Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go?
TL;DR: A systems biology approach merging the numerous clinical phenotypes with robust biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD.
Abstract: Atopic dermatitis (AD) is a paradigmatic chronic inflammatory skin disease characterized by a complex pathophysiology and a wide spectrum of the clinical phenotype. Despite this high degree of heterogeneity, AD is still considered a single disease and usually treated according to the "one-size-fits-all" approach. Thus more tailored prevention and therapeutic strategies are still lacking. As for other disciplines, such as oncology or rheumatology, we have to approach AD in a more differentiated way (ie, to dissect and stratify the complex clinical phenotype into more homogeneous subgroups based on the endophenotype [panel of biomarkers]) with the aim to refine the management of this condition. Because we are now entering the era of personalized medicine, a systems biology approach merging the numerous clinical phenotypes with robust (ie, relevant and validated) biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD. This approach will not only allow an optimized prevention and treatment with the available drugs but also hopefully help assign newly developed medicinal products to those patients who will have the best benefit/risk ratio.
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TL;DR: Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand the ability to dissect the relative contribution of each of these pathways to disease perpetuation.
Abstract: Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional "one-size-fits-all" therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation.
313 citations
TL;DR: Fezakinumab was well‐tolerated, with sustained clinical improvements after last drug dosing, andSignificance was primarily obtained in severe AD.
Abstract: Background Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. Objective Evaluate interleukin 22 blockade in adults with moderate-to-severe atopic dermatitis (AD). Methods We performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinumab monotherapy every 2 weeks for 10 weeks, with follow-up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. Results At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 ± 2.7 in the fezakinumab arm and 8.0 ± 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a baseline SCORAD of ≥50), SCORAD decline was significantly stronger in the drug-treated patients than placebo-treated patients at 12 weeks (21.6 ± 3.8 vs 9.6 ± 4.2, P = .029) and 20 weeks (27.4 ± 3.9 vs 11.5 ± 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug-treated than placebo-treated patients (12.4% ± 2.4 vs 6.2% ± 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug-treated than placebo-treated patients (0.7 ± 0.2 vs 0.3 ± 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. Limitations The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. Conclusion Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing.
231 citations
Additional excerpts
...89 As child only 4 (20) 6 (15) No 10 (50) 22 (55) Yes 6 (30) 12 (30)...
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TL;DR: Improved identification and characterization of AD phenotypes and endotypes are required to optimize the precision medicine approach to AD.
Abstract: The epidermis contains epithelial cells, immune cells, and microbes which provides a physical and functional barrier to the protection of human skin. It plays critical roles in preventing environmental allergen penetration into the human body and responsing to microbial pathogens. Atopic dermatitis (AD) is the most common, complex chronic inflammatory skin disease. Skin barrier dysfunction is the initial step in the development of AD. Multiple factors, including immune dysregulation, filaggrin mutations, deficiency of antimicrobial peptides, and skin dysbiosis contribute to skin barrier defects. In the initial phase of AD, treatment with moisturizers improves skin barrier function and prevents the development of AD. With the progression of AD, effective topical and systemic therapies are needed to reduce immune pathway activation and general inflammation. Targeted microbiome therapy is also being developed to correct skin dysbiosis associated with AD. Improved identification and characterization of AD phenotypes and endotypes are required to optimize the precision medicine approach to AD.
198 citations
Cites background from "Clinical phenotypes and endophenoty..."
...cytokines that contribute to skin barrier dysfunction by altering protein and lipid content in the skin (Table 1).(2,4,57,58) FLG is a key epidermal barrier protein....
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...Patients with persistent or severe AD suffer from profound impairment of their quality of life.(2,6,7) Additionally, AD places a heavy economic burden on patients and their family....
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...1).(2,4,16,19,20) These factors interact with each other and may modify skin barrier function....
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...Atopic dermatitis (AD) is the most common chronic skin disease worldwide.(1,2) It affects about 20% of children and 5% of adults....
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TL;DR: An update on the role of IL‐13 in AD is provided and the different strategies aimed at interfering with its biologic activity as well as their potential in a precision medicine approach in the management of AD are discussed.
Abstract: Atopic dermatitis (AD) is a common inflammatory skin condition that has traditionally been considered a paradigmatic type 2 immunity (T2)-driven disease. Interleukin (IL)-4 and IL-13 are both pivotal cytokines involved in the generation of allergic diseases. Currently, besides dupilumab, which blocks the binding of both cytokines to their receptors, a number of new pharmacologic entities have been designed to target both T2 cytokines and/or their receptors and/or receptor-associated signal transduction machinery such as Janus kinases. Recently, IL-13 has been suggested to be the key T2 cytokine driving inflammation in the periphery, while IL-4 may merely have a central effect. There is increasing evidence that this concept holds true for the inflammatory reaction underlying AD, where IL-13 is overexpressed locally and has a significant impact on skin biology, including the recruitment of inflammatory cells, the alteration of the skin microbiome, and the decrease in the epidermal barrier function. This review provides an update on the role of IL-13 in AD and discusses the different strategies aimed at interfering with its biologic activity as well as their potential in a precision medicine approach in the management of AD.
