Ten-year incidences of self-reported non-vertebral fractures in Japanese patients with rheumatoid arthritis: discrepancy between disease activity control and the incidence of non-vertebral fracture.

UNLABELLED: Despite improvements in rheumatoid arthritis disease activity of in the past 10 years, the incidence of self-reported non-vertebral fractures did not decrease in our cohort of 9,987 patients. This study may indicate that osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the rheumatoid arthritis disease activity. INTRODUCTION: Although rheumatoid arthritis (RA) is a risk factor for osteoporosis and fractures, few studies have described the association between disease activity and the fracture incidence in patients with RA. This study aimed to investigate changes in the non-vertebral fracture incidence between 2001 and 2010 in our Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort. METHODS: The IORRA is a prospective observational cohort study of Japanese RA patients. A total of 9,987 patients with RA were enrolled in this cohort from 2000 to 2010. The clinical parameter and non-vertebral fracture occurrence data were collected biannually through self-reported questionnaires. Incidences of self-reported non-vertebral fractures were also analyzed via standardization according to gender, age, and disease activity during each 2-year period. RESULTS: From 2001 to 2010, the percentage of patients with 28-joint disease activity score remission increased from 7.8 to 39.7%, prednisolone intake decreased from 51.4 to 41.3%, and bisphosphonate intake increased from 5.0 to 23.4%. The non-vertebral fracture incidence rates were 24.6/1,000 person-years in 2001 and 35.5/1,000 person-years in 2010, with no apparent change even after standardization. The overall non-vertebral fracture incidence was significantly higher in the autumn/winter than in the spring/summer (p = 0.02). CONCLUSION: Despite improvements in disease activity and functional disability, the non-vertebral fracture incidence exhibited no apparent change between 2001 and 2010 in our patients with RA. Osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the disease control in patients with RA.

Risk factors associated with the occurrence of hip fracture in Japanese patients with rheumatoid arthritis: a prospective observational cohort study.

UNLABELLED: Risk factors associated with the occurrence of hip fracture in Japanese patients with rheumatoid arthritis (RA) were evaluated in a prospective, observational cohort study. Physical disability, advanced age, history of total knee replacement (TKR), and low body mass index (BMI) appear to be associated with the occurrence of hip fracture. INTRODUCTION: This study seeks to evaluate the association between potential risk factors and the occurrence of hip fractures in Japanese RA patients. METHODS: A total of 9,720 patients (82.1% female; mean age, 55.7 years) with RA were enrolled in a prospective observational study from 2000 to 2010. Self-reported hip fractures were verified using patient medical records. Cox proportional hazards models were used to analyze independent contributions of various risk factors to hip fracture occurrence. RESULTS: During a mean follow-up of 5.2 years, 152 patients reported 152 hip fractures. Among these patients, 97 hip fractures in 97 patients (15 males, 82 females) were verified with medical records. Japanese version of the Health Assessment Questionnaire (J-HAQ) disability score [per 1 score, hazard ratio (HR), 2.64; 95% confidence interval (CI), 1.94-3.58], age (per 10 years; HR, 1.53; 95% CI, 1.25-1.87), history of TKR (HR, 3.75; 95% CI, 1.57-8.96), and BMI (per 1 kg/m2, HR, 0.92; 95% CI, 0.86-0.99) were significantly associated with hip fractures. Among the scores on the eight domains of the J-HAQ, J-HAQ (arising) (HR, 1.74; 95% CI, 1.28-2.36) and J-HAQ (hygiene) (HR, 1.58; 95% CI, 1.11-2.24) were significantly correlated with the occurrence of hip fracture. CONCLUSIONS: High J-HAQ disability score, advanced age, history of TKR, and low BMI appear to be associated with the occurrence of hip fractures in Japanese RA patients. Among the eight domains of the J-HAQ, arising and hygiene disabilities appear to be correlated with the occurrence of hip fractures in this patient population.

Vaccination against seasonal influenza is effective in Japanese patients with rheumatoid arthritis enrolled in a large observational cohort.

OBJECTIVE: To investigate the effectiveness of influenza vaccination in patients with rheumatoid arthritis (RA) from a large practice-based cohort. METHOD: Patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort completed self-administered questionnaires as part of the April IORRA surveys of 2001, 2002, 2003, and 2007, which included their influenza vaccination status and occurrence of an actual influenza attack. Vaccine coverage rate and attack rates were calculated in each season. Relative risks (RRs) of vaccination for an actual influenza attack were evaluated and risk factors for influenza infection were determined by multiple logistic regression analysis. RESULTS: Data from 3529, 4518, 4816, and 4872 patients in the 2000/01, 2001/02, 2002/03, and 2006/07 seasons, respectively, were analysed. Coverage rates were increased from 12.2% in the 2000/01 season to 38.7% in the 2006/07 season. For each season, the attack rates in vaccinated patients trended lower than the rates in unvaccinated patients but the differences were not significant; however, by combining these four seasonal results, the attack rate was significantly lower for vaccinated patients [RR 0.83, 95% confidence interval (CI) 0.71-0.95, p < 0.01]. Male gender [odds ratio (OR) 1.48, 95% CI 1.25-1.76, p < 0.001] was associated with increased risk whereas vaccination was associated with reduced risk for influenza attack (OR 0.76, 95% CI 0.63-0.91, p < 0.01). There were no associations between influenza attacks and RA disease activity, treatment with methotrexate (MTX) or corticosteroids. CONCLUSION: Influenza vaccination was effective in patients with RA regardless of disease activity or treatment.

Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese.

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.

Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA.

