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To identify priorities for future research into the treatment of bullous pemphigoid, mucous membrane pemphigoid and pemphigus vulgaris, we conducted a Priority Setting Partnership using James Lind Alliance methodology. The top 10 priorities identified in this PSP represent the key questions that patients, carers and healthcare professionals have about the treatment of these diseases and which future research will hopefully address.

Background Eczema is a common and chronic, relapsing, inflammatory skin disorder. It seriously impacts quality of life and economic outcomes, especially for those with moderate to severe eczema. Various treatments allow sustained control of the disease; however, their relative benefit remains unclear due to the limited number of trials directly comparing treatments. Objectives To assess the comparative efficacy and safety of different types of systemic immunosuppressive treatments for moderate to severe eczema using NMA and to generate rankings of available systemic immunosuppressive treatments for eczema according to their efficacy and safety. Search methods We searched the following databases up to August 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. Selection criteria All randomised controlled trials (RCTs) of systemic immunosuppressive agents for moderate to severe atopic eczema when compared against placebo or any other eligible eczema treatment. Data collection and analysis We synthesised data using pair-wise analysis and NMA to compare treatments and rank them according to their effectiveness. Effectiveness was assessed primarily by determining the proportion of participants who achieved at least 75% improvement in the Eczema Area and Severity Index (EASI75) and improvement in the Patient-Oriented Eczema Measure (POEM). Safety was evaluated primarily by considering the proportion of participants with serious adverse events (SAEs) and infection. We deemed short-term follow-up as ≤ 16 weeks and long-term follow-up as > 16 weeks. We assessed the certainty of the body of evidence from the NMA for these primary outcomes using six domains of CiNEMA grading. Main results We included a total of 74 studies, with 8177 randomised participants. Approximately 55% of participants were male, with average age of 32 years (range 2 to 84 years), although age and gender were unreported for 419 and 902 participants, respectively. Most of the included trials were placebo controlled (65%), 34% were head-to-head studies (15% assessed the effects of different doses of the same drug), and 1% were multi-armed studies with both an active comparator and a placebo. All trials included participants with moderate to severe eczema, but 62% of studies did not separate data by severity; 38% of studies assessed only severe eczema. The total duration of included trials ranged from 2 weeks to 60 months, whereas treatment duration varied from a single dose (CIM331, KPL-716) to 60 months (methotrexate (MTX)). Seventy studies were available for quantitative synthesis; this review assessed 29 immunosuppressive agents from three classes of interventions. These included (1) conventional treatments, with ciclosporin assessed most commonly; (2) small molecule treatments, including phosphodiesterase (PDE)-4 inhibitors, tyrosine kinase inhibitors, and Janus kinase (JAK) inhibitors; and (3) biological treatments, including anti-CD31 receptors, anti-interleukin (IL)-22, anti-IL-31, anti-IL-13, anti-IL-12/23p40, anti-OX40, anti-TSLP, anti-CRTH2, and anti-immunoglobulin E (IgE) monoclonal antibodies, but most commonly dupilumab. Most trials (73) assessed outcomes at a short-term duration ranging from 2 to 16 weeks, whereas 33 trials assessed long-term outcomes, with duration ranging from 5 to 60 months. All participants were from a hospital setting. Fifty-two studies declared a source of funding, and of these, pharmaceutical companies funded 88%. We rated 37 studies as high risk; 21, unclear risk, and 16, low risk of bias, with studies most commonly at high risk of attrition bias. Network meta-analysis suggests that dupilumab ranks first for effectiveness when compared with other biological treatments. Dupilumab is more effective than placebo in achieving EASI75 (risk ratio (RR) 3.04, 95% confidence interval (CI) 2.51 to 3.69) and improvement in POEM score (mean difference 7.30, 95% CI 6.61 to 8.00) at short-term follow-up (high-certainty evidence). Very low-certainty evidence means we are uncertain of the effects of dupilumab when compared with placebo, in terms of the proportion of participants who achieve EASI75 (RR 2.59, 95% CI 1.87 to 3.60) at longer-term follow-up. Low-certainty evidence indicates that tralokinumab may be more effective than placebo in achieving short-term EASI75 (RR 2.54, 95% CI 1.21 to 5.34), but there was no evidence for tralokinumab to allow us to assess short-term follow-up of POEM or long-term follow-up of EASI75. We are uncertain of the effect of ustekinumab compared with placebo in achieving EASI75 (long-term follow-up: RR 1.17, 95% CI 0.40 to 3.45; short-term follow-up: RR 0.91, 95% CI 0.28 to 2.97; both very low certainty). We found no evidence on ustekinumab for the POEM outcome. We are uncertain whether other immunosuppressive agents that targeted our key outcomes influence the achievement of short-term EASI75 compared with placebo due to low- or very low-certainty evidence. Dupilumab and ustekinumab were the only immunosuppressive agents evaluated for longer-term EASI75. Dupilumab was the only agent evaluated for improvement in POEM during short-term follow-up. Low- to moderate-certainty evidence indicates a lower proportion of participants with SAEs after treatment with QAW039 and dupilumab compared to placebo during short-term follow-up, but low- to very low-certainty evidence suggests no difference in SAEs during short-term follow-up of other immunosuppressive agents compared to placebo. Evidence for effects of immunosuppressive agents on risk of any infection during short-term follow-up and SAEs during long-term follow-up compared with placebo was of low or very low certainty but did not indicate a difference. We did not identify differences in other adverse events (AEs), but dupilumab is associated with specific AEs, including eye inflammation and eosinophilia. Authors' conclusions Our findings indicate that dupilumab is the most effective biological treatment for eczema. Compared to placebo, dupilumab reduces eczema signs and symptoms in the short term for people with moderate to severe atopic eczema. Short-term safety outcomes from clinical trials did not reveal new safety concerns with dupilumab. Overall, evidence for the efficacy of most other immunosuppressive treatments for moderate to severe atopic eczema is of low or very low certainty. Given the lack of data comparing conventional with newer biological treatments for the primary outcomes, there remains high uncertainty for ranking the efficacy and safety of conventional treatments such as ciclosporin and biological treatments such as dupilumab. Most studies were placebo-controlled and assessed only short-term efficacy of immunosuppressive agents. Further adequately powered head-to-head RCTs should evaluate comparative long-term efficacy and safety of available treatments for moderate to severe eczema.

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE). It provides a summary of key findings from 12 systematic reviews (SRs) that were published or indexed during 2014, and focuses on the treatment and prevention of AE. For an update of SRs on the epidemiology, mechanisms of disease and methodological issues, see Part 1 of this update. Although phototherapy and various systemic medications (including ciclosporin, azathioprine and methotrexate) are commonly used to treat AE, many of these have not been robustly assessed in head-to-head randomized controlled trials. Educational interventions may improve AE severity and quality of life for children and their families. Intake of probiotics prenatally and postnatally may help prevent AE, but there is little evidence to suggest a role in the treatment of AE. Although no benefit was found for allergen avoidance in preventing AE, the use of immunotherapy to treat AE-associated aeroallergen sensitivity requires further evaluation. There is insufficient evidence for Vitamin D supplementation for the treatment of AE This overview of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with the most recent evidence for the treatment and prevention of AE.

Summary This review summarizes key findings from nine systematic reviews on atopic eczema (AE) published or first indexed in 2014. It focuses on epidemiology, disease processes and methodological issues. There is reasonable evidence to conclude that high birth weight (> 4000 g) is a risk factor for the development of AE. A lower socioeconomic position is associated with lower prevalence of AE. The effect of exposure to traffic-related air pollution in childhood on the development of AE is uncertain. CD14 polymorphisms do not appear to have an effect in AE. There may be a role for interleukin-18 in AE development. Patients with AE are at decreased risk of brain tumours, but at increased risk of developing attention deficit hyperactivity disorder. Evidence supports the view that normal-appearing skin in AE is in fact structurally abnormal. Lower success rates at inducing remission in AE are associated with increased risk of relapse during long-term follow-up. The Eczema Area Severity Index (EASI) has been agreed as the preferred core instrument to measure clinical signs in future research. There remains a lack of consensus on the definition of an AE flare.

A woman in her 70s presented to the dermatology clinic with a two year history of blue-grey hyperpigmentation on her face, which symmetrically involved her forehead, eyelids, cheeks, nose, and perioral skin (fig 1). Similar blue-grey discoloration was noted on her gingiva (fig 2). Fig 1 Marked discoloration to the eyebrows, forehead, cheeks, and perioral skin Fig 2 Blue-grey discoloration also involving the gingiva The patient had had rosacea since her late teens, for which she had been taking oral minocycline intermittently for more than 20 years. Three months before this presentation she was advised to stop the minocycline because it was …

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of different types of systemic immunosuppressive treatments for eczema. To generate rankings of the available systemic immunosuppressive treatments for eczema, according to their efficacy and safety.

This review is part of a series of annual updates summarizing the evidence base for atopic eczema (AE). It provides a summary of key findings from 28 systematic reviews that were published or indexed during 2016 with a focus on treatment and prevention of AE. There is reasonable evidence of benefit for topical corticosteroids, calcineurin inhibitors, a glycyrrhetinic acid-containing preparation (Atopiclair® ), oral ciclosporin, oral azathioprine, narrowband ultraviolet B radiation and education programmes. Overall, there is evidence that topical corticosteroids and calcineurin inhibitors have similar efficacy and that both can prevent AE flares when used twice weekly as maintenance therapy. However, topical calcineurin inhibitors are costlier and have more adverse reactions, thus topical corticosteroids should remain the standard of care for patients with AE. There is no evidence that multiple applications are better than once-daily application of topical corticosteroid. There is inconsistent evidence to support omalizumab and specific allergen immunotherapy use in AE. There is some evidence that vitamin D supplementation and synbiotics reduce AE severity, although the margin of improvement may not be clinically meaningful. There is little evidence to support the use of wet wraps or of complementary/alternative medicine (including Chinese herbal medicine). There is some evidence to suggest that a diet high in fish in infancy may be preventative for AE, but other dietary interventions for the prevention of AE show little promise. This review provides a succinct guide for clinicians and patients wishing to remain up to date with the latest evidence for the treatment and prevention of AE.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE), providing a succinct guide for clinicians and patients. It presents the key findings from 14 systematic reviews published in 2016, focusing on AE epidemiology, aetiology and risk factors. For systematic reviews on the treatment and prevention of AE and for nomenclature and outcome assessments, see Parts 1 and 3 of this update, respectively. The annual self-reported prevalence of AE is a range of 11.4-24.2%, compared with a general practioner-diagnosed prevalence of 1.8-9.5%. The mean age of AE diagnosis is 1.6 years. Persistent AE is associated with more severe disease at the time of diagnosis, onset after the age of 2 years and female sex. There is a significant association between having AE and subsequent development of food allergy. Food allergy is also associated with more severe and persistent AE. No consistent association was found between the timing of allergenic food introduction and the risk of developing AE. Evidence from heterogeneous studies indicates that skin absorption is increased in patients with AE, and that there is increased colonization with Staphylococcus aureus in lesional and nonlesional skin and the nasal mucosa of patients with AE compared with controls. There is uncertain evidence indicating an association between AE and smoking exposure, antenatal infection and low maternal vitamin D levels during pregnancy. Weak evidence suggests an increased risk of basal cell carcinoma, but not of melanoma or squamous cell carcinoma, while the risk of glioma is reduced.

Effective atopic eczema (AE) control not only improves quality of life but may also prevent the atopic march. The Royal College of General Practitioners’ (RCGP) curriculum does not currently provide specific learning outcomes on AE management. We aimed to gain consensus on learning outcomes to inform curriculum development. A modified Delphi method was used with questionnaires distributed to gather the views of a range of health care professionals (HCPs) including general practitioners (GPs), dermatologists, dermatology nurses and parents of children with AE attending a dedicated paediatric dermatology clinic. Ninety-one questionnaires were distributed to 61 HCPs and 30 parents, 81 were returned. All agreed that learning should focus on the common clinical features, complications and management of AE and the need to appreciate its psychosocial impact. Areas of divergence included knowledge of alternative therapies. Parents felt GPs should better understand how to identify, manage and refer severe AD and recognized the value of the specialist eczema nurse. Dermatologists and parents highlighted inconsistencies in advice regarding topical steroids. This study identifies important areas for inclusion as learning outcomes on AE management in the RCGP curriculum and highlights the importance of patients and parents as a valuable resource in the development of medical education.

Summary This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE). It provides a summary of key findings from 12 systematic reviews (SRs) that were published or indexed during 2014, and focuses on the treatment and prevention of AE. For an update of SRs on the epidemiology, mechanisms of disease and methodological issues, see Part 1 of this update. Although phototherapy and various systemic medications (including ciclosporin, azathioprine and methotrexate) are commonly used to treat AE, many of these have not been robustly assessed in head-to-head randomized controlled trials. Educational interventions may improve AE severity and quality of life for children and their families. Intake of probiotics prenatally and postnatally may help prevent AE, but there is little evidence to suggest a role in the treatment of AE. Although no benefit was found for allergen avoidance in preventing AE, the use of immunotherapy to treat AE-associated aeroallergen sensitivity requires further evaluation. There is insufficient evidence for Vitamin D supplementation for the treatment of AE This overview of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with the most recent evidence for the treatment and prevention of AE.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE), providing a succinct guide for clinicians and patients. It provides a summary of key findings from 26 systematic reviews that were published during 2015, and focuses on the treatment and prevention of AE. For systematic reviews on the epidemiology and methodological issues, see Part 1 of this update. Topical corticosteroid withdrawal syndrome, 'steroid addiction', has been evaluated in a high-quality systematic review, which helps better define this entity and the risk factors for it. A Cochrane Review has not demonstrated any association between topical corticosteroid use in pregnancy and adverse outcomes, although very large quantities of potent/very potent topical corticosteroids may be associated with reduced birth weight. House dust mite avoidance strategies do not appear to prevent AE. Exposure to probiotics prenatally and in early infancy may help prevent AE, but there is no evidence that maternal diet or supplementation has a preventative effect.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE), providing a succinct guide for clinicians and patients. It provides a summary of key findings from 15 systematic reviews that were published during 2015, and focuses on the epidemiology and methodology issues of AE. For systematic reviews on the prevention and treatment of AE, see Part 2 of this update. The worldwide prevalence of AE during childhood has been calculated to be 7.89% (95% CI 7.88-7.89), based on studies of 1 430 329 children from 102 countries. Children with AE are four times more likely than controls to have allergic rhinitis and asthma [relative risk (RR) = 4.24, 95% CI 3.75-4.79]. Twin studies show the heritability of AE to be about 75%. AE is more prevalent in patients with vitiligo and alopecia, and is positively associated with a high body mass index in America and Asia but not in Europe. Possible relationships between AE and exercise, maternal folate supplementation, maternal stress and autism spectrum disorder (ASD) have been assessed, but more high-quality studies are needed for definitive conclusions. The Harmonising Outcomes Measures for Eczema (HOME) Initiative is developing a core set of outcome measures for AE trials. Suitable instruments for measuring quality of life are yet to be agreed, and use of Investigator Global Assessment in trials requires standardization. Transparent reporting of AE trials remains problematic.

Summary Background. The rate of skin cancer in the UK continues to rise. Aim. To identify the current knowledge and awareness of and attitudes towards the avoidance of skin cancer among a variety of patient groups to aid the design of future UK sun-awareness campaigns. Methods. Patients aged ≥ 16 years presenting to one of three general practices (two urban, one rural) in the UK during the period 1 June to 31 July 2010 were invited to complete a paper-based questionnaire collecting data on their sun-exposure behaviour, with significance assessed by the Fisher exact test. Results. In total, 1000 patients (327 male, 673 female) responded. Those aged 16–30 years were significantly more likely to get sunburn than the older age groups. The understanding of ways to avoid skin cancer in 16–30-year-olds was also rated as significantly worse than that of all other age groups. Compared with the older age groups, this group was also less likely to avoid midday sun exposure (P

We read with interest the article by Vigarios et al.1 describing eight patients treated with a variety of BRAF inhibitors who developed asymptomatic hyperkeratotic oral mucosal lesions. These were frequently multifocal and presented following a mean onset of three months of treatment with a BRAF inhibitor. In one patient, one such lesion rapidly developed into oral squamous cell carcinoma requiring excision. We would like to highlight delayed oral toxicity in a long-term responder to a BRAF inhibitor.

Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation play a role in pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and while CD1a-expressing Langerhans cells are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. Here we observed that house dust mite (HDM) generates neolipid antigens for presentation by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth and showed rapid effector function, consistent with antigen-driven maturation. To define the underlying mechanisms, we analyzed HDM-challenged human skin and observed allergen-derived phospholipase (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2 and such cells infiltrated the skin after allergen challenge. Filaggrin insufficiency is associated with atopic dermatitis, and we observed that filaggrin inhibits PLA2 activity and inhibits CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity, such as Gell and Coombs are predicated on the idea that non-peptide stimulants of T cells act as haptens that modify peptides or proteins. However our results point to a broader model that does not posit haptenation, but instead shows that HDM proteins generate neolipid antigens which directly activate T cells. Specifically, the data identify a pathway of atopic skin inflammation, in which house dust mite-derived phospholipase A2 generates antigenic neolipids for presentation to CD1a-reactive T cells, and define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach.

The rate of skin cancer in the UK continues to rise.To identify the current knowledge and awareness of and attitudes towards the avoidance of skin cancer among a variety of patient groups to aid the design of future UK sun-awareness campaigns.Patients aged ≥ 16 years presenting to one of three general practices (two urban, one rural) in the UK during the period 1 June to 31 July 2010 were invited to complete a paper-based questionnaire collecting data on their sun-exposure behaviour, with significance assessed by the Fisher exact test.In total, 1000 patients (327 male, 673 female) responded. Those aged 16-30 years were significantly more likely to get sunburn than the older age groups. The understanding of ways to avoid skin cancer in 16-30-year-olds was also rated as significantly worse than that of all other age groups. Compared with the older age groups, this group was also less likely to avoid midday sun exposure (P0.001) or to cover up in the sun (P0.001). There was no significant difference in sun exposure or frequency of sunburn between those with or without a personal or family history of skin cancer. Those with a positive history were more likely to wear sunscreen (P0.01), but not to cover up or avoid the midday sun.UK-based sun-awareness programmes should target younger age groups. In addition, healthcare professionals must ensure that opportunities are taken to reinforce the importance of safe sun exposure for patients presenting with skin cancer.

Objective To explore associations between bullous pemphigoid (BP) and previous drug use in the United Kingdom. Design A case-control study comparing the drug history of consecutive patients with BP and control subjects. Setting Tertiary care center for immunobullous diseases and skin tumor clinics at Oxford University Hospitals. Patients or Other Participants Eighty-six consecutive BP patients and 134 consecutive controls from the same region and similar in age and sex who presented with other dermatological diagnoses. Main Outcome Measures Crude and adjusted odds ratios and 95% confidence interval of BP in relation to each drug. Results Loop diuretics were used significantly more frequently by the BP patients (crude odds ratio, 2.4 [95% CI, 1.2-5.0; P = .02]; adjusted odds ratio, 3.8 [1.5-9.7; P = .006]). No significant differences were found between groups for use of other diuretics, aspirin, antidepressants, antiepileptics, antihypertensives, or central nervous system agents (eg, antipsychotics). Patients with BP used calcium or vitamin D supplements, antibiotics, antihistamines, and prednisolone significantly more often on multivariate analysis. Conclusions The findings of our study demonstrate increased use of loop diuretics in patients with BP before the development of BP. The mechanism behind such an association clearly warrants further investigation.

Filaggrin null mutations associate with atopic eczema and also with asthma when present with eczema. However, while epidermal dysfunction is an important factor in disease pathogenesis, it is unclear how such dysfunction interacts with immune responses to contribute to cutaneous and other inflammatory atopic disease.To gain a better understanding of the mechanisms underlying such predisposition in order to understand different disease phenotypes and possibly identify potential treatment targets.We studied 33 individuals with atopic eczema and used interleukin-4 immunospot and human leucocyte antigen class II tetrameric complexes to investigate the peripheral blood allergen-specific CD4+ T-cell responses.Filaggrin null mutations associated with significantly (P0·05) higher frequencies of allergen-specific CD4+ T-helper 2 cell responses.These data would support a model where barrier dysfunction possibly promotes greater allergen penetration and delivery to drive allergen-specific CD4+ T cells. This could further contribute to respiratory and cutaneous inflammatory disease.