Nami Okamoto

Effects of Alpha Tocopherol and Probucol Supplements on Allergen-Induced Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma

Objective: We investigated the role of antioxidants in airway hyperresponsiveness to acetylcholine using young asthma model mice, which were sensitized and stimulated with ovalbumin. Methods: The mice had been fed either a normal diet, an α-tocopherol-supplemented diet or a probucol-supplemented diet 14 days before the first sensitization. They were immunized with antigen at intervals of 12 days and, starting from 10 days after the second immunization, they were exposed to antigen 3 times every 4th day using an ultrasonic nebulizer. Twenty-four hours after the last antigen inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was collected. A blood and lung tissue study was also carried out. Results: Twenty-four hours after the last antigen challenge, both IL-4 and IL-5 in the BALF of α-tocopherol-supplemented mice were significantly decreased. The IL-5 level in probucol-supplemented mice was also decreased, but there was no difference in IL-4 levels. The serum IgE level was decreased in probucol-supplemented mice. Differential cell rates of the fluid revealed a significant decrease in eosinophils due to antioxidant supplementation. Airway hyperresponsiveness to acetylcholine was also repressed in antioxidant-supplemented mice. In histological sections of lung tissue, inflammatory cells and mucus secretion were markedly reduced in antioxidant-supplemented mice. We investigated the antioxidant effect on our model mice by examining 8-isoprostane in BALF and lung tissue, and acrolein in BALF; however, our experiment gave us no evidence of the antioxidant properties of either α-tocopherol or probucol contributing to the reduction of airway inflammation. Conclusion: These findings indicate that α-tocopherol and probucol suppress allergic responses in asthma model mice, although these two drugs cause suppression in different ways that are unrelated to antioxidation.

Febrile seizures associated with influenza A

To clarify the clinical impact of influenza A on the development of febrile seizures (FS), consecutive FS patients brought to our hospital between October 2003 and September 2004 were prospectively surveyed. Patients infected with influenza A (influenza A patients) and those uninfected with influenza (non-influenza patients) were compared with regard to clinical characteristics of FS. Influenza infection was determined by rapid antigen test and/or serologically. Associations of influenza A with atypical findings of FS, including partial seizures, prolonged seizures, multiple seizures during the same illness, and 30-min or longer prolonged postictal impairment of consciousness (PPIC), were analyzed by multiple logistic regression. A total of 215 patients (47 influenza A and 168 non-influenza patients) were enrolled in the study. Age was significantly higher in the influenza A group (39.85+/-22.16 months vs. 27.51+/-17.14 months, P<0.001). Of 42 patients aged 48 months or older, which corresponded to the 80th percentile for age, 15 (35.7%) were influenza A patients, with a significantly higher incidence of such patients than in the subgroup of patients aged 47 months or younger (32/173, 18.5%) (P=0.015). On multiple logistic regression analysis, influenza A was independently associated with PPIC (odds ratio: 4.44, 95% confidence interval: 1.52-12.95, P=0.006), but not with other atypical findings. The positive association of influenza A with PPIC suggests that influenza may affect state of consciousness at the same time that it induces seizures with fever.

Evidence-based clinical practice guideline for adult Still’s disease

Abstract Objectives: Using an expert- and data-driven methodology, we have constructed the first clinical practice guidelines (CPGs) for adult Still’s disease (ASD) after complete systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. Methods: The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process includes (1) clarification of the purpose of CPG, (2) organization of the steering committee, (3) organization of the CPG committee and secretariat, (4) defining the scope (setting of clinical questions (CQs)), (5) SR, (6) development of recommendations, (7) drafting the CPG, (8) external evaluation and public comments, and (9) release. Because we wanted to construct CPG for ASD to encompass both adult-onset Still’s disease (AOSD) and adult patients with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study. Results: Twenty-six CQs were selected and roughly divided into the following items: (1) clinical findings (CQs 1–4), (2) laboratory findings (CQs 5–8), (3) complications (CQs 9–13), (4) treatment with oral medicine (CQs 14–19), (5) treatment with biological reagents (CQs 20–23), and (6) treatments for sJIA (CQs 25–26). Recommendations and the strength of the recommendations for these CQs were decided by a modified Delphi method. Conclusion: We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26 CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other healthcare providers, medical and health-related students, and patients and their family members to understand and treat ASD.

