Search

Objectives: Molecular biological approaches have recently identified urate transporters in renal proximal tubular cells. Human sodium-dependent phosphate cotransporter type 1 encoded by SLC17A1 is a urate transporter localised to the renal proximal tubular cells and candidate molecule to secret urate from renal tubular cells to urine. This study investigated the roles of SLC17A1 in the development of gout., Patients and Methods: Single nucleotide polymorphisms in the human SLC17A1 gene (rs1165176, rs1165151, rs1165153, rs1165196, rs1165209, rs1165215, rs1179086, rs3799344 and rs3757131) were selected, and an association study was conducted using male patients with gout (n=175) and male controls (n=595)., Results: There were significant differences between gout and control groups in the distribution of genotypes at rs1165196 (T806C; Ile269Thr, odds ratio (OR) 0.55, p=0.0035), rs1179086 (OR 0.57, p=0.0018) and rs3757131 (OR 0.54, p=0.0026). In controls, T806C alone had no effect on serum uric acid (sUA) levels. However, T806C showed significant interaction with a reduction of sUA in obese individuals (body mass index > or = 25) using multiple regression analysis., Conclusions: Our data suggest that SLC17A1 polymorphisms are associated with the development of gout.

Objective: The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed., Methods: A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay., Results: Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04)., Conclusion: Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.

Objectives: The aim of this study was to examine the effect of efficient management of rheumatoid arthritis (RA) in relation to disability levels in a large cohort of patients with RA over a period of 3 years., Methods: We studied 2775 patients with RA who had continuous enrolment for at least 3 years from 7511 patients with RA enrolled in an observational cohort study (Institute of Rheumatology, Rheumatoid Arthritis (IORRA)) from October 2000 to April 2005. The 28-joint Disease Activity Scores (DAS28) were calculated at 6 month intervals for all the patients and a value <2.6 was considered as a tight control. We have set up a new variable for each patient, "Avg-Dscore", based on the transition of each patient's DAS28 value, taking the threshold level of 2.6 into consideration. The "Avg-DAS28" is the average of DAS28 values over all the phases. Functional disability status was assessed by J-HAQ, the validated Japanese version of the Health Assessment Questionnaire (HAQ). The relationship of "Avg-Dscore" and "Avg-DAS28" with the functional disability level was determined using Spearman correlation coefficients and multiple linear regression models., Results: The baseline features of these 2775 patients were: female 83.7%, mean age 56.8 years, mean RA duration 9.5 years, mean initial DAS28 4.0, mean initial J-HAQ score 0.79, and mean final J-HAQ score 0.86. There was a statistically significant correlation between "Avg-DAS28" and final J-HAQ score (r = 0.57, p<0.001), indicating that tighter disease control has significant association with lower disability levels. A similar relationship was observed between "Avg-Dscore" and final J-HAQ score (r = 0.47, p<0.001). Multiple linear regression analysis, after adjusting for all the covariates, revealed that "Avg-Dscore" and "Avg-DAS28" were the most significant factors contributing to final J-HAQ score, and confirmed the strong relationship between disease activity and functional disability., Conclusions: In patients with RA efficient disease management, by maintaining the DAS28 values at a level under 2.6, has significant association with improving functional capability. The threshold DAS28 level of 2.6 may be useful in developing targeted treatment guidelines for patients with RA.

Objectives: A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA)., Methods: The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly., Results: Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. "Infections" or "respiratory disorders" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab., Conclusion: This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.

Objective: To estimate the disease activity score (DAS)28-C-reactive protein (CRP) threshold values that correspond to DAS28-erythrocyte sedimentation rate (ESR) values for remission, low disease activity and high disease activity in patients with rheumatoid arthritis., Methods: DAS28 data were analysed using a large observational study (Institute of Rheumatology Rheumatoid Arthritis) database of 6729 patients with rheumatoid arthritis. Firstly, the relationship between the DAS28-ESR and the DAS28-CRP values was analysed. Secondly, the best DAS28-CRP trade-off values for each threshold were calculated using receiver operating characteristic (ROC) curves., Results: The correlation coefficient of ESR versus CRP was 0.686, whereas that of DAS28-ESR versus DAS28-CRP was 0.946, showing the strong linear relationship between DAS28-ESR and DAS28-CRP values. DAS28-CRP threshold values corresponding to remission, low disease activity and high disease activity were 2.3, 2.7 and 4.1, respectively. The sensitivity and specificity from the ROC curves were gradually reduced as DAS28 values became lower., Conclusions: This study showed that DAS28-CRP and DAS28-ESR were well correlated, but the threshold values should be reconsidered. As the results were derived from only Japanese patients, it is essential to compare DAS28-CRP threshold values in people of other ethnic groups.

