Genetic testing for prevention of severe drug-induced skin rash.

BACKGROUND:Drug-induced skin reactions present with a range of clinical symptoms, from mild maculopapular skin rashes to potentially fatal blistering skin rashes - such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) - which may result in death. Milder reactions may be troublesome and lead to low drug compliance. The pathogenesis of these drug reactions is not yet fully understood; however, there is evidence that pretreatment genetic testing may help to predict and prevent these reactions in some cases. OBJECTIVES:To assess the effects of prospective pharmacogenetic screening to reduce drug-associated skin reactions in a patient population. SEARCH METHODS:We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA:We included RCTs of participants who had prospective pharmacogenetic screening to determine genetic variants associated with hypersensitivity reactions, compared with those who did not have prospective pharmacogenetic screening. We included participants in any setting, who were of any age, gender, and ethnicity, who had been prescribed drugs known to cause delayed type hypersensitivity reactions. DATA COLLECTION AND ANALYSIS:We used standard methodological procedures expected by Cochrane. To assess studies for inclusion, two review authors independently screened all of the titles and abstracts of publications identified by the searches. Because there was only one included study, many of the planned data analyses were not applicable to the review. We used GRADE to assess the quality of the included study.The review's primary outcomes were the incidence of severe skin rashes with systemic symptoms (such as fever and multiple organ involvement), and long-term effects (such as scarring of eyelids or lung tissue). Secondary outcomes were hospitalisation for drug-induced skin reactions, blistering skin reactions (such as SJS, hypersensitivity (HSS) syndrome), and death. MAIN RESULTS:One study, which was a randomised, double-blind, controlled, multicentre trial, fulfilled our inclusion criteria. The trial included 1956 adult participants (74% men, with a mean age of 42 years) across 265 centres (medical centres, hospitals, outpatient clinics) in 19 countries around the world who were infected with HIV-type 1 and who had not received abacavir previously. The participants, who had a clinical need for treatment with an antiretroviral-drug regimen containing abacavir, were randomly assigned to undergo prospective human leukocyte antigen (HLA) Class I, locus B, allele 57:01 (HLA-B*57:01) screening (prospective-screening group) before this treatment, or to undergo a standard-care approach of abacavir use without prospective HLA-B*57:01 screening (control group). Participants who tested positive for HLA-B*57:01 were not given abacavir; instead, they received antiretroviral therapy that did not include abacavir. The control group did have retrospective HLA-B*57:01 pharmacogenetic testing. The trial duration was six months. Each participant was observed for six weeks. Assessments were performed at the time of study entry, at baseline (day one of abacavir treatment), and at weeks one, two and six. This study was funded by the manufacturer of abacavir, GlaxoSmithKline.The study did not assess any of our primary outcomes, and it measured none of our secondary outcomes in isolation. However, it did assess an outcome of (characteristically severe) hypersensitivity reaction which included (but was not limited to) our secondary outcomes of HSS and SJS/TEN.The study demonstrated that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir. The incidence of clinically diagnosed HSS reaction to abacavir was lower in the screening arm (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.28 to 0.67; 1650 participants; moderate-quality evidence), as was immunologically confirmed HSS reaction (RR 0.02, 95% 0.00 to 0.37; 1644 participants; moderate-quality evidence). A positive result from an epicutaneous patch test performed six to ten weeks after clinical diagnosis provided immunological confirmation.Overall, the study demonstrates a low risk of bias across five out of seven domains. There was a high risk of detection bias because hypersensitivity reactions were diagnosed by the principal investigator at the recruitment site without the use of predefined clinical criteria. Although there was also high risk of attrition bias due to excluding participants with incomplete follow-up from analyses, the authors did undertake a series of sensitivity analyses based on the intention-to-treat population, which demonstrated consistent results with the primary analysis. We rated the study quality as moderate-quality using GRADE criteria. AUTHORS' CONCLUSIONS:Prospective screening for HLA-B*57:01 probably reduces severe hypersensitivity skin reactions to abacavir in patients positive for HIV-type 1. However, these results are only based on one study, which was at high risk of attrition and detection bias.Our primary outcomes (incidence of severe skin rashes with systemic symptoms, and long-term effects) were not assessed by the trial, and only one of the review's secondary outcomes was measured (hypersensitivity reaction); thus, we found no evidence relating to hospitalisation, death, or long-term conditions resulting from drug injury.We found no eligible evidence on genetic testing for severe drug-induced skin rash in relation to different drugs and classes of drugs. Further clinical trials based on other drugs, and in different patient populations, would be useful for advising policy changes for improving the prevention of adverse skin reactions to drug treatments

