Clinical characteristics and risk factors for Pneumocystis jirovecii pneumonia in patients with rheumatoid arthritis receiving adalimumab: a retrospective review and case-control study of 17 patients.

OBJECTIVES: To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab. METHODS: We conducted a multicenter, retrospective, case-control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected. RESULTS: For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older (p < 0.05) and had more structural changes (p < 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died. CONCLUSIONS: PCP may occur early in the course of adalimumab therapy in patients with RA. Careful monitoring, early diagnosis, and proper management are mandatory to secure a good prognosis for these patients.

Slam-associated protein plays a key role in development of autoimmunity.

In 1995, the SLAM-associated protein (SAP) gene was cloned in our laboratory, and patents were subsequently filed in the USA, EU and Canada. In 1998, the SAP gene was shown to be defective in patients with X-linked lymphoproliferative disease. Since this discovery, the gene has been demonstrated to play a significant role in viral protection, cytokine production and life-long immune memory (vaccination). This article reviews the crucial role of SAP in the development of autoimmunity.

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.

Helicobacter pylori upregulates peripheral platelet counts mainly in female patients.

To evaluate the influence of Helicobacter pylori and sex difference on peripheral platelet counts, dyspeptic patients without immunohaematologic disorders were evaluated. H. pylori infection was verified with the rapid urease test and serum anti-H. pylori IgG antibody. Platelet counts were analysed with a reference to H. pylori infection and sex difference. Among H. pylori-eradicated patients, changes in platelet counts were separately evaluated. Totally, 655 patients were enrolled: 340 patients were infected with H. pylori and 178 patients received eradication therapy, with a success rate of 88.2% (157/178). Females with H. pylori infection definitely manifested elevated platelet counts (infected vs. uninfected 244 ± 57 vs. 219 ± 54 × 10(9)/l; p < 0.0001). H. pylori eradication reduced peripheral platelets by 8 weeks, 5-6 months, 1, 2 and ≥3 years after eradication in females from 248 ± 54 to 237 ± 49, 237 ± 54, 229 ± 48, 238 ± 61 and 232 ± 50 × 10(9)/l (p = 0.0003, 0.0182, 0.0041, 0.0398 and 0.0289), respectively. In males, the reduction was verified by 8 weeks, 1 year and ≥3 years from 226 ± 52 to 217 ± 47, 214 ± 44 and 200 ± 49 × 10(9)/l (p = 0.0464, 0.0164 and 0.0016), respectively. In conclusion, H. pylori infection upregulates platelet counts mainly in females, and eradication reduced peripheral platelets in both sexes. Females appeared more susceptible to H. pylori infection than males with regard to upregulation of platelet counts.

Increases in Nonspecific Immunoglobulin E and Eosinophils after H. pylori Eradication.

Helicobacter pylori infection has been reported to be inversely associated with allergic disorders. We by chance experienced a patient with atrophic gastritis who presented marked elevations of both nonspecific serum immunoglobulin E and eosinophil counts after H. pylori eradication. A 49-year-old Japanese man received eradication of H. pylori using lansoprazole 60 mg/day, amoxicillin 1,500 mg/day, and clarithromycin 400 mg/day for 7 days. Serum immunoglobulin E increased to more than four times its pretreatment level, 306 → 485 → 1,325 U/ml, and peripheral eosinophil counts increased to more than three times, 99 → 139 → 298 per µl. Deducing from the current case, H. pylori eradication might develop allergic disorders in some patients.

Long term changes in platelet counts after H. pylori eradication in non-ITP patients.

Helicobacter pylori eradication is becoming a first-line therapy against idiopathic thrombocytopenic purpura (ITP) and its long term efficacy has already been reported. In contrast, eradication therapy reduced peripheral platelets in non-ITP patients 8 weeks later. To confirm the long term efficacy of Helicobacter eradication on platelet counts in non-ITP patients, we evaluated changes in peripheral platelet counts in endoscopically diagnosed patients with Helicobacter infection. Endoscopically diagnosed patients with Helicobacter infection received eradication therapy using amoxicillin (1500 mg/day), clarithromycin (400 mg/day) and lansoprazole (60 mg/day). The changes in platelet counts after Helicobacter eradication were serially evaluated for as long as 3 years or more. In total, 294 patients were enrolled: 243 patients successfully received eradication therapy and 51 were unsuccessfully treated. As a whole, peripheral platelet counts significantly decreased after Helicobacter eradication, being reduced by more than 1.0 × 109/l by 5-6 months, 1 year, 2 years and 3 years or more (from 24.2+/-5.6 to 23.1+/-5.0, 23.0+/-5.0, 22.1+/-4.5, 22.4+/-5.6, and 21.6+/-5.3 × 109/l: p = <0.0001, <0.0001, 0.0001, 0.0052, and <0.0001, respectively). Helicobacter pylori eradication finally reduced peripheral platelet counts around 2.0 × 109/l in non-ITP patients. There was a definite difference in platelet regulation by Helicobacter pylori between ITP and non-ITP patients. These bivalent effects, upregulation and downregulation, on the peripheral platelet induced by Helicibacter pylori infection appeared to originate from quite different mechanisms.