Objective: To determine the risk for tuberculosis infection in patients with rheumatoid arthritis before the anti-cytokine era in Japan., Patients and Methods: A database of a single-institute-based large observational cohort study for rheumatoid arthritis at the Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, was analysed. Information on the history of tuberculosis infection was collected by patient self-reporting during April and October 2003. The age-adjusted incidence rate and relative risk for tuberculosis infection were investigated., Results: Among 5044 patients with rheumatoid arthritis, 483 (9.6%) patients claimed to have a history of tuberculosis infection before October 2002. The frequency of history of tuberculosis increased according to the age of the patient. Four cases of new-onset tuberculosis were identified among 5544 patients with rheumatoid arthritis during 1 year. The age-adjusted incidence of tuberculosis was 42.4/100,000 patients. The relative risk for tuberculosis was 3.21 (95% confidence interval (CI) 1.21 to 8.55), and that of men and women was 10.59 (95% CI 3.42 to 32.78) and 1.41 (95% CI 0.2 to 10), respectively., Conclusion: There was an increased risk of tuberculosis infection in Japanese patients with rheumatoid arthritis, especially in male patients before the introduction of anti-tumour necrosis factor treatment. These data should form the basis for the risk management of anti-cytokine treatment in Japan.

Background: An association between susceptibility to rheumatoid arthritis and the Fc receptor-like 3 gene (FCRL3) has been reported in a Japanese population. A case-control study showed that the strongest evidence of the association was derived from a polymorphism in the promoter region of FCRL3, which has a regulatory effect on the expression of the gene., Objective: To validate the findings of this previous report by examining the -169C-->T single nucleotide polymorphism (SNP) in a large cohort., Methods: 752 unrelated cases and 940 controls were genotyped. All the samples were from the same ethnic background as the original study. Genotyping was done using 5' allelic discrimination assays. Association between susceptibility to rheumatoid arthritis and -169C-->T SNP was examined by chi(2) testing., Results: As in the previous study, the SNP showed significant differences between cases and controls (p = 0.022, odds ratio = 1.18, 95% confidence interval 1.02 to 1.35)., Conclusions: This result supports a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis.

Background: An imbalance in cytokine homoeostasis is thought to have a key role in the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and recently, a role for chemokines has been noted., Objective: To compare concentrations of monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebral spinal fluid (CSF) of patients with SLE, and with and without neuropsychiatric symptoms., Methods: CSF was obtained from 185 patients with SLE: 96 with NPSLE and 89 patients with SLE without neuropsychiatric symptoms (non-NPSLE patients). MCP-1/CCL2 concentrations were measured with an ELISA., Results: The average concentration of CSF MCP-1/CCL2 in patients with NPSLE was 1959 pg/ml, and in non-NPSLE patients 712 pg/ml. The average MCP-1/CCL2 concentration was significantly higher in the NPSLE group than in the non-NPSLE group (p<0.001). In one representative patient with NPSLE, MCP-1/CCL2 levels in the CSF decreased in parallel with a decline in neuropsychiatric symptoms., Conclusions: CSF MCP-1/CCL2 levels are higher in patients with NPSLE than in non-NPSLE patients. MCP-1/CCL2 may have an important role in the expression of NPSLE. These results indicate that CSF MCP-1/CCL2 reflects an inflammatory activity in the brain, suggesting that it might be used as a diagnostic tool and a monitor for therapeutic responses in patients with NPSLE.

Background: The major histocompatibility complex (MHC) class II transactivator (CIITA) is a master switch of antigen presentation and activates expression of the MHC II gene. Insufficient up regulation of MHC class II molecules is reported to be one of the major immunological mechanisms in systemic lupus erythematosus (SLE)., Objective: To examine the association between single nucleotide polymorphisms (SNPs) in the human CIITA gene (MHC2TA) and SLE., Methods: Promoters and coding regions of MHC2TA were evaluated for polymorphisms in 100 patients with SLE and 100 healthy donors. Eight oligonucleotide primer sets that covered the coding region and each promoter region were used for genomic analysis of SNPs., Results: Allele frequencies of previously reported SNPs did not differ between healthy donors and patients with SLE. Additionally, a new polymorphism in an intronic region at nt 485 (A-->A/G) was identified, which is close to the polymorphism at nt 474 that has been associated with one of the disease causing CIITA cDNA mutations in bare lymphocyte syndrome. This SNP was found in 11% of patients with SLE and in 3% of healthy donors, suggesting it may have a role in the pathogenesis of SLE., Conclusions: A newly identified polymorphism in an intronic region at nt 485 (A-->A/G) may have an important role in the pathogenesis of SLE.

