Minako Tomiita

Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial.

BACKGROUND Systemic-onset juvenile idiopathic arthritis does not always respond to available treatments, including antitumour necrosis factor agents. We investigated the efficacy and safety of tocilizumab, an anti-interleukin-6-receptor monoclonal antibody, in children with this disorder. METHODS 56 children (aged 2-19 years) with disease refractory to conventional treatment were given three doses of tocilizumab 8 mg/kg every 2 weeks during a 6-week open-label lead-in phase. Patients achieving an American College of Rheumatology Pediatric (ACR Pedi) 30 response and a C-reactive protein concentration (CRP) of less than 5 mg/L were randomly assigned to receive placebo or to continue tocilizumab treatment for 12 weeks or until withdrawal for rescue medication in a double-blind phase. The primary endpoint of the double-blind phase was an ACR Pedi 30 response and CRP concentration of less than 15 mg/L. Patients responding to tocilizumab and needing further treatment were enrolled in an open-label extension phase for at least 48 weeks. The analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, numbers NCT00144599 (for the open-label lead-in and double-blind phases) and NCT00144612 (for the open-label extension phase). FINDINGS At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%), and 38 (68%) patients, respectively. 43 patients continued to the double-blind phase and were included in the efficacy analysis. Four (17%) of 23 patients in the placebo group maintained an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L compared with 16 (80%) of 20 in the tocilizumab group (p<0.0001). By week 48 of the open-label extension phase, ACR Pedi 30, 50, and 70 responses were achieved by 47 (98%), 45 (94%), and 43 (90%) of 48 patients, respectively. Serious adverse events were anaphylactoid reaction, gastrointestinal haemorrhage, bronchitis, and gastroenteritis. INTERPRETATION Tocilizumab is effective in children with systemic-onset juvenile idiopathic arthritis. It might therefore be a suitable treatment in the control of this disorder, which has so far been difficult to manage.

High prevalence of autoantibodies to muscarinic-3 acetylcholine receptor in patients with juvenile-onset Sjögren syndrome

Sjogren syndrome (SS) is an autoimmune disease characterised pathologically by lymphocytic infiltration into the lacrimal and salivary glands, and clinically by dry eyes and mouth. Lymphocytic infiltration is also found in the kidneys, lungs, thyroid, and liver. Immunohistochemical studies have shown that most infiltrating lymphocytes around the labial salivary and lacrimal glands and the kidneys are CD4-positive αβT cells.1 Candidate autoantigens recognised by T cells that infiltrate the labial salivary glands of SS have been analysed and Ro/SS-A 52 kDa,2 α-amylase, heat shock protein, and TCR BV63 have been identified, although Ro/SS-A 52 kDa reactive T cells were not increased in peripheral blood. …

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 studys results indicate that, in different ethnic groups, different genetic factors contribute to the development of RSV bronchiolitis.

IL‐10 gene polymorphism, but not TGF‐β1 gene polymorphisms, is associated with food allergy in a Japanese population

The regulatory IL‐10 and TGF‐β1 cytokine gene polymorphisms have been associated with allergic diseases in different populations, like Caucasian, Chinese and Indians. We investigated the association between the polymorphisms IL‐10 A−1082G, C−819T, C−627A and TGF‐β1 T+869C, G+915C, C−509T and food allergy in Japanese children. One hundred and eleven children with food allergy and 115 atopic control children without food allergy were recruited. DNA samples from these subjects were genotyped by using PCR. The odds ratio of IL‐10 −1082 AA genotype was 2.5 (95% CI, 1.0–6.4) for food allergy risk when compared with atopic control subjects (p = 0.03). There were no significative differences in the frequency of TGF‐β1 gene polymorphisms between both groups. Our results indicate that IL‐10 A−1082G gene polymorphism is associated with food allergy susceptibility in atopic Japanese children.

Long-term treatment of systemic juvenile idiopathic arthritis with tocilizumab: results of an open-label extension study in Japan

Systemic-onset juvenile idiopathic arthritis (sJIA) is a chronic childhood disease associated with many complications.1–5 Treatments comprise non-steroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic drugs and biologics,6–9 including tocilizumab, an interleukin-6 receptor monoclonal antibody.10 Results of a randomised, placebo-controlled, phase III trial of tocilizumab in sJIA patients at eight Japanese hospitals, as well as the first 48 weeks of an open-label extension, have been published.3 Protocols and amendments for this extension phase were approved by the Japanese Ministry of Health, Labor and Welfare and the institutional review board at each centre. Of 56 patients initially enrolled, six withdrew during the open-label, lead-in phase (anti-tocilizumab antibodies, three; anaphylactoid reaction, one; gastrointestinal haemorrhage, one; non-efficacy, one). During the double-blind phase, one patient from each treatment arm withdrew because of adverse events (AEs) but re-entered the open-label extension after the resolution of AEs. In total, 50 patients responding to tocilizumab and needing further treatment entered the open-label extension; two patients subsequently withdrew within the first year because of AEs. Herein, the long-term efficacy and safety of treatment through 144 weeks are presented. …

Longterm Safety and Effectiveness of the Anti-interleukin 6 Receptor Monoclonal Antibody Tocilizumab in Patients with Systemic Juvenile Idiopathic Arthritis in Japan

