Summary
Background
Atopic dermatitis (AD) is a heterogeneous disease with a multifactorial aetiology and complex pathophysiology. This heterogeneity translates into different trajectories of disease ...progression with respect to severity, persistence and risk of development of atopic comorbidities. Determining which possible disease trajectories or comorbidities any individual child might develop is challenging in clinical practice. Tools that help identify paediatric patients at higher risk of disease progression would greatly aid clinicians.
Methods
We reviewed recent cohort studies to synthesize and simplify the epidemiological data to try to identify shared clinically relevant characteristics that may help physicians estimate the risk of disease progression in paediatric patients with AD.
Results
Despite the variability in data collection and methods of analysis and their limitations, there are common patterns of early‐childhood AD that may aid in the estimation of risk for disease progression. Factors associated with risk of AD progression include younger age of onset, family history of atopy, greater AD severity, filaggrin mutations, urban environment and polysensitization and/or allergic multimorbidity. Based on these factors, we provide a practitioner's guide for identifying, counselling and/or referring infants and children with AD at potentially higher risk of developing persistent AD and atopic comorbidities. We also present clinical scenarios to illustrate how these data relate to real‐life situations.
Conclusions
Useful insights are provided for physicians and patients to inform them better about the risk of AD progression and to help guide care pathways for the paediatric population with AD.
What's already known about this topic?
The complex pathophysiology of atopic dermatitis (AD) translates into a heterogeneous clinical presentation and trajectories of disease progression.
Although the consensus is that most paediatric patients with AD will eventually ‘outgrow’ the disease or follow the longitudinal trajectory known as the ‘atopic march’, a significant proportion will develop persistent AD and/or other atopic conditions.
No known factors conclusively predict the risk of progression or development of comorbidities.
What does this study add?
Recent analyses of data from large cohorts of paediatric patients with AD have suggested the existence of potentially discrete clusters of patients who present with relatively common AD phenotypes.
These studies have shed some light onto the factors associated with risk of progression, which we review in this article.
A practitioner's guide with clinical scenarios is provided to help identify patients at high risk of progression to determine whether a patient should be monitored and/or would require specialist referral.
Linked Comment: Silverberg. Br J Dermatol 2019; 181:883–884.
Plain language summary available online
Summary
Patients with atopic dermatitis (AD) have an increased risk of bacterial skin infections, which cause significant morbidity and, if untreated, may become systemic. Staphylococcus aureus ...colonizes the skin of most patients with AD and is the most common organism to cause infections. Overt bacterial infection is easily recognized by the appearance of weeping lesions, honey‐coloured crusts and pustules. However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with oedema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging. Furthermore, some features may be masked because of anatomical site‐ and skin‐type‐specific features, and the high frequency of S. aureus colonization in AD makes positive skin swab culture of suspected infection unreliable as a diagnostic tool. The host mechanisms and microbial virulence factors that underlie S. aureus colonization and infection in AD are incompletely understood. The aim of this article is to present the latest evidence from animal and human studies, including recent microbiome research, to define the clinical features of bacterial infections in AD, and to summarize our current understanding of the host and bacterial factors that influence microbial colonization and virulence.
Summary
Background
Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread.
Objectives
To reach consensus among an international group ...of AD experts on the use of systemic corticosteroids for AD.
Methods
A survey consisting of statements accompanied by visual analogue scales ranging from ‘strongly disagree’ to ‘neutral’ to ‘strongly agree’ was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if < 30% of respondents marked to the left of ‘neutral’ towards ‘strongly disagree’.
Results
Sixty of 77 (78%) IEC members participated. Consensus was reached on 12 statements, including that systemic corticosteroids should generally be avoided but can be used rarely for severe AD under certain circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event or in the most severe cases. If used, treatment should be limited to the short term. Most respondents agreed that systemic corticosteroids should never be used in children, but consensus was not reached on that statement. The conclusions of our expert group are limited by a dearth of high‐quality published evidence. If more stringent consensus criteria were applied (e.g. requiring < 20% of respondents marking towards ‘strongly disagree’), consensus would have been reached on fewer statements.
Conclusions
Based on expert opinion from the IEC, routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for special circumstances.
What's already known about this topic?
Despite recommendations against their use in practice guidelines, systemic corticosteroids are commonly used for atopic dermatitis (AD).
