Nodoka Sakurai

Pathogenesis of systemic inflammatory diseases in childhood: “Lessons from clinical trials of anti-cytokine monoclonal antibodies for Kawasaki disease, systemic onset juvenile idiopathic arthritis, and cryopyrin-associated periodic fever syndrome”

Abstract Inflammation has often been considered to be a nonspecific response and to play a bridging role in the activation of adaptive immunity. However, it is now accepted that inflammation is the product of an independent innate immune system closely linked to the adaptive immune system. The key mediators of inflammation are inflammatory cytokines, as determined by multiple lines of evidence both in vitro and in vivo. Due to the crucial role of inflammatory cytokines in the pathogenesis of autoimmune disorders, anti-cytokine treatment has been developed as a therapy for rheumatoid arthritis, juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases. We recently completed several clinical trials of anti-cytokine treatment for children with systemic inflammatory diseases: anti-IL-6 receptor monoclonal antibody (tocilizumab) for children with two subtypes of JIA (poly-JIA and systemic JIA), anti-TNF-α monoclonal antibody (infliximab) for children with Kawasaki disease, and anti-IL-1-β monoclonal antibody (canakinumab) for children with cryopyrin-associated periodic syndrome. This review summarizes the basis of inflammation in terms of innate immunity and adaptive immunity in these systemic inflammatory diseases, clinical efficacy, and tolerability of these biologic agents, and attempts to determine the roles of individual inflammatory cytokines in disease pathogenesis.

Usefulness of two interferon-γ release assays for rheumatic disease.

The aim of this study was to evaluate the performance of two interferon‐γ release assays (IGRA), QuantiFERON‐TB Gold In‐Tube (QFT‐GIT) and T‐SPOT.TB, for pediatric patients with rheumatic disease in Japan and to analyze the frequencies of indeterminate test results with these kits.

Characteristics of FDG-PET findings in the diagnosis of systemic juvenile idiopathic arthritis

Abstract Objective: To examine and delineate inflammatory focus in patients with juvenile idiopathic arthritis (JIA), 18F-Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) (18F-FDG-PET) was applied to patients with JIA, and the images of these patients were compared. Methods: Sixty-eight children (59 with systemic JIA (s-JIA) and 9 with polyarticular JIA) were included. The diagnosis of JIA was done to meet the International League of Associations for Rheumatology (ILAR) criteria. After 6-h fasting, whole-body positron emission tomography (PET) scans were acquired 60 min after intravenous injection of 3–5 MBq/kg 18F-FDG. The interpretation of 18F-FDG uptake was based on visual characteristics. Results: Two types of PET images were outstanding in s-JIA; one was 18F-FDG uptake in red bone marrow, such as the spine, pelvis, and long bones as well as spleen (12 cases), and other type was the uptake in the major joints, such as hips, elbows, wrists, knees, and ankles (8 cases). The former findings were correlated with elevated levels of inflammatory markers, while the latter were with significantly increased levels of MMP-3 (p < 0.05). Conclusion: There was a noticeable accumulation of 18F-FDG uptake in bone marrow of s-JIA patients which may indicate the inflammatory focus of this disease and play an important role in the pathogenic basis of arthritis and systemic inflammation of s-JIA.

PReS-FINAL-2189: Tocillizumab for patients with takayasu arteritis in childhood refractory to conventional therapy

Takayasu arteritis (TA) is a chronic systemic granulomatous vasculitis of large vessels. Corticosteroids may induce remission. However, over half of patients flare with tapering of corticosteroids. There are anecdotal reports of treatment with methotrexate, azathioprine, and biologics such as infliximab. Cyclophosphamide is recommended for life-threatening or organ-threatening patients. However, patients, especially with HLA B52-positive, are frequently refractory to these treatments. Since serum levels of interleukin (IL)-6 are correlated with disease activity, an open-label trial of tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, was conducted for 6 pediatric patients with TA.

PReS-FINAL-2166: Long-term safety and effectiveness of anti-interleukin-6 receptor monoclonal antibody, tocilizumab, in patients with systemic juvenile idiopathic arthritis in Japan

Systemic-onset juvenile idiopathic arthritis (sjia) is a form of childhood chronic arthritis of unknown etiology with systemic manifestations such as remittent fever and erythematous rash, lymph adenopathy, hepatosplenomegaly, and/or serositis. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor monoclonal antibody that has been approved for the treatment of patients with sjia. Results of the lead-in phase; the placebo-controlled, double-blind phase; and the first 48 weeks of an open-label extension have been already published.

