Research techniques made simple: workflow for searching databases to reduce evidence selection bias in systematic reviews

Clinical trials and basic science studies without statistically significant results are less likely to be published than studies with statistically significant results. Systematic reviews and meta-analyses that omit unpublished data are at high risk of distorted conclusions. Here, we describe methods to search beyond bibliographical databases to reduce evidence selection bias in systematic reviews. Unpublished studies may be identified by searching conference proceedings. Moreover, clinical trial registries—databases of planned and ongoing trials—and regulatory agency websites such as the European Medicine Agency (EMA) and the United States Food and Drug Administration (FDA) may provide summaries of efficacy and safety data. Primary and secondary outcomes are prespecified in trial registries, thus allowing the assessment of outcome reporting bias by comparison with the trial report. The sources of trial data and documents are still evolving, with ongoing initiatives promoting broader access to clinical study reports and individual patient data. There is currently no established methodology to ensure that the multiple sources of information are incorporated. Nonetheless, systematic reviews must adapt to these improvements and cover the new sources in their search strategies

Which acne treatment has the best influence on health-related quality of life? Literature review by the European Academy of Dermatology and Venereology Task Force on Quality of Life and Patient Oriented Outcomes

According to results of a recent literature search performed by the European Academy of Dermatology and Venereology (EADV) Task Forces (TF) on Quality of Life and Patient Oriented Outcomes (QoL and PO) and Acne, Rosacea and Hidradenitis Suppurativa (ARHS), most of the publications where health‐related (HR) QoL of acne patients was studied were clinical trials. Members of the EADV TF on QoL and PO decided to detect which acne treatment has the best influence on HRQoL of acne patients. A new literature search was organized to find publications on acne treatment where the HRQoL of patients was assessed as an outcome measure. From 186 papers with HRQoL assessment, 37 papers were included for further analysis. Our results revealed that oral isotretinoin had the best influence on HRQoL of acne patients. Several other treatment methods also showed good effects on the HRQoL of acne patients. Oral isotretinoin and norethindrone acetate/ethinyl estradiol, topical clindamycin phosphate/benzoyl peroxide and adapalene/benzoyl peroxide showed significantly better effect on HRQoL than placebo. There is limited number of the high‐quality studies on acne treatment where HRQoL was assessed. Dermatology‐specific and acne‐specific instruments showed much better sensitivity to successful therapeutic intervention than generic HRQoL instruments. The most frequently used HRQoL instrument was the Dermatology Life Quality Index questionnaire.FSW - Self-regulation models for health behavior and psychopathology - ou

A systematic review of the use of quality-of-life instruments in randomized controlled trials for psoriasis

This is the peer reviewed version of the following article: F. M. Ali, A. C. Cueva, J. Vyas, A. A. Atwan, M. S. Salek, A. Y. Finlay, and V. Piguet, ‘A systematic review of the use of quality-of-life instruments in randomized controlled trials for psoriasis’, British Journal of Dermatology, Vol. 176 (3): 577-593, March 2017, which has been published in final form at https://doi.org/10.1111/bjd.14788. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Planners of interventional studies in psoriasis face the dilemma of selecting suitable quality-of-life (QoL) measures. Systematic reviews have the potential of identifying psychometrically sound measures in a given therapeutic area, while guiding the development of practice guidelines. The aim of this systematic review was to generate evidence of the use of QoL instruments in randomized controlled trials (RCTs) for interventions in psoriasis. The methodology followed the PRISMA guidelines. Six databases were searched with 388 search terms. Abstracts of articles were reviewed independently by two assessors, and a third adjudicator resolved any opinion differences. Risk of bias was assessed using the Jadad scale. Of 3646 screened publications, 99 articles (100 trials) met the eligibility criteria for inclusion, describing research on 33 215 patients. Thirty-three trials tested topical therapy, 18 systemic, 39 biologics, nine phototherapy and 10 other interventions. The Dermatology Life Quality Index (DLQI) was the most commonly used QoL instrument (83 studies, 83%), followed by the 36-Item Short Form Survey (SF-36) (31, 31%), EuroQoL-5D (EQ-5D) (15, 15%), Psoriasis Disability Index (14, 14%) and Skindex (five, 5%). There was widespread inconsistency in the way that QoL data were reported. Of the 100 trials identified, 37 reported minimal clinically important difference (MCID): 32 for DLQI, 10 for SF-36 and six for EQ-5D. QoL measurement is increasingly being reported in RCTs of psoriasis. Formal guidelines are needed for assessment and publishing of QoL data. Researchers should consider whether MCID information is available, and development of MCID data should be encouraged.Peer reviewedFinal Accepted Versio

