Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder characterized by itching and eczematous lesions. It is often associated with a personal or familial history of allergic ...diseases. Allergic inflammation induced by immunoglobulin E and T-helper type 2 (Th2) cell responses to common environmental agents has been suggested to play an essential role in AD pathogenesis. The standard therapies for AD, including topical or systemic agents, focus on controlling skin inflammation. Recently developed monoclonal antibody to interleukin-4 receptor alpha or Janus kinase inhibitors can provide significant clinical improvements in patients with AD by inhibiting Th2 cell-mediated skin inflammation. However, the clinical efficacy of the Th2 cell-targeted therapy is transient and incomplete in patients with AD. Patients with AD are seeking a permanent cure. Therefore, the development of novel immunomodulatory strategies that can improve a long-term clinical outcome and provide a long-term treatment-free clinical remission of AD (disease-modifying therapy) is needed. Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance and suppress the development of autoimmune and allergic diseases. This review provides three working hypotheses and perspectives for the treatment of AD by Treg cell activation. (1) A decreased number or function of Treg cells is a critical event that causes the activation of Th2 cells, leading to the development and maintenance of AD. (2) Activation of Treg cells is an effective therapeutic approach for AD. (3) Many different immunomodulatory strategies activating Treg cells can provide a long-term clinical improvement of AD by induction of immune tolerance. The Treg cell-targeted immunomodulatory therapies for AD include allergen immunotherapy, microbiota, vitamin D, polyvalent human immunoglobulin G, monoclonal antibodies to the surface antigens of T cell or antigen-presenting cell, and adoptive transfer of autologous Treg cells or genetically engineered Treg cells expanded in vitro.
The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of ...autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases.
studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4
CD25
T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4
Foxp3
Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4
Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing "idiotypic network theory" and "Treg cell theory" into an "anti-idiotypic Treg cell theory." Based on this hypothesis, an "active anti-idiotypic therapy" for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.
Education on inhaler technique is critical for effective asthma treatment. However, traditionally used face-to-face education is time-consuming, costly, and often laborious. The current study ...evaluated the efficacy of a newly developed video-based inhaler technique education method.
A total of 184 subjects with well-controlled or partly-controlled asthma were enrolled from 12 hospitals in South Korea from 30 November 2015 to 01 June 2016. Subjects were randomly divided into two groups in a 1:1 ratio; a control group that received face-to-face education, and a study group that received video education. All subjects received fluticasone propionate plus salmeterol xinafoate (Fluterol® 250/50 inhalation capsules) for 12 weeks. The primary outcome measure was forced expiratory volume in the 1st second (FEV1) at 12 weeks. The secondary outcome measures were change in FEV1 at 4 weeks, change in asthma control test (ACT) score, and changes in various inhaler technique parameters. These measures were assessed with a non-inferiority margin of 10% between the control group and the study group.
FEV1 was significantly improved at 12 weeks in the control group and the study group. After adjustment, FEV1 improvement was not significantly inferior in the study group compared to the control group. The secondary outcome measures, including change in FEV1 at 4 weeks, ACT score, and various parameters pertaining to inhaler technique and satisfaction at 4 and 12 weeks did not differ significantly in the two groups. In subgroup analysis of elderly subjects and subjects with well-controlled asthma, FEV1 was significantly improved at 12 weeks in the study group but not the control group.
The newly developed video education technique investigated functioned as a suitable substitute for face-to-face education on inhaler technique (dry powder inhalation capsule) in patients with stable asthma, particularly in elderly patients and patients with well-controlled asthma.
The favorable clinical efficacies of intramuscular injection of autologous blood in patients with atopic dermatitis (AD) and intramuscular injection of autologous serum in patients with chronic ...urticaria have been demonstrated by randomized clinical trials. In this study, we assessed the clinical effectiveness and safety of the intramuscular injection of autologous serum in patients with AD.
In this randomized, placebo-controlled, and double-blind trial, 23 adolescent and adult patients with moderate-to-severe AD were enrolled. The patients were randomized to receive eight intramuscular injections of 5 mL of autologous serum (n=11) or saline (n=12) over 4 weeks, and were followed up until week 8. Changes in the clinical severity scores of AD assessed by SCORing Atopic Dermatitis (SCORAD), patient-reported Dermatology Life Quality Index (DLQI) score, and incidence of adverse events were assessed from baseline to week 8.
