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.

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.

Inhibition of skin sclerosis by 15deoxy delta12,14-prostaglandin J2 and retrovirally transfected prostaglandin D synthase in a mouse model of bleomycin-induced scleroderma.

Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme involved in production of the PGD and J series, which have various role in inflammation and immunity. We evaluated the effect of treatment with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or the injection of prostaglandin D(2) synthase (PGDS) cDNA expressing-retrovirally transfected fibroblasts on bleomycin (BLM)-induced scleroderma-like skin sclerosis. Daily injection of BLM (30 microg) for 4 weeks induced histological evidence of dermal sclerosis in C3H mice. We examined the effect of injection of 15d-PGJ(2) (30 ng twice a day) or PGDS expressing-retrovirally transfected fibroblast on BLM-induced dermal sclerosis. Administration of 15d-PGJ(2) (a nonenzymatic metabolite of PGD(2)) injection of PGDS cDNA-expressing fibroblasts significantly reduced dermal sclerosis, the hydroxyproline content, and dermal thickness. Moreover, 15-d PGJ2 down-regulation of the expression of transforming growth factor beta(1) and connective tissue growth factor which had been induced by BLM. Mast cells were also increased in the skin by BLM injection and there was prominent degranulation of these mast cells along with elevated plasma histamine levels. 15-d PGJ(2) and PGDS-expressing cells also suppressed degranulation of cultured mast cells and histamine release by these cells. These results show that 15-d PGJ(2) and PGDS-expressing cells can prevent experimental skin sclerosis induced by BLM and raise the possibility of therapeutic approaches targeting of PPARgamma for the skin lesion of scleroderma.

[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.

Down-regulation of lipoxin A4 receptor by thromboxane A2 signaling in RAW246.7 cells in vitro and bleomycin-induced lung fibrosis in vivo.

Lipoxins (LXs) are members of eicosanoid family that can be endogenously produced during cell-to-cell interactions such as platelet-leukocyte interactions. Anti-inflammatory function of lipoxin A4 (LXA4) as "braking signals" is mediated by the receptor. On the other hand, thromboxane A2 (TXA2) produced by catalysis of cyclooxygenase and thromboxane synthetase is released during platelet aggregation as a vasoconstrictor and a pro-inflammatory factor. To investigate interaction of TXA2 receptor (TP) and LXA4 receptor, effects of a TP agonist and a thromboxane synthetase inhibitor on expression of LXA4 receptor were examined in vitro and in vivo. A TP agonist, U46619 showed a down-regulation of LXA4 receptor induced by interleukin-1beta (IL-1beta) in RAW246.7 cells. In bleomycin-induced lung fibrosis in mice, administration of a thromboxane synthetase inhibitor DP-1904 increased LXA4 receptor mRNA and decreased type I collagen mRNA. In vitro experiments indicate that LXA4 significantly prevented enhanced proliferation of NIH3T3 fibroblasts and the collagen expression by transforming growth factor-beta (TGF-beta). These results suggest that TXA2-TP signaling could cause negative regulation of lipoxin A4 receptor under the transcriptional level during inflammatory process mediated by IL-1beta and TGF-beta induce the expression of LXA4 receptor. Furthermore, the down-regulation of LXA4 receptor by TXA2 implies a possibility that a cellular signaling by TXA2 may have a novel and potential function as a pro-inflammatory factor to inhibit anti-inflammatory effect of LXA4. Concomitantly, selective blockade of TXA2-TP signaling could be suggested to lead to anti-inflammation through active role of LXA4.

Prolongation of functional life-span of neutrophils by recombinant verotoxin 2.

OBJECTIVE: Verotoxin-producing Escherichia coli (VTEC) strains of serotype O157 : H7 have been implicated in a wide spectrum of diseases, including blood diarrhea, hemorrhagic colitis and hemolytic uremic syndrome (HUS). To further explore the pathological role of verotoxin (VT) in HUS and other VTEC associated diseases, we investigated the effects of recombinant verotoxin 2 (rVT2) on the biological activity of neutrophils. METHODS: The technique of flow cytometry, a fluorescent probe 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester (BCECF/AM), and the assay of reduced cytochrome c to detect superoxide production were used in this study. RESULTS: gammaVT2 significantly inhibited spontaneous apoptosis in neutrophils. Neutrophils with prolonged survival due to gammaVT2 maintained various biological functions, such as the expression of adhesion molecules (shading CD62L and raising CD11b/CD18), adherence to human umbilical vein endothelial cells (HUVECs), and generation of superoxide (O(2)(-)). CONCLUSION: Prolongation of the functional life-span of neutrophils by gammaVT2 may accelerate inflammatory responses at sites of inflammation. This may play a crucial role in neutrophil-mediated tissue injury in HUS and other VTEC-associated diseases.

[Legionella pneumonia which occurred in a private whirlpool bath user].

A 88 year old female with active rheumatoid arthritis treated by low dose of prednisolone and methotrexate was admitted to our hospital because of severe bilateral pulmonary infiltration and acute respiratory distress syndrome. On admission, she had consciousness disturbance and was intubated because of severe respiratory failure. We heard from her family of her habit she had taking a private whirlpool bath 2 or 3 times everyday. So, we suspected a Legionella pneumophila infection. We started intravenous erythromycin (EM) (1,500mg/day) and methylprednisolone pulse therapy (1,000mg x 3days) and full controlled mechanical ventilation supported with PEEP. Her respiratory failure was gradually improved and she was discharged on the 44 the hospital day. Legionella pneumophila (serogroup 6) was isolated in her sputum by B-CYE alpha culture. Legionella pneumophila (serogroup 6) was isolated in her private whirlpool bath too. Both samples revealed the same by genetic analysis with pulse field gel electrophoresis (PFGE). This is the first adult case of Legionella pneumophila pneumonia infected from a private whirlpool bath confirmed by genetic analysis. We should always suspect Legionella pneumonia as one of the severe community-acquired pneumonia, because Legionella pneumophila were frequently detected among various water sources including the private whirlpool bath.

[Early diagnosis and treatment of the bone and cartilage lesions in rheumatoid arthritis].

Rheumatoid arthritis (RA) is chronic destructive synovitis affecting the bone and joints. The early suppression of disease activity during the first several months in RA has been reported to be exclusively important to prevent joint destruction and functional decline. Effective treatment of active RA requires early diagnosis. Diagnostic criteria for early RA was proposed in Japan, and this criteria has still problems for accurate diagnosis. Some new diagnositic methods have been developed such as MRI evaluation of joints and nti-CCP antibodies.

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.

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.