Etanercept in the treatment of disease-modifying anti-rheumatic drug (DMARD)-refractory polyarticular course juvenile idiopathic arthritis: experience from Japanese clinical trials.

Efficacy, safety, and pharmacokinetics results from 4 studies-3 open-label (OL) and 1 randomized double-blind (DB)-have provided data for approval of etanercept for treatment of disease-modifying anti-rheumatic drug (DMARD)-refractory juvenile idiopathic arthritis (JIA) in Japan. Results from the 3 shorter-term (2 OL and 1 DB) studies are reported here. Subjects (4-17 years) enrolled in the OL studies had active JIA, i.e. ≥5 swollen joints and ≥3 joints with limitation of motion and pain or tenderness. Subjects enrolled in the primary OL study received etanercept 0.4 mg/kg subcutaneously twice weekly; in the lower-dose OL study subjects received etanercept 0.2 mg/kg. Subjects in the primary OL study who completed ≥48 weeks could continue into a 12-week DB dose-down extension study in which subjects received etanercept 0.4 or 0.2 mg/kg twice weekly. The primary endpoint in all 3 studies, i.e. 30% improvement in the American College of Rheumatology criteria for JIA (ACR Pedi 30) at 12 weeks, was achieved by ≥80% of subjects by week 2 and sustained to week 12. Common adverse events reported were injection site reactions, nasopharyngitis, and gastroenteritis. These results provide further evidence that etanercept is effective therapy for DMARD-refractory polyarticular JIA patients.

[A case of aortitis syndrome diagnosed with 18F-fluorodeoxyglucose-positron tomography (18F-FDG-PET) in the early pre-pulseless phase].

A 14-year-old girl with aortitis syndrome in the early pre-pulseless phase was admitted to our hospital because of slight fever, neck bruit, asymmetrical blood pressure, stenosis or dilatation of the main branch arteries in aorta on chest computed tomography. Laboratory examination revealed a high level of C-reactive protein and an elevated erythrocyte sedimentation rate, as well as hypergammaglobulinemia, and 18F-FDG-PET revealed an accumulation of 18 fluorodeoxyglucose in the great vessels. She was first given pulse therapy with a combination of methylprednisolone and intravenous cyclophosphamide, and then maintenance therapy with oral prednisolone and azathioprine. All the abnormal laboratory parameters improved to normal levels within a month. We suggest that early diagnosis of aortitis syndrome may permit early treatment in the early pre-pulseless phase and could possibly prevent progression to the occlusive phase.

[A case report of childhood systemic lupus erythematosus complicated with lupus cystitis].

The patient was a 13-year-old girl. In August 2000, she presented with a fever, together with diarrhea, vomiting, arthralgia, nasal bleeding and malaise, and was examined by another physician. Because her platelet count was low, and there were positive reactions for anti-nuclear antibodies, anti-DNA antibodies and platelet-associated IgG, idiopathic thrombopenic purpura, and systemic lupus erythematosus (SLE) was suspected. From January 2001, when she caught measles, she reported abdominal pain, and urinalysis indicated urinary protein and occult blood, and the left kidney was found hydronephrotic. At the same time left ureter stenosis and dilatation were demonstrated. Symptoms were disappeared by hydration and treatment with NSAIDs, but 2 months later fever and erythematous patches seen on both cheeks led to the proper diagnosis of SLE, and she was admitted to our hospital. Intravenous pyelography revealed hydronephrosis on left kidney, constriction and dilatation of the left ureter, and intracystic endoscopy showed erythema at the orifice of the left ureter. The pathological examination indicated the presence of vasculitis, and finally lupus cystitis was diagnosed. Intravenous cyclophosphamide (IVCY)-pulse therapy was introduced to a total of 8 times over the period of a year, and maintenance therapy with predonisolone and azathioprin was also used. After completion of the IVCY-pulse therapy, the hydronephrosis and constriction of the ureter were disappeared. No side effects of IVCY-pulses were observed, and the patient is now in remission. We reported a case of childhood SLE complicated with lupus cystitis and successfully treated by IVCY-pulse therapy and maintenance predonisolone and azathioprin.