Clinical significance of subcutaneous fat and fascial involvement in juvenile dermatomyositis

Abstract Objectives: Subcutaneous involvement, including calcinosis and panniculitis, is a more common complication in juvenile dermatomyositis (JDM) than in adult dermatomyositis. Magnetic resonance imaging (MRI) is useful for evaluating disease distribution. We investigated the clinical significance of subcutaneous involvement in JDM. Methods: Thighs and hips in 18 newly diagnosed JDM patients were evaluated with fat-suppression MRI. Bilateral muscle, fascial and subcutaneous fat involvement were scored from 0 to 8 points according to the severity of distribution on MRI. Associations between clinical manifestations, serum muscle enzymes, and MRI scores were also evaluated. Results: Abnormal MRI findings in muscle, fascia and subcutaneous fat were observed in 18, 18, and 10 patients, respectively. Subcutaneous fat scores were significantly higher in early-diagnosed JDM patients (diagnosed less than 2 months from onset) than in late-diagnosed JDM patients (diagnosed later) (p = .025). Serum aldolase was elevated in all patients, although only eight demonstrated elevated serum creatine phosphokinase. Serum aldolase was significantly correlated with MRI scores for subcutaneous fat (p < .0001, ρ = .787) and fascia (p = .013 ρ = 0.574), but not muscle. Additionally, serum aldolase was significantly correlated with serum triglycerides (p = .009, ρ = 0.629). Conclusion: Subcutaneous fat involvement is a characteristic finding in early-diagnosed JDM and correlates with elevated serum aldolase.

A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan.

Purpose. To conduct a national survey of systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Based on current information on the use of MMF, we aimed to evaluate its efficacy and safety for childhood-onset (c-) SLE. Target. We evaluated 115 patients by questionnaire on MMF use for c-SLE in medical facilities specializing in pediatric rheumatic and renal diseases. Results. Average age at SLE onset was 10.6 (range, 2–15) years; average age at the time of starting MMF was 12.3 (range, 2–15) years. Average dose per body surface area was 1,059.3 mg/m2/day. Corticosteroid dosing was 20.9 mg/day before treatment but 7.7 mg/day after treatment. Laboratory values before and after MMF treatment were as follows: C3 increased from 67.0 to 84.9 mg/dl (p < 0.001), C4 increased from 10.2 to 15.1 mg/dl (p < 0.001), and anti-DNA antibody decreased from 154.2 to 18.4 IU/ml (p < 0.001). 24 adverse events in 21 cases were reported, but MMF was not discontinued in any. Conclusions. The amount of MMF for c-SLE in Japan is similar to the standard dose in other countries. Reduction of corticosteroid dose and improvement of laboratory values represent efficacy of MMF. The side effects recorded here indicated tolerability of the drug.

PReS-FINAL-2172: Efficacy of corticosteroids and intravenous cyclophosphamide for patients with juvenile systemic sclerosis

Systemic sclerosis (ssc) is a rare multisystemic disease characterized by inflammation, vascular abnormalities, and fibrosis that affects the skin and various internal organs. Juvenile ssc accounts for fewer than 10% of all adults with ssc. Regarding effective treatment there were no specific pediatric data available, and the long-term efficacy of treatment for children with ssc has not been investigated.

PReS-FINAL-2110: Tocilizumab for patients with oligoarticular juvenile idiopathic arthritis refractory to conventional therapy

Because most children with oligoarticular juvenile idiopathic arthritis (o-JIA) were mildly affected (Steinblocker functional class I, c.a.85%), o-JIA is tend to be thought of as a mild subtype of JIA. However, 6% of them were unable to participate in a full school program 5 years after diagnosis, and 0.5% of children with o-JIA progressed to class III or IV, severe to terminal stages. Moreover, in 20% of o-JIA patients there is a progressive increase in the number of affected joints after the first 6 months of disease (extended type). These severe patients had never gone into remission despite the conventional therapy.