Toxic epidermal necrolysis and Stevens-Johnson syndrome

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at "high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease

Contribution of systematic reviews and network metanalaysis in Dermatology

La décision médicale nécessite d’avoir à disposition une synthèse rigoureuse et actualisée des données de la recherche. Les revues systématiques (RS) et méta-analyses (MA) sont la méthode la plus rigoureuse pour produire ces synthèses. Nous avons réalisé des RS et MA Cochrane sur trois maladies chroniques en dermatologie. Notre objectif était de produire une synthèse des données, de proposer des pistes d’amélioration pour la recherche à venir et d’ouvrir sur des projets de méta-recherche.La première revue avait pour objectif d’évaluer l’efficacité et la tolérance des traitements de la pustulosepalmoplantaire. Nous avons inclus 36 essais contrôlés randomisés (ECR) comprenant un total de 1504 patients. Le comparateur était le placebo ou aucun traitement dans 31 ECR. Au total, nous avons trouvé un faible degré de certitude que l’analogue topique de la vitamine D (maxacalcitrol) était plus efficace que le placebo à court terme ; que l'alitrétinoïne et trois traitements biologiques n'étaient pas plus efficaces que le placebo ; enfin un degré de certitude modéré que le secukinumab (anti IL17) était supérieur au placebo. Dans cette revue, aucune donnée probante n’a été retrouvée pour les principaux traitements utilisés en pratique courante (corticoïdes locaux, photothérapie, acitrétine, méthotrexate, ciclosporine).La méta-analyse en réseau est une méthode statistique permettant de déterminer l’efficacité relative de l’ensemble des traitements y compris pour les comparaisons qui n’ont pas été évaluées dans un ECR. Cette méthode a été appliquée dans les deux revues suivantes.La deuxième revue avait pour objectif d’évaluer l’efficacité et la tolérance relative d’un traitement suppressif par aciclovir, valaciclovir ou famciclovir dans l’herpès génital du sujet immunocompétent. Nous avons inclus 26 ECR portant sur un total de 6950 patients. Les résultats montraient que l'aciclovir, le famciclovir et le valaciclovir diminuaient le risque d’avoir au moins une récidive d'herpès génital sous traitement comparativement au placebo. La méta-analyse en réseau n'a révélé aucune différence statistiquement significative entre les traitements. Dans cette revue, le manque de comparaisons directes, l’absence des critères de jugement pertinents pour les patients, le risque de biais élevé et non clair pour une majorité d’essais et une hétérogénéité importante limitent la pertinence et le niveau de confiance dans les résultats.La troisième revue avait pour objectif d’évaluer l’efficacité et la tolérance relative des traitements systémiques du psoriasis modéré à sévère chez l’adulte. Nous avons identifié 109 essais pertinents pour un total de 39,882 patients. Soixante-quatorze essais ont été inclus dans la méta-analyse en réseau. Cette étude a montré que l’ixekizumab était le meilleur traitementversus placebo (RR 32.45, 95% IC 23.61 à 44.60; (haut degré de certitude)), suivi par le secukinumab (haut degré de certitude), puis le brodalumab (degré de certitude modéré), puis guselkumab (degré de certitude modéré), le certolizumab (degré de certitude modéré), et l’ustekinumab (haut degré de certitude). Dans cette revue, malgré un nombre conséquent d’essais, un certain nombre de points limites diminuaient le degré de confiance dans les résultats : peu d’essais face-face, peu d’essais évaluant et rapportant la qualité de vie, l’absence d’évaluation au long court et l’inclusion d’une population sélectionnée.Ces trois revues ont permis de mettre en évidence des biais récurrents pouvant s’appliquer au traitement de maladies chroniques en dermatologie notamment le manque d’essai face-face, l’évaluation le plus souvent à court terme et le peu d’essais rapportant un critère de qualité de vie. Ce travail permet également de guider les essais à venir