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.
Summary
A number of studies have suggested that early life exposure to antibiotics can lead to an increased risk of developing eczema. This systematic review and meta‐analysis of observational ...studies, involving children or young adults aged 0–25 years, assessed the impact of antibiotic exposure either in utero or during the first 12 months of life on subsequent eczema risk. Twenty studies examined the association between prenatal and/or postnatal exposure to antibiotics and development of eczema. The pooled odds ratio (OR) for the 17 studies examining postnatal antibiotic exposure was 1·41 95% confidence interval (CI) 1·30–1·53. The pooled OR for the 10 longitudinal studies was 1·40 (95% CI 1·19–1·64), compared with a pooled OR of 1·43 (95% CI 1·36–1·51) for the seven cross‐sectional studies. There was a significant dose–response association, suggesting a 7% increase in the risk of eczema for each additional antibiotic course received during the first year of life pooled OR 1·07 (95% CI 1·02–1·11). Finally, the pooled OR for the four studies relating to antenatal exposure was 1·30 (95% CI 0·86–1·95). We conclude that exposure to antibiotics in the first year of life, but not prenatally, is more common in children with eczema.
What's already known about this topic?
A number of studies have suggested that early life exposure to antibiotics may lead to an increased risk of subsequent eczema.
The evidence to date is conflicting and no systematic review has been conducted.
What does this study add?
Antibiotic exposure in early life may increase the risk of subsequent eczema by up to 40%, with broad‐spectrum antibiotics having a more pronounced effect.
Each additional antibiotic course may confer a further 7% risk increase.
Antibiotics should be prescribed with caution, especially in high‐risk children.
With biologic drugs dominating the therapeutic space for severe immune‐mediated inflammatory disease, it is critical for clinicians to be familiar with the concept of drug immunogenicity, with the ...potential for our patients to develop antidrug antibodies (ADA) of clinical relevance. Whilst there are clear differences between different therapeutic biologics in terms of reported ADA rates, there is no accepted dermatology guideline or grouping of drugs by risk of clinically relevant ADA, nor a consensus on approach to ADA management. This is partly because making valid comparisons of immunogenicity across drugs is fundamentally flawed: the differing types of ADA assay, trial design and included patient population – as well as the molecular structure of the biologic molecules themselves – are all highly influential on reported ADA prevalence and impact on clinical response. Therefore, the first part of this article aims to give an overview of ADA that also clarifies common misconceptions on the subject, whilst the second part of this article outlines Phase III immunogenicity data on commonly used biologics for psoriasis, the most common dermatological indication. Based on this, and acknowledging current limitations in available evidence, we propose a working categorization of biologics together with a broad approach to management: Group 1 – biologics with higher risk of clinically relevant ADA; Group 2 – biologics with lower risk of clinically relevant ADA; and Group 3 – biologics with no established risk of clinically relevant ADA. However, these groupings represent a working concept only; more research is required, using comparable ADA assays and consistent reporting of related outcomes. Finally, there is an urgent need for better characterization of individuals at particular risk of developing ADA to inform future clinical decision‐making.
Summary
Aim
El‐Khalawany et al. (Eur J Pediatr 2012; 172: 351–6) aimed to compare the efficacy and safety of methotrexate vs. ciclosporin in the treatment of children with severe atopic eczema.
...Setting and design
This multicentre, parallel group (ratio 1 : 1), randomized controlled trial was conducted in a secondary care setting in Egypt.
Study exposure
Children with severe atopic eczema were randomly assigned to receive either methotrexate (7·5 mg weekly) or ciclosporin (2·5 mg kg−1 daily) for 12 weeks, followed by a 12‐week follow‐up period.
Outcomes
Eczema severity was measured using the SCORing of Atopic Dermatitis (SCORAD) index. The authors also recorded the number of patients on each therapy experiencing adverse effects.
Primary outcome measures
The primary outcome was the mean change in SCORAD after 12 weeks of treatment.
Results
Forty patients with a mean age of 11·6 ± 1·52 years were included in the trial. At week 12, patients in the methotrexate group had a mean ± SD absolute reduction in SCORAD of 26·25 ± 7·03, compared with 25·02 ± 8·21 in the ciclosporin group (P = 0·93). Both drugs were associated with minor adverse effects, none of which necessitated changing the treatment regimen.
