Taichi Kanetaka

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.

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.

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.

Fever Responses Are Enhanced with Advancing Age during Respiratory Syncytial Virus Infection among Children under 24 Months Old

The most important risk factor for severe respiratory syncytial virus (RSV) infection is considered young age due to the immature immune system. The risk at young age is reported greater for RSV than for other respiratory infectious agents. Based on the strong association between young age and severity of RSV infection due to immature immunity, we aimed to assess whether there were any age-related differences in fever responses, as one clinical aspect of the immune response. In our observational study over two seasons (2014-2015 and 2015-2016), daily body temperatures of children under 3 years old with RSV infection were recorded from the first medical visit during the acute phase to defervescence. The body temperature records were analyzed among 171 children of four age groups (< 6, < 12, < 24 and ≥ 24 months), in terms of fever development, degrees of fever onset, the highest fever during the period, and fever duration. There were 54 patients in the group of < 6 months, 41 in the group of < 12 months, 58 in the group of < 24 months, and 18 in the group of ≥ 24 months. We thus found the correlation between age and fever responses under 24 months old; namely, the more the age advanced, the more frequently high and prolonged fever was experienced. Importantly, infants under 6 months old tend to show the suppressed fever responses. In conclusion, young infants with reduced fever response during RSV infection do not implicate less severity and needs attentive management.

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.

SAT0407 Association between the rates of enlarged nailfold capillaries and serum FDP-E levels reflects microvascular injuries in juvenile dermatomyositis

Background One indicator of the active microvascular damages of juvenile dermatomyositis (JDM) is enlarged nailfold capillary (NFC). We have reported that serum FDP–E level is a marker of fibrinogenolysis and reflects maicroangiopathy in JDM patients. Objectives To determine clinical factors associated with the rates of enlarged NFCs. Methods Forty NFC images of fifteen JDM patients (7.3±3.9 years at first visit) were evaluated. NFC findings of 4 fingers of hand, excluding thumb were recorded in maintaining a constant room temperature of range 24–26°C. The rates of enlarged capillaries (>20 μm) to total number of end raw loops per millimeter in 4 digits were evaluated. Correlations between the rates of enlarged NFCs and serum level of CK, aldorase, FDP-E and ESR were examined. Associations between clinical manifestations (skin involvemrnts and muscle weakness) and the rates of enlarged NFCs were also evaluated. The rates of enlarged NFCs were devided into four groups in this study (group 1=0∼25%, group 2=26∼50%, group 3=51∼75%, group 4=76∼100%), and rates of abnormal levels of serum CK, aldolase, FDP-E, and ESR were evaluated, respectively. Results The rates of enlarged NFCs were significantly associated with serum FDP-E levels (r=0.34, P<0.05). Skin involvements were associated with higher rates of enlarged NFCs. Furthermore, abnormal FDP-E levels were found in 33% in group 1, whereas in group 4 abnormal FDP-E levels were found in all patients (p=0.0034). Conclusions Enlarged NFCs may reflect microangiopathy in active disease of JDM. Serum FDP-E levels will indicate microvascular inflammation especially in skin involvements. References Takayuki K, et al. Clinical analysis of juvenile dermatomyositis; a retrospective study of 45 Japanese. Eular congress. 2009 Disclosure of Interest None Declared