Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a phase I study.

OBJECTIVE: The primary objective of this study was to evaluate the tolerability of single and multiple doses of abatacept in Japanese patients with rheumatoid arthritis. Secondary objectives included evaluating its pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. METHODS: This dose-escalation, single- and multiple-dose, multicenter, open-label study was conducted at nine sites in Japan. Seven patients were enrolled at each of three dose levels (2, 8 and 16 mg/kg) and received a single intravenous dose of abatacept on day 1 of the single-dose phase. The multiple-dose phase, at the same dose, started once the patients had completed the single-dose phase and when it was confirmed that there were no safety issues. RESULTS: Twenty patients started the single-dose phase. Single and multiple doses of abatacept were well tolerated, and adverse events were of mild to moderate intensity. There were no discontinuations or deaths due to adverse events. The pharmacokinetics of abatacept were linear, with no notable accumulation. There were no immunogenic effects on the safety, efficacy, or pharmacokinetics of abatacept. Multiple doses of abatacept improved individual items of the American College of Rheumatology core set. CONCLUSION: Single and multiple doses of abatacept showed favorable tolerability and efficacy in Japanese patients with rheumatoid arthritis.

Clinical features of 405 Japanese patients with systemic sclerosis.

We aimed to clarify the clinical features of Japanese patients with systemic sclerosis (SSc), especially with reference to organ involvement and autoantibodies. A cohort of 405 patients with SSc who attended our institution from 1973 to 2008 was identified retrospectively. Data on clinical features, including autoantibodies, organ involvement, and overlap of other connective tissue diseases, were obtained by following the medical records until 2009. The percentage of male patients during or after 1990 was greater than that before 1990 (3.9 vs. 10.6%, respectively). Limited cutaneous SSc (lSSc) was twice as frequent as diffuse cutaneous SSc (dSSc). About half of the patients had lung involvement (50.4%), while only 3.2% had scleroderma renal crisis. Male gender was associated with lung involvement, and dSSc was associated with most organ involvements except for pulmonary arterial hypertension (PAH). Anti-Scl-70 antibody was associated with lung or heart involvement, while anti-U1-RNP antibody was only associated with PAH. Conversely, patients with anti-centromere antibody had less organ involvement. SSc-Sjögren overlap syndrome was related to lSSc, further overlapping systemic lupus erythematosus (SLE), and less lung or heart involvement. In conclusion, these results not only confirmed previous reports but revealed several other findings, such as the increased proportion of male patients in recent years and the relationships between clinical features.

Association of an overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis with cytomegalovirus infection.

A 63-year-old woman, who presented with severe jaundice and elevated serum conjugated bilirubin level, denied alcohol and drug use and showed no evidence of viral hepatitis. Based on clinical and laboratory features, she was diagnosed with autoimmune hepatitis with primary biliary cirrhosis. Hematological and immunochemical assays, radiographic imaging, clinical examination, and liver biopsy were conducted. Laboratory results were the following: negative for fluorescence antinuclear antibody, negative for antismooth muscle antibodies but positive for antinuclear antibody (enzyme-linked immunosorbent assay) and antimitochondrial M2 antibody, high titers of serum globulin, and positive for cytomegalovirus IgM. Liver biopsy showed submassive lobular necrosis, inflammation with broad areas of parenchymal collapse, and chronic nonsuppurative destructive cholangitis. The patient responded well to corticosteroid therapy. This case might illustrate an association between cytomegalovirus infection and the occurrence of autoimmune hepatitis.

Acute intrahepatic cholestasis accompanied with Chlamydophila pneumoniae infection.

We report a case of Chlamydophila (C.) pneumoniae infection presenting with fever and rapid intrahepatic cholestasis. A 63-year-old man had a week-long history of intermittent high fever and rapidly progressive jaundice with atypical erythema. The results of liver function tests were recorded. The results of all serological tests were negative; the IgM, IgG, and IgA titers for C. pneumoniae had increased, which indicates a C. pneumoniae infection. The patient's fever and liver dysfunction improved upon administration of minocycline. Light microscopic findings showed the presence of enlarged liver cells with clear cytoplasm, a few mitotic figures, multinucleated cells, and bile cholestasis. The electron microscopic appearance of liver biopsy showed that bile canaliculi exhibited intrahepatic forms of cholestasis. From the results of light and electron microscopy, we inferred atypical intrahepatic cholestasis, probably resulting from the C. pneumoniae infection.