Objective. To assess the longterm safety and effectiveness of tocilizumab (TCZ) in systemic-onset juvenile idiopathic arthritis (sJIA). Methods. The longterm extension phase of 2 pivotal studies (phase II with 11 patients and phase III with 56 patients) in patients with active sJIA was analyzed. Patients received open-label TCZ (8 mg/kg, every 2 weeks) without concomitant use of disease-modifying antirheumatic drugs. Results. In total, 67 patients were enrolled. All patients received corticosteroid at baseline. Median duration of exposure to TCZ was 3.4 years. Nine patients withdrew from the study [4 because of adverse events (AE), 4 because of the development of anti-TCZ antibodies, and 1 because of inadequate response]. Rates of AE and serious AE were 803.7/100 patient-years (PY) and 34.7/100 PY, respectively. The most common serious AE were infections (13.2/100 PY). No cases of malignancy or death were reported. Two serious infusion reactions were reported in patients testing negative for anti-TCZ antibodies. One definite macrophage activation syndrome (MAS) case and 1 potential MAS case were identified. American College of Rheumatology (ACR) response rates attained early in the TCZ treatment period were maintained throughout the study: at Week 168, JIA ACR 30, 50, 70, 90, and 100 response rates were 80.3%, 80.3%, 75.4%, 60.7%, and 18.0%, respectively. In total, 22 of 67 patients (32.8%) completely discontinued corticosteroids without flare. Conclusion. TCZ has demonstrated durability of effectiveness in the longterm treatment of children with sJIA and has shown good tolerability and a low discontinuation rate associated with AE, development of anti-TCZ antibodies, or inadequate response. (ClinicalTrials.gov NCT00144599 and NCT00144612). (First Release March 15 2014; J Rheumatol 2014;41:759-67; doi:10.3899/jrheum.130690)

Abnormal expression of the genes involved in cytokine networks and mitochondrial function in systemic juvenile idiopathic arthritis identified by DNA microarray analysis.

Objectives: Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic disease in childhood characterised by systemic symptoms and a relatively poor prognosis. Peripheral leukocytes are thought to play a pathological role in sJIA although the exact cause of the disease is still obscure. In this study, we aimed to clarify cellular functional abnormalities in sJIA. Methods: We analysed the gene expression profile in peripheral leukocytes from 51 patients with sJIA, 6 patients with polyarticular type JIA (polyJIA) and 8 healthy children utilising DNA microarrays. Gene ontology analysis and network analysis were performed on the genes differentially expressed in sJIA to clarify the cellular functional abnormalities. Result: A total of 3491 genes were differentially expressed in patients with sJIA compared to healthy individuals. They were functionally categorised mainly into a defence response group and a metabolism group according to gene ontology, suggesting the possible abnormalities in these functions. In the defence response group, molecules predominantly constituting interferon (IFN)γ and tumour necrosis factor (TNF) network cascades were upregulated. In the metabolism group, oxidative phosphorylation-related genes were downregulated, suggesting a mitochondrial disorder. Expression of mitochondrial DNA-encoded genes including cytochrome c oxidase subunit 1(MT-CO1) and MT-CO2 were suppressed in patients with sJIA but not in patients with polyJIA or healthy children. However, nuclear DNA-encoded cytochrome c oxidases were intact. Conclusion: Our findings suggest that sJIA is not only an immunological disease but also a metabolic disease involving mitochondria disorder.

The clinical features of Sjögren's syndrome in Japanese children

Sjögrens syndrome (SS) is thought to be uncommon in children. An epidemiological study to describe the clinical features distinguishing SS in Japanese children was performed by sending questionnaires to hospitals. A total of 61 cases of SS were reported from 1290 hospitals. The diagnosis of SS was based on histopathological changes and/or sialographic changes in the salivary glands. Forty‐two cases had primary SS and 19 were secondary SS with other autoimmune disorders. Fourteen cases (65%) of secondary SS were associated with systemic lupus erythematosus. In primary SS, the initial symptoms were systemic manifestations (fever, exanthema, arthralgia, etc) except for sicca symptoms. In laboratory studies, antinuclear antibodies, elevated serum IgG, rheumatoid factor, anti‐Ro/SS‐A antibodies and anti‐La/SS‐B antibodies were frequently observed.

Cytokine biomarker candidates in breast milk associated with the development of atopic dermatitis in 6-month-old infants.

Background: A few studies have reported that the quantity of selected cytokines/chemokines in breast milk might be associated with atopic dermatitis (AD). Using the multiplex cytokine assay system, we examined cytokines/chemokines in human milk in order to identify new biomarkers related to AD. Methods: We recruited 49 infants with or without AD who participated in a birth cohort and measured the concentrations of cytokines/chemokines in the colostrum (collected within 4–5 days after birth) and mature milk (collected at 1 month postpartum) received by the infants. Results: There were significant differences in the concentrations of interleukin (IL)-1β and IL-12p40 in the colostrum, and in those of IL-4, eotaxin, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α2 and MIP-1α in the mature milk between the milk received by infants who developed AD at the age of 6 months and that received by the control infants. There was weak to moderate correlation between those 6 cytokines/chemokines in mature milk. Atopic history and IgE levels of mothers were not related to cytokine/chemokine concentrations in breast milk. Logistic regression analyses showed that high levels of eotaxin in the mature milk were a risk for the development of AD at 6 months of age. Conclusion: These results suggest that several cytokines/chemokines, especially eotaxin, are potential biomarkers for development of AD in early infancy.

Functional variants in the thromboxane A2 receptor gene are associated with lung function in childhood‐onset asthma

The thromboxane A2 receptor (TBXA2R) gene is associated with asthma, but no functional genetic variations are known to associate with the disease or its related phenotypes.