Although a new classification algorithm for systemic vasculitides was proposed by Watts et al. and the Chapel Hill Consensus Conference (CHCC) was updated in 2012, there are currently no validated diagnostic criteria for systemic vasculitides. The Diagnostic and Classification Criteria for Vasculitis study (DCVAS) is a global study to develop and improve the diagnostic criteria for systemic vasculitides. The epidemiology of systemic vasculitides differs widely among countries. For example, in the case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, patients with microscopic polyangiitis (MPA) and with positivity for MPO-ANCA are predominant in Asian countries, whereas patients with granulomatosis with polyangiitis (GPA) and with positivity for PR3-ANCA are predominant in northern Europe and the United States. Interstitial lung disease (ILD) occurs more frequently in Asian patients compared with patients in Europe. The incidence and the prevalence of large-vessel vasculitis also differ significantly. Giant cell arteritis (GCA) occurs frequently in northern Europe, unlike Takayasu arteritis (TAK). The ethnic and regional differences in the incidence, prevalence and clinical characteristics of patients with vasculitis should be recognized when we diagnose and treat patients with vasculitis using criteria, and should also be considered when interpreting the results from clinical studies.
Autoantibody (autoAb) production in patients with systemic autoimmune diseases is a hallmark of disease entity, activity and prognosis. Although a large number of autoAbs have been discovered to date, there is a limited number of autoAbs whose pathogenic roles have been clearly determined. However, intriguing evidence has recently been provided of possible pathogenic roles for anti-neutrophil cytoplasmic Abs (ANCAs) against myeloperoxidase (MPO) in ANCA-associated vasculitides (AAV) and for anti-citrullinated protein Abs (ACPAs) in rheumatoid arthritis (RA). Of note, these autoAbs are thought to display both direct and indirect effects on organ failure. Additionally, some autoAbs have been reported to play pathogenic roles in brain damage in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), which is one of the most refractory autoimmune disorders. Thus the binding of autoAbs to a certain sequence of the N-methyl-D-aspartate receptor subunit NR2 (anti-NR2 Abs) may directly induce hippocampal neuronal injury. On the other hand, anti-U1 ribonucleoprotein (RNP) Abs might be pathogenic by inducing neurotoxic inflammatory mediators intrathecally. Such autoAb measurements are also clinically meaningful for treatment selection.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is histologically characterized by systemic necrotizing vasculitis and is clinically classified into two phases, systemic or localized. Recently, otological symptoms such as otitis media and hearing loss, not previously often associated with AAV, have been reported in AAV cases. In these cases we propose a diagnosis of otitis media with AAV (OMAAV). The ANCA titer is important for the diagnosis of OMAAV, and in most cases rapid progressive hearing loss is observed as localized AAV. Peripheral facial nerve palsy or hypertrophic pachymeningitis are coupled with 25% of cases and 18% of cases respectively. Proteinase 3-ANCA (PR3-ANCA) positive otitis media causes granulomatous formation or middle ear effusion in the middle ear, on the other hand myeloperoxidase-ANCA (MPO-ANCA) positive otitis media predominantly presents as otitis media with effusion. The early diagnosed case and the sensorineural hearing loss not progressed deaf could be recovered by the immunosuppressive therapy. Delayed diagnosis of AAV occasionally leads to progression to the irreversible phase; therefore, diagnosis at the early-localized stage is important for treating AAV. In this review, we discuss the current understanding of this newly proposed concept of OMAAV.
Histamine plays important roles in inflammation and nervous irritability in allergic disorders, including atopic dermatitis (AD). It has been shown to regulate the expression of pruritic factors, such as nerve growth factor and semaphorin 3A, in skin keratinocytes via histamine H1 receptor (H1R). Furthermore, H1R antagonist reduced the level of IL-31, a cytokine involving the skin barrier and pruritus, in chronic dermatitis lesions in NC/Nga mice and patients with AD. Histamine plays roles in the induction of allergic inflammation by activating eosinophils, mast cells, basophils, and Th2 cells via histamine H4 receptor (H4R). H4R, in addition to H1R, is expressed on sensory neurons, and a decrease in scratching behaviors was observed in H4R-deficient mice and mice treated with a H4R antagonist. We found that the combined administration of H1R and H4R antagonists inhibited the itch response and chronic allergic inflammation, and had a pharmacological effect similar to that of prednisolone. Although the oral administration of H1R antagonists is widely used to treat AD, it is not very effective. In contrast, JNJ39758979, a novel H4R antagonist, had marked effects against pruritus in Japanese patients with AD in a phase II clinical trial. Next generation antihistaminic agents possessing H1R and H4R antagonistic actions may be a potent therapeutic drug for AD.