What does this study add?
The International Eczema Council reached consensus on circumstances in which systemic corticosteroids can be used for AD, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event, or in the most severe cases.
Clinicians should limit the use of systemic corticosteroids for severe AD to those circumstances.
Plain language summary available online
Respond to this article
Summary
Background
Biomarkers of atopic dermatitis (AD) are largely lacking, especially in infant AD. Those that have been examined to date have focused mostly on serum cytokines, with few on ...noninvasive biomarkers in the skin.
Objectives
We aimed to explore biomarkers obtainable from noninvasive sampling of infant skin. We compared these with plasma biomarkers and structural and functional measures of the skin barrier.
Methods
We recruited 100 infants at first presentation with AD, who were treatment naive to topical or systemic anti‐inflammatory therapies, and 20 healthy children. We sampled clinically unaffected skin by tape stripping the stratum corneum (SC). Multiple cytokines and chemokines and natural moisturizing factor were measured in the SC and plasma. We recorded disease severity and skin barrier function.
Results
Nineteen SC and 12 plasma biomarkers showed significant differences between healthy and AD skin. Some biomarkers were common to both the SC and plasma, and others were compartment specific. Identified biomarkers of AD severity included T helper 2‐skewed markers interleukin (IL)‐13, CCL17, CCL22, IL‐5; markers of innate activation (IL‐18, IL‐1α, IL1β, CXCL8) and angiogenesis (Flt‐1, vascular endothelial growth factor); and others (soluble intercellular adhesion molecule‐1, soluble vascular cell adhesion molecule‐1, IL‐16, IL‐17A).
Conclusions
We identified clinically relevant biomarkers of AD, including novel markers, easily sampled and typed in infants. These markers may provide objective assessment of disease severity and suggest new therapeutic targets, or response measurement targets for AD. Future studies will be required to determine whether these biomarkers, seen in very early AD, can predict disease outcomes or comorbidities.
What's already known about this topic?
Atopic dermatitis is a clinically heterogeneous condition with multiple clinical manifestations and a complex pathogenesis.
Systemic biomarkers of severity have been identified in adults, but are less well defined in children.
Biomarkers from the skin compartment have been based on biopsies to date.
What does this study add?
Noninvasive sampling can detect clinically relevant biomarkers in AD skin.
These biomarkers may be useful for disease stratification, and provide insights into the pathogenesis of infant AD.
Innate immune activation is important in the epidermis in infantile AD.
What is the translational message?
Noninvasive biomarkers can yield significant insights into infantile AD.
They identify innate activation, the T helper 2 pathway and angiogenesis as important pathways in this condition.
Respond to this article
Linked Comment: Hijnen. Br J Dermatol 2019; 180:455–456.
Plain language summary available online
Summary
Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions, immunodysregulation, disrupted epidermal barrier function and IgE‐mediated sensitization to food and ...environmental allergens. Identification of the aetiology of AD has become increasingly a priority, as it is clear that the disease burden exceeds AD alone, with many children suffering severe, multi‐system and occasionally life‐threatening allergic disease. Previous approaches to understanding AD have centred on mechanisms in the adaptive immune system, often with an emphasis on the Th1–Th2 paradigm. Recently, the conceptual focus has increasingly shifted to include a primary defect in the epithelial barrier as a threshold event in moderate‐to‐severe AD. Familial aggregation of the disease is well established through many family studies of AD, asthma and allergic rhinitis, suggesting a significant heritable component. The identification of loss‐of‐function mutations in the filaggrin (FLG) gene, whose product is a key structural protein in the outermost layer of the epidermis in up to 50% of patients with AD, provides a significant insight into explaining disease initiation and points to a complex secondary interplay of environmental and immunological sequelae once barrier disruption is established. The elucidation of the environmental, genetic and immunobiological modifiers of this structural molecule may also direct our understanding of the pathomechanisms and endotypes central to the atopic diathesis. The recent identification of a murine model for FLG‐AD, with the detection of a homozygous frame‐shift mutation in the Flg gene in flaky‐tail (ft/ft) mice, stands to rapidly accelerate our understanding of mechanisms and therapeutic intervention points in AD. Refining the molecular understanding of AD and its subtypes will allow for specific diagnostic, treatment and ultimately, preventative algorithms, and has opened an exciting new world of investigative challenges and collaborations.
