Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.

BACKGROUND: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma. METHODS: Thirty-eight Japanese children (aged 7-16 years) who completed the 24-week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886). RESULTS: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9-151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p < 0.001 for QOL, 1.33 vs 0.16, p < 0.001 for hospitalization, 0.68 vs 0.15, p = 0.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state. CONCLUSIONS: Long-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified.

Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy.

BACKGROUND: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression). METHODS: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 µg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study. RESULTS: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study. CONCLUSIONS: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well.

Association study of matrix metalloproteinase-12 gene polymorphisms and asthma in a Japanese population.

BACKGROUND: Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population. METHODS: We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro. RESULTS: N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00-2.56, p = 0.047; OR 1.40, 95% CI 1.04-1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-ß. CONCLUSIONS: Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue.

The use of complementary and alternative medicine by pediatric food-allergic patients in Japan.

BACKGROUND: In developed countries, increasing food allergy prevalence and concern regarding food allergies have been reported. Although the use of complementary and alternative medicine (CAM) for the treatment of allergic diseases has increased in some Western countries, the actual proportion and patterns of CAM use for pediatric food allergies in Japan are still unknown. METHODS: Fourteen allergy centers in Japan participated in the study using a questionnaire survey regarding the use of CAM by pediatric patients. A diagnosis of food allergy was made at each hospital by pediatric allergists. RESULTS: Surveys were completed by parents/guardians, and data were collected for a total of 962 pediatric food-allergic patients. Overall, 8.4% of the participants used CAM to treat a food allergy. The major CAM therapies used were herbal teas (22.2%), including several Japanese herbal teas, Chinese herbal medicine (18.5%) and lactic acid bacteria (16%). Among the participants using CAM to treat food allergy, 13.6% thought that the CAM being used was very effective, while 11.1% of participants thought that CAM caused some type of side effect. CONCLUSIONS: Our study is the first large-scale national survey regarding the use of CAM in pediatric patients with food allergies in Japan. Unlike in the USA, which has a higher rate of CAM use (17%), approximately 8.4% of food-allergic patients used CAM in Japan. Interestingly, the major types of CAM used in Japan differed from those used in the USA. Cultural differences and food customs may affect the use of CAM.

In-Depth Serum Proteomics by DIA-MS with In Silico Spectral Libraries Reveals Dynamics during the Active Phase of Systemic Juvenile Idiopathic Arthritis.

In serum proteomics using mass spectrometry, the number of detectable proteins is reduced due to high-abundance proteins, such as albumin. However, recently developed data-independent acquisition mass spectrometry (DIA-MS) proteomics technology has made it possible to remarkably improve the number of proteins in a serum analysis by removing high-abundance proteins. Using this technology, we analyzed sera from patients with systemic juvenile idiopathic arthritis (sJIA), a rare pediatric disease. As a result, we identified 2727 proteins with a wide dynamic range derived from various tissue leakages. We also selected 591 proteins that differed significantly in their active phases. These proteins were involved in many inflammatory processes, and we also identified immunoproteasomes, which were not previously found in serum, suggesting that they may be involved in the pathogenesis of sJIA. A detailed high-depth DIA-MS proteomic analysis of serum may be useful for understanding the pathogenesis of sJIA and may provide clues for the development of new biomarkers.

The influence of tonsillectomy on allergic diseases in pediatric patients.

BACKGROUND: The influence of tonsillectomy on allergic airway diseases is not well known. OBJECTIVES: In the present study, the influence of tonsillectomy on perennial allergic rhinitis (PAR) and bronchial asthma (BA) among pediatric subjects was prospectively investigated. METHODS: The tonsillectomy (surgery group) and the age-matched non-surgical subjects (control group) were examined and followed prospectively. In addition, immunological analysis was conducted. RESULTS: After in vitro allergen stimulation, the production of a small number of allergen-specific Th2 cells was induced in the tonsillar cells, even in sensitized subjects. Flow cytometry analysis detected more effector regulatory T cells (Tregs) in the tonsils than in peripheral blood. Clinically, after surgery, the PAR and BA symptoms improved in the surgery group but not in the control group. The total IgE in the surgery group was significantly lower than in the control group; after surgery, IgE levels slightly increased but remained lower. The postoperative Dermatophagoides farina (Der f)-specific IgE level increased in the sensitized subjects but not in the non-sensitized subjects. CONCLUSION: Tonsillectomy did not improve the underlying mechanisms of the allergy, however the decreased risk of infection and upper airway obstruction could lead to improved symptoms of allergic airway diseases.

Sublingual immunotherapy with house dust extract for house dust-mite allergic rhinitis in children.

BACKGROUND: House dust extract is used in conventional immunotherapy for house dust-mite (HDM) allergic rhinitis in Japan. However, an alternative administration route is desired. The aims of the present double blind, placebo-controlled trial were to evaluate the therapeutic efficacy and safety of sublingual immunotherapy (SLIT) with house dust extract in pediatric patients with HDM allergic rhinitis. METHODS: The study population comprised 31 subjects (21 males and 10 females) aged from 7 to 15 years old. Twenty patients (the active group) received house dust extract and 11 received placebo via sublingual administration. Extract or placebo (1 ml) was administered at 10-fold dilution once weekly for 40 weeks. During the study period, the subjects recorded their daily nasal symptoms and use (dose and frequency) of other medications in a nasal allergy diary. RESULTS: The symptom scores in the active group began to decrease about 24 weeks after initiation of treatment and significant differences between the active and placebo groups were observed after 30 weeks. The average scores for the last four weeks of the study were significantly lower than those for the first four weeks in the active group but not in the placebo group. The only local adverse effect was a bitter taste reported by one patient. There were no other local or systemic adverse effects associated with SLIT. CONCLUSIONS: Our results suggest that SLIT with house dust extract for more than 30 weeks is safe and effective treatment for HDM allergic rhinitis in children.

Pranlukast reduces asthma exacerbations during autumn especially in 1- to 5-year-old boys.

BACKGROUND: Leukotriene receptor antagonists have been used to prevent virus-induced asthma exacerbations in autumn. Its efficacy, however, might differ with age and sex. OBJECTIVE: This study aimed to investigate whether pranlukast added to usual asthma therapy in Japanese children during autumn, season associated with the peak of asthma, reduces asthma exacerbations. It was also evaluated the effect of age and sex on pranlukast's efficacy. METHODS: A total of 121 asthmatic children aged 1 to 14 years were randomly assigned to receive regular pranlukast or not according to sex, and were divided in 2 age groups, 1-5 years and 6-14 years. The primary outcome was total asthma score calculated during 8 weeks by using a sticker calendar related to the days in which a child experienced a worsening of asthma symptoms. This open study lasted 60 days from September 15 to November 14, 2007. RESULTS: Significant differences in pranlukast efficacy were observed between sex and age groups. Boys aged 1 to 5 years had the lower total asthma score at 8 weeks (p = 0.002), and experienced fewer cold episodes (p = 0.007). There were no significant differences between pranlukast and control group in total asthma score at 8 weeks (p = 0.35), and in the days in which a child experienced a worsening of asthma symptoms (p = 0.67). CONCLUSION: There was a substantial benefit of adding pranlukast to usual therapy in asthmatic children, especially in boys aged 1 to 5 years, during autumn season.

Induction of the Matrix Metalloproteinase 13 Gene in Bronchial Epithelial Cells by Interferon and Identification of its Novel Functional Polymorphism.

Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon ß (IFN-ß) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-κB inhibitor), while stimulation by IFN-ß was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-κB) and that poly(I:C) stimulated IFN secretion in an NF-κB-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells.

CD14 -550 C/T, which is related to the serum level of soluble CD14, is associated with the development of respiratory syncytial virus bronchiolitis in the Japanese population.

BACKGROUND: The contribution that genetic polymorphisms of Toll-like receptor (TLR) 4 and of CD14--both of which recognize respiratory syncytial virus (RSV) in the innate immune response--make to RSV bronchiolitis in the Japanese population has not yet been clarified. METHODS: This study genotyped 2 TLR4 mutations, Asp299Gly and Thr399Ile, and 2 single-nucleotide polymorphisms (SNPs) of CD14, -550 C/T and -159 C/T, in 54 children with RSV bronchiolitis and in 203 control subjects. CD14 SNPs and the serum level of soluble CD14 (sCD14) also were examined in 67 cord-blood specimens and in serum samples from 73 6-year-old children. RESULTS: No TLR4 mutations were found. The frequencies of both the CC genotype and the C allele of CD14 -550 C/T were significantly higher in children with RSV bronchiolitis than in the control subjects. The serum level of sCD14 was significantly higher in children with the CC genotype of CD14 -550 C/T than in those with the CT and TT genotypes. CONCLUSIONS: CD14 -550 C/T, which is related to the serum level of sCD14, is associated with the development of RSV bronchiolitis in the Japanese population. This study's results indicate that, in different ethnic groups, different genetic factors contribute to the development of RSV bronchiolitis.