Clinical activity after 12 weeks of treatment with nonbiologics in early rheumatoid arthritis may predict articular destruction 2 years later.

OBJECTIVE: To investigate earlier prediction of future articular destruction in patients with early rheumatoid arthritis (RA). METHODS: We randomly allocated patients with RA with disease duration < 2 years to different nonbiologic disease modifying antirheumatic drug (DMARD) therapies in a double-blind trial. Progression of articular destruction over the 96-week treatment period was assessed using the modified Sharp method. RESULTS: Progression of articular destruction correlated more strongly with the American College of Rheumatology (ACR) core set measures after 12 weeks of treatment than with pretreatment values. Multiple regression analysis of data after 12 weeks yielded a correlation coefficient of 0.711. The sensitivity and specificity to predict articular destruction over the 75th percentile of the cohort were 78.6% and 84.6%, respectively. Patients who showed articular destruction over the 75th percentile of the cohort had low response to treatment at 12 weeks, and continued to have high clinical disease activity thereafter. Contrasting data were found in patients with slow progression of articular destruction. CONCLUSION: In patients with early RA, ACR core set measures after 12 weeks of nonbiologic DMARD treatment may predict articular destruction 2 years later. Low response to treatment at 12 weeks and continuing high disease activity thereafter were found in patients with rapid radiological progression. These data can be used to determine the appropriateness of treatment at 12 weeks and aid the decision to introduce biologic DMARD.

Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome concomitant with systemic sclerosis, immune thrombocytopenic purpura.

A 58-year-old Japanese woman presented with chronic fluctuating liver dysfunction with purpura. Raynaud's phenomenon had been diagnosed 4 years previously. At the initial examination, skin biopsy showed limited cutaneous systemic sclerosis (SSc). Laboratory investigations revealed liver dysfunction. Anti-nuclear antibodies, anti-mitochondria M2 antibody, anti-thyroglobulin antibody, and platelet-associated IgG were positive. Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) were diagnosed serologically, clinically and histologically. Immune thrombocytopenic purpura (ITP) was diagnosed by bone marrow puncture, clinical and laboratory findings, and Helicobacter pylori IgG was positive. She was treated with prednisolone 30 mg/day, ursodeoxycholic acid 600 mg/day, and a 7-day course of lansoprazole plus amoxicillin and clarithromycin. Thrombocytes increased rapidly and transaminase improved at day 7. We report a rare case of PBC-AIH overlap syndrome with concurrent ITP and SSc which suggest the presence of shared genetic susceptibility factors in multiple autoimmune conditions including PBC, AIH, ITP and SSc.

Effects of long-acting beraprost sodium (TRK-100STP) in Japanese patients with pulmonary arterial hypertension.

The long-acting beraprost preparation TRK-100STP is formulated to provide sustained release of an orally active prostacyclin derivative to maintain the optimal plasma concentration for a longer period of time compared with the currently used conventional beraprost sodium. In the present study, we evaluated the efficacy of this newly developed formulation for pulmonary arterial hypertension (PAH).An open-label, 12-week multicenter clinical trial was performed in 46 patients with PAH. They were initially treated with 120 microg of TRK-100STP divided into 60 microg twice daily, followed by a stepwise increase to 360 microg given as 180 microg twice daily. The 6-minute walking distance showed a significant increase by 33.4+/-66.0 m (95% confidence interval [CI], 13.4 to 53.5) from the baseline measurement. Mean pulmonary artery pressure, total pulmonary vascular resistance, and pulmonary vascular resistance decreased by -2.8+/-5.5 mmHg (95% CI, -4.6 to -1.0), by -0.92+/-2.63 mmHg*L(-1)*min (95% CI, -1.78 to -0.05), and by -0.89+/-2.81 mmHg*L(-1)*min (95% CI, -1.84 to 0.06), respectively, from the baseline measurements. A higher efficacy was observed in patients with a maximum tolerated dose of 360 microg daily than those of 240 microg daily or less.Treatment with TRK-100STP for a 12-week period improved the exercise capacity, mean pulmonary artery pressure, and total pulmonary vascular resistance. TRK-100STP was effective for Japanese patients with PAH.