Conclusions
El‐Khalawany et al. conclude that both methotrexate and ciclosporin in low doses are clinically effective, relatively safe, and well tolerated as treatments for severe atopic eczema in children.
Summary
Aim
Warren et al. set out to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate‐to‐severe chronic plaque psoriasis.
Setting and design
...This was a prospective, double‐blind, randomized (3 : 1), placebo‐controlled study, conducted across 16 centres in Germany, France, the Netherlands and the U.K.
Study exposure
Methotrexate‐naive adults with a diagnosis of moderate‐to‐severe chronic plaque psoriasis for at least 6 months before baseline were randomly assigned to receive weekly subcutaneous injections of either methotrexate at a starting dose of 17·5 mg, or placebo for 16 weeks (first phase). Dose escalation to 22·5 mg per week was implemented after 8 weeks if patients did not achieve ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50). Treatment was combined with folic acid 5 mg per week. The first phase of the study was followed by an open‐label period from 16 to 52 weeks (second phase), in which both groups received weekly methotrexate injections. At week 24, dose escalation to 22·5 mg per week was possible in patients not achieving PASI 50.
Outcomes
Psoriasis severity was measured using PASI. The authors also used two other psoriasis severity measures and two quality‐of‐life measures, looked at safety indices and performed a substudy analysing paired skin biopsies at baseline and week 16 (histopathology, immunohistochemistry and expression of interleukin‐17A, interferon‐γ and tumour necrosis factor‐α).
Primary outcome measures
The primary outcome was the proportion of patients reaching PASI 75 at week 16.
Results
In total 120 patients were included in this trial, most of whom were middle‐aged white men with long‐standing psoriasis, and the mean body mass index was 30·1 kg m−2. PASI 75 was achieved in 41% of patients receiving methotrexate vs. 10% of patients receiving placebo (relative risk 3·93, 95% confidence interval 1·31–11·81; P = 0·0026) at week 16. Subcutaneous methotrexate was generally well tolerated, with no serious adverse events related to this treatment over the 52‐week study.
Conclusion
Warren et al. conclude that the 52‐week risk–benefit profile of subcutaneous methotrexate is favourable in patients with psoriasis.
Plain language summary available online
Summary
Background
Registry data suggest that people with immune‐mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID‐19) ...outcomes compared with patients receiving no systemic treatments.
Objectives
We used international patient survey data to explore the hypothesis that greater risk‐mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation.
Methods
Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk‐mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed‐effects model.
Results
Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk‐mitigating behaviour (classified here under the umbrella term ‘shielding’). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35–1·97. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23–1·56). Shielding was associated with established risk factors for severe COVID‐19 male sex (OR 1·14, 95% CI 1·05–1·24), obesity (OR 1·37, 95% CI 1·23–1·54), comorbidity burden (OR 1·43, 95% CI 1·15–1·78), a primary indication of RMDs (OR 1·37, 95% CI 1·27–1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36–1·80). Modest differences in the proportion shielding were observed across nations.
Conclusions
Greater risk‐mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID‐19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence‐based patient communication on risk‐mitigation strategies and may help inform updated public health guidelines as the pandemic continues.
What is already known about this topic?
At the beginning of the coronavirus disease 2019 (COVID‐19) pandemic, patients with immune‐mediated inflammatory diseases (IMIDs) on targeted systemic therapies were considered to be at higher risk of severe COVID‐19.
Subsequent clinician‐reported registry data suggest that targeted systemic therapy use is associated with fewer adverse COVID‐19 outcomes compared with no systemic therapy.
What does this study add?
We characterize shielding behaviour in 3720 patients with IMIDs from a global self‐report survey.
Use of targeted systemic therapy associates with increased shielding behaviour, compared with standard systemics or no therapy, as do demographic risk factors for severe COVID‐19 including male sex and obesity.
Greater risk‐mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID‐19 outcomes.
Behaviour variation across treatment groups reinforces the need for clear, evidence‐based patient communication on risk‐mitigation strategies.
These data may help to inform updated public health guidelines as the pandemic continues.
Linked Comment: G. Becher and A.D. Burden. Br J Dermatol 2021; 185:7–8.
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