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Shumpei Yokota,
Tomoyuki Imagawa,
Masaaki Mori,
Takako Miyamae,
Syuji Takei, Naomi Iwata,
Hiroaki Umebayashi,
Takuji Murata,
Mari Miyoshi,
Minako Tomiita,
Norihiro Nishimoto,
Tadamitsu Kishimoto
Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
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Rheumatology (Oxford, England) 10/2012; · 4.24 Impact Factor
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ABSTRACT: BACKGROUND: Inhibition of interleukin-6 (IL-6) signaling by tocilizumab is highly effective for treatment of refractory juvenile idiopathic arthritis (JIA). It appears that IL-6 plays an important role in the immune response to the influenza virus, but it is not clear whether treatment with tocilizumab affects the severity of influenza. METHODS: We retrospectively collected clinical and laboratory data from JIA patients (n = 33) treated with tocilizumab. Ten patients who developed influenza (tocilizumab group; 10.1 %, 10/99 patient-years) were analyzed. Eleven JIA patients who experienced influenza during conventional treatments, without tocilizumab (control group), were compared with the tocilizumab group. RESULTS: Of the 10 patients in the tocilizumab group, 6 patients did not have high fever (>38 °C), and the other 4 febrile patients recovered from fever in 1 day. White blood cell counts and lymphocyte counts were significantly lower at the acute phase of infection compared with data from before influenza infection. The degree of fever and level of C-reactive protein in the tocilizumab group were significantly reduced compared with the control group. CONCLUSIONS: IL-6 inhibition by tocilizumab reduced inflammation associated with infection and resulted in mild symptoms during influenza. Leukopenia might be a useful indicator of viral infection, including influenza, during tocilizumab treatment.
Modern Rheumatology 10/2012; · 1.58 Impact Factor
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Tomoyuki Imagawa,
Syuji Takei,
Hiroaki Umebayashi,
Kenichi Yamaguchi,
Yasuhiko Itoh,
Toshinao Kawai, Naomi Iwata,
Takuji Murata,
Ikuo Okafuji,
Mari Miyoshi,
Yasuhiro Onoe,
Yoshifumi Kawano,
Noriko Kinjo,
Masaaki Mori,
Neelufar Mozaffarian,
Hartmut Kupper,
Sourav Santra,
Gina Patel,
Shinichi Kawai,
Shumpei Yokota
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ABSTRACT: The objective of this study was to evaluate the efficacy, pharmacokinetics, and safety of adalimumab in patients with polyarticular juvenile idiopathic arthritis (JIA) in Japan. Patients aged 4 to 17 years were enrolled in a single-arm, open-label, multicentre study of adalimumab. Patients weighing <30 kg received 20 mg every other week (eow), and those ≥30 kg received 40 mg eow. Concomitant methotrexate (MTX) was allowed (≤10 mg/m(2) per week). The primary efficacy outcome was the percent of patients with American College of Rheumatology Pediatric 30 response (ACR Pedi 30) at week 16. JIA core variables, serum adalimumab concentrations, and anti-adalimumab antibodies (AAAs) were analysed. Patients were monitored for adverse events (AEs). Twenty-five patients (20 with concomitant MTX at baseline and 5 without) were enrolled: 24 patients completed 16 weeks of therapy and 22 patients completed 60 weeks. At week 16, 90 % of patients with MTX and 100 % without MTX achieved ACR Pedi 30; response rates were maintained through week 60 in 94 and 80 % of patients, respectively. Each JIA core variable improved over time. Six patients became AAA positive (two each at weeks 8, 16, and 60), some of which were transient. All six AAA-positive patients achieved ACR Pedi 30 at week 16, and four maintained that response at week 60. Six patients (all with MTX) experienced nine serious AEs (JIA, pyrexia, arthralgia, pneumonia, hepatitis B infection, pharyngitis, dehydration, pharyngeal pain, and pneumonia). In pediatric patients with polyarticular JIA in Japan, adalimumab was safe and effective for reducing disease activity for up to 60 weeks.