Cite this as: G. M. O'Regan and A. D. Irvine, Clinical & Experimental Allergy, 2010 (40) 965–972.
To cite this article: Kezic S, O’Regan GM, Yau N, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, Irwin McLean WH, Irvine AD. Levels of filaggrin degradation products are ...influenced by both filaggrin genotype and atopic dermatitis severity. Allergy 2011; 66: 934–940.
Background: Filaggrin, coded by FLG, is the main source of several major components of natural moisturizing factor (NMF) in the stratum corneum (SC), including pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). Loss‐offunction mutations in FLG lead to reduced levels of filaggrin degradation products in the SC. It has recently been suggested that expression of filaggrin may additionally be influenced by the atopic inflammatory response. In this study, we investigated the levels of several breakdown products of filaggrin in the SC in healthy controls (CTRL) and patients with atopic dermatitis (AD) in relation to FLG null allele status. We examined the relationship between NMF (defined here as the sum of PCA and UCA) and AD severity.
Methods: The SC levels of filaggrin degradation products including PCA, UCA, histidine (HIS) and tyrosine were determined in 24 CTRL and 96 patients with moderate‐to‐severe AD. All subjects were screened for 11 FLG mutations relevant for the study population.
Results: The levels of PCA, UCA and HIS correlated with FLG genotype. Furthermore, these levels were higher in the CTRL when compared to AD patients with no FLG mutations. Multiple regression analysis showed that NMF levels were independently associated with FLG genotype and severity of disease.
Conclusion: Decreased NMF is a global feature of moderate‐to‐severe AD; within AD, FLG genotype is the major determinant of NMF, with disease severity as a secondary modifier. NMF components are reliably determined by a noninvasive and relatively inexpensive tape stripping technique.
Summary
Background
For many years dermatologists have had access to few therapies for patients with moderate‐to‐severe atopic eczema (AE). New promising therapies are entering the market but ...conventional phototherapies and systemic therapies have more well‐known safety profiles, lower costs and wider availability.
Objectives
To provide insight into current prescribing practices of conventional phototherapy and systemic immunomodulatory therapies for adults with chronic AE, and the factors influencing these prescribing practices, before biologics and other novel therapeutics become routine clinical practice.
Methods
In this exploratory study dermatologists were invited to participate in an online survey via a mailing list of the European Academy of Dermatology and Venereology and national societies. Data were collected on participant characteristics (including clinical practice data), the use of phototherapies and systemic therapies, and factors influencing their use.
Results
From 30 European countries, 238 out of 361 dermatologists willing to participate (65·9%) completed the survey, with 229 meeting the inclusion criteria. For phototherapy (prescribed by 84·7%), most preferred narrowband ultraviolet B as first line (80·9%) and psoralen plus ultraviolet A as second (21·6%). For systemic therapy (prescribed by 95·2%) ciclosporin (54·1%), oral corticosteroids (32·6%) and methotrexate (30·7%) were used first line. Dermatologists relied mostly on personal experience for prescribing phototherapy and systemic therapy. Azathioprine and mycophenolic acid were prescribed by only 135 (59·0%) and 85 (37·1%) participants in total, mostly due to a lack of personal experience.
Conclusions
This study provides insight into prescribing practices for conventional phototherapy and systemic therapy in Europe and shows that off‐label therapies are also preferred as first‐line choice of systemic therapy.
What is already known about this topic?
Varying prescribing practices were found for adult (in the UK) and paediatric (in Northern America and Europe) patients with moderate‐to-severe atopic eczema (AE).
Not much is known about the prescription of phototherapy and (off‐label) systemic therapy for adult patients in Europe.
Although therapies like dupilumab are promising new treatment modalities, better‐known safety profiles, lower costs and better availability are reasons to improve the evidence profile of conventional systemic therapies like ciclosporin.
What does this study add?
Prescribing practices of European dermatologists treating adult patients with moderate‐to-severe AE show diversity.
Most dermatologists prefer narrowband ultraviolet B as first‐line phototherapy, followed by psoralen plus ultraviolet A as second line.
Next to ciclosporin, which is most commonly prescribed, (off‐label) methotrexate and oral corticosteroids are also frequently used as first‐line systemic agents in chronic AE.