175 citations
TL;DR: The data support the pathogenic role of type 2 immune activation in AD skin lipid metabolism and downregulation of ELOVL3/ELOVL6 expression in keratinocytes by siRNA decreased the proportion of long-chain fatty acids globally and in sphingolipids.
Abstract: Lipids in the stratum corneum of atopic dermatitis (AD) patients differ substantially in composition from healthy subjects. We hypothesized that hyperactivated type 2 immune response alters AD skin lipid metabolism. We have analyzed stratum corneum lipids from nonlesional and lesional skin of AD subjects and IL-13 skin-specific Tg mice. We also directly examined the effects of IL-4/IL-13 on human keratinocytes in vitro. Mass spectrometric analysis of lesional stratum corneum from AD subjects and IL-13 Tg mice revealed an increased proportion of short-chain (N-14:0 to N-24:0) NS ceramides, sphingomyelins, and 14:0-22:0 lysophosphatidylcholines (14:0-22:0 LPC) with a simultaneous decline in the proportion of corresponding long-chain species (N-26:0 to N-32:0 sphingolipids and 24:0-30:0 LPC) when compared with healthy controls. An increase in short-chain LPC species was also observed in nonlesional AD skin. Similar changes were observed in IL-4/IL-13-driven responses in Ca2+-differentiated human keratinocytes in vitro, all being blocked by STAT6 silencing with siRNA. RNA sequencing analysis performed on stratum corneum of AD as compared with healthy subjects identified decreased expression of fatty acid elongases ELOVL3 and ELOVL6 that contributed to observed changes in atopic skin lipids. IL-4/IL-13 also inhibited ELOVL3 and ELOVL6 expression in keratinocyte cultures in a STAT6-dependent manner. Downregulation of ELOVL3/ELOVL6 expression in keratinocytes by siRNA decreased the proportion of long-chain fatty acids globally and in sphingolipids. Thus, our data strongly support the pathogenic role of type 2 immune activation in AD skin lipid metabolism.
155 citations
References
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TL;DR: Biomarker measurements provide an avenue for researchers to gain a mechanistic understanding of the differences in clinical response that may be influenced by uncontrolled variables (for example, drug metabolism).
Abstract: genome are dramatically reshaping the research and development pathways for drugs, vaccines, and diagnostics. The growth in the number of molecular entities entering the drug development pipeline has accelerated as a consequence of powerful discovery and screening technologies such as combinatorial chemistry, mass spectrometry, high throughput screening, celland tissue-based DNA microarrays, and proteomic approaches.1 As a consequence, there is an escalating number of therapeutic candidates, which has caused the need for new technologies and strategies to streamline the process to make safe and effective therapies available to patients. One approach to the achievement of more expeditious and informative therapeutic research is the use of precise clinical measurement tools to determine disease progression and the effects of interventions (drugs, surgery, and vaccines). For example, gene-based approaches such as single nucleotide polymorphism maps are now being developed to distinguish the molecular and cellular basis for variations in clinical response to therapy.2 Another approach is the use of a wide array of analytical tools to assess biological parameters, which are referred to as biomarkers. Biomarker measurements can help explain empirical results of clinical trials by relating the effects of interventions on molecular and cellular pathways to clinical responses. In doing so, biomarkers provide an avenue for researchers to gain a mechanistic understanding of the differences in clinical response that may be influenced by uncontrolled variables (for example, drug metabolism). There are a variety of ways that biomarker measurements can aid in the development and evaluation of COMMENTARY
5,665 citations
TL;DR: The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
Abstract: Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
5,321 citations
"Clinical phenotypes and endophenoty..." refers background in this paper
...Endophenotypes are defined asmeasurable components unseen by the unaided eye along the pathway between disease and distal genotype.(38) Thus the endophenotype is made of a collection of biomarkers between the clinical phenotype and genotype....
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TL;DR: It is shown that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis.
Abstract: Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
2,605 citations
Oregon Health & Science University1, University of Bonn2, Icahn School of Medicine at Mount Sinai3, University of Rochester4, Regeneron5, University of Sheffield6, Northwestern University7, Aarhus University8, Centre Hospitalier Universitaire de Nice9, University of Tartu10, Ludwig Maximilian University of Munich11, Charité12, Laval University13, Sanofi S.A.14
TL;DR: Dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo in two phase 3 trials of identical design.
Abstract: BackgroundDupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. MethodsIn two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. ResultsWe enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who...
1,318 citations