dans ces trois domaines afin d’améliorer l’agenda de la recherche, la diffusion des résultats et la rédaction de recommandations.Medical decision-making requires a rigorous and up-to-date synthesis of research data. Systematic reviews (SR) and meta-analyses (MA) are the most rigorous method for producing these syntheses. Cochrane is an independent international organization whose mission is to produce and disseminate systematic reviews. We have performed RS and MA Cochrane on three chronic diseases in dermatology. Our objective was threefold: to produce a rigorous synthesis of the data, to propose ways of improving future research in these fields and finally to open up to meta-research projects. The first review aimed to evaluate the efficacy and tolerance of treatments for palmoplantarpustulosis, a chronic inflammatory disease characterized by the presence of pustules on palms and plants. We included 36 randomized controlled trials (RCTs) that encompassed a total of 1,504 patients. Overall, we found that the topical analogue of vitamin D (maxacalcitrol) was more effective than placebo in the short term; alitretinoin and three biological treatments (etanercept (anti TNF), ustekinumab (anti IL17-IL23) and guselkumab (anti IL23)) were no more effective than placebo (low degree of certainty); and secukinumab (anti IL17) was superior to placebo (moderate degree of certainty). In this first review, we observed a situation where no evidence was found for the main treatments (local corticosteroids, phototherapy, acitretin, methotrexate, and cyclosporine) used. Network meta-analysis is a statistical method for determining the relative effectiveness of all treatments, including comparisons that have not been evaluated in an RCT. This method was applied in the following two reviews.The objective of the second review was to evaluate the efficacy and relative safety of suppressive treatment with acyclovir, valaciclovir or famciclovir in genital herpes in the immunocompetent subject. We included 26 RCTs with a total of 6,950 patients. The results showed that acyclovir, famciclovir and valaciclovir reduced the risk of having at least one recurrence of genital herpes under treatment compared to placebo. The network meta-analysis revealed no statistically significant differences between treatments. No conclusions on adverse reactions could be drawn due to the poor quality of their description. The lack of direct comparison, the absence of the most relevant judgment criteria for patients, the risk of high and unclear bias in a majority of trials and a heterogeneity whose causes could not be explored alter the relevance and level of confidence in the results.The objective of the third review was to evaluate the efficacy and relative tolerance of systemic treatments for moderate to severe psoriasis in adults. We included 109 trials for a total of 39,882 patients. Seventy-four of these trials were included in the network meta-analysis. This study showed that ixekizumab was the best treatment. (versus placebo: RR 32.45, 95% CI 23.61 to 44.60; (high certainty), followed by secukinumab (high certainty), then brodalumab (moderate certainty), then guselkumab (moderate certainty), certolizumab (moderate certainty), and ustekinumab (high certainty). In this third review, the number of trials allowed us to conduct a network meta-analysis and classify the treatments. However, a number of points decreased the degree of confidence in the results: the few face-to-face trials, few trials evaluating and reporting on quality of life, the absence of long-term short evaluation and the inclusion of a selected population.These three reviews highlighted recurrent biases that could be applied to other chronic dermatological diseases, including the lack of face-to-face testing, primarily short term evaluations, and the lack of reports including a quality of life criterion. This work also provides guidance for future trials in these three areas in terms of comparisons to be made and bias to be avoided