Localized, splenic, diffuse large B-cell lymphoma presenting with hypersplenism: risk and benefit of splenectomy.

Herein we report a case of a localized, massive, diffuse large B-cell splenic lymphoma diagnosed by splenectomy. A 57-year-old man complaining of weight loss and abdominal pain, was admitted to our hospital. Enhanced computed tomography scanning showed an irregularly enhanced effect in the spleen suggesting a diffuse splenic tumor. Splenectomy was done and the operation progressed without severe complications. The resected spleen weighed 3,500 g. After the operation, the patient recovered from the pancytopenia and pathology diagnosed diffuse large B-cell lymphoma. Standard CHOP plus rituximab chemotherapy was given. Complete remission has continued for 30 months.

Effect of L-asparaginase combined with vincristine and prednisolone on acute myeloblastic leukemia (M0) associated with non-Hodgkin lymphoma.

A 66-year-old Japanese woman was referred to us because of severe anemia and fever and presented at our hospital. She was eventually diagnosed as having acute myeloblastic leukemia (AML; M0) with non-Hodgkin lymphoma (NHL). We investigated the therapeutic efficacy of L-asparaginase (L-Asp), vincristine and prednisolone for both her AML and NHL. Asparagine synthetase (AS) activity in her AML blast cells was undetectable. A lymph node biopsy specimen revealed NHL of the marginal zone B cell type. Complete remission (CR) of AML and NHL was achieved. CR of the AML lasted for 18 months without further consolidation therapy. We conclude that L-Asp can be an effective drug for the treatment of AML in which blasts are negative for AS.

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.

Unilateral developments of osteoarthritis and Charcot's joint in a patient with neurofibromatosis.

BACKGROUND: Precise mechanism of developing neuropathic arthropathy known as Charcot's joint is not fully understood. CASE REPORT: A 55-year-old Japanese woman with neurofibromatosis-1 complained of right gonalgia in December 2001. Physical examination revealed a huge tumor in the right lower leg without signs of inflammation. Laboratory findings were unremarkable. Radiographic examination disclosed the presence of osteoarthropathy in the right knee joint. In contrast, radiologic findings of the right foot and ankle were compatible with neuropathic arthropathy. Further investigations could not reveal abnormal findings in the nervous system. To improve patient's quality of life, partial resection of the tumor was performed. The resected tissues were compatible with neurofibromatosis without malignant transformation. The patient newly noticed pains in the right ankle and tarsal joints one year after the operation. Restricted mobility and insufficient blood supply in the right knee arising from the huge tumor might accelerate development of osteoarthropathy through malnutrition of the chondrocytes. Because the patient did not experience the arthralgia before the operation, the tumor might damage the peripheral nerves unabling to receive afferent signals from such joints resulting in neuropathic arthropathy. CONCLUSIONS: The damaged peripheral nerves might be contributory to developing or accelerating neuropathic arthropathy.

Efficacy and safety of rebamipide for the treatment of dry mouth symptoms in patients with Sjögren's syndrome: a double-blind placebo-controlled multicenter trial.

The effects of rebamipide on dry mouth and salivary secretion in Sjögren's syndrome patients were investigated in a double-blind placebo-controlled study. Rebamipide (100 mg TID) or placebo was administered for eight weeks and patient-assessed improvement of dry mouth and increase in salivary secretion measured by the Saxon test were evaluated. At two, four, and eight weeks, dry mouth improvement rates were, respectively, 26.0, 44.0, and 46.9% for rebamipide and 20.0, 27.1, and 39.1% for placebo, and mean increases in salivary secretion were, respectively, 0.14, 0.24, and 0.35 g for rebamipide and 0.03, 0.09, and 0.17 g for placebo, indicating higher values in the rebamipide group for both parameters at all timepoints but no significant differences between the two groups. Analysis by baseline characteristics suggested a statistically significant salivary secretion increasing effect of rebamipide in cases of primary Sjögren's syndrome. No difference in the incidence of adverse events was seen between the two groups, confirming the safety of rebamipide. As a salivary secretion increasing effect was strongly suggested in cases of primary Sjögren's syndrome, further study on the administration of rebamipide for the treatment of dry mouth in patients with Sjögren's syndrome is required.

[The possible curative therapy for rheumatoid arthritis--EBV infection control gene SAP and its application].