[A case of systemic scleroderma complicating pulmonary hypertension].

The patient was a 7-year-old girl. At the age of 6, deposits of pigment had appeared on the skin of her face and limbs, the skin had become sclerosed, and she had developed dyspnea on exertion. Her previous physician had hospitalized her. She was diagnosed as systemic scleroderma that accompanied pulmonary hypertension by her symptoms and laboratory findings. She was referred to our hospital at 7 years of age, and she was hospitalized. At that time, the entire skin showed deposition of brown pigment, the skin of the limbs was sclerotic. And the face was mask-like, flexion of the joints of the fingers and knees was limited, and the fingertips were ulcerated. Raynaud's phenomenon was present. She was positive for antinuclear antibodies, and negative for other autoantibodies. Echocardiography revealed pulmonary hypertension. After admission, steroid pulse therapy and cyclophosphamide (CY) pulse therapy were initiated, and for aftercare, 15 mg/day of prednisolone (PSL) and mizolibin (MZB) were administered orally. After several months, the sclerosis of the skin improved and the restriction of limb flexion was almost eliminated. The pulmonary hypertension advanced temporarily (maximum: 70 mmHg), but after oral administration of a PGI2 preparation and low-flow supplemental oxygen therapy and the initiation of anticoagulant therapy, the systolic pressure of the pulmonary artery improved to 34 mmHg. The CY pulse therapy was terminated after two years, and internal use of PSL and MZB was continued. The patient's condition is now stable. This case was treated from an early stage with steroid pulse therapy and CY pulse therapy, accompanied with oral administration of a PGI2 preparation for the pulmonary hypertension. The dermal symptoms improved, and it was possible to maintain a state of remission.

[Three cases of childhood-onset male systemic lupus erythematosus (SLE) successfully treated with a combination of pulse methylprednisolone and pulse cyclophosphamide].

We reported three cases of childhood-onset male systemic lupus erythematosus (SLE), all of whom successfully treated with a combination of pulse methylprednisolone (mPSL) and pulse cyclophosphamide (IVCY). All of them had severe lupus nephritis and were complicated with other collagen diseases. Two cases were complicated with Sjögren syndrome (SS) and the other was complicated with both SS and anti-phospholipid syndrome (APS). After a combination of pulse mPSL and IVCY for a year, followed by oral predonisolone (PSL) and azathioprine (AZA), following up renal biopsy were performed in all cases, which showed histological improvement in glomerulonephritis. One case had flares a year later, but no flares were observed either in clinical symptoms or in laboratory examinations in the others. Their autoantibodies except anti-nuclear antibody (ANA) were eliminated. We suggest a combination of pulse mPSL and IVCY is effective for the patients who are suffering with severe lupus nephritis complicated with the other collagen diseases.

Clinical study of tocilizumab in children with systemic-onset juvenile idiopathic arthritis.

Systemic-onset juvenile idiopathic arthritis (sJIA) is a severe and steroid-dependent disease of unknown etiology that sometimes progresses to a fatal disease known as the macrophage activation syndrome. The investigation of inflammatory cytokines and receptor levels revealed an increase in interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) in serum of patients with active sJIA. The clinical symptoms and signs of the disease are presumably attributable to the continuous elevation of IL-6 and sIL-6R levels in serum. The characteristic fever spikes parallel IL-6 levels. In children, a long-term exposure to high levels of IL-6 causes severe growth impairment, as suggested by recently established studies of IL-6 transgenic mice. The biological functions of IL-6 are expressed through the binding of IL-6/IL-6R complex to gp130. The administration of tocilizumab (a recombinant humanized anti-IL-6R monoclonal antibody) exerts its action by preventing the binding of IL-6 to its receptor and, therefore, preventing the activation of gp130. After a few cases of compassionate use of tocilizumab, phase I and II studies of tocilizumab were conducted in children with sJIA, revealing that tocilizumab abruptly reduced the typical symptoms of inflammation and improved laboratory abnormalities. This article describes the experience in Japan regarding the treatment of sJIA with tocilizumab and supports the hypothesis that high levels of IL-6 may play an important role in the pathogenesis and maintenance of this disease. A confirmation of the role of tocilizumab in the treatment of sJIA will be provided by the results of the ongoing phase III study in Japan.