Lack of personal experience with azathioprine and mycophenolic acid was the most important reason against their prescription.
What are the clinical implications of the work?
The results from this study might help to improve the experience with, and prescribing of, all available conventional phototherapies and (off‐label) systemic therapies.
Guidelines developers might use these results to develop and implement treatment algorithms.
Linked Comment: Bruin‐Weller. Br J Dermatol 2020; 183:987–988.
Plain language summary available online
Cobaltite-based double perovskite oxides with high electrocatalytic activity and conductivity have been developed as high-performance cathode alternatives for solid oxide fuel cells (SOFCs). However, ...the use of cobaltite-based double perovskites on Y
2
O
3
stabilized ZrO
2
(YSZ)-based SOFCs requires the application of a doped ceria barrier layer. This is due to their poor chemical and physical compatibility with the YSZ electrolyte during high-temperature sintering and fabrication processes. Here we report a viable approach to
in operando
assemble double perovskites such as PrBa
0.5
Sr
0.5
Co
1.5
Fe
0.5
O
5+
δ
(PBSCF), on YSZ electrolyte and thus effectively form an electrode/electrolyte interface without high-temperature processing. The electrochemical performance of the
in situ
assembled PBSCF cathode is comparable to that of the cathode prepared by conventional methods. A single cell with an
in situ
assembled PBSCF-GDC (Gd-doped ceria) cathode achieved a peak power density (PPD) of 1.37 W cm
−2
at 750 °C and exhibited a high stability at 500 mA cm
−2
and 750 °C for 100 h. Surface and cross-sectional microstructure analysis offer solid evidence that the PBSCF-GDC cathode/YSZ electrolyte interface was formed by electrochemical polarization. This work offers new opportunities to effectively and effortlessly use high-performance double perovskite cathodes in commercial SOFCs.
Cathode/electrolyte interface could be formed by electrochemical polarization, offering new opportunities for direct application of double perovskites to YSZ-based SOFCs.
Summary
Background
Atopic dermatitis (AD) disease activity and severity is highly variable during childhood. Early attempts to identify subtypes based on disease trajectory have assessed AD presence ...over time without incorporating severity.
Objectives
To identify childhood AD subtypes from symptom severity and trajectories, and determine associations with genetic risk factors, comorbidities and demographic and environmental variables.
Methods
We split data from children in the Avon Longitudinal Study of Parents and Children birth cohort into development and validation sets. To identify subtypes, we ran latent class analyses in the development set on AD symptom reports up to age 14 years. We regressed identified subtypes on nongenetic variables in mutually adjusted, multiply imputed (genetic: unadjusted, complete case) multinomial regression analyses. We repeated analyses in the validation set and report confirmed results.
Results
There were 11 866 children who contributed to analyses. We identified one Unaffected/Rare class (66% of children) and four AD subtypes: Severe–Frequent (4%), Moderate–Frequent (7%), Moderate–Declining (11%) and Mild–Intermittent (12%). Symptom patterns within the first two subtypes appeared more homogeneous than the last two. Filaggrin (FLG) null mutations, an AD polygenic risk score (PRS), being female, parental AD and comorbid asthma were associated with higher risk for some or all subtypes; FLG, AD‐PRS and asthma associations were stronger along a subtype gradient arranged by increasing severity and frequency; FLG and AD‐PRS further differentiated some phenotypes from each other.
Conclusions
Considering severity and AD trajectories leads to four well‐defined and recognizable subtypes. The differential associations of risk factors among and between subtypes is novel and requires further research.
What’s already known about this topic?
Atopic dermatitis (AD) is a heterogeneous condition in terms of both disease activity and severity.
Childhood AD phenotypes in previous studies have focused only on disease activity.
What does this study add?
We incorporate disease severity over time to derive four clinically recognizable AD phenotypes using data‐driven methods.
Disease severity improved over time in all phenotypes (even in those with high probability of activity in late childhood and adolescence).
Several established risk factors, including genetic associates, were associated with our proposed phenotypes, with most factors more strongly associated with phenotypes reporting the worst symptoms. Fewer factors differentiated between more Frequent and Declining/Intermittent phenotypes.
Linked Comment: C. Vestergaard. Br J Dermatol 2021; 185:477.
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