Epstein-Barr virus (EBV) belong to herpes virus group. This virus is transmitted by human contact and cause primary infection and may exist even for years in a latent state in healthy individuals. This virus may be reactivated by the dysregulation of the host immune system or possibly by virus mutation. Here we have firstly demonstrated the host defense of EBV infection and association of EBV with rheumatoid synovitis, and then discussed our own ideas of the possible treatment in near future. The key points of this new therapy are SAP (signaling lymphocytic-activation molecule associated protein) or SH2D1A (Src homology 2 domain-containing protein). SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain. In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome (Duncan disease), a disease characterized by an inappropriate response to EBV infection. SAP is essential for late B cell help and the development of long-term humoral immunity. New approach to the therapeutic method for EBV might be opened by the regulation of this molecule (SAP).

Novel wide-range quantitative nested real-time PCR assay for Mycobacterium tuberculosis DNA: clinical application for diagnosis of tuberculous meningitis.

Although the "gold standard" for diagnosis of tuberculous meningitis (TBM) is bacterial isolation of Mycobacterium tuberculosis, there are still several complex issues. Recently, we developed an internally controlled novel wide-range quantitative nested real-time PCR (WR-QNRT-PCR) assay for M. tuberculosis DNA in order to rapidly diagnose TBM. For use as an internal control calibrator to measure the copy number of M. tuberculosis DNA, an original new-mutation plasmid (NM-plasmid) was developed. Due to the development of the NM-plasmid, the WR-QNRT-PCR assay demonstrated statistically significant accuracy over a wide detection range (1 to 10(5) copies). In clinical applications, the WR-QNRT-PCR assay revealed sufficiently high sensitivity (95.8%) and specificity (100%) for 24 clinically suspected TBM patients. In conditional logistic regression analysis, a copy number of M. tuberculosis DNA (per 1 ml of cerebrospinal fluid) of >8,000 was an independent risk factor for poor prognosis for TBM (i.e., death) (odds ratio, 16.142; 95% confidence interval, 1.191 to 218.79; P value, 0.0365). In addition, the copy numbers demonstrated by analysis of variance statistically significant alterations (P < 0.01) during the clinical treatment course for 10 suspected TBM patients. In simple regression analysis, the significant correlation (R(2) = 0.597; P < 0.0001) was demonstrated between copy number and clinical stage of TBM. We consider the WR-QNRT-PCR assay to be a useful and advanced assay technique for assessing the clinical treatment course of TBM.

Novel wide-range quantitative nested real-time PCR assay for Mycobacterium tuberculosis DNA: development and methodology.

Previously, we designed an internally controlled quantitative nested real-time (QNRT) PCR assay for Mycobacterium tuberculosis DNA in order to rapidly diagnose tuberculous meningitis. This technique combined the high sensitivity of nested PCR with the accurate quantification of real-time PCR. In this study, we attempted to improve the original QNRT-PCR assay and newly developed the wide-range QNRT-PCR (WR-QNRT-PCR) assay, which is more accurate and has a wider detection range. For use as an internal-control "calibrator" to measure the copy number of M. tuberculosis DNA, an original new-mutation plasmid (NM-plasmid) was developed. It had artificial random nucleotides in five regions annealing specific primers and probes. The NM-plasmid demonstrated statistically uniform amplifications (F = 1.086, P = 0.774) against a range (1 to 10(5)) of copy numbers of mimic M. tuberculosis DNA and was regarded as appropriate for use as a new internal control in the WR-QNRT-PSR assay. In addition, by the optimization of assay conditions in WR-QNRT-PCR, two-step amplification of target DNA was completely consistent with the standard curve of this assay. Due to the development of the NM-plasmid as the new internal control, significantly improved quantitative accuracy and a wider detection range were realized with the WR-QNRT-PCR assay. In the next study, we will try to use this novel assay method with actual clinical samples and examine its clinical usefulness.

The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients.

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33-86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3-4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR +/- PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.

Eye movement and random number in NP lupus evaluation.

We evaluated the vulnerability of central nervous system (CNS) in patients with systemic lupus erythematosus (SLE) using exploratory eye movement analysis and random number generation (RNG), and compared the tests in evaluating CNS vulnerability. Nineteen patients received the tests more than a month after SLE onset in nonpsychotic status. Exploratory eye movements were analyzed using an eye-mark recorder that detects corneal reflection of infrared light, and numbers of eye fixations were counted to calculate responsive search score (RSS). Using digits 0 through 9, 100 numbers were vocally generated at a random fashion. "Seriality score" was calculated from the recorded 100 numbers. RSS of SLE patients was similar to that of normal individuals, irrespective of neuropsychiatric lupus history. Seriality score of patients having a history of neuropsychiatric lupus was higher than that of never having it (p < 0.05). No relations were confirmed between RSS and seriality score. The current study suggested heterogeneous nature of SLE in CNS vulnerability when evaluating with seriality score, but not with RSS. There seemed to be a difference between exploratory eye movement analysis and RNG in evaluating CNS vulnerability. Each test seemed to evaluate different aspects of brain function.

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.