Hepatic granulomas as primary presentation of Mycobacterium avium infection in an HIV-negative, nonimmunosuppressed patient.

Nontuberculous hepatic granuloma in patients not infected by human immunodeficiency virus (HIV) is rare. We report an 89-year-old woman who presented with hepatic granuloma without lung involvement. Ultrasonography and computed tomography (CT) of the abdomen showed low-density lesions in the liver. Histopathological examination of a liver biopsy revealed florid, caseating granulomatous reaction with aggregates of epithelioid histiocytes and Langerhans-type giant cells in a predominantly portal and periportal distribution. Gastric juice cultures were positive for Mycobacterium avium. The patient was treated with antimycobacterial therapy. Her clinical condition improved dramatically within 1 month of starting therapy, with marked reduction in hepatomegaly together with normalization of liver biochemistry and CT findings.

Autoimmune hepatitis associated with pulmonary arterial hypertension.

A 46-year-old woman presented with arthralgia. She had a history of fluctuating liver function impairment for 6 months. Laboratory investigations revealed elevated liver function test results, positive antinuclear antibodies and elevated serum IgG. The histological findings of a liver biopsy were interface hepatitis accompanied by plasmocytic infiltration with bridging fibrosis. There was no evidence of cirrhosis on pathological examination and no portal hypertension on endoscopic and radiographic studies. Autoimmune hepatitis was diagnosed, and treatment with prednisolone improved the liver dysfunction. After 6 months, she complained of dyspnea. Doppler echocardiography showed a dilated right ventricle, severe tricuspid insufficiency, and systolic pulmonary arterial pressure indicative of pulmonary arterial hypertension. We report this rare case of autoimmune hepatitis with pulmonary arterial hypertension.

A case of primary hepatic non-Hodgkin's lymphoma with chronic hepatitis C.

We report a case of primary hepatic non-Hodgkin's lymphoma in a 67-year-old man with chronic hepatitis C. Laboratory data revealed slightly elevated liver function parameters and positive for hepatitis C virus (HCV) antibody. Abdominal ultrasonography showed hypoechoic lesions approximately 5 mm in diameter in the whole liver. Magnetic resonance imaging showed that the tumors were isointense in relationship to the liver on T(1)-weighted images but were slightly hyperintense on T(2)-weighted images. Under a clinical diagnosis of liver tumor, liver biopsy was performed. Histological examination confirmed a diagnosis of non-Hodgkin's diffuse large B-cell lymphoma, and the immunophenotype was identified to be the germinal cell type.

Comparison of trimethoprim-sulfamethoxazole and aerosolized pentamidine for primary prophylaxis of Pneumocystis jiroveci pneumonia in immunocompromised patients with connective tissue disease.

To evaluate the efficacy of primary prophylaxis for Pneumocystis jiroveci pneumonia (PCP) in patients with connective tissue disease (CTD) and immunosuppression, we compared trimethoprim-sulfamethoxazole (TMP-SMZ) with aerosolized pentamidine. Forty-eight CTD patients of Kitasato University Hospital whose CD4+ lymphocyte count in the peripheral blood was less than 300 microl(-1) were reviewed from 2002 to 2004. Twenty-seven patients received TMP-SMZ and none of them developed PCP. Among 18 patients receiving aerosolized pentamidine, three patients developed PCP. These data indicate that TMP-SMZ is better for prophylaxis than aerosolized pentamidine.

Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial.

This multicenter clinical trial was performed to evaluate the efficacy and safety of mizoribine for the treatment of Sjögren's syndrome. Fifty-nine patients with a definite diagnosis of Sjögren's syndrome received 150;Smg of mizoribine daily for 16 weeks. The salivary secretion volume was determined at baseline, at weeks 8 and 16 after the start of the study treatment by the Saxon test, and clinical manifestations were assessed by the investigator and the patients using a 10-cm visual analog scale (VAS). Adverse drug reactions were reported in 18 patients, of whom 6 patients had to discontinue the study due to such adverse reactions; however, no serious adverse drug reactions definitely related to the study drug were noted. The salivary secretion volume, the rate of change in salivary secretion, the patients' own assessments of dry mouth and dry eyes, the investigators' assessment of oral sicca symptoms, and the investigators' overall assessment improved following the treatment regimen with statistical significance at week 16 after the start of treatment in comparison to the baseline values. These results suggested that mizoribine may be effective in producing a subjective and objective amelioration of the glandular symptoms in patients with Sjögren's syndrome, without observing any serious adverse effects related to this drug.