Clinical Rheumatology 10/2012; · 2.00 Impact Factor
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ABSTRACT: Methotrexate (MTX) is widely used for the treatment of articular-type juvenile idiopathic arthritis (JIA), but patients receiving MTX for rheumatoid arthritis have been reported to be at increased risk of reactivation of Epstein-Barr virus (EBV) and the development of lymphoproliferative disorder. The association between MTX and reactivation of herpesviruses in pediatric patients is not yet understood. We prospectively monitored the viral load of EBV, cytomegalovirus (CMV), and herpesvirus 6 (HHV-6) in four JIA patients treated with MTX for 12-24 months. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, was added to the therapeutic regimen in three patients during the observation period. Prior to the administration of MTX, EBV and HHV-6 were detected by PCR in two patients. Significant increases in EBV and HHV-6 load were not observed following the administration of MTX or tocilizumab. In one patient, a relatively high EBV load remained detectable during 21 months of observation in the absence of clinical symptoms. CMV was not detected throughout the observation period in any patient. This is the first report monitoring the longitudinal DNA loads of EBV and other herpesviruses in JIA patients. EBV and HHV-6 were often detectable, but treatment with MTX and tocilizumab did not appear to influence the viral load.
Modern Rheumatology 11/2011; 22(4):565-70. · 1.58 Impact Factor
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Tomoyuki Imagawa,
Shumpei Yokota,
Masaaki Mori,
Takako Miyamae,
Syuji Takei,
Hiroyuki Imanaka,
Yasuhito Nerome, Naomi Iwata,
Takuji Murata,
Mari Miyoshi,
Norihiro Nishimoto,
Tadamitsu Kishimoto
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ABSTRACT: We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.
Modern Rheumatology 06/2011; 22(1):109-15. · 1.58 Impact Factor
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ABSTRACT: The therapeutic efficacy of corticosteroids and immunosuppressants on secretary glands of children with Sjögren syndrome was investigated examining the lip-biopsy specimen on both lymphocyte infiltration and fibrosis. Six children with primary Sjögren syndrome and two children with lupus-associated secondary Sjögren syndrome were evaluated according to the intensity of therapy. The shorter the term of medications of corticosteroids and immunosuppressants were, the lesser the extents of lymphocyte infiltration and fibrosis were, and the lower the doses of medications were, the lesser the efficacy was. Thus, in childhood Sjögren syndrome, appropriate corticosteroids and immunosuppressants may provide the suppressive effects on the progressive inflammatory destruction of secretary glands. Further evaluation with more patients is needed to determine the inclusion criteria of these treatments for sicca syndrome, especially in cases with no other organ involvement.
Japanese Journal of Clinical Immunology 07/2009; 32(3):195-200.
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ABSTRACT: Acute retinal necrosis (ARN), which is characterized by rapidly progressing peripheral retinal necrosis, is caused mainly by herpes simplex virus type 1, herpes simplex virus type 2 (HSV-2), or varicella-zoster virus. A previously healthy 3-year-old Japanese boy developed ARN in his left eye after being bruised by a milk container. HSV-2 DNA was detected in the aqueous humor of the affected eye. Serological testing suggested that the route of infection was from mother to child, although there was no past history of apparent HSV-2 infection. Childhood ARN has not been previously reported in Japan, possibly because of the low seroprevalence of HSV-2 in Japanese women. Pediatricians must be aware of this rare disease, which can affect individuals without a previous history of HSV even in a country with a low seroprevalence of HSV-2.
European Journal of Pediatrics 01/2009; 168(9):1125-8. · 1.88 Impact Factor
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ABSTRACT: Sjögren syndrome (SS) is a common autoimmune disease that exhibits broad organ-specific and systemic manifestations, the most prevalent being decreased lacrimal and salivary gland function, xerostomia, and keratoconjunctivitis sicca. Secondary SS occurs associated with autoimmune diseases, most commonly systemic lupus erythematosus (SLE). Thirty-four childhood-onset SLE patients (2 boys and 32 girls, mean onset age 11.5+/-2.6 years) were evaluated for the presence of secondary SS using the classification criteria for SS revised by Japanese Ministry of Welfare in 1999. Clinical manifestations, serological findings, and renal pathology in SLE patients complicated with SS (SLE+SS, n=14) were compared with those in SLE with no SS autoantibodies (Ro/SS-A or La/SS-B) (SLE-no SS antibodies, n=14). Of all 34 cases, 20 (58.8%) were with positive Ro/SS-A or La/SS-B antibody. Fourteen of the 20 (70.0%) were diagnosed as having secondary SS and all of them were subclinical SS with no sicca symptoms. However, findings of Schirmer test, salivary flow test and minor salivary gland biopsy were positive in 2 of 16 (13.3%), 5 of 16 (31.3%), and 14 of 17 (82.4%) patients, respectively. Compared with the SLE-no SS antibodies group, patients with SLE+SS showed higher level of serum IgG and had higher frequency of anti-U1 RNP antibody and significantly more severe renal involvement. The revised criteria is useful for diagnosis of SS in early stage before the development of exocrine gland damage and appears to be helpful for long term follow-up in childhood-onset SLE associated with SS.
Japanese Journal of Clinical Immunology 07/2008; 31(3):166-71.
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S Ishikawa,
T Mima,
C Aoki,
N Yoshio-Hoshino,
Y Adachi,
T Imagawa,
M Mori,
M Tomiita, N Iwata,
T Murata,
M Miyoshi,
S Takei,
Y Aihara,
S Yokota,
K Matsubara,
N Nishimoto
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ABSTRACT: 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.
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.
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)gamma 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.
Our findings suggest that sJIA is not only an immunological disease but also a metabolic disease involving mitochondria disorder.
Annals of the rheumatic diseases 05/2008; 68(2):264-72. · 8.11 Impact Factor
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Shumpei Yokota,
Tomoyuki Imagawa,
Masaaki Mori,
Takako Miyamae,
Yukoh Aihara,
Shuji Takei, Naomi Iwata,
Hiroaki Umebayashi,
Takuji Murata,
Mari Miyoshi,
Minako Tomiita,
Norihiro Nishimoto,
Tadamitsu Kishimoto
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ABSTRACT: 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.
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).
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.
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.
The Lancet 03/2008; 371(9617):998-1006. · 38.28 Impact Factor
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ABSTRACT: To investigate the safety and efficacy of a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL-6 in children with systemic-onset juvenile idiopathic arthritis (JIA) refractory to high-dose, long-term corticosteroids.
An individual escalating-dose trial was conducted in 11 children with active systemic-onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4-mg/kg dose. Those without disease flares at this dose received a second 4-mg/kg dose 2 weeks later and a third 4-mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.
MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute-phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.
MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute-phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL-6 and adverse events.
Arthritis & Rheumatism 04/2005; 52(3):818-25. · 7.87 Impact Factor
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ABSTRACT: Systemic-onset juvenile idiopathic arthritis (JIA) is a severe and steroid-dependent disease, which sometimes progresses to the fatal disease macrophage activation syndrome. An investigation of inflammatory cytokine levels revealed increases in IL-6 in serum of systemic-onset disease patients. Continuously elevated levels of IL-6 in serum may play a important role in manifesting the clinical symptoms and signs of systemic-onset JIA, including spiking fever, rash, arthritis, and serositis. The characteristic fever spikes parallel IL-6 levels. Long-term exposure to high levels of IL-6 in children results in severe growth impairment, which was strongly suggested by the recent establishment of IL-6 transgenic mice. To avoid disease progression to macrophage activation syndrome and the adverse effects of high-dose corticosteroids, it might be reasonable to inhibit the formation of IL-6/IL-6R complex in order to block the binding to gp130 receptor, a biologically active receptor for IL-6. This review will provide evidence of the relationship between IL-6 homeostasis and systemic-onset JIA, and our recent trials of anti-IL-6R antibody (MRA) for children with acute systemic disease intractable to long-term and high-dose corticosteroid therapy. MRA could be a therapeutic modality for children with systemic-onset JIA intractable to high-dose corticosteroids.
Modern Rheumatology 02/2004; 14(1):12-7. · 1.58 Impact Factor
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ABSTRACT: We encountered three patients with pediatric systemic sclerosis. Patient 1 had systemic scleroderma, pigmentation and interstitial pneumonia at the age of 10 years. Nine months after disease onset, she was treated with intravenous cyclophosphamide pulse therapy as induction therapy. After the initial treatment, the following clinical manifestations were dramatically improved: interstitial pneumonia, scleroderma and total skin score. Patient 2 was a 7-year-old girl, who complained of systemic scleroderma and pigmentation, and was found to have pulmonary hypertension. Six months after disease onset, she was administrated intravenous cyclophosphamide pulse therapy. Her scleroderma and total skin score were improved and the pulmonary hypertension did not deteriorate. Patient 3 was a 15-year-old girl. Her initial treatment was vitamin E alone. She was admitted to our hospital two and half years after disease onset. Although she was given immunosuppressive therapy including cyclophosphamide, the severe condition of persisted, and she died after five months. It became possible for patient 1 and 2 to achieve and maintain a marked improvement of the clinical manifestations as a result of cyclophosphamide pulse therapy early in the course of the disease. We further observed that their total skin score was decreasing while the clinical manifestations improved.
Ryūmachi. [Rheumatism] 11/2003; 43(4):660-6.