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies

Definitions and outcome measures for mucous membrane pemphigoid: Recommendations of an international panel of experts

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index

Stratum corneum biomarkers in atopic dermatitis: Biological and spatial variability

Background: Atopic dermatitis is a highly heterogeneous skin disease, mainly affecting children. Introduction of biological therapies has urged the development of biomarkers to facilitate personalized therapy. Stratum corneum biomarkers emerged as a promising non-invasive alternative to skin biopsy, yet validation of spatial and biological variability is essential for their application in clinical research. Objective: To assess spatial and biological variability of stratum corneum biomarkers for atopic dermatitis. Methods: Stratum corneum was collected from 17 atopic dermatitis patients by consecutive application of eight adhesive tapes to a lesional skin site and 2 cm and 4 cm from the lesion. Two non-lesional sites at a 2 cm distance from the same lesion were collected to determine biological variability. Filaggrin degradation products (NMF) were determined by liquid chromatography and thirteen cytokines (IL-4, IL-13, IL-18, IL-31, IL-33, CCL17, CCL22, CCL27, CXCL8, IL-1α, IL-RA, IL-18, IL-22) by multiplex immunoassay. Results: Biomarker levels showed gradual changes from lesional to non-lesional skin sites at 2 cm and 4 cm; magnitude and direction of change were biomarker-specific. Intra-subject variability ranged from 17.3% (NMF) to 85.1% (CXCL8). Biomarker levels from two stratum corneum depths were highly correlated; several biomarkers showed significant depth dependence. Conclusion: Stratum corneum enables non-invasive collection of relevant immune and epidermal biomarkers, but biomarker-specific spatial and biological variability emphasizes the importance of standardized procedures for stratum corneum collection

Developing classification criteria for discoid lupus erythematosus: an update from the World Congress of Dermatology 2015 meeting

Currently, no standardized classification criteria exist for cutaneous lupus erythematosus. With increased interest in studying cutaneous lupus erythematosus, specifically discoid lupus erythematosus, it is our aim to apply previously adopted methods from rheumatology to dermatologic diseases to develop feasible, validated, and standardized classification criteria useful in both academic and community practice. Here we report the progress to date to define discoid lupus erythematosus using clinical, histopathologic, and serologic features by means of a Delphi method—using a series of iterative questionnaires sent to expert stakeholders. We present specific updates from the World Congress of Dermatology 2015 meeting, at which a nominal group of expert stakeholders met to discuss the results of round 1 of the Delphi process to further clarify and harmonize specific classification items for inclusion into round 2

Development of classification criteria for discoid lupus erythematosus: Results of a Delphi exercise

Background: No classification criteria currently exist for discoid lupus erythematosus (DLE), which has led to problematic heterogeneity in both observational and interventional research efforts. Objectives: We sought to develop DLE classification criteria based on consensus of international expert opinion of relevant stakeholders in the field. Methods: Using a Delphi consensus process and nominal group techniques, potential items for classification criteria were generated. Experts ranked items in terms of their appropriateness and ability to discriminate DLE from other diagnoses, and items were subsequently eliminated using consensus exercises. Results: A final list of 12 clinical and histopathologic items was generated for potential inclusion into a set of DLE classification criteria through a formal ongoing validation process. Limitations: The participants are predominantly composed of DLE experts in North America and Europe. Conclusion: This work represents a key step toward the development of formal DLE classification criteria

Developing classification criteria for discoid lupus erythematosus: an update from the World Congress of Dermatology 2015 meeting

Currently, no standardized classification criteria exist for cutaneous lupus erythematosus. With increased interest in studying cutaneous lupus erythematosus, specifically discoid lupus erythematosus, it is our aim to apply previously adopted methods from rheumatology to dermatologic diseases to develop feasible, validated, and standardized classification criteria useful in both academic and community practice. Here we report the progress to date to define discoid lupus erythematosus using clinical, histopathologic, and serologic features by means of a Delphi method—using a series of iterative questionnaires sent to expert stakeholders. We present specific updates from the World Congress of Dermatology 2015 meeting, at which a nominal group of expert stakeholders met to discuss the results of round 1 of the Delphi process to further clarify and harmonize specific classification items for inclusion into round 2. Key words: Discoid Lupus Erythematosus, Cutaneous Lupus Erythematosus, Lupus, Connective Tissue Diseases, Delphi method, classification criteria, World Congress of Dermatolog

Corrigendum:S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV)

In the version of this article initially published,1 Prof. Angelo Valerio Marzano affiliation was listed as “Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy”. His correct affiliations are the 3Dermatology Unit, Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico, Milan, Italy and 56Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. The error has been corrected in the online version of the article.</p

European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome