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Summary: Background: Atopic dermatitis is the most common chronic inflammatory skin disorder, affecting up to 20% of children and 10% of adults in industrialized countries. This highly debilitating condition poses a considerable burden to both the individual and society at large. The pathophysiology of atopic dermatitis is complex, encompassing both genetic and environmental risk factors. Methods: This is a narrative review based on a systematic literature search. Conclusions: Dysregulation of innate and adaptive immunity plays a key role; however, recent epidemiological, genetic and molecular research has focused interest on skin barrier dysfunction as a common precursor and pathological feature. Current understanding of the aetiology of atopic dermatitis highlights disruption of the epidermal barrier leading to increased permeability of the epidermis, pathological inflammation in the skin, and percutaneous sensitization to allergens. Thus, most novel treatment strategies seek to target specific aspects of the skin barrier or cutaneous inflammation. Several studies have also shown promise in preventing atopic dermatitis, such as the early use of emollients in high‐risk infants. This may have broader implications in terms of halting the progression to atopic comorbidities including food allergy, hay fever and asthma. What's already known about this topic? Atopic dermatitis is a common and highly debilitating chronic inflammatory skin disorder.Immune dysregulation plays a key role, but recent evidence has shifted the focus to skin barrier disruption as the key precursor.Loss‐of‐function mutations in the filaggrin gene are the strongest known genetic risk factor, but there are numerous environmental and immunological factors that influence the disease manifestation and course.The current therapeutic armamentarium is limited to simple lipid‐based barrier‐enhancing emollients, topical anti‐inflammatory agents and systemic immunosuppressive therapies. What does this study add? We review how defects in structural epidermal proteins and environmental factors converge to impair skin barrier function, resulting in increased susceptibility to atopic dermatitis.We explore the impact of the defective skin barrier on immune responses and the skin microbiome, highlighting how the complex interplay between the skin barrier and immune activation determines the response to environmental factors such as allergens and microbes.We outline emerging strategies for treating and preventing atopic dermatitis. Linked Comment:Silverberg. Br J Dermatol 2019; 180:447–448. [ABSTRACT FROM AUTHOR]

Summary: Aim: There are numerous systemic medications in use for psoriasis, with additional investigational agents being studied. However, head‐to‐head, randomized clinical trials are rare and cannot feasibly compare all treatments. A network meta‐analysis (NMA) synthesizes the available evidence to provide estimates for all pairwise comparisons. Here, we summarize and appraise two recent NMAs that assessed systemic therapies for moderate‐to‐severe psoriasis. Setting and design: Two systematic reviews searched databases and the grey literature to identify relevant randomized clinical trials. Study participants: The reviews mostly included trials that involved adults with moderate‐to‐severe psoriasis. One of the reviews also included two trials involving children. Study exposure: Interventions common to both reviews include adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, secukinumab and methotrexate. One of the reviews included additional interventions, primarily other biological agents along with new small‐molecule treatments and systemic conventional treatments. Primary outcomes: One review focused on 'clear/nearly clear' and withdrawals from adverse events as study outcomes, while the second review focused on improvement of ≥ 90% measured on the Psoriasis Area and Severity Index (PASI 90) and serious adverse events. Outcomes: Additional outcomes included quality of life, PASI 75, Physician's Global Assessment of 0/1 and any adverse event. Results: Overall, both NMAs are of high quality and provide a comprehensive summary of the evidence base and treatment effects. Results, in terms of both estimates and rankings, suggest that newer biologics targeting the interleukin (IL)‐12/23 and IL‐17 axes appear to be more effective than older biologics and oral agents. Conclusions: Patients, clinicians and policy makers can use the relative efficacy assessments of NMAs to inform decision making regarding the clearance of psoriasis skin lesions at relevant time points and improvement in quality of life. [ABSTRACT FROM AUTHOR]

Summary: Background: Oral systemic immunomodulatory medication is regularly used off‐licence in children with severe atopic eczema. However, there is no firm evidence regarding the effectiveness, safety, cost‐effectiveness and impact on quality of life from an adequately powered randomized controlled trial (RCT) using systemic medication in children. Objectives: To assess whether there is a difference in the speed of onset, effectiveness, side‐effect profile and reduction in flares post‐treatment between ciclosporin (CyA) and methotrexate (MTX), and also the cost‐effectiveness of the drugs. Treatment impact on quality of life will also be examined in addition to whether FLG genotype influences treatment response. In addition, the trial studies the immune–metabolic effects of CyA and MTX. Methods: Multicentre, parallel group, assessor‐blind, pragmatic RCT of 36 weeks' duration with a 24‐week follow‐up period. In total, 102 children aged 2–16 years with moderate‐to‐severe atopic eczema, unresponsive to topical treatment will be randomized (1 : 1) to receive MTX (0·4 mg kg−1 per week) or CyA (4 mg kg−1 per day). Results: The trial has two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o‐SCORAD) and time to first significant flare following treatment cessation. Conclusions: This trial addresses important therapeutic questions, highlighted in systematic reviews and treatment guidelines for atopic eczema. The trial design is pragmatic to reflect current clinical practice. What's already known about this topic? Oral systemic immunomodulatory medication is regularly used off‐licence in children with severe atopic eczema.Ciclosporin is the commonest first‐line systemic agent used in this context, but methotrexate has emerged as an important therapeutic alternative.There is currently no adequately powered randomized controlled trial that compares both treatments in children. What does this study add? The TREatment of severe Atopic eczema Trial (TREAT) addresses this gap and compares the effectiveness, safety, cost‐effectiveness and impact on patient's quality of life of these two drugs.TREAT also examines the effects of both drugs using systemic and cutaneous markers of inflammation and the effect of filaggrin (FLG) genotype and T‐cell cytokine signatures on treatment response.Respond to this article Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Case reports and case series remain an important part of journals and are often first to document medical breakthroughs. This article reviews their characteristics, aims and limitations. It provides information on how to increase the validity of the bedside decision‐making process that these studies report, using tools such as validated outcomes and split‐body or n‐of‐1 trials. A section describing tools to improve writing of case reports and case series provides suggestions for detailed reporting and good evaluation of novelty, validity and relevance. It includes general and British Journal of Dermatology‐specific guidance. [ABSTRACT FROM AUTHOR]

Background Little is known about U.K. dermatologists' treatment approaches towards adult patients with recalcitrant moderate-to-severe atopic eczema. Objectives We wanted to learn about (i) treatment approaches used for this disease in the U.K.; (ii) factors that influence treatment decisions and (iii) perceived gaps in evidence on treatment safety and efficacy, and priorities for future trials. Methods We conducted an online survey of consultant-level dermatologists in the U.K. Results Sixty-one respondents from over 30 centres reported on management of moderate-to-severe atopic eczema in adults, outwith the context of an acute flare. Phototherapy or psoralen-ultraviolet A was the most common therapeutic modality chosen first line (46%), and this was usually narrowband ultraviolet B. Systemic therapy was chosen as a first-line approach by 36% of dermatologists. Azathioprine was the commonest drug reported being used as first line followed by oral corticosteroids, ciclosporin and methotrexate. Methotrexate was the most common second-line treatment of respondents. The key factors that influenced decision making on the use of phototherapy and systemic agents were the respondent's clinical experience, results of baseline tests (systemic agents) and knowledge of both efficacy and acute and chronic side-effect profiles. The most important evidence gaps identified were the relative effectiveness of treatments, the alternatives to current approaches and the safety of long-term maintenance treatment. With regard to future trials, respondents suggested that priority should be given to studies involving methotrexate. Conclusions While survey study designs have limitations, we found that phototherapy, in particular narrowband ultraviolet B, was respondents' preferred first-line treatment for adults with recalcitrant moderate-to-severe atopic eczema, perhaps reflecting access to, and clinical experience of, this approach. Azathioprine is widely used as a longer-term maintenance treatment. [ABSTRACT FROM AUTHOR]

Background There is a substantial body of evidence on the epidemiology of allergic conditions, which has advanced the understanding of these conditions. We aimed to systematically identify systematic reviews and meta-analyses on the epidemiology of allergic diseases to assess what has been studied comprehensively and what areas might benefit from further research. Methods We searched PubMed and EMBASE up to 12/2014 for systematic reviews on epidemiological research on allergic diseases. We indexed diseases and topics covered and extracted data on the search characteristics of each systematic review. Results The search resulted in 3991 entries after removing duplicates, plus 20 other items found via references and conference abstracts; 421 systematic reviews were relevant and included in this overview. The majority contained some evidence on asthma (72.9%). Allergic rhinitis, atopic eczema and food hypersensitivity were covered in 15.7%, 24.5% and 9.0%, respectively. Commonly studied risk factors for atopic eczema included dietary and microbial factors, while for asthma, pollution and genetic factors were often investigated in systematic reviews. There was some indication of differing search characteristics across topics. Conclusion We present a comprehensive overview with an indexed database of published systematic reviews in allergy epidemiology. We believe that this clarifies where most research interest has focussed and which areas could benefit from further research. We propose that this effort is updated every few years to include the most recently published evidence and to extend the search to an even broader list of hypersensitivity/allergic disorders. [ABSTRACT FROM AUTHOR]

The article discusses a 2019 survey of the treatment of patients with severe chronic spontaneous urticaria (CSU) in Great Britain. Topics covered include the condition's manifestations and usual management, the common use of omalizumab and ciclosporin as first-line agents, and the varying prescriptions of agents by dermatology, allergy, and immunology consultants. Also noted is the prime barrier of potential adverse effects (AE) in prescribing systemic medications.

There is a growing desire to explain the worldwide rise in the prevalence of atopic dermatitis ( AD). Trend data on the burden of AD suggest that the picture in the developing world may soon resemble that of wealthier nations, where AD affects over 20% of children. This, combined with significant variations in prevalence within countries, emphasizes the importance of environmental factors. Many hypotheses have been explored, from the modulation of immune priming by hygiene, gut microbiota diversity, and exposure to endotoxins through farm animals to the effects of pollution, climate, and diet. The discovery of the filaggrin skin barrier gene and its importance in AD development and severity has brought the focus on gene-environment interactions and the identification of environmental factors that impact on skin barrier function. This article reviews our current understanding of the epidemiology of AD, with an emphasis on the findings reported in the international literature over the last 5 years. [ABSTRACT FROM AUTHOR]

There has been a steep rise in the burden of atopic dermatitis ( AD), and up to 20% of children in developed countries now suffer of the disease. At present, treatment at best achieves symptom control rather than cure, and there is a strong need to identify new methods of disease prevention. While earlier approaches focused on allergen avoidance strategies, there has been a clear shift towards attempts to induce tolerance and enhancement of skin barrier function, as skin barrier breakdown plays an important role in AD development. This article reviews the latest developments in the prevention of AD. [ABSTRACT FROM AUTHOR]

Skin diseases are the fourth most common cause of all human disease, affecting almost one-third of the world's population, yet their burden is often underestimated, despite their visibility.1,2 Burden of disease is a concept that was first developed in the 1990s by the Harvard School of Public Health, the World Bank and the World Health Organization (WHO) to describe death and loss of health due to diseases, injuries and risk factors for all regions of the world. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. [Extracted from the article]

The article discusses childhood eczema. It elaborates the causes, diagnostic criteria and physiological manifestations of the disease. Mild eczema can be treated using topical anti-inflammatory agents or ultra violet (UV) light. Severe eczema however may not respond to these treatments. topical calceneurin inhibitors and systemic immunomodulatory agents like azathioprine, ciclosporin A and methotrexate are indicated for management of severe eczema. INSET: A PATIENT¿S PERSPECTIVE (A, AGED 8 YEARS).

Summary Background Exclusive breastfeeding for at least 4 months is recommended by many governments and allergy organizations to prevent allergic disease. Objectives To investigate whether exclusive breastfeeding protects against childhood eczema. Methods Study subjects comprised 51 119 randomly selected 8- to 12-year-old schoolchildren in 21 countries. Information on eczema and breastfeeding was gathered by parental questionnaire. Children were also examined for flexural eczema and underwent skin prick testing. Odds ratios (ORs) were calculated for each study centre and then pooled across populations. Results There was a small increase in the risk of reported 'eczema ever' in association with 'breastfeeding ever' and breastfeeding < 6 months [pooled adjusted OR 1·11, 95% confidence interval (CI) 1·00-1·22 and OR 1·10, 95% CI 1·02-1·20, respectively]. There was no significant association between reported 'eczema ever' and breastfeeding > 6 months (pooled adjusted OR 1·09, 95% CI 0·94-1·26). Risk estimates were very similar for exclusive breastfeeding < 2 months, 2-4 months and > 4 months and for eczema symptoms in the past 12 months and eczema on skin examination. As for more severe eczema, breastfeeding per se conveyed a risk reduction on sleep disturbed eczema (pooled adjusted OR 0·71, 95% CI 0·53-0·96), but this effect was lost where children had been exclusively breastfed for > 4 months (pooled adjusted OR 1·02, 95% CI 0·67-1·54). Allergic sensitization and a history of maternal allergic disease did not modify any of these findings. Conclusions Although there was a protective effect of ever having been breastfed on more severe disease, we found no evidence that exclusive breastfeeding for 4 months or longer protects against eczema. Our results are consistent with findings from a recent systematic review of prospective studies. The U.K. breastfeeding guidelines with regard to eczema should be reviewed. Intervention studies are now required to explore how and when solids should be introduced alongside breastfeeding to aid protection against eczema and other allergic diseases. [ABSTRACT FROM AUTHOR]

Summary Aim Hwang et al. aimed to evaluate the risk of malignancy among individuals with eczema, allergic rhinitis (AR) and asthma, compared with the general Taiwanese population. Hypothesis People with atopic conditions, including eczema, have an altered risk of malignancy. Setting and design This was a prospective nationwide cohort study. The authors used the Taiwanese National Health Insurance Research Database (NHIRD) to compare the incidence of cancers among people with established allergic disease relative to the risk in the general population. Study exposure Exposure was the presence of one or more atopic conditions (eczema, AR or asthma). Data were extracted on 997 729 randomly selected people registered on the NHIRD at any time point between 1996 and 2008. Eczema was identified via ICD-9-CM codes with the diagnosis being made by a dermatologist, paediatrician or allergist. Follow-up was until 2008, date of first cancer or death. Outcomes The outcome was a new diagnosis of malignancy, identified via catastrophic illness insurance certificates, again using ICD-9-CM diagnostic codes. Primary outcome measure Standardized incidence ratios (SIRs) for cancers overall and different types of malignancy among patients with eczema, AR or asthma were calculated against the expected number of cancer cases in the general population, adjusted for age and sex. Results The number of patients identified with eczema, AR and asthma was 34 263, 225 315 and 107 601, respectively. Overall cancer rates in patients with these conditions were not significantly different from those in the general population [SIR eczema = 0·97 (95% confidence interval 0·87-1·09), SIR AR = 1·02 (0·98-1·05) and SIR asthma = 1·01 (0·97-1·04)]. However, when the results for eczema were stratified by age, people aged between 20 and 39 years appeared to have a 56% increase in risk in relation to 'any cancer' [SIR = 1·56 (1·13-2·09)]. Looking at individual cancer types in patients with eczema, only the risk of brain cancer was significantly raised [SIR = 2·52 (1·15-4·79)]. Patients who had had all three allergic conditions had a reduced SIR for 'cancers overall' [SIR = 0·59 (0·37-0·88)]. This inverse association was less strong for those with eczema and asthma [SIR = 0·73 (0·55-0·97)] or asthma and AR [SIR = 0·79 (0·73-0·84)] and statistically only of borderline significance for those with eczema and AR [SIR = 0·85 (0·67-1·07)]. Conclusions Hwang et al. conclude that the relationship between allergic diseases and cancer risk is complex and site specific. The risk of malignancy was highest in all atopic conditions in the 20-39-year age group. In patients with eczema, the incidence of brain cancer was higher than expected, which the authors note is at odds with previous studies. However, numbers were too small to allow stratification by histological subtypes. The authors warn against deriving conclusions for rarer cancers and that borderline SIRs must be interpreted with caution. [ABSTRACT FROM AUTHOR]