Apport des revues systématiques et méta-analyses en réseau en Dermatologie

Medical decision-making requires a rigorous and up-to-date synthesis of research data. Systematic reviews (SR) and meta-analyses (MA) are the most rigorous method for producing these syntheses. Cochrane is an independent international organization whose mission is to produce and disseminate systematic reviews. We have performed RS and MA Cochrane on three chronic diseases in dermatology. Our objective was threefold: to produce a rigorous synthesis of the data, to propose ways of improving future research in these fields and finally to open up to meta-research projects. The first review aimed to evaluate the efficacy and tolerance of treatments for palmoplantarpustulosis, a chronic inflammatory disease characterized by the presence of pustules on palms and plants. We included 36 randomized controlled trials (RCTs) that encompassed a total of 1,504 patients. Overall, we found that the topical analogue of vitamin D (maxacalcitrol) was more effective than placebo in the short term; alitretinoin and three biological treatments (etanercept (anti TNF), ustekinumab (anti IL17-IL23) and guselkumab (anti IL23)) were no more effective than placebo (low degree of certainty); and secukinumab (anti IL17) was superior to placebo (moderate degree of certainty). In this first review, we observed a situation where no evidence was found for the main treatments (local corticosteroids, phototherapy, acitretin, methotrexate, and cyclosporine) used. Network meta-analysis is a statistical method for determining the relative effectiveness of all treatments, including comparisons that have not been evaluated in an RCT. This method was applied in the following two reviews.The objective of the second review was to evaluate the efficacy and relative safety of suppressive treatment with acyclovir, valaciclovir or famciclovir in genital herpes in the immunocompetent subject. We included 26 RCTs with a total of 6,950 patients. The results showed that acyclovir, famciclovir and valaciclovir reduced the risk of having at least one recurrence of genital herpes under treatment compared to placebo. The network meta-analysis revealed no statistically significant differences between treatments. No conclusions on adverse reactions could be drawn due to the poor quality of their description. The lack of direct comparison, the absence of the most relevant judgment criteria for patients, the risk of high and unclear bias in a majority of trials and a heterogeneity whose causes could not be explored alter the relevance and level of confidence in the results.The objective of the third review was to evaluate the efficacy and relative tolerance of systemic treatments for moderate to severe psoriasis in adults. We included 109 trials for a total of 39,882 patients. Seventy-four of these trials were included in the network meta-analysis. This study showed that ixekizumab was the best treatment. (versus placebo: RR 32.45, 95% CI 23.61 to 44.60; (high certainty), followed by secukinumab (high certainty), then brodalumab (moderate certainty), then guselkumab (moderate certainty), certolizumab (moderate certainty), and ustekinumab (high certainty). In this third review, the number of trials allowed us to conduct a network meta-analysis and classify the treatments. However, a number of points decreased the degree of confidence in the results: the few face-to-face trials, few trials evaluating and reporting on quality of life, the absence of long-term short evaluation and the inclusion of a selected population.These three reviews highlighted recurrent biases that could be applied to other chronic dermatological diseases, including the lack of face-to-face testing, primarily short term evaluations, and the lack of reports including a quality of life criterion. This work also provides guidance for future trials in these three areas in terms of comparisons to be made and bias to be avoided.La décision médicale nécessite d’avoir à disposition une synthèse rigoureuse et actualisée des données de la recherche. Les revues systématiques (RS) et méta-analyses (MA) sont la méthode la plus rigoureuse pour produire ces synthèses. Nous avons réalisé des RS et MA Cochrane sur trois maladies chroniques en dermatologie. Notre objectif était de produire une synthèse des données, de proposer des pistes d’amélioration pour la recherche à venir et d’ouvrir sur des projets de méta-recherche.La première revue avait pour objectif d’évaluer l’efficacité et la tolérance des traitements de la pustulosepalmoplantaire. Nous avons inclus 36 essais contrôlés randomisés (ECR) comprenant un total de 1504 patients. Le comparateur était le placebo ou aucun traitement dans 31 ECR. Au total, nous avons trouvé un faible degré de certitude que l’analogue topique de la vitamine D (maxacalcitrol) était plus efficace que le placebo à court terme ; que l'alitrétinoïne et trois traitements biologiques n'étaient pas plus efficaces que le placebo ; enfin un degré de certitude modéré que le secukinumab (anti IL17) était supérieur au placebo. Dans cette revue, aucune donnée probante n’a été retrouvée pour les principaux traitements utilisés en pratique courante (corticoïdes locaux, photothérapie, acitrétine, méthotrexate, ciclosporine).La méta-analyse en réseau est une méthode statistique permettant de déterminer l’efficacité relative de l’ensemble des traitements y compris pour les comparaisons qui n’ont pas été évaluées dans un ECR. Cette méthode a été appliquée dans les deux revues suivantes.La deuxième revue avait pour objectif d’évaluer l’efficacité et la tolérance relative d’un traitement suppressif par aciclovir, valaciclovir ou famciclovir dans l’herpès génital du sujet immunocompétent. Nous avons inclus 26 ECR portant sur un total de 6950 patients. Les résultats montraient que l'aciclovir, le famciclovir et le valaciclovir diminuaient le risque d’avoir au moins une récidive d'herpès génital sous traitement comparativement au placebo. La méta-analyse en réseau n'a révélé aucune différence statistiquement significative entre les traitements. Dans cette revue, le manque de comparaisons directes, l’absence des critères de jugement pertinents pour les patients, le risque de biais élevé et non clair pour une majorité d’essais et une hétérogénéité importante limitent la pertinence et le niveau de confiance dans les résultats.La troisième revue avait pour objectif d’évaluer l’efficacité et la tolérance relative des traitements systémiques du psoriasis modéré à sévère chez l’adulte. Nous avons identifié 109 essais pertinents pour un total de 39,882 patients. Soixante-quatorze essais ont été inclus dans la méta-analyse en réseau. Cette étude a montré que l’ixekizumab était le meilleur traitementversus placebo (RR 32.45, 95% IC 23.61 à 44.60; (haut degré de certitude)), suivi par le secukinumab (haut degré de certitude), puis le brodalumab (degré de certitude modéré), puis guselkumab (degré de certitude modéré), le certolizumab (degré de certitude modéré), et l’ustekinumab (haut degré de certitude). Dans cette revue, malgré un nombre conséquent d’essais, un certain nombre de points limites diminuaient le degré de confiance dans les résultats : peu d’essais face-face, peu d’essais évaluant et rapportant la qualité de vie, l’absence d’évaluation au long court et l’inclusion d’une population sélectionnée.Ces trois revues ont permis de mettre en évidence des biais récurrents pouvant s’appliquer au traitement de maladies chroniques en dermatologie notamment le manque d’essai face-face, l’évaluation le plus souvent à court terme et le peu d’essais rapportant un critère de qualité de vie. Ce travail permet également de guider les essais à venir dans ces trois domaines afin d’améliorer l’agenda de la recherche, la diffusion des résultats et la rédaction de recommandations