[A case of autoimmune hepatitis needed to be differentiated from EBV hepatitis, in that the histology of liver biopsy specimen was useful for diagnosis].

A 10-year-old girl with autoimmune hepatitis (AIH) was reported. She was admitted to our hospital because of cholestasis and elevation of liver enzymes for 2 months. Laboratory examination revealed that EBV-DNA copy number in the PBMNC (peripheral mononuclear cells) was 1.2 x 10(3) copies/microg of DNA, hypergammaglobulinemia, and positive antinuclear antibody, positive anti-smooth muscle antibody. The histology of her liver biopsy specimen revealed interface hepatitis, dense mononuclear cell infiltrates, mild fibrosis, and negative for EBV in situ hybridization assay indicating AIH and not EBV-associated hepatitis. She was treated firstly with methylprednisolone pulses, then will prednisolone p.o.+azathioprine p.o.. Intravenous cyclophosphamide pulse therapy was introduced because of her abnormal immune pathology. All abnormal laboratory parameters improved to normal levels within 2 months, and EBV-DNA copy number in the PBMNC became negative after 4 months. The histology of liver biopsy specimen was useful for the diagnosis of AIH in such a difficult case needed to be differentiated from EBV hepatitis.

Pharmacokinetics, efficacy, and safety of short-term (12 weeks) etanercept for methotrexate-refractory polyarticular juvenile idiopathic arthritis in Japan.

We examined and evaluated the pharmacokinetics, efficacy, and safety of etanercept in patients with methotrexate (MTX)-refractory polyarticular juvenile idiopathic arthritis (JIA) in Japan. All MTX-refractory polyarticular JIA patients 4-17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to 3 months in the open-label, prospective, and multicenter trial. A response was defined as an improvement of 30%, 50%, 70%, or more from baseline in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30% from baseline (30%, 50%, or 70% definition of improvement, respectively), and disease activity score (DAS28) by EULAR (European League Against Rheumatism) response criteria. At the end of the 12-week study, 20 of the 22 patients (90.9%) had responses with both 30% and 50% definition of improvement after etanercept treatment. To our surprise, 15 of 22 patients (68.2%) had a response with 70% definition of improvement. Moreover, in DAS28, eight patients were evaluated as having a good response and there were no patients with a poor response to etanercept. Treatment had to be stopped in one patient who developed joint contracture during the study period, but there were no significant adverse events in the other patients. In conclusion, treatment with etanercept leads to significant improvement in patients with active polyarticular JIA in Japan. Etanercept is well tolerated by pediatric patients as well as adults.

[Usefulness of interferon-gamma-based diagnosis of Mycobacterium tuberculosis infection in childhood tuberculosis].

We studied the usefulness of interferon-gamma measurement reagent QuantiFERON-TB 2 G (QFT-2G), used to diagnose tubercle bacilli infections, as an indicator both for diagnosing primary tuberculosis (PTB) and for assessing therapeutic amorg pediatric Tuberculosis Outpatent cases effectiveness. Five cases showing typical PTB findings, such as cavitation, swollen lymph nodes, and nodular shadows at the pulmonary hilum, and diagnosed as tubercle bacillus infections, all showed positive reactions to QFT-2G, and in 3 asymptomatic cases without abnormalities detected in diagnostic imaging but QFT-2G-positive, one developed tuberculosis (TB) later. Among 12 patients who gave negative reactions to QFT-2G at their first visit and during observation from 6 months to 1 year, no TB occurrences was seen. Patients who were vaccinated for BCG and were tuberculin-positive showed negative reactions to QFT-2G, confirming that QFT-2G is not affected by BCG. One case of nontuberculous acid-fast bacilli in which Mycobacterium avium was detected was QFT-2G-negative. In 1 case, QFT-2G decreased as the patient's conditiorl improved. Without being influenced by BCG vaccination, QFT-2G demonstrated its usefulness in primary TB cases both for diagnosis and for assessing treatment effectiveness. Our results strougly suggested that QFT-2G is a potentially powerful tool with wide applications in diagnosis and assessment of treatment effectiveness in primary TB, even when bacterial elimination is low and diagnosis is difficult.

An infant with γ-globulin-induced hypersensitivity syndrome who developed Evans' syndrome after a second γ-globulin treatment.

Abstract One month after treatment with γ-globulin for Kawasaki disease, an 18-month-old girl developed Evans' syndrome in addition to drug-induced hypersensitivity syndrome (DIHS) after a second γ-globulin treatment. She suffered from hyperbilirubinemia, hemolytic anemia, and thrombocytopenia. The findings and her clinical course involved plasma exchange and treatment with prednisolone, with good results. Peripheral lymphocyte stimulation tests indicated that γ-globulin was the likeliest cause of the DIHS. A real-time polymerase chain reaction test showed the human herpes virus (HHV)-6 genome in peripheral blood. We demonstrated that a primary infection or infection reactivation by the HHV-6 virus was involved in the development of γ-globulin-induced hypersensitivity and Evans' syndrome.

[Effects of therapies on childhood systemic lupus erythematosus].

We analyzed the effects of three therapies on 30 patients with childhood systemic lupus erythematosus, and classified the patients into three groups. The therapies were as follows; Group A (8 cases), methylpredni-solone (mPSL) pulses plus oral prednisolone (PSL) alone, Group B (10 cases), mPSL pulses plus oral PSL and mizoribine (MZB) or azathioprine (AZP), Group C (12 cases), mPSL pulses and intravenous cyclophosphamide (IVCY) pulse therapy plus oral PSL and MZB or AZP. Three years after treatment, we compared the laboratory data (C3, C4, CH50 and anti-DNA antibody), the SLEDAI scores and numbers of relapses in these three groups. We demonstrated that group C had the best data, and this data indicated that the median C3, C4 and CH50 increased and that the median anti-DNA antibody and the mean of the numbers of relapses decreased. In conclusion, the combination of immunosuppressants and IVCY appeared to offer great benefits in childhood systemic lupus erythematosus.

[Human parvovirus B19 infection which first presented with petechial hemorrhage, followed by papular-purpuric gloves and socks syndrome and erythema infectiosum].

A case of human parvovirus B19 (B19) infection is reported. A 6-year-old previously healthy girl was admitted to our hospital complaining of slight fever and petechial hemorrhage on her neck, trunk and the proximal parts of extremities. On admission, the platelet count was within normal range (180 x 10(3)/microliter) but white blood cells and reticulocytes were moderately suppressed (2.4 x 10(3)/microliter and 1@1000, respectively). The purpura disappeared in a week and the blood cell counts fully recovered without any specific treatment. Detection of B19 DNA and anti-B19 IgM antibody in the serum on admission led to the final diagnosis. Since the cellular receptor for B19, the blood group P antigen, is expressed on vascular endothelial cells as well as erythroid progenitor cells, the purpura was considered to be the result of direct vascular injury. She was very unique as she subsequently exhibited papular-purpuric gloves and socks syndrome and erythema infectiosum during follow-up. This case may provide a new insight into the pathogenesis of cutaneous manifestations of B19 infection.