracy of this test is sufficient to be clinically relevant.

Use of methodological search filters to identify diagnostic accuracy studies can lead to the omission of relevant studies.

OBJECTIVE: To determine the usefulness of methodological filters in search strategies for diagnostic studies in systematic reviews. STUDY DESIGN AND SETTING: We made an inventory of existing methodological search filters for diagnostic accuracy studies and applied them in PubMed to a reference set derived from 27 published systematic reviews in a broad range of clinical fields. Outcome measures were the fraction of not identified relevant studies and the reduction in the number of studies to read. RESULTS: We tested 12 search filters. Of the studies included in the systematic reviews, 2%-28% did not pass the sensitive search filters, 4%-24% did not pass the accurate filters, and 39%-42% did not pass the specific filters. Decrease in number-needed-to-read when a search filter was used in a search strategy for a diagnostic systematic review varied from 0% to 77%. CONCLUSION: The use of methodological filters to identify diagnostic accuracy studies can lead to omission of a considerable number of relevant studies that would otherwise be included. When preparing a systematic review, it may be preferable to avoid using methodological filters.