Laser-mediated microdissection for analysis of gene expression in synovial tissue.

In experimental rheumatology, transcriptomics is one of the most important methods for investigating the pathogenesis of diseases. The biological material of most studies on rheumatoid arthritis has been bulk rheumatoid synovial tissues, but they are not suitable because they consist of several kinds of cells or structures. Laser-mediated microdissection (LMM) is a useful tool for isolating particular cells from tissue specimen to assess the functions of each cell. The LMM system employs a combination of a microscope and a laser-beam generator to cut out target areas on cryosections. Tissue compartments or even a single viable cell can be isolated using a non-focused laser beam without direct contact to avoid contamination, and this process is called laser pressure catapulting. An ultraviolet-A laser enables target cells to be procured without any influence on the surrounding. This technique has already been used in several studies in rheumatology, and its validity has been confirmed. Combined with other new techniques such as real-time quantitative polymerase chain reaction or microarray analysis, LMM is becoming more important in the analysis of gene expression in rheumatology.

Coexistence of nodular regenerative hyperplasia of the liver and pulmonary arterial hypertension in patients with connective tissue diseases: report of three cases and review of the literature.

Nodular regenerative hyperplasia of the liver (NRH) is known to be a rare condition in patients with connective tissue diseases (CTD). In this report, we document three patients with CTD who had both NRH and pulmonary hypertension (PH). All three patients developed PH during their course and thereafter developed NRH. The clinical course of these patients suggests that circulatory disturbance caused by PH might be a trigger for NRH.

Comparison of tacrolimus and mizoribine in a randomized, double-blind controlled study in patients with rheumatoid arthritis.

OBJECTIVE: To compare the efficacy and safety of tacrolimus and mizoribine in patients with rheumatoid arthritis (RA). METHODS: Adult patients with RA with an insufficient response to at least one disease modifying antirheumatic drug (DMARD) were randomized to receive 28 weeks of double-blind treatment with tacrolimus 3 mg once daily or mizoribine 50 mg three times daily. The primary efficacy endpoint was the American College of Rheumatology 20% (ACR20) response. Safety was evaluated by adverse events. RESULTS: A total of 204 patients were enrolled for study (103 in the tacrolimus group, 101 in the mizoribine group). Significantly more patients receiving tacrolimus achieved an ACR20 response compared with mizoribine (48.5 vs 10.0%, respectively; p = 0.001). Tacrolimus was also superior to mizoribine in ACR50 and ACR70 response rate, tender and painful joint counts, swollen joint counts and patient and physician assessments of pain, disease activity, and patient's physical function assessment based on the Modified Health Assessment Questionnaire (p < 0.001). Adverse events were more frequent in the tacrolimus group than the mizoribine group (65.0 vs 59.4%); however, there were no statistically significant differences between treatment groups. CONCLUSION: Tacrolimus improves RA symptoms to a significantly greater extent than mizoribine in patients with RA inadequately controlled with at least one prior DMARD. Tacrolimus has the potential to be a useful and highly effective treatment for RA.

NOS2 polymorphisms associated with the susceptibility to pulmonary arterial hypertension with systemic sclerosis: contribution to the transcriptional activity.

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis. One of several complications of SSc, pulmonary arterial hypertension (PAH) can be refractory to treatment, both novel and established. In the present study we investigated the ratio of circulating nitric oxide to endothelin-1 in patients with both SSc and PAH, and determined whether polymorphisms in NOS2 (the nitric oxide synthase 2 gene) are associated with susceptibility to PAH. Endothelin-1 in plasma and nitric oxide metabolites (nitrate and nitrite) in serum were measured. The nitric oxide/endothelin-1 ratio was significantly lower in patients with both SSc and PAH than in patients with SSc only or in healthy control individuals. We confirmed the presence of two single nucleotide polymorphisms at positions -1,026 and -277 and a pentanucleotide repeat (CCTTT) at -2.5 kilobases. There were significant differences in single nucleotide polymorphisms between patients with SSc who had PAH and those who did not, and between patients with both SSc and PAH and healthy control individuals. The CCTTT repeat was significantly shorter in patients with both SSc and PAH than in patients with SSc only or in healthy control individuals. Transcriptional activity were analyzed using the luciferase reporter assay. The transcriptional activity of NOS2 was much greater in fibroblasts transfected by a vector with a long allele of the CCTTT repeat than in those transfected by a vector with a short allele. Polymorphisms in the NOS2 gene are associated with transcriptional activity of the NOS2 gene and with susceptibility to SSc-related PAH.