National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics

Abstract Objectives: Mevalonate kinase deficiency (MKD), a rare autosomal recessive autoinflammatory syndrome, is caused by disease-causing variants of the mevalonate kinase (MVK) gene. A national survey was undertaken to investigate clinical and genetic features of MKD patients in Japan. Methods: The survey identified ten patients with MKD. Clinical information and laboratory data were collected from medical records and by direct interviews with patients, their families, and their attending physicians. Genetic analysis and measurement of MVK activity and urinary excretion of mevalonic acid were performed. Results: None of the 10 patients harbored MVK disease-causing variants that are common in European patients. However, overall symptoms were in line with previous European reports. Continuous fever was observed in half of the patients. Elevated transaminase was observed in four of the 10 patients, two of whom fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. About half of the patients responded to temporary administration of glucocorticoids and NSAIDs; the others required biologics such as anti-IL-1 drugs. Conclusion: This is the first national survey of MKD patients in a non-European country. Although clinical symptoms were similar to those reported in Europe, the incidence of continuous fever and elevated transaminase was higher, probably due to differences in disease-causing variants.

The findings of musculoskeletal ultrasonography on primary Sjögren’s syndrome patients in childhood with articular manifestations and the impact of anti-cyclic citrullinated peptide antibody

Abstract Objective: We researched the findings of musculoskeletal ultrasound sonography (MSUS) on primary Sjogren’s syndrome in childhood (pSS-C) with articular manifestations. The correlation of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were investigated to evaluate the usefulness of MSUS on their articular prognosis. Method: The objective patients are pSS-C cases who visited our hospital complaining joint pain and/or joint swelling and for whom MSUS was performed. Result: Eight patients included 6 female and 2 male, 5 RF-positive patients and 3 ACPA- positive patients. The mean age of onset was 11.1 ± 3.0 years (352 physical joint findings and 284 MSUS findings. The number of joints found clinical articular manifestations was 58/352 joints, and arthritis detected by MSUS was 30/284 joints). In multivariate analysis, the odds ratio of clinical articular manifestations was significant high in RF-positivity (2.9, 95%CI 1.5–6.2). The odds ratio of arthritis detected by MSUS in ACPA-positivity was significant high (3.7, 95%CI 1.5–11.6), although odds ratio in RF-positivity had no statistical significance and a similar trend was seen in odds ratios of subclinical arthritis (4.9, 95%CI 1.6–18.0). Conclusion: It was indicated that MSUS is useful for pSS-C. ACPA-positive pSS-C patients have arthritis and subclinical arthritis more frequently than ACPA-negative patients.

Validation of Classification Criteria of Macrophage Activation Syndrome in Japanese Patients With Systemic Juvenile Idiopathic Arthritis

To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world.

A paediatric case of granulomatosis with polyangiitis accompanied with dorsalis pedis artery occlusion and prominent cryofibrinogenaemia

Abstract Granulomatosis with polyangiitis (GPA) is characterised by necrotizing angiitis of the arterioles, capillary and venules in the respiratory tract and kidney. GPA patients show other various symptoms and emergent progression, though skin lesions caused by obstruction of the middle arteries is not frequent. GPA is rare in children and little is known about the incidence of GPA in children and adolescents. Cryofibrinogen is cryoprecipitate in the plasma and cryofibrinogenaemia is a rare disorder that may develop skin manifestation after cold exposure. The symptom of cryofibrinogenaemia is usually mild, though it sometimes presents severe manifestations. We will report a first paediatric case who overlapped GPA and cryofibrinogenaemia, also accompanying skin gangrene.

Features of Japanese juvenile spondyloarthritis patients in our hospital.

Spondyloarthritis (SpA) is thought to be very rare in Japan, because possession rate of HLA-B27 in healthy people is 0.4% and it is significantly lower than that of other countries (5%). This makes it difficult for Japanese physicians to diagnose SpA early. Since 10-20% of SpA patients experience symptoms in their childhood, it is very important to distinguish them from other chronic arthritis patients for pediatric rheumatologists.

Musculoskeletal ultrasound findings of articular manifestations on juvenile primary sjogren’s syndrome

Articular manifestations (joint swelling, joint tenderness) are common extra-glandular manifestations of primary Sjogren’s syndrome (SjS). In past studies those have been reported that anti-cyclic citrullinated peptide antibody (ACPA) is associated with arthritis in adult SjS and that there is no clear method to distinguish arthritis of primary SjS from early rheumatoid arthritis, but there is no report on children. Musculoskeletal ultrasound (MSUS) can clearly evaluate arthritis or enthesitis which are difficult to assess in detail by only physical examination.