Naoto Tamura

The soluble CD40 ligand sCD154 in systemic lupus erythematosus

We found that the plasma of patients with active systemic lupus erythematosus (SLE) could induce a human B-cell line (Ramos) to express high levels of immune accessory molecules that are commonly found on blood B cells of patients with active SLE. The ability of SLE plasma to induce such phenotypic changes could be abrogated by neutralizing antibodies specific for the CD40 ligand (CD154) but not by antibodies to TNF-alpha. Immunoprecipitation studies with anti-CD154 identified a 20-kDa protein in the plasma of SLE patients with active disease, but not in plasma of normal donors, indicating that such plasma contained soluble CD154 (sCD154). Using a quantitative ELISA method, we found that the plasma of patients with active disease had levels of sCD154 that were significantly higher than those found in plasma of normal donors. Levels of CD154 transcripts in SLE blood lymphocytes correlated with the relative concentrations of sCD154 found in SLE plasma. Furthermore, plasma levels of sCD154 correlated with the titers of anti-double-stranded DNA autoantibody and with clinical disease activity. These studies indicate that sCD154 of patients with SLE may act as a functional ligand for CD40 that is associated with SLE disease activity.

Incidence and Risk Factors for Serious Infection in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors: A Report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety

Objective. To compare tumor necrosis factor-α (TNF-α) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA). Methods. Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.4 patient-years (PY)]. The remaining 498 patients received nonbiological DMARD with no biologics (unexposed group: 454.7 PY). Results. In the unexposed group, the incidence rate for all serious adverse events (SAE) was 9.02/100 PY and for serious infections, 2.64/100 PY. In the exposed group, SAE occurred in 16.04/100 PY and serious infections in 6.42/100 PY. The crude incidence rate ratio comparing serious infections in the exposed group with the unexposed group was 2.43 (95% CI 1.27–4.65), a significant increase. A multivariate analysis revealed that the use of TNF inhibitors is a significant independent risk factor for serious infection (relative risk 2.37, 95% CI 1.11–5.05, p = 0.026). Conclusion. Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD.

Expression of arthritis-causing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium.

HLA-B27 confers a very strong genetic predisposition to development of a reactive arthritis after infection by bacteria such as Salmonella typhimurium. This study examines the role of HLA-B27 in the initiation of the earliest host activities after exposure to Salmonella, namely activation of the immediate early genes in the epithelial cells. Our major finding is that in Hela cells, the expression of c-fos was induced by Salmonella invasion only when the cells expressed the transfected HLA-B27 gene, but not the HLA-A1 gene or a truncated HLA-B27 gene lacking the exons encoding the cytoplasmic domain. C-fos is potentially capable of complexing with members of the c-jun family to become the AP-1 transcription complex. Parallel to c-fos expression, we found that only with the HLA-B27 transfectant was there expression of AP-1. AP-1 potentially controls the expression of a large number of genes. On screening a panel of proinflammatory molecules, we found that Salmonella invasion induced expression of monocyte chemoattractant protein-1 in the HLA-B27 cells. Since each of these separate positive findings belong to the same cascade of events after cell activation, together they reinforce the hypothesis that HLA-B27 plays a modulatory role in the early signal transduction events induced by Salmonella invasion. This hypothesis adds another item to the list of allele-specific activities carried out by HLA class I molecules. If similar activation also occurs in the joints, it may play a major role in arthritis.

Time‐dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis

To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long‐Term Safety (REAL) database.

Immunoadsorbent plasmapheresis for a patient with antiphospholipid syndrome during pregnancy.

The case of a 34 year old woman with systemic lupus erythematosus with a history of three previous recurrent abortions and lupus anticoagulant and anticardiolipin antibodies is reported. Immunoadsorbent plasmapheresis with a dextran sulphate column was used to remove lupus anticoagulant, anticardiolipin antibodies, and antibodies to DNA during her fourth pregnancy in combination with low doses of aspirin and prednisolone. Although during the course of treatment prednisolone was transiently increased to 30 mg/day owing to an asymptomatic increase of lupus anticoagulant and anticardiolipin antibodies, the levels of lupus anticoagulant, anticardiolipin antibodies, and antibodies to DNA were decreased by immunoadsorbent plasmapheresis and a baby girl was delivered successfully by caesarean section. Therefore, immunoadsorbent plasmapheresis with dextran sulphate seems to reduce the risk of recurrent abortion in patients with the antiphospholipid syndrome.

Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules

Objective To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). Method This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan–Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. Results The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. Conclusions Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.

Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice

IntroductionTargeting joint destruction induced by osteoclasts (OCs) is critical for management of patients with rheumatoid arthritis (RA). Since phosphoinositide 3-kinase (PI3-K) plays a critical role in osteoclastogenesis and bone resorption, we examined the effects of ZSTK474, a novel phosphoinositide 3-kinase (PI3-K)-specific inhibitor, on murine OCs in vitro and in vivo.MethodsThe inhibitory effect of ZSTK474 on OC formation was determined and compared with other PI3-K inhibitors by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells after culturing murine bone marrow monocytic OC precursors, and RAW264.7 cells. Activation of Akt and expression of nuclear factor of activated T cells (NFAT) c1 in cultured RAW264.7 cells were examined. The suppressing effect of ZSTK474 on bone resorption was assessed by the pit formation assay. The in vivo effects of ZSTK474 were studied in collagen-induced arthritis (CIA) in the mouse. Oral daily administration of ZSTK474 was started either when more than half or when all mice developed arthritis. Effects of ZSTK474 were evaluated using the arthritis score and histological score of the hind paws.ResultsZSTK474 inhibited the differentiation of bone marrow OC precursors and RAW264.7 cells in a dose-dependent manner. The inhibitory effect of ZSTK474 was much stronger than that of LY294002, the most commonly used PI3-K inhibitor. In addition, ZSTK474 suppressed the bone resorbing activity of mature OCs. Moreover, oral daily administration of ZSTK474, even when begun after the development of arthritis, ameliorated CIA in mice without apparent toxicity. Histological examination of the hind paw demonstrated noticeable reduction of inflammation and of cartilage destruction in ZSTK474-treated mice. ZSTK474 also significantly decreased OC formation adjacent to the tarsal bone of the hind paw.ConclusionsThese findings suggest that inhibition of PI3-K with ZSTK474 may potentially suppress synovial inflammation and bone destruction in patients with RA.

Hypocomplementemic urticarial vasculitis with Jaccoud’s arthropathy and valvular heart disease: case report and review of the literature

We describe a female Japanese patient with concomitant hypocomplementemic urticarial vasculitis, Jaccoud’s arthropathy and valvular heart disease. In 1996, she developed arthritis with swelling of both proximal interphalangeal joints and urticarial vasculitis on both arms that was resolved by administration of glucocorticoid (prednisolone 30 mg/day). Tests for antineutrophil cytoplasmic antibodies, antinuclear antibody and rheumatoid factor gave negative results. The findings of a skin biopsy examination were consistent with ‘leukocytoclastic vasculitis’. During 10 years of observation, the patient manifested polyarthritis leading to progressive deformity of the joints of the hands and feet (without loss of cartilage or erosion of bone), persistent urticaria exacerbated by cold and accompanied by hypocomplementemia and progressive cardiac valvular disease with mitral valve regurgitation. There are only three reports described previously documenting five patients with this rare combination of manifestations.

Acute acalculous cholecystitis induced by mesenteric inflammatory veno-occlusive disease (MIVOD) in systemic lupus erythematosus

A 43-year-old woman with systemic lupus erythematosus (SLE) was treated for lupus pleurisy. During the course of her illness, she abruptly suffered severe right hypochondriac pain and high-grade fever. Abdominal ultrasonography revealed a thickening of the gallbladder wall without cholelithiasis, and she was diagnosed with acute acalculous cholecystitis (AAC). Laparoscopic cholecystostomy was performed. Pathological examination revealed lymphocytic venulitis without arteritis. Antiphospholipid antibodies were not demonstrated during the course of illness. From these findings, the cause of AAC was revealed as a mesenteric inflammatory veno-occlusive disease (MIVOD), which is a novel venopathy mainly affecting the mesenteric vein and/or its branches, causing serious ischemic complications. MIVOD should be considered as a possible cause of AAC.

Churg–Strauss syndrome (CSS) in a patient receiving pranlukast

Pranlukast is a cysteinyl leukotriene receptor I antagonist (LTRAs) approved for treatment of asthma in Japan since 1995. Compared to other LTRAs, such as zafilukast and montelukast, only few cases with Churg-Strauss syndrome (CSS) have been reported in association with treatment with pranlukast. We describe a 17-year-old Japanese male patient who developed CSS with a 13 month history of mild asthma receiving pranlukast for 11 months without systemic and/or inhaled corticosteroid administration prior to development of CSS. From the aspect of temporal relationship between treatment with pranlukast and development of CSS, a direct induction of CSS by pranlukast is suggested in our case.