Filaggrin loss-of-function ( FLG) mutations are associated with eczema and skin barrier impairment, but it is unclear whether skin barrier impairment precedes phenotypic eczema in FLG mutation carriers. To study the association between FLG mutations, skin barrier impairment and clinical eczema at 3 months of age. A total of 88 infants were examined for eczema. Disease severity was determined by the SCORAD eczema severity score. Transepidermal water loss (TEWL) was measured on unaffected forearm skin. Venous blood samples were screened for the four most common FLG mutations found in the U.K. white population (R501X, 2282del4, R2447X and S3247X). Median SCORAD and TEWL measurements in children with and without eczema and FLG mutations were compared. Thirty-three per cent (29/88) of children had clinical eczema. Median SCORAD was 10·6 (range 3·5-31·0). TEWL (g m h) was higher in children with eczema compared with unaffected infants (median TEWL 14·24 vs. 11·24, P < 0·001). Higher TEWL was associated with more severe disease ( r = 0·59, P < 0·001, median TEWL, SCORAD < 15, 13·1 vs. 29·6, SCORAD ≥ 15, P = 0·029). Clinically dry skin was associated with higher TEWL, even in the absence of eczema (median TEWL 17·55 vs. 11·08, P = 0·008). Seventeen per cent (15/88) of children carried at least one FLG mutation. FLG mutation carriers were significantly more likely to have clinically dry skin, even in the absence of eczema [odds ratio (OR) 8·50, 95% confidence interval (CI) 1·09-66·58, P = 0·042]. FLG mutation carriers were also more likely to have eczema by 3 months of age (OR 4·26, 95% CI 1·34-13·57, P = 0·014). FLG mutations were significantly associated with higher median TEWL (all children, FLG'yes' 21·59 vs. FLG'no' 11·24, P < 0·001), even without clinical eczema ( FLG'yes' 15·99 vs. FLG'no' 10·82, P = 0·01). By the age of 3 months, FLG mutations are associated with an eczema phenotype, dry skin and TEWL. The observation that TEWL is elevated in unaffected FLG mutation carriers suggests that skin barrier impairment precedes clinical eczema. [ABSTRACT FROM AUTHOR]

Linked Editorial:Yiu et al. Br J Dermatol 2020; 183:1–2. [ABSTRACT FROM AUTHOR]

Linked Article: Yiu et al. Br J Dermatol 2020; 183:188–189. [ABSTRACT FROM AUTHOR]

European Task Force on Atopic Dermatitis statement on severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection and atopic dermatitis Atopic dermatitis (AD) is a complex disease with elevated risk of respiratory comorbidities.[[1]] Severely affected patients are often treated with immune-modulating systemic drugs.[[3]] On 11 March 2020, the World Health Organization declared the 2019 novel coronavirus severe acute respiratory syndrome (SARS-Cov-2) epidemic to be a pandemic. If systemic treatment of AD needs to be paused, patients should be supplied with ample topical therapy and guidance on the amount needed to prevent flares until systemic therapy can be reinstated. [Extracted from the article]

Dear Editor, Research waste is a major issue in atopic eczema.[1] One contributor is the premature discontinuation of trials. Although termination of trials is essential when participants are exposed to harm, many trials terminate for potentially avoidable reasons.[[2]] Such avoidable trial termination presents many issues. Three types of trial status on ClinicalTrials.gov were considered discontinued: trials that commenced recruitment, enrolling participants, but later discontinued ("terminated"); trials that discontinued before commencing recruitment ("withdrawn"); and trials that were active but had not updated the study record for two or more years ("unknown").[4] Trial discontinuation and reported reasons are presented as frequencies and percentages. [Extracted from the article]