Efficacy and safety of minodronic acid hydrate in patients with steroid-induced osteoporosis.

OBJECTIVES: Minodronic acid hydrate, an oral bisphosphonate, has a greater inhibitory effect on bone resorption than do other approved drugs; however, this has been studied only in patients with primary osteoporosis. Here, we administered minodronic acid hydrate to patients with steroid-induced osteoporosis who have been treated with steroids for rheumatoid arthritis or other collagen diseases, and the efficacy and safety of minodronic acid hydrate were prospectively investigated. METHODS: Twenty-five patients treated in our rheumatology clinic received minodronic acid hydrate 1 mg/day. The changes in bone mineral density (BMD) and bone turnover markers were investigated at 3 and 6 months, and adverse events, including the presence or absence of an incident osteoporotic fracture, were examined over a period of 6 months. RESULTS: Percent changes in BMD of the lumbar spine and femur significantly increased. The values of bone turnover markers significantly decreased. There were no patients with a radiographically apparent incident fracture. Adverse events included toothache for which the patient discontinued the treatment and three cases of gastrointestinal disorder that did not lead to discontinuation, and thus minodronic acid hydrate was well tolerated. CONCLUSIONS: Here, we show that minodronic acid hydrate is effectively and safely used for treatment of steroid-induced osteoporosis.

[Diagnostic value of brain biopsy in intravascular large B-cell lymphoma mimicking progressive multifocal leukoencephalopathy: case report].

We report a 68-years-old woman with systemic sclerosis and interstitial pneumonia (IP). She had developed subacute progressively encephalopathy and dementia while treated with oral cyclophosphamide and prednisolone. She admitted to our hospital because of syncope. Laboratory tests indicated slight elevated cerebrospinal fluid protein, and levels of serum C-reactive protein (CRP), levels of soluble IL-2 receptor was normal. But, magnetic resonance imaging (MRI) of the brain showed multiple infarct-like lesions mainly in the white matter, which mimics progressive multiple leukoencephalopathy (PML). Twenty days after admission, the retested MRI of the brain disclosed initial lesions progressively enlarged and numbers of the lesions were increased. The polymerase chain reaction (PCR) for JC virus of cerebrospinal fluid was negative. To make diagnosis, brain biopsy was performed. Microscopic examination revealed that small vessels were filled with lymphoma cells (CD20+, CD79+, CD3-), and intravascular lymphoma (IVL) was diagnosed. She treated with regimens of R-CHOP. After chemotherapy her consciousness and dementia were gradually improved. IVL of central nerve system (CNS) is a rare disease, and its common symptoms are ischemia, infarction and dementia. Diagnosis of IVL of CNS is difficult when the lesion mimics PML, and patient with similar laboratory examinations and radiographic findings of PML should undergo brain biopsy detected malignant cell in small vessels, which is a value of diagnosis.

Epstein-Barr virus induces erosive arthritis in humanized mice.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of rheumatoid arthritis (RA) on the basis of indirect evidence, such as its presence in affected joint tissues, antigenic cross reactions between EBV and human proteins, and elevated humoral and cellular anti-EBV immune responses in patients. Here we report development of erosive arthritis closely resembling RA in humanized mice inoculated with EBV. Human immune system components were reconstituted in mice of the NOD/Shi-scid/IL-2Rγ(null) (NOG) strain by transplantation with CD34(+) hematopoietic stem cells isolated from cord blood. These humanized mice were then inoculated with EBV and examined pathologically for the signs of arthritis. Erosive arthritis accompanied by synovial membrane proliferation, pannus formation, and bone marrow edema developed in fifteen of twenty-three NOG mice transplanted with human HSC and inoculated with EBV, but not in the nine NOG mice that were transplanted with HSC but not inoculated with EBV. This is the first report of an animal model of EBV-induced arthritis and strongly suggest a causative role of the virus in RA.

Efficacy and safety of antifungal prophylaxis with oral itraconazole solution among patients receiving corticosteroids: who should be given prophylaxis?

The incidence of systemic fungal infections has risen, as shown by increases in the numbers of immunosuppressed or immunocompromised patients. The consequences of these fungal infections are occasionally serious. However, the efficacy of antifungal prophylaxis in patients receiving corticosteroid treatment has not been well investigated, even though they are susceptible to severe fungal infections. Therefore, we retrospectively evaluated the prophylactic efficacy of an antifungal agent-oral itraconazole solution (ITCZ-OS)-for immunosuppressed patients receiving corticosteroids in a single institution. Of 39 patients, 18 received prophylaxis with ITCZ-OS at a dose of 200 mg/day, and 21 did not. As a result, no fungal infections developed in the prophylactic group, but 7 of the 21 patients (33%) in the non-prophylactic group suffered from fungal infections consisting of 3 non-invasive candidiases, 2 invasive candidiases, and 2 invasive pulmonary aspergilloses. Among the non-prophylactic group, aging and hypoalbuminemia were statistically significantly associated with incidence of invasive fungal infections. Of the four patients with invasive fungal infections, three had concomitant chronic illness such as diabetes. Toxicity among the prophylactic group was not statistically significantly different from that of the non-prophylactic group. In addition, none needed discontinuation of the drug. These results indicate the potential antifungal prophylactic effect of ITCZ-OS for a subset of patients treated with moderate or high doses of corticosteroids.

Epstein-Barr-Virus-Infected CD15 (Lewis X)-Positive Hodgkin-Lymphoma-Like B Cells in Patients with Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA), especially those who are treated with methotrexate (MTX), might have an increased risk of Hodgkin lymphoma (HL), a malignancy that is associated with Epstein-Barr virus (EBV). Here we describe a monoclonal EBV-infected B-lymphoblastoid cell line (LCL) called TKS-1 that was established from cells that spontaneously converted from an MTX-treated RA patient. TKS-1 has properties similar to HL cells and it is distinctly different from control LCLs established from normal individuals. TKS-1 cells express the HL -associated surface markers CD15 and CD30 (Takei et al. 1989). Like Hodgkin Reed-Sternberg (H-RS) cells of EBV-positive HL, TKS-1 cells express EBNA1 mRNA transcribed from the Qp promoter of the virus, whereas control LCLs use the Cp or Wp promoter to transcribe mRNA. TKS-1 cells can proliferate in an anchorage-independent manner and possess a cloning efficiency comparable to that of the Burkitt lymphoma (BL) line Raji. In addition, two EBV-positive LCLs established by cocultivated CD34+ cells isolated from the bone marrow of patients with RA and peripheral blood B lymphocytes from a healthy EBV-seronegative individual also expressed CD15. These results indicate that EBV-infected B-lymphoblastoid cells from patients with RA tend to acquire properties similar to HL cells.

SLAM-associated protein solves a mystery of autoimmunity.

SLAM-associated protein (SAP) is essential for viral protection, lifelong immune memory (vaccination), and lifelong autoantibody production. We discuss how SAP is a key player in the development of autoimmune disease.

What is after cytokine-blocking therapy, a novel therapeutic target--synovial Epstein-Barr virus for rheumatoid arthritis.

There has been significant progress in cytokine-blocking therapy for treatment of rheumatoid arthritis (RA) However, inhibition of cytokines involved in immune defense raises severe side effects. The cost of cytokine-blocking treatment is another major issue. Why are levels of inflammatory cytokines increased in RA patients? We have a large amount of circumstantial and direct evidence for the presence of Epstein-Barr virus (EBV) in RA synovial cells. Here, we provide an overview of the implications for novel approaches to therapy for RA patients, based on the most recent available evidences of anti-viral agents.