Naomi Iwata

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.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

UNLABELLED : Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

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. …

Clinical and laboratory features of fatal rapidly progressive interstitial lung disease associated with juvenile dermatomyositis

OBJECTIVE Rapidly progressive interstitial lung disease (RP-ILD) is a rare but potentially fatal complication of JDM. The aim of this study was to establish markers for the prediction and early diagnosis of RP-ILD associated with JDM. METHODS The clinical records of 54 patients with JDM were retrospectively reviewed: 10 had RP-ILD (7 died, 3 survived), 19 had chronic ILD and 24 were without ILD. Routine tests included a high-resolution CT (HRCT) scan of the chest and measurement of serum levels of creatine phosphokinase, ferritin and Krebs von den Lungen-6 (KL-6). Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies and IL-18 levels were measured by ELISA. RESULTS No differences were found in the ratio of juvenile clinically amyopathic DM between the three groups. Initial chest HRCT scan findings were variable and could not distinguish between RP-ILD and chronic ILD. Anti-MDA5 antibodies were positive in all 8 patients with RP-ILD and 10 of 14 with chronic ILD, but none of the patients without ILD. Serum levels of anti-MDA5 antibody, ferritin, KL-6 and IL-18 were significantly higher in the RP-ILD group than in the chronic ILD and non-ILD groups. Serum levels of IL-18 positively correlated with serum KL-6 (R = 0.66, P < 0.001). CONCLUSION High serum levels of IL-18, KL-6, ferritin and anti-MDA5 antibodies (e.g. >200 units by ELISA) are associated with RP-ILD. These can be used as an indication for early intensive treatment. Both alveolar macrophages and autoimmunity to MDA5 are possibly involved in the development of RP-ILD associated with JDM.

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.

A nationwide survey of Aicardi–Goutières syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study

OBJECTIVES Aicardi-Goutières syndrome (AGS) is a rare, genetically determined, early onset progressive encephalopathy associated with autoimmune manifestations. AGS is usually inherited in an autosomal recessive manner. The disease is rare, therefore the clinical manifestations and genotype-phenotype correlations, particularly with regard to autoimmune diseases, are still unclear. Here we performed a nationwide survey of AGS patients in Japan and analysed the genetic and clinical data. METHODS Patients were recruited via questionnaires sent to paediatric or adult neurologists in Japanese hospitals and institutions. Genetic analysis was performed and clinical data were collected. RESULTS Fourteen AGS patients were identified from 13 families; 10 harboured genetic mutations. Three patients harboured dominant-type TREX1 mutations. These included two de novo cases: one caused by a novel heterozygous p.His195Tyr mutation and the other by a novel somatic mosaicism resulting in a p.Asp200Asn mutation. Chilblain lesions were observed in all patients harbouring dominant-type TREX1 mutations. All three patients harbouring SAMHD1 mutations were diagnosed with autoimmune diseases, two with SLE and one with SS. The latter is the first reported case. CONCLUSION This study is the first to report a nationwide AGS survey, which identified more patients with sporadic AGS carrying de novo dominant-type TREX1 mutations than expected. There was a strong association between the dominant-type TREX1 mutations and chilblain lesions, and between SAMHD1 mutations and autoimmunity. These findings suggest that rheumatologists should pay attention to possible sporadic AGS cases presenting with neurological disorders and autoimmune manifestations.

Serum microRNAs as Potential Biomarkers of Juvenile Idiopathic Arthritis

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression of targeted mRNAs, which are important in the pathogenesis of autoimmune diseases. MiRNAs may have the potential to serve as biomarkers of disease. We evaluated serum levels of selected miRNAs and their associations with disease activity in juvenile idiopathic arthritis (JIA). Sera and peripheral blood leukocytes were collected from patients with JIA (8 systemic onset, 16 polyarthritis) and healthy controls. Levels of miR-16, miR-132, miR-146a, miR-155, and miR-223 were quantified. Levels of miR-223 in sera were significantly higher in patients in the active phase of systemic onset JIA than in controls. MiRNAs of peripheral blood leukocytes did not exhibit any difference between patients with JIA and controls. In both systemic onset JIA and polyarthritis patients, levels of miR-223 and miR-16 correlated with erythrocyte sedimentation rate and matrix metalloproteinase-3, respectively. MiR-146a and miR-223 in polyarthritis showed correlations with matrix metalloproteinase-3. Expressions of miRNAs were altered in patients with JIA. Serum levels of miR-223 may be a potential disease biomarker. Investigation of miRNAs could be helpful in understanding the pathogenesis of JIA and could aid in the identification of additional disease biomarkers.

Pediatric Rheumatology Association of Japan recommendation for vaccination in pediatric rheumatic diseases

Abstract Pediatric Rheumatology Association of Japan has developed evidence-based guideline of vaccination in pediatric rheumatic diseases (PRDs) as a part of Guideline of Vaccination for Pediatric Immunocompromised Hosts. Available articles on vaccination in both adult rheumatic diseases and PRDs were analyzed. Non-live vaccines are generally safe and effective in patients with PRDs on corticosteroid, immunosuppressant, and/or biologics, although efficacy may be attenuated under high dose of the drugs. On the other hand, efficacy and safety of live-attenuated vaccine for the patients on such medication have not been established. Thus, live-attenuated vaccines should be withheld and, if indicated, may be considered as a clinical trial under the approval by Institutional Review Board. All patients with PRDs anticipating treatment with immunosuppressants or biologics should be screened for infection of hepatitis B and C and tuberculosis before the commencement of medication. Varicella vaccine should be considered in sensitive patients ideally 3 weeks or longer before the commencement of immunosuppressants, corticosteroids, or biologics. Bacille Calmette-Guérin should be withheld at least for 6 months after birth, if their mothers have received anti-tumor necrosis factor-α antibodies during the second or third trimester of pregnancy.

Increased Serum B Cell Activating Factor and a Proliferation-inducing Ligand Are Associated with Interstitial Lung Disease in Patients with Juvenile Dermatomyositis.

Objective. Rapidly progressive interstitial lung disease (RP-ILD) is an intractable and fatal complication of juvenile dermatomyositis (JDM). This study evaluated serum levels of B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in JDM patients with complicating ILD, and their association with ILD phenotypes, clinical variables, and anti-melanoma differentiation-associated gene 5 (MDA5). Methods. We measured the levels of BAFF, APRIL, and anti-MDA5 in the sera of 23 JDM patients with ILD [8 in the RP-ILD group and 15 in the chronic ILD (C-ILD) group], 17 JDM patients without ILD (non-ILD group), and 10 age-matched controls, using the ELISA method. ILD was identified by high-resolution computed tomography. Results. Serum BAFF titers were significantly higher in the JDM patients with RP-ILD versus those with C-ILD (p = 0.011) and in healthy controls (p = 0.0004). The C-ILD group had significantly higher levels of BAFF versus controls (p ≤ 0.0001). Serum APRIL was markedly elevated in the RP-ILD group as compared with the C-ILD group (p = 0.003) and controls (p = 0.006). In patients with ILD, both BAFF and APRIL levels were correlated with serum Krebs von den Lungen-6 and interleukin 18. Subjects with high titer anti-MDA5 (> 200 U) had higher levels of BAFF and APRIL than those with low titer anti-MDA5 (< 100 U; p = 0.019 and p = 0.0029, respectively), which may have been due to a relationship between RP-ILD and high anti-MDA5 titer. Conclusion. Our findings of markedly elevated levels of BAFF and APRIL in patients with RP-ILD JDM suggest the potential importance of these cytokines in the diagnosis and treatment of RP-ILD accompanying JDM.