Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other ...comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.
Background It has frequently been speculated that pruritus and skin lesions develop after topical exposure to aeroallergens in sensitized patients with atopic dermatitis (AD). Objective We sought to ...study cutaneous reactions to grass pollen in adult patients with AD with accompanying clear IgE sensitization to grass allergen in an environmental challenge chamber using a monocenter, double-blind, placebo-controlled study design. Methods Subjects were challenged on 2 consecutive days with either 4000 pollen grains/m3 of Dactylis glomerata pollen or clean air. The severity of AD was assessed at each study visit up to 5 days after challenge by (objective) scoring of AD (SCORAD). Additionally, air-exposed and non–air-exposed skin areas were each scored using local SCORAD scoring and investigator global assessments. Levels of a series of serum cytokines and chemokines were determined by using a Luminex-based immunoassay. The primary end point of the study was the change in objective SCORAD scores between prechallenge and postchallenge values. Results Exposure to grass pollen induced a significant worsening of AD. A pronounced eczema flare-up of air-exposed rather than covered skin areas occurred. In grass pollen–exposed subjects a significantly higher increase in CCL17, CCL22, and IL-4 serum levels was observed. Conclusions This study demonstrates that controlled exposure to airborne allergens of patients with a so-called extrinsic IgE-mediated form of AD induced a worsening of cutaneous symptoms.
Background Exposure to house dust mites (HDMs) aggravates the course of atopic dermatitis (AD) in patients sensitized to HDMs. Objectives This study investigated the efficacy and safety of ...subcutaneous allergen-specific immunotherapy with the use of depigmented polymerized mite extract as an add-on therapy to basic (ie, topical and, as necessary, systemic) medication. Methods Patients (n = 168) were recruited in a randomized, double-blind, placebo-controlled parallel group phase III study conducted in Germany (21 sites), in adult patients with AD aggravated by HDMs. The primary end points of the study were the assessments of the area under the curves of the total Severity Scoring Atopic Dermatitis (SCORAD) score and of the use of basic medication during the 18-month treatment period. Post hoc subgroup analyses were also performed. Results Overall efficacy analysis of the intention-to-treat and per-protocol study populations showed no statistically significant differences between the active treatment and placebo groups. However, the subgroup of patients with severe AD (SCORAD > 50) showed a statistically significant reduction of the median total SCORAD by 18% ( P = .02) compared with placebo. The frequency of adverse reactions was similar in both groups, suggesting the safety of the active treatment. Conclusion Although subcutaneous allergen-specific immunotherapy showed no statistically significant difference in the overall population of patients with AD, statistically significant reduction of the total SCORAD could be achieved in a subgroup of patients with severe AD.
Background Perioral dermatitis (POD) is a common dermatosis without standard therapy. Objective We sought to evaluate pimecrolimus cream 1% in POD. Methods We conducted a multicenter, randomized, ...double-blind, parallel-group study in adult patients with POD treated twice daily with pimecrolimus cream 1% or vehicle until clearance for up to 4 weeks. Follow-up took place 4 and 8 weeks after treatment. Results Patients treated with pimecrolimus had an average POD Severity Index score of 2.6 compared with 3.5 for patients treated with vehicle. Both groups had baseline scores of 5.2. The between-group difference was 0.9 (95% confidence level 0.4, 1.4, P = .0011). Patients with history of topical corticosteroids benefited most. Pimecrolimus-treated patients reported greater improvement in quality of life. There were no group differences regarding safety. Limitations Pimecrolimus vehicle is not a true placebo. Conclusions Pimecrolimus rapidly improves clinical symptoms and quality of life of patients with POD, being most effective in corticosteroid-induced POD.
International consensus on allergy immunotherapy Jutel, Marek, MD; Agache, Ioana, MD; Bonini, Sergio, MD ...
Journal of allergy and clinical immunology,
09/2015, Volume:
136, Issue:
3
Journal Article
Peer reviewed
Open access
Allergen immunotherapy (AIT) has been used to treat allergic disease since the early 1900s. Despite numerous clinical trials and meta-analyses proving AIT efficacious, it remains underused and is ...estimated to be used in less than 10% of patients with allergic rhinitis or asthma worldwide. In addition, there are large differences between regions, which are not only due to socioeconomic status. There is practically no controversy about the use of AIT in the treatment of allergic rhinitis and allergic asthma, but for atopic dermatitis or food allergy, the indications for AIT are not well defined. The elaboration of a wider consensus is of utmost importance because AIT is the only treatment that can change the course of allergic disease by preventing the development of asthma and new allergen sensitizations and by inducing allergen-specific immune tolerance. Safer and more effective AIT strategies are being continuously developed both through elaboration of new allergen preparations and adjuvants and alternate routes of administration. A number of guidelines, consensus documents, or both are available on both the international and national levels. The international community of allergy specialists recognizes the need to develop a comprehensive consensus report to harmonize, disseminate, and implement the best AIT practice. Consequently, the International Collaboration in Asthma, Allergy and Immunology, formed by the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the World Allergy Organization, has decided to issue an international consensus on AIT.
In an article reviewing the status of gastrointestinal allergy in the New England Journal of Medicine in 1949, Ingelfinger et al1 decried the reliance on patients' "incrimination" of specific foods, ...outcome of trial diets, or association of abdominal complaints with symptoms believed to be allergic in making the diagnosis of food allergy. Recently, the National Institutes of Health-sponsored expert panel "Guidelines for the diagnosis and management of food allergy," reaffirmed the utility of the DBPCFC for diagnosing food allergy after an extensive review of the current literature.11 However, the expert panel noted that open or single-blind challenges could also be acceptable when the challenge outcome is negative or when objective symptoms are elicited that exactly recapitulate the history of the reaction.
This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal . The conclusions below ...focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein.
To the Editor: IL-33 is a member of the IL-1 family of cytokines that is constitutively expressed in healthy skin and was found to be increased in the skin of patients with atopic dermatitis (AD). ...Because it can be released after tissue damage or physical stress including scratching of the skin,1 it has been classified as an alarmin concerned with alerting the immune system.2 It enhances TH2 responses by inducing IL-5 and IL-13 as well as TH1 responses via upregulation of IFN-γ. Because existing FLG within the stratum corneum is not expected to be affected by 24-hour stimulation, evaluation was restricted to keratinocytes with detectable nuclear counterstaining.
In AD pruritus is often resistant to H1-antihistamine treatment. ...other mediators, including neuropeptides, neurotransmitters, proteinases, arachidonic derivates, and cytokines, have been suggested ...for a pathophysiologic role of pruritus in AD.2 Recently, the novel 4-helix-bundle cytokine IL-31 has been described to be involved in the development of chronic dermatitis through the induction of severe pruritus in transgenic mice with lymphocyte-specific overexpression of IL-31.3 The expression of skin IL31 mRNA levels was significantly higher in NC/Nga mice with scratching behavior than in mice without scratching behavior.4 In addition, scratching counts in mice with long-lasting scratching behavior correlated with skin IL31 mRNA expression.5 In human subjects IL31 mRNA is overexpressed in pruritic AD but not in nonpruritic psoriatic lesions compared with healthy skin.6 Interestingly, increased IL31 mRNA levels were also found in nonlesional skin of patients with AD compared with those seen in healthy control subjects. IL-31 expression is largely restricted to CD45RO+ memory effector T cells.8 Furthermore, IL-31 protein in culture supernatants and IL31 mRNA have been found in higher levels in CLA+ T cells compared with CLA- subsets in patients with AD, with a trend higher than that of healthy individuals. ...increased serum levels of IL-31 might also account for other cell types than T cells, including eosinophil granulocytes, a possibility that is currently under investigation.
Background Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. ...Objective Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. Methods The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. Results We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. Conclusion H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.
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