Le test-retest dans un modèle animal d'anxiété chez la souris (sensibilisation, discrimination dans le test des quatre-plaques )

Une procédure de test-retest dans un modèle animal d'anxiété entraîne une augmentation du comportement anxieux et une perte de l'activité anxiolytique des benzodiazépines (BZDs). L'objectif principal de ce travail était d'évaluer la capacité d'un protocole de test-retest dans le modèle des quatre-plaques (FPT) à mettre en évidence des différences d'activité entre diverses substances anxiolytiques, possédant des mécanismes d'action distincts et d'essayer d'apporter une explication à ces modifications comportementales et pharmacologiques observées lors d'une 2ème confrontation des souris au modèle. Contrairement aux BZDs et aux antidépresseurs [la paroxétine, un inhibiteur sélectif de la recapture de la sérotonine (5-HT) et la venlafaxine, un inhibiteur mixte de la recapture de la 5-HT et de la noradrénaline] étudiés, le DOI, un agoniste des récepteurs 5-HT2A/2C conserve son effet de type anxiolytique chez des souris confrontées une 2ème fois au FPT. Son effet s'exerce par l'intermédiaire des récepteurs 5-HT2A. Chez les souris naïves, l'effet anti-punitif du DOI est supprimé par un prétraitement par la clonidine (un agoniste des récepteurs alpha2), le sulpiride (un antagoniste des récepteurs D2), le SCH 23390 (un antagoniste des récepteurs D1) et la buspirone (un agoniste partiel des récepteurs 5-HT1A et antagoniste des récepteurs D2). Chez les souris pré-testées, seuls le sulpiride et le SCH 23390 s'opposent à l'activité du DOI. La lésion des neurones dopaminergiques abolit l'effet du DOI chez les souris pré-testées, mais pas chez les souris naïves. Contrairement au DOI, le diazépam perd son effet de type anxiolytique chez les souris naïves déplétées en 5-HT.A test-retest protocol in animal models of anxiety induces an increase of anxious behaviour and a loss of benzodiazepines (BZD)-induced effect. The aim of this study was to evaluate if the test-retest protocol in the four-plates-test is able to discriminate between anxiolytic compounds with distinct mechanism of action and tried to explain the changes in behaviour and pharmacological response in retested mice. In contrast to BZDs and antidepressants [paroxetine, a selective serotonin (5-HT) reuptake inhibitor and venlafaxine, a 5-HT and noradrenaline reuptake inhibitor], the 5-HT2A/2C receptor agonist DOI, conserves its anxiolytic-like effect in mice when retested on FPT. DOI exerts its anxiolytic-like effect in the FPT test-retest paradigm through 5-HT2A receptors. In naive mice, DOI-induced anti-punishment effect was abolished by pretreatment with clonidine (an alpha2 receptor agonist), sulpiride (a D2 receptor antagonist), SCH 23390 (a D1 receptor antagonist) and buspirone (a 5-HT1A partial agonist and D2 receptor antagonist). Only sulpiride and SCH 23390 antagonized the DOI-induced activity in experienced mice. The Lesion of dopaminergic neurons suppress the DOI-induced effect in retested mice, but not in naive mice. In contrast to DOI, diazepam lost its anxiolytic-like effect in 5-HT depleted naive mice.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF