Kimihiro Okubo

Association of serum interleukin‐33 level and the interleukin‐33 genetic variant with Japanese cedar pollinosis

Background IL‐33, an IL‐1‐like cytokine, is a ligand for IL1RL1, which is an important effector molecule of type 2 T helper responses. Although IL‐33/IL1RL1 interaction has been suggested to be important in induction of allergic airway inflammation, serum levels of IL‐33 and the genetic influences of the polymorphisms of IL‐33 in human allergic diseases are unclear.

Changes in nasal metachromatic cells during allergen immunotherapy

We have investigated changes of nasal metachromatic cell number, nasal symptoms and nasal provocation at the third and sixth month during allergen immunotherapy. Twenty‐five subjects with perennial allergic rhinitis (house dust (23), Alternaria (2)) were divided into two groups: an immunotherapy‐treated group (n= 14) and a control group (n=11). At the first visit nasal symptom scores, nasal provocation reactions and the number of metachromatic cells in nasal mucosal epithelial scrapings were not significantly different between groups. At the third and sixth month after immunotherapy nasal symptom scores, nasal provocation and the metachromatic cells in epithelial scrapings were significantly reduced (P < 0.05) compared with the pretreatment values in the immunotherapy group, but unchanged in the control group. These results suggest that the reduction in metachromatic cell number at the nasal mucosal surface may be one of the mechanisms which could explain the improvement of nasal allergic symptoms by immunotherapy.

Increased Expression and Role of Thymic Stromal Lymphopoietin in Nasal Polyposis

Purpose Nasal polyposis is a chronic inflammatory disease of the upper airways often associated with asthma and characterized by markedly increased numbers of eosinophils, Th2 type lymphocytes, fibroblasts, goblet cells and mast cells. Previous studies have shown elevated levels of thymic stromal lymphopoietin (TSLP) in atopic diseases like asthma, atopic dermatitis and mainly in animal models of allergic rhinitis (AR). Here, we investigated the expression of TSLP in nasal polyps from atopics and non-atopics in comparison with the nasal mucosa and its potential role in nasal polyposis. Methods Messenger RNA expression for TSLP, thymus and activation-regulated chemokine (TARC) and macrophage derived chemokine (MDC) in nasal polyps and nasal mucosa of atopics and non-atopics was analyzed by real time PCR. Immunoreactivity for TSLP in nasal polyps and in the nasal mucosa of patients with AR and non-allergic rhinitis (NAR) was analyzed by immunohistochemistry. Eosinophil counts was analyzed by Wright-Giemsa staining and nasal polyp tissue IgE, by ELISA. Results Messenger RNA expression for TSLP,TARC and MDC was markedly higher in nasal polyps as compared to the allergic nasal mucosa. Immunoreactivity for TSLP was detected in epithelial cells, endothelial cells, fibroblasts and inflammatory cells of the nasal mucosa and nasal polyps. The number of TSLP+ cells was significantly greater in the nasal mucosa of AR than NAR patients. The number of TSLP+ cells in nasal polyps from atopics was significantly greater than that of non-atopics and that in the allergic nasal mucosa. The number of TSLP+ cells correlated well with the number of eosinophils and the levels of IgE in nasal polyps. Conclusions The high expression of TSLP in nasal polyps and its strong correlation to eosinophils and IgE suggest a potential role for TSLP in the pathogenesis of nasal polyps by regulating the Th2 type and eosinophilic inflammation.

A Randomized Double-Blind Comparative Study of Sublingual Immunotherapy for Cedar Pollinosis

BACKGROUND Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollen is a substantial problem in Japan. Sublingual immuno-therapy (SLIT) is safer than conventional antigen-specific immunotherapy, the only treatment modality by which complete cure of the disease can be expected. We investigated the safety and efficacy of SLIT in the treatment of cedar pollinosis patients compared to placebo. METHODS A randomized, placebo-controlled, double-blind study was conducted in 61 cedar pollinosis patients. Increasing doses of standardized Japanese cedar extract or placebo were administered sublingually in intervals ranging from daily to once a week after six weeks. The primary efficacy variable was the mean of the daily total symptom scores (TSS) during the pollen dispersing period. Secondary efficacy variables included the QOL scores and related variables. RESULTS Primary efficacy variable scores were significantly lower for some days in the SLIT group than in the placebo group (P < .01 or P < .05). Secondary efficacy for the QOL score in SLIT group was almost of half of placebo group. There was no significant difference in the overall incidence of side effects between the SLIT group and the placebo group. CONCLUSIONS SLIT was effective and safe in the treatment of cedar pollinosis.

Expression of Pendrin Periostin in Allergic Rhinitis Chronic Rhinosinusitis

BACKGROUND Pendrin and periostin are newly identified mediators of the inflammatory process. The expression of these proteins in human sinonasal tissue and their roles in allergic rhinitis and chronic rhinosinusitis remain to be elucidated. This study investigated the expression of pendrin and periostin in sinonasal tissue of patients with allergic rhinitis, chronic rhinosinusitis, and aspirin-induced asthma. Prospective control study conducted at Yamagata University, Japan. METHODS Surgical samples were investigated by means of real-time reverse transcription-polymerase chain reaction to evaluate the expression of pendrin and periostin mRNA. The presence and location of pendrin and periostin were determined by immunohistochemistry and Western blotting. RESULTS Pendrin and periostin production was significantly higher in patients with nasal disorders than in controls. Further significant increases in periostin expression were noted in patients with chronic rhinosinusitis with nasal polyps and in those with aspirin-induced asthma. Immunohistochemistry revealed positive staining for pendrin in epithelial cells and submucosal glands and for periostin in the basement membrane in all three disorders, and additionally for periostin in nasal polyp tissue in chronic rhinosinusitis and aspirin-induced asthma. CONCLUSIONS Production of pendrin and periostin is upregulated in allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma. These findings suggest that pendrin can induce mucus production and that periostin can induce tissue fibrosis and remodeling in the nasal mucosa. Therefore, these mediators may be therapeutic target candidates for allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma.

Fexofenadine improves the quality of life and work productivity in Japanese patients with seasonal allergic rhinitis during the peak cedar pollinosis season.

Background: Although currently in its infancy, quality of life (QOL) research in Japan is rapidly expanding and is expected to become a standard outcome measure in clinical trials. In Japan, QOL has not previously been assessed in patients with allergic rhinitis (AR); we report the first clinical study applying the recently validated Japanese translations of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) Questionnaire to assess the effects of the oral antihistamine, fexofenadine, on QOL and work productivity due to cedar pollinosis. Patients and Methods: A randomized, double-blind, placebo-controlled, single-site study was conducted during the peak cedar pollinosis season in Japan. After a 7-day run-in period, subjects were randomized to receive fexofenadine HCl 60 mg twice daily (bid) or placebo for 2 weeks. Results: Overall, 206 Japanese subjects with AR were included in the intention-to- treat population (fexofenadine, n = 104, and placebo, n = 102). Fexofenadine statistically significantly improved overall QOL compared with placebo (p = 0.005) and improvements were reported in the RQLQ domains: activities (p = 0.047), practical problems (p = 0.003), nasal symptoms (p = 0.003) and eye symptoms (p ≤ 0.001). Clinically significant improvements in practical problems, eye symptoms and activity limitations, exceeding the 0.05 level, were observed with fexofenadine. These improvements in QOL were associated with significant symptom relief (p < 0.001 vs. placebo). Improvements in impairment at work were also reported with fexofenadine. Conclusion: In Japan, this is the first clinical study to show that fexofenadine HCl (60 mg b.i.d.) improves overall QOL and work productivity in patients with seasonal AR using validated Japanese instruments.

Japanese Guideline for Allergic Rhinitis 2014.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 7th edition was published in 2013, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2013. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Examination, diagnosis and classification for Japanese allergic rhinitis: Japanese guideline

Many countries throughout the world have experienced an increase in the prevalence of allergic rhinitis (AR), which has come to be a major cause of morbidity in developed countries. The pathology underlying AR is regarded as IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. In Japan, AR caused by Japanese cedar pollen, the most common allergic disease, has become a salient public health challenge. Almost all primary care physicians and otorhinolaryngologists have been consulted by AR patients between February and April. Although most such patients have received treatment, numerous patients with AR have not received proper examinations for AR. Clinical guidelines are systematically developed statements that are designed to help practitioners make decisions about appropriate and effective health care. Guidelines in many countries including Japan have been published for AR. Unfortunately, those guidelines have remained untested. Moreover, they might be difficult for non-specialists to use. In this review, we specifically examine the present standard examination for diagnosis of AR and optimal classification for AR in Japan. We hope that this review would be used not only for the support of daily practice but also for selection of AR patients for clinical trials.

Efficacy and Safety of Sublingual Immunotherapy for Two Seasons in Patients with Japanese Cedar Pollinosis

Background: Japanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Standardized JC pollen extract is available for subcutaneous immunotherapy, but this treatment is limited by potentially serious side effects. The aim of this double-blind, randomized comparative study was to evaluate the efficacy and safety of standardized JC pollen extract in a new oral formulation (CEDARTOLEN®, Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for sublingual immunotherapy (SLIT) for JC pollinosis. Methods: A total of 531 subjects with JC pollinosis were randomized into 2 groups at a ratio of 1:1 to receive daily sublingual administration of standardized JC pollen extract with a maintenance dose of 2,000 Japanese allergy units (JAU) or placebo for 2 consecutive pollen seasons. The efficacy was evaluated using the total nasal symptom and medication score (TNSMS) as the primary end point. Secondary end points included the total ocular symptom and medication score (TOSMS) and scores for individual symptoms and medication. Results: The TNSMS was significantly lower (p < 0.0001) in the SLIT group than in the placebo group in the peak symptom period by 18 and 30% in the first and second seasons, respectively. All secondary end points were also significantly lower in the SLIT group in both seasons. No systemic anaphylaxis occurred. Conclusions: SLIT with daily administration of standardized JC pollen extract was effective for improving nasal and ocular symptoms of JC pollinosis and reducing the use of relief medication. The JC pollen extract was well tolerated with only local adverse events.

Omalizumab is more effective than suplatast tosilate in the treatment of Japanese cedar pollen-induced seasonal allergic rhinitis

Background Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollens is a major problem in Japan. Omalizumab, a humanized monoclonal anti‐IgE antibody, improves symptoms associated with SAR, but a comparative study with an anti‐allergy drug has not yet been conducted.