Background: Fluticasone furoate nasal spray (FFNS) is a glucocorticoid developed for the treatment of allergic rhinitis (AR). This is the first randomized clinical trial to assess the efficacy and safety of FFNS in Japanese children with perennial AR (PAR). Methods: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study, 261 children aged 6 to <15 years were treated with FFNS 55μg, once daily or placebo for two weeks. Nasal and ocular symptoms were rated by parents/guardians/patients in the patient daily diary. The primary endpoint was the mean change from baseline in the three total nasal symptom score (3TNSS). In addition, rhinoscopic findings were rated by the investigators as an efficacy measure. As a safety measure, adverse events and clinical chemistry and hematology were evaluated. Results: Mean change from baseline over the entire treatment period in 3TNSS was greater in the FFNS 55μg group compared with placebo, and the difference was statistically significant (p < 0.001). Significant improvements in rhinoscopic findings of swelling of inferior turbinate mucosa and quantity of nasal discharge were also observed. The total ocular symptom score (TOSS) was reduced significantly in the FFNS 55μg group, compared with placebo, in the second week in a subgroup of patients with baseline TOSS > 0. The incidence of adverse events was similar between FFNS 55μg (18%) and placebo (19%). Conclusions: Two-week treatment with FFNS 55μg, once daily is effective and tolerable in Japanese children aged 6 to <15 years with PAR.
Background: The prevalence of allergic rhinitis and other allergies has risen worldwide. Dietary habits are considered to be among the potential risk factors. The aim of this study was to evaluate the prevalence of allergic rhinitis and its relationship with dietary habits and other risk factors among 6 to 7-year-old Turkish schoolchildren. Methods: In this cross-sectional study, a total of 11483 children aged 6-7 years were surveyed. The prevalence of symptoms of allergic rhinitis was assessed using the ISAAC protocol. Dietary information was collected using a food frequency questionnaire. Results: Of them, 9875 (50.7% M 49.3% F) questionnaires were appropriately completed. The prevalence rates of lifetime rhinitis, current rhinitis, current rhinoconjunctivitis and physician-diagnosed allergic rhinitis, were 44.3%, 29.2%, 8.5% and 8.1%, respectively. Consumption of rice, and cereals ≥3 times per week showed protective effect on physician-diagnosed allergic rhinitis (aOR = 0.53, 95% CI = 0.32-0.87 and aOR = 0.58, 95% CI = 0.36-0.92). Eating pasta, and chocolates ≥3 times per week showed protective effect on current rhinoconjunctivitis (aOR = 0.45, 95% CI = 0.25-0.79 and aOR = 0.50, 95% CI = 0.29-0.86). Eating lollipops, candies and animal fats ≥3 times per week was positively associated with current rhinoconjunctivitis (aOR = 1.47, 95% CI = 1.00-2.17 and aOR = 2.25, 95% CI = 1.11-4.56). Protective effect of the Mediterranean diet was not significant. Conclusions: Frequent consumption of cereals, rice, pasta and chocolates may have beneficial effect on symptoms of rhinoconjunctivitis. Although dietary habits may affect the prevalence of symptoms of current rhinoconjunctivitis, the Mediterranean diet alone may not be protective against rhinoconjunctivitis.
Background: In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC). Results: Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics Conclusions:S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.
Background: Probiotic administration may be a useful method for preventing allergies in infants; however, there have been controversial results about the efficacy. We investigated the effects of bifidobacterial supplementation on the risk of developing allergic diseases in the Japanese population. Methods: In an open trial, we gave Bifidobacterium breve M-16V and Bifidobacterium longum BB536 prenatally to 130 mothers beginning 1 month prior to delivery and postnatally to their infants for 6 months. Another 36 mother-infant pairs served as controls and did not receive the bifidobacterial supplementation. Development of allergic symptoms in the infants was assessed at 4, 10 and 18 months of age. Fecal samples were collected from the mothers and infants. Results: The risk of developing eczema/atopic dermatitis (AD) during the first 18 months of life was significantly reduced in infants in the probiotic group (OR: 0.231 [95% CI: 0.084-0.628] and 0.304 [0.105-0.892] at 10 and 18 months of age, respectively). Pyrosequencing analyses indicated an altered composition of the fecal microbiota at 4 months for infants who developed eczema/AD at 4 and 10 months of age. The proportion of Proteobacteria was significantly lower (P = 0.007) in mothers at the time of delivery who received the supplementation when compared with the control group and was positively correlated (r = 0.283, P = 0.024) with that of infants at 4 months of age. No adverse effects were related to the use of probiotics. Conclusions: These data suggest that the prenatal and postnatal supplementation of bifidobacteria is effective in primary preventing allergic diseases. Some limited changes in the composition of fecal microbiota by the bifidobacterial supplementation were observed.
Background: Depression has been linked to poorer asthma control in asthmatic patients. Although the Japanese version of the Asthma Control Test (ACT-J) is frequently used as a simple, practical evaluation tool in clinical care settings in Japan, knowledge regarding its efficacy for assessing asthma control in asthmatic patients with depression is limited. Thus, we retrospectively investigated cut-off values of the ACT-J for well-controlled asthma, and explored depression's influence on the test with a questionnaire survey. Methods: Data were analyzed on 1,962 adult asthmatic patients who had completed both the ACT-J and the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) in 2008 questionnaire survey conducted by the Niigata Asthma Treatment Study Group. Patients were classified into low (LD: J-PHQ-9 score of 0-4) or high depression (HD: J-PHQ-9 score of 5-27) groups. In both groups, the efficacy of the ACT-J was confirmed. We then compared the optimal cut-off points for uncontrolled asthma in both groups by performing a receiver operating characteristic (ROC) analysis, using the original classification referred to the GINA classification as the "true" classification. Results: Cronbach's alpha in the LD and HD group was 0.808 and 0.740 respectively. In both groups, the sub-group with existence of work absenteeism or frequent attacks during the previous 12 months scored lower on the ACT-J. The area under the curve and optimal cut-off point for patients with LD and HD were 0.821 and 0.846, and 23 and 20 respectively. Conclusions: The efficacy of the ACT-J was confirmed in depressive patients with asthma. Because asthma control as evaluated with the ACT-J can be worse than actual control under depressive states, physicians should also pay attention to a patient's depressive state at evaluation. Further investigations focus on the association between the ACT-J and depression are required.
Background: Hereditary angioedema (HAE) is a rare but life-threatening condition that results from mutations in C1-inhibitor (C1-INH). Since distinguishing HAE from other causes of angioedema (AE) is a critical problem in emergencies, the objective of the present study was to clarify the differences between HAE and other forms of AE. Methods: Seventy-two patients with AE were enrolled in this study. The medical history and laboratory data of patients with HAE at the first visit were compared to those with other types of AE. Results: Subjects included 23 patients with HAE, 33 with mast cell-mediated AE, 5 with drug-induced AE and 11 with idiopathic AE. The average age of HAE onset (19.5 ± 8.0 years old) was significantly lower than in other groups. A family history of AE was noted in 82.6% of HAE patients, which was significantly higher than other groups. Swelling affecting the extremities and gastrointestinal (GI) tract was observed in the majority (60 to 80%) of HAE patients. Life threatening laryngeal edema was observed in 30.4% of HAE patients. In 95.6% of HAE patients serum levels of C4 were less than the lower limit of the normal range. In our subjects, the sensitivity and specificity of low C4 for HAE were 95.6% and 93.8%, respectively. Conclusions: Early onset of AE, positive family history, recurrent AE in the extremities and GI tract, and suffocation are distinctive characteristics of HAE. A low serum level of C4 is a useful marker for making a differential diagnosis of HAE.
Background: The Modified Pulmonary Index Score (MPIS) was developed as an indicator of the severity of acute asthma in children. The objective of this study is to evaluate the reliability and validity of the MPIS for children with acute asthma, including those five years or younger in age. Methods: We evaluated the inter-rater reliability and internal consistency of the MPIS by having at least two trained physicians and a nurse—each of whom was blinded to the others' scores—simultaneously examine inpatients with asthma exacerbation and rate them according to the MPIS. We also evaluated the intraclass correlation coefficient (ICC), kappa, Cronbach's α and correlations between the MPIS and other indicators associated with asthma severity. Results: A total of 25 children (median age, five years; 13 patients were five years or younger in age) were enrolled in this study. The MPIS showed excellent inter-rater reliability (all ages: ICC = 0.95, 95% CI = 0.94-0.97; five years or younger: ICC = 0.93, 95% CI = 0.89-0.96) and good internal consistency (all ages: Cronbach's α = 0.87; five years or younger: Cronbach's α = 0.85). The MPIS showed good correlation with a visual analogue scale assessed by the physicians. Conclusions: The MPIS was a sufficiently reliable assessment tool for children with acute asthma, including those five years or younger in age.