Objectives: This prospective study was designed to clarify the frequency, causes, and clinical course of renal disease in patients with early rheumatoid arthritis (RA)., Methods: 235 patients (185 women, mean age 49.4 years) with early RA of less than one year's duration were enrolled and assessed monthly. Proteinuria was defined as a positive dipstick result and microscopic haematuria was defined as the presence of > or =5 red blood cells per high power field. Urinary abnormalities lasting three months or longer were defined as persistent abnormalities., Results: At entry, 40 patients exhibited haematuria, two had a raised serum creatinine concentration, and none had proteinuria. During the observation period (average 42 months), persistent haematuria was found in 43, persistent proteinuria in 17, and a raised serum creatinine concentration in 14 patients. Persistent proteinuria was caused by drugs in 14 of 17 patients and disappeared in most cases. Risk factors for drug induced proteinuria included a raised C reactive protein and erythrocyte sedimentation rate and age over 50 at entry. Drugs resulted in a raised serum creatinine concentration in eight of 14 patients. The incidence of haematuria at entry did not differ among patients who had been treated with non-steroidal anti-inflammatory drugs, disease modifying antirheumatic drugs, or no drugs. In some patients with isolated haematuria, the haematuria appeared when the activity of RA was high and resolved when it was low., Conclusions: This study suggests that a raised serum creatinine concentration or persistent proteinuria in patients with early RA is predominantly drug related whereas, in contrast, isolated haematuria is more directly associated with the activity of the disease process.

Objective: To investigate the clinical manifestations and the treatment strategy of a very rare entity of disease manifesting as multiple extra-articular cystic synovitis with recurrent polyarthralgia., Methods: A 47 year old male patient with multiple extra-articular synovial cysts was followed up prospectively for 13 years. The clinical manifestations and response to various treatments were recorded. Comparisons are made among the five reported cases (including the present case)., Results: Multiple synovial cysts over the tendon sheath and bursae appeared successively with and without antecedent growth of nodules during 13 years of follow up. Although polyarthralgia and high titred rheumatoid factor persisted throughout the course, there were no roentgenographical changes of joints specific to rheumatoid arthritis (RA). The synovial cysts and arthralgia failed to respond to any of the disease modifying anti-rheumatic drugs (DMARDs) prescribed. Systemic involvements such as pulmonary interstitial fibrosis and skin ulcers were also noted, but they were not progressive., Conclusions: Multiple extra-articular cystic synovitis is an uncommon disease entity closely related to RA. It has been reported exclusively in Japanese subjects and therefore some cultural factors, either genetic or environmental, may contribute to its development.

Objective: To characterise IgG4 rheumatoid factor (RF) at the molecular level from a patient with rheumatoid arthritis., Methods: B cells were cloned from the peripheral blood of a patient with rheumatoid arthritis, using EB virus transformation. The supernatants of the clones were screened for IgG RF activity by ELISA. Nucleotide sequences of the expressed immunoglobulin heavy and light chain genes of one IgG RF producing clone were determined by direct sequencing of the products of a polymerase chain reaction., Results: One clone producing monospecific IgG4 RF was obtained. Sequence analysis of the heavy and light chain genes suggested the accumulation of somatic mutations resulting in amino acid replacement in complementarity determining regions., Conclusions: The results may suggest an antigen driven response in the generation of IgG4 RF in rheumatoid arthritis disease processes.

Objective: To define the mechanisms whereby methotrexate (MTX) manifests its effects in patients with rheumatoid arthritis., Methods: T and B cells from peripheral blood and rheumatoid synovial tissues, synovial adherent cells, and the human fibrosarcoma cell line HT1080 and its mutant (defective in an enzyme in the nucleotide salvage pathway) were tested for clonal growth when cultured with MTX. Normal human fibroblasts and those with a deficiency in a salvage pathway were cultured with MTX in the presence or absence of purine and pyrimidine bases., Results: Clonal growth of T and B cells, but not synovial cells, was inhibited by clinically relevant concentrations of MTX. Slowly proliferating fibroblast lines were resistant to MTX, whereas their rapidly proliferating counterparts were not. However, mutant fibroblast lines deficient in a salvage pathway were sensitive to MTX despite slow proliferation. Similarly, while skin fibroblasts were resistant to MTX, germline mutant fibroblasts deficient in a salvage pathway were sensitive to small concentrations of MTX., Conclusion: T and B lymphocytes, but not synovial cells, may be the target of MTX in vivo. Resistance to MTX may be associated with slow proliferation and the ability to synthesise nucleotides via salvage pathways. MTX can inhibit proliferation of even slowly growing cells by restricting the supply of nucleotides obtained via a salvage pathway, by removal of purine and pyrimidine bases, or by inducing a deficiency in a salvage pathway. It may be possible to manipulate the therapeutic effect of MTX by adjusting the amounts of purines and pyrimidines available to the cells in vivo.