Tomo Nozawa

Efficacy and limitation of infliximab treatment for children with Kawasaki disease intractable to intravenous immunoglobulin therapy: report of an open-label case series.

Objective. Kawasaki disease (KD) is an acute febrile disease in infants and young children. Five percent to 8% of cases will be complicated with coronary dilatation or aneurysm, although introduction of high-dose intravenous immunoglobulin (IVIG) therapy has provided remarkable results for reducing the frequency of cardiac involvement. We describe the results of an open-label trial of infliximab, an anti-tumor necrosis factor-α monoclonal antibody, for suppressing the progression of coronary artery lesions in cases of KD refractory to extensive IVIG therapy. Plasma exchange (PE) was available as a rescue therapy for patients refractory to infliximab. Methods. Twenty eligible patients fulfilled the diagnostic criteria for KD, and were primarily treated with IVIG up to 4 g/kg. “Refractory to IVIG” was defined as persisting or reemerging fever > 38°C and positive fractional changes of C-reactive protein, white blood cell counts, or neutrophil counts 48 hours after IVIG infusion. These cases were treated with infliximab, 5 mg/kg, which should begin within 10 days of disease onset. PE for patients refractory to infliximab was performed with 5% albumin. Results. There was rapid improvement of inflammatory symptoms as well as normalization of the inflammatory markers. Sequential examination by echocardiography up to disease Day 30 revealed that the inflamed and mildly dilated coronary artery at the beginning of the study regressed to normal size in the convalescent phase. Two out of 20 patients showed incomplete improvement of inflammatory symptoms after infliximab treatment, and were provided with PE therapy, with no complications. Conclusion. Eighteen of 20 patients were effectively treated with infliximab, and 2 cases were effectively treated with PE to prevent progression to coronary artery lesions. No adverse event such as anaphylactoid reaction, heart failure, severe infectious diseases, or tuberculosis was observed in this trial.

Analysis of Gender Differences in Genetic Risk: Association of TNFAIP3 Polymorphism with Male Childhood-Onset Systemic Lupus Erythematosus in the Japanese Population

Background Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies. Methodology/Principal Findings The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P<0.05). Conclusions Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

Mycophenolate mofetil as maintenance therapy for childhood-onset systemic lupus erythematosus patients with severe lupus nephritis

Abstract Objectives. We evaluated histological changes occurring in renal biopsy specimens, between the time before initial induction therapy and after 12 months’ maintenance therapy, as well as changes in laboratory parameters, SLE disease activity (SLEDAI), and dosage of corticosteroid (CS) in childhood-onset systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Methods. A retrospective analysis was performed on nine patients diagnosed with childhood-onset SLE and lupus nephritis. They were treated with pulsed mPSL and intravenous cyclophosphamide as induction therapy and MMF (500–1500 mg/day) plus CS as maintenance therapy. Renal biopsy was performed before the initial induction therapy and after 12 months’ maintenance therapy. Results. Pathological findings at second biopsy were improved in eight of nine patients (89%). The findings of SLEDAI, urinalysis, and blood tests also showed improvement. CS doses could be tapered satisfactorily. Adverse events were observed in two patients. No patients treated with MMF experienced any disease flares during maintenance therapy. Conclusions. MMF as maintenance therapy might be useful in that not only the histological findings of lupus nephritis were improved, but also CS doses could be beneficially tapered. Nonetheless, this is a retrospective report of only nine cases and further prospective multicenter studies are necessary.

Coronary-Artery Aneurysm in Tocilizumab-Treated Children with Kawasaki’s Disease

Four patients with Kawasaki’s disease resistant to IVIG treatment had a response to the anti–interleukin-6 antibody tocilizumab, but coronary-artery aneurysms developed in two of the patients. Such aneurysms occur at very low frequency among patients who receive this treatment.

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.

Guidance on the use of canakinumab in patients with cryopyrin-associated periodic syndrome in Japan

Cryopyrin-associated periodic syndrome (CAPS) is an orphan disease with incidence of about one in 1,000,000 persons. This autoinflammatory disease develops in the neonatal period or early childhood, with various inflammatory symptoms occurring repeatedly throughout the patient’s lifetime. It is caused by abnormality of the NLRP3 protein which mediates the intracellular signal transduction mechanism of inflammatory processes, resulting in continuous overproduction of interleukin (IL)-1β, which induces chronic inflammation and progressive tissue damage. Definitive diagnosis of CAPS is difficult, and treatment has also been difficult because of a lack of effective medications in Japan. Clinical studies of human anti-human IL-1β monoclonal antibody (canakinumab) treatment were conducted in Japan, and approval was granted for therapeutic use of canakinumab for CAPS in September 2011. Similar to other biological drugs, canakinumab is clinically highly effective. However, sufficient attention to the method of use and adverse drug reactions is necessary. This guidance describes the use of canakinumab in Japan for CAPS in relation to exclusion criteria, method of use, evaluation criteria, and adverse drug reactions.

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.

Primary varicella infection in children with systemic juvenile idiopathic arthritis under tocilizumab therapy

Abstract We report the clinical course and outcome of primary varicella infection in six children with systemic juvenile idiopathic arthritis (sJIA) receiving tocilizumab. None had disseminated or fatal varicella infection, but one patient developed macrophage activation syndrome (MAS) and another had an arthritis relapse. All patients had a significant elevation of serum IL-6 levels, and the two children who developed MAS or arthritis relapse showed high serum IL-18 levels, which could cause a sJIA flare-up.

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.