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Thursday, July 9, 2015

Respiratory allergy caused by house dust mites: What do we really know?

The house dust mite (HDM) is present in human habitats around the globe, and it is a significant factor in allergic rhinitis and allergic asthma. Sensitization to mite allergens in early life compromises lung function and leads to wheezing in children, and it associates with poorer outcomes in a patient’s respiratory health in the long term. Calderón et al review the epidemiology of HDM allergy and the effect of HDM allergens on the human immune system (J Allergy Clin Immunol 2015; 136(1): 38-48).

Both assessing prevalence of HDM sensitivity and controlling a patient’s exposure to the allergen pose challenges. Prevalence data for HDM sensitization vary according to targeted population: from estimating 65 million to 130 million people in the global general population may be affected to as many as 50% of those with asthma. In addition, results vary within geographic locations, meaning studies have found significant differences in prevalence within a given country or region. In terms of a patient’s exposure, house dust mites are ubiquitous. Humidity levels have been shown to affect HDM propagation, and a recent practice parameter recommends the use of a hygrometer in the home. Studies indicate that HDM allergen levels should be maintained at less than 2 μg/g to decrease the likelihood of sensitization, yet measures to decrease HDM exposure have shown little benefit on symptoms in sensitized patients. Finally, the quantitative relationship between exposure to HDM and symptoms in asthmatic patients is complicated, as many of these patients are sensitized to more than one allergen.

Allergenic effects in HDM allergy are thought to be orchestrated via two main routes: through the CD4+ TH2 cells that induce and drive the IgE-dependent allergic response and through the innate immune system. It is this combined effect of adaptive and innate immune reactions that makes the allergen so powerful. Current guidelines for allergic rhinitis and allergic asthma classify disease based on severity of symptoms. That HDM is often the underlying cause is an important step in managing clinical control, as well as potentially preventing disease progression.

Thursday, July 2, 2015

Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

Psoriasis is a chronic immune-mediated inflammatory skin disease with a global incidence of approximately 2%. The extent of the affected body surface area and degree of erythema, induration, and scaling in four areas define its severity, and approximately 25% of patients have moderate-to-severe disease. Genome-wide association studies have linked variants in the gene for the IL-23 receptor and the p19 subunit of IL-23 to psoriasis susceptibility. IL-23 induces differentiation of TH17 cells and TH22 cells. The former are a primary cellular source of proinflammatory cytokines, including IL-17, and the latter are a primary source of IL-22. Both interleukins can mediate the development of the epidermal hyperplasia and tissue inflammation that occurs in psoriasis.

Krueger et al present the first-in-human proof-of-concept study to evaluate the clinical and biological effects of BI 655066 in patients with moderate-to-severe psoriasis. BI 655066 is a novel, fully human IgG1 mAb selective for IL-23A. It binds to IL-23A with high affinity and blocks the biologic activity of IL-23 (J Allergy Clin Immunol 2015; 136(1):116-124).

Thirty-nine patients received single-dose BI 655066 intravenously, subcutaneously, or placebo. The patients who received the antibody showed clinical improvement after two weeks that, in a subset of those treated, was maintained for up to 66 weeks after treatment. After 12 weeks, 87% of treated patients experienced a decrease in the Psoriasis Area and Severity Index of at least 75% (PASI75). The three groups reported adverse events with similar frequency.  The authors measured strong inhibition of IL-17 and disease-related genes related to the IL-23/Th17 axis, in addition to a significant correlation between treatment-associated molecular changes and improvement in PASI scores. The results support a new model for treating psoriasis and raise the possibility of attaining long-term remission from a single drug intervention. 

Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33

Little is known about the mechanisms regulating the persistence of chronic asthma. Because many allergens are perennially present, it has been difficult to ascertain whether persistence depends on this proximity. Studies of patients with occupational asthma have shown they experience symptoms for years after occupational exposure has ended. Christianson et al developed a mouse model in which asthma persisted for six months after allergen exposure ceased. They then used a combination of immunologic, genetic, microarray, and pharmacologic approaches to identify the factors contributing to symptom persistence (J Allergy Clin Immunol 2015; 136(1):59-68).

The authors found increased ILC2 levels characterize chronic asthma. In addition, IL-33-driven ILC2s prove to be an essential factor. The blockade of epithelial IL-33 led to a complete resolution of airway hyperactivity and a significant reduction of airway inflammation. They found IL-13, a product of ILC2s, can induce production of IL-33. It also generates a forward-feed mechanism on IL-33R expression, creating a positive feedback loop. Elimination of any component of the circuit resulted in disease resolution. They found finally that elimination of T-cells resolved airway inflammation but not airway hyperactivity or remodeling.

While previous studies have shown increased IL-33 in bronchoalveolar lavage (BAL) fluid, here the authors demonstrate an increase in ILC2 numbers. The results have implications for the treatment of chronic illnesses in general, suggesting that they depend on feedback and feed-forward circuits, interconnected systems that fail if a component is removed, and that it is these circuits that transition a disease from an acute condition to a chronic one.

The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage

It is acknowledged that key events that determine risk for the development of allergic disease frequently occur years before manifestation of symptoms. Recent culture-based studies, in combination with population-wide bacterial metagenomic data, suggest that parallel bacterial interactions may contribute to disease development. Holt reviews these and related issues of immune competence in infancy (J Allergy Clin Immunol 2015; 136(1): 15-22).

A number of factors specific to  infancy can contribute to disease development. Prospective tracking of postnatal IgE titres in serum samples collected over the first five years of life strongly suggests IgE antibody production against aeroallergens rarely begins before the age of six months. Airway mucosal dendritic cells (AMDC) transmit aeroallergen-specific signals from the airway mucosal surface to the central immune system and program the balance between the Th2 and T regulatory cell components of the immunological memory that results. The immaturity of this network in infants is likely a risk factor for early respiratory infection, itself a risk factor for early atopic asthma.

The focus on respiratory pathogens that contribute to the immunopathogenesis of atopic asthma has in the past been almost exclusively on viral pathogens: respiratory syncitial virus (RSV) and human rhinovirus (HrV). Emerging studies include consideration of the role of bacterial pathogens. Data suggests qualitative and quantitative differences in the lower airway bacterial populations of asthmatic children, including the mix of the strains present and the overall bacterial burden. The findings call for an accurate understanding of the full spectrum of strains that constitute the respiratory tract microbiome, particularly  nasopharyngeal microbial populations which function as a resevoir from which seeding into the lower airways occurs, in terms of population level and dynamics, across the average age range for asthma onset. The Perth CAS cohort study of 234 infants has provided the first foundation for this work. Questions, such as whether the replacement of commensal bacteria species in the nasopharyngeal microbiome of infants with known pathogens precede or result from local viral infection, remain to be answered.

The allergy epidemics: 1870-2010

Allergic reactions were virtually unknown prior to 1870, and this is still the case in pre-hygiene villages in parts of the world today. While it has been previously implied that the increase in allergic disease was unimodal, Platts-Mills traces how history indicates this is not the case. Hay fever was first reported in the UK and the United States in 1870, the first clear reports of an increase in pediatric asthma appeared in the 1970s, and the current epidemic of food allergy became apparent in the 1990s. In a fascinating review, Platts-Mills traces the emergence and development of respiratory and food allergies and asthma (J Allergy Clin Immunol 2015; 136(1): 3-13).

Sequential changes in agriculture and trade, hygiene, diet, lifestyle, and environment in the past 150 years have likely contributed to an increase in allergic disease. In England and the US in the latter half of the nineteen century and start of the twentieth century, cultivation of land and the introduction of non-native plant species occurred at the same time that urban centers established clean public water systems. Thyphoid and cholera became rare, and hay fever rose. By the mid-1950s to mid-1960s, the first reports of increasing incidences of asthma appeared, with house dust mites cited as the dominant allergen. Homes during this time were increasingly airtight and carpeted, and with the advent of television children were spending more time inside them. By the 1990s in the US, parents were strongly advised both to avoid giving peanuts to small children and to frequently wash and sanitize children’s hands. Early exposure to peanuts can be protective against the allergy, and it is conceivable that skin permeability to foreign proteins has changed.

Finally, with the influx of technology, we as a culture from childhood forward are increasingly indoors. This has shown consequences including the rise in obesity and decline in physical fitness. The consequences most relevant to the topic at hand are the steady increase in exposure to indoor allergens, the decline in outdoor exposure, and exercise. Changes in environment and lifestyle will likely continue to result in unforeseen allergic developments.