One patient in the treatment group and two patients in the placebo group were lost to follow-up before week 8. The intramuscular administration of autologous serum, compared with saline, decreased the SCORAD clinical severity score (-14.8% vs. 10.7%,
=0.006) and improved the DLQI score (-32.6% vs. 19.5%,
=0.01) from baseline to week 8. Serious adverse events were not observed.
Intramuscular injection of autologous serum may be effective in treating AD. Further studies are needed to evaluate the clinical usefulness of this intervention for AD (KCT0001969).
We hypothesized that intramuscular administration of autologous total immunoglobulin G (IgG) could induce an immunomodulatory effect in human subjects. In our previous studies, we showed that ...intramuscular administration of autologous total IgG could induce significant clinical improvements and increases of the serum levels of interleukin-10 (IL-10) and interferon-gamma (IFN-γ) in patients with atopic dermatitis.
To investigate the mechanism of immunomodulation induced by intramuscular administration of autologous total IgG, we evaluated changes in T cells before and after intramuscular administrations of autologous total IgG in this study.
Thirteen healthy adults received 8 intramuscular injections of 50 mg autologous total IgG for 4 weeks (from week 0 to week 4). The percentages of IL-10- or IFN-γ-producing peripheral blood T cells, as well as serum levels of IL-10, IFN-γ, and immunoglobulins, were measured at baseline (week 0) and at weeks 4, 8, and 12.
The percentage of IL-10-producing CD4+ T cells was significantly increased at weeks 8 and 12 compared to baseline (P < .05), while the percentage of IFN-γ-producing CD3+ T cells was significantly increased at week 12 compared to baseline (P < .05). There were no significant differences in the serum levels of IL-10, IFN-γ, and immunoglobulins before and after intramuscular administration of autologous total IgG (P > .05). No serious adverse events were observed.
Intramuscular administration of autologous total IgG induced immunomodulatory effects on T cells in healthy human subjects. This simple intervention could be a safe, effective, and economical T cell immunomodulation method for human subjects (NCT03695757).
No attempt has yet been made to classify asthma phenotypes in the elderly population. It is essential to clearly identify clinical phenotypes to achieve optimal treatment of elderly patients with ...asthma.
To classify elderly patients with asthma by cluster analysis and developed a way to use the resulting cluster in practice.
We applied k-means cluster to 872 elderly patients with asthma (aged ≥ 65 years) in a prospective, observational, and multicentered cohort. Acute asthma exacerbation data collected during the prospective follow-up of 2 years was used to evaluate clinical trajectories of these clusters. Subsequently, a decision-tree algorithm was developed to facilitate implementation of these classifications.
Four clusters of elderly patients with asthma were identified: (1) long symptom duration and marked airway obstruction, (2) female dominance and normal lung function, (3) smoking male dominance and reduced lung function, and (4) high body mass index and borderline lung function. Cluster grouping was strongly predictive of time to first acute asthma exacerbation (log-rank P = .01). The developed decision-tree algorithm included 2 variables (percentage of predicted forced expiratory volume in 1 second and smoking pack-years), and its efficiency in proper classification was confirmed in the secondary cohort of elderly patients with asthma.
We defined 4 elderly asthma phenotypic clusters with distinct probabilities of future acute exacerbation of asthma. Our simplified decision-tree algorithm can be easily administered in practice to better understand elderly asthma and to identify an exacerbation-prone subgroup of elderly patients with asthma.
Purpose Dupilumab is recommended to be administered biweekly to treat adult patients with moderate-to-severe atopic dermatitis (AD). Real clinical practice data on the clinical efficacy of monthly ...dupilumab therapy are limited. We analyzed real clinical practice data on the clinical efficacy of monthly dupilumab therapy and predictive markers for favorable clinical responses to the therapy. Methods Medical records of 57 adult patients with moderate-to-severe AD who received dupilumab therapy every 4 weeks for 16 weeks were analyzed retrospectively. Eczema Area and Severity Index (EASI) were recorded at baseline and week 16. Clinical responses to monthly dupilumab therapy were defined as the proportion of patients with decreased EASI scores of at least 50% or 75% from baseline at week 16 (EASI-50 or EASI-75). Blood eosinophil counts and serum lactate dehydrogenase (LDH) levels were measured at baseline and week 16. Results Monthly dupilumab therapy showed EASI-50 and EASI-75 clinical responses in 48 (84.2%) and 27 (47.4%) of 57 patients at week 16, respectively. The percentage decrease in EASI scores from baseline at week 16 was significantly inversely correlated with baseline blood eosinophil count (correlation coefficient r = −0.405, P = 0.002) and baseline serum LDH level (r = −0.466, P < 0.001). The EASI-75 response rate was higher in patients with low (< 500/µL, 73.3%) than in those with high (≥ 500/µL, 37.5%) baseline blood eosinophil counts (P = 0.032), and was higher in patients with low (< 400 U/L, 55.6%) than those with high (≥ 400 U/L, 10.0%) baseline serum LDH levels (P = 0.013). Conclusions Monthly dupilumab therapy was clinically effective in adult patients with moderate-to-severe AD in real clinical practice. Baseline blood eosinophil count and serum LDH level could be predictive markers for clinical response to dupilumab therapy.
Recent studies recommend periostin as a systemic biomarker of eosinophilic airway inflammation to predict responses to novel treatments that targets eosinophilic TH2-driven inflammation in asthmatic ...patients.
To investigate the clinical implications of serum periostin levels in patients with aspirin-exacerbated respiratory disease (AERD) based on its overlapping TH2-mediated pathogenesis with the eosinophilic asthma.
Serum periostin levels were measured by human periostin enzyme-linked immunosorbent assay (ELISA) in serum samples from 277 adults with asthma. Serum periostin levels were compared between patients with AERD and aspirin tolerant asthma (ATA) with other asthma phenotypes, such as severe or nonsevere asthma and eosinophilic or noneosinophilic asthma. The association of serum periostin levels with clinical parameters (including disease severity and comorbid condition) was analyzed.
Serum periostin levels were significantly higher in patients with AERD vs ATA, patients with severe asthma vs nonsevere asthma, and patients with eosinophilic asthma vs noneosinophilic asthma (P=.005, P=.02, and P=.001, respectively). Multivariate regression analysis revealed serum periostin levels as a significant parameter to predict AERD phenotype (P=.006) together with severe asthma phenotype (P=.04). In addition, serum periostin levels correlated with blood eosinophil counts (Spearman ñ = 0.244, P<.001) and sputum eosinophil counts (Spearman ñ = 0.261, P < 0.001). Higher serum periostin levels were noted in comorbid AERD patients with more severe chronic rhinosinusitis (Lund-Mackay stages 3 and 4) than those with less severe chronic rhinosinusitis (Lund-Mackay stages 1 and 2) (P = .03).
Serum periostin levels are significantly elevated in AERD patients and associated with AERD phenotype and disease severity.
The current standard medical therapy for atopic dermatitis (AD) mainly focuses on symptomatic relief by controlling skin inflammation with topical corticosteroids and/or topical calcineurin ...inhibitors. However, the clinical efficacy of pharmacological therapy is often disappointing to both patients and physicians. The terminology of AD contains a historical meaning of eczematous dermatitis caused by hypersensitivity reaction to environmental inhalant or food allergen. Complex interrelationships among genetic abnormalities, environmental triggers, skin barrier defects, and immune dysfunction resulting in a vicious domino-circle seem to be involved in the development and maintenance of AD. In the viewpoint of AD as an allergic disease, complete avoidance of clinically relevant allergen or induction of specific immune tolerance through administrations of allergen (allergen immunotherapy) can provide clinical remission by breaking the vicious domino-circle maintaining a chronic disease state. In recent clinical studies, monoclonal antibodies including the anti-interleukin-4 receptor antibody and anti-B cell antibody induced significant clinical improvements in patients with AD. The detailed characteristics of immune dysfunction are heterogeneous among patients with AD. Therefore, a personalized combination of immunomodulatory therapies to reduce hypersensitivity (allergen immunotherapy) and correct immune dysfunction (monoclonal antibody therapy) could be a reasonable therapeutic approach for patients with AD. Future immunomodulatory therapies for AD should be developed to achieve long-term treatment-free clinical remission by induction of immune tolerance.
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