Recurrent paralytic ileus associated with strongyloidiasis in a patient with systemic lupus erythematosus.

We present an interesting case of recurrent paralytic ileus due to strongyloidiasis in a woman who was being treated with corticosteroids and immunosuppressants for systemic lupus erythematosus (SLE). She was also a carrier of human T-cell leukemia virus type I. She had a history of strongyloidiasis 8 years earlier. Recurrent episodes of paralytic ileus due to strongyloidiasis occurred during treatment of her SLE with corticosteroids. Ivermectin was given and improved the symptoms. This case shows that symptomatic strongyloidiasis can be induced in immunocompromised hosts by immunosuppressive therapy. It is important to rule out strongyloidiasis prior to starting immunosuppressive therapy in patients from endemic areas.

Induction of triggering receptor expressed on myeloid cells 1 in murine resident peritoneal macrophages by monosodium urate monohydrate crystals.

OBJECTIVE: Triggering receptor expressed on myeloid cells 1 (TREM-1) is a cell surface molecule that was recently identified on monocytes and neutrophils. TREM-1 has been implicated in the early inflammatory responses induced by microbes, but its pathophysiologic role in nonmicrobial inflammation remains unknown. In the present study, we investigated the role of TREM-1 in acute inflammation induced by monosodium urate monohydrate (MSU) crystals. Induction of TREM-1 expression by MSU crystal-stimulated murine resident peritoneal macrophages and infiltrating leukocytes in a murine air-pouch model of crystal-induced acute inflammation was determined. The biologic role of TREM-1 in crystal-induced cytokine production by resident peritoneal macrophages was also investigated. METHODS: TREM-1 expression by resident peritoneal macrophages and infiltrating leukocytes in a murine air-pouch model was determined by quantitative real-time polymerase chain reaction, Western blot analysis, and flow cytometry. Cytokine production by resident peritoneal macrophages after incubation with MSU crystals in the presence or absence of an anti-TREM-1 agonist antibody was determined by enzyme-linked immunosorbent assay. RESULTS: TREM-1 expression by resident peritoneal macrophages was significantly induced after stimulation with the crystals. Maximum expression of TREM-1 transcripts and protein occurred at 1 and 4 hours after exposure to the crystals, respectively. Costimulation of resident peritoneal macrophages with MSU crystals and an anti-TREM-1 agonist antibody synergistically increased the production of both interleukin-1beta and monocyte chemotactic protein 1 compared with stimulation with the crystals alone. MSU crystals also induced TREM-1 expression in infiltrating leukocytes in a murine air-pouch model of crystal-induced acute inflammation. CONCLUSION: These findings suggest that rapid induction of TREM-1 expression on resident peritoneal macrophages and neutrophils by MSU crystals may contribute to the development of acute gout through enhancement of inflammatory responses.

[Combined effect of micafangin and itraconazole on severe aspergillosis of the bilateral pleural cavities in a patient with Wegener's granulomatosis].

Visceral fungal infections are difficult to manage in patients with collagen diseases and immunocompromised hosts. In particular aspergillosis can be a life-threatening complication in these patients. Here we report that combined use of two antifungal agents (micafangin and itraconazole) was effective against severe aspergillosis of the bilateral pleural cavities in a 48-year old male patient diagnosed with Wegener's granulomatosis. Immunosuppressive therapy with corticosteroids and cyclophosphamides improved his nasal and pulmonary symptoms, but inflammation of the bilateral pleural cavities caused bronchial fistulas. Aspergillus fumigatus then infected the bilateral pulmonary cavities through these fistulas. This patient was treated with combined therapy of ITCZ and MCFG was given to this patient because of the risk of renal dysfunction associated with AMPH-B. After 5 weeks of treatment his clinical findings had improved and the fungus was suppressed.