OBJECTIVES: To investigate mortality, cause of death, and risk factors related to mortality in Japanese patients with rheumatoid arthritis (RA). METHODS: The IORRA cohort is a large observational cohort established in 2000 at the Institute of Rheumatology, Tokyo Women's Medical University. Essentially, all RA patients were registered and clinical parameters were assessed biannually. For patients who failed to participate in subsequent surveys, simple queries were mailed to confirm survival. Standardized mortality ratios (SMRs) were calculated and mortality risk factors were analysed using a Cox proportional hazard model. RESULTS: We analysed 7926 patients (81.9% females; mean age 56.3 ± 13.1 years; mean disease duration 8.5 ± 8.3 years) with RA who enrolled in IORRA from October 2000 to April 2007. During the observational period (35 443.0 person-years), 289 deaths were reported. Major causes of death included malignancies (24.2%), respiratory involvement (24.2%) including pneumonia (12.1%) and interstitial lung disease (ILD) (11.1%), cerebrovascular disease (8.0%), and myocardial infarction (7.6%). As death was not confirmed in all patients, the SMR was deduced to be between 1.46 [95% confidence interval (CI) 1.32-1.60] and 1.90 (95% CI 1.75-2.07) for all patients, between 1.45 (95% CI 1.22-1.70) and 1.70 (95% CI 1.45-1.97) for men, and between 1.46 (95% CI, 1.29-1.65) and 2.02 (95% CI 1.82- 2.24) for women. Factors associated with increased mortality included male gender, older age, worse physical disability, positive rheumatoid factor (RF), corticosteroid use, and presence of ILD. CONCLUSION: The mortality of Japanese RA patients is comparable to that in previous reports from western countries, even though the causes of death were significantly different.

A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis.

OBJECTIVE: Environmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis. METHODS: Human synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with alpha-naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDD-AhR interaction, we used inhibitors of nuclear factor-kappaB (NF-kappaB) and extra-cellular stimulus-activated kinase (ERK). RESULTS: Higher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1beta, IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-kappaB and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-alpha. CONCLUSION: TNF-alpha activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-kappaB and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.

Effect of matrix metalloproteinase-3 functional SNP on serum matrix metalloproteinase-3 level and outcome measures in Japanese RA patients.

OBJECTIVE: A bi-allelic polymorphism on the promoter region, -1612 ins/del A, was found to influence the production of MMP-3. Since MMP-3 plays a particularly pivotal role in joint destruction, the MMP-3 gene is thought to be an interesting target gene of disease severity in RA. We attempt to determine whether the MMP-3 promoter polymorphism is associated with serum titre of MMP-3, disease activity and severity in Japanese RA patients. METHODS: DNA samples were obtained from 1504 RA patients as part of the Institute of Rheumatology Rheumatoid Arthritis observational cohort study. From the 2006 spring data, serum MMP-3 levels of 820 patients were available by enzyme immunoassay. Joint damage score at 5-yr disease duration could be measured using the Sharp/van der Heijde method in 162 patients. Genotyping of -1612 ins/del A was performed using fluorescent-labelled fragment analysis. Differences in serum MMP-3 level and joint damage score among genotypes of -1612 ins/del A polymorphism were analysed by linear regression analysis. RESULTS: No significant differences were found among MMP-3 genotypes on patient characteristics including disease activity score (P = 0.51) or health assessment questionnaire (P = 0.99). A significant effect of risk allele on serum MMP-3 level was observed (P = 0.038), while no significant effect was observed on radiographic joint damage (P = 0.47). CONCLUSION: We conclude that MMP-3 functional polymorphism is associated with serum MMP-3 titre, but is not a direct predictor for outcome measures in Japanese RA patients.

Inhibition of NF-kappaB signaling by fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, presents a therapeutic strategy for rheumatoid arthritis.

OBJECTIVES: Inflammatory mediators such as interleukin-6 and tumor necrosis factor-alpha play an important role in the pathogenesis of rheumatoid arthritis (RA) by promoting chronic inflammation and joint damage. NF-kappaB is a transcriptional activator of genes for these cytokines. It also plays an important role in the regulation of osteoclast differentiation which plays a key role in joint destruction in RA. Ligands for peroxisome proliferator-activated receptor (PPAR) -gamma have recently been reported to inhibit the development of RA. In this study, we investigated the role of PPARalpha in RA. METHODS: We analyzed the protein expression of PPAR-alpha and -gamma in rheumatoid synovial fibroblasts (RSF) from RA patients and analyzed the effects of ligands for PPAR-alpha and -gamma on cytokine production from RSF NF-kappaB activations in RSF and osteoclast differentiation from osteocalst progenitor in the peripheral blood. Moreover, we analyzed the effects of oral administration of PPAR-alpha and -gamma ligands on the development of adjuvant-induced arthritis (AIA) in female Lewis rats. RESULTS: We confirmed the expression of PPAR-alpha in RSF and also demonstrated that fenofibrate, a ligand for PPAR-alpha, inhibited cytokine production from RSF, NF- kappaB activation in RSF, and osteoclast differentiation from osteoclast progenitor cells. Furthermore, we demonstrated that fenofibrate inhibits the development of arthritis in a rat model of human RA. CONCLUSIONS: These results indicate that fenofibrate suppresses the development of arthritis by inhibition of NF-kappaB signaling; therefore, this compound offers possible anti-rheumatic drug.

Synovial histology in three Behçet's disease patients with orthopedic surgery.

Specimens of synovial tissues from 5 affected joints of 3 patients with Behçet's disease were available for histopathological examination. All specimens were infiltrated by lymphocytes and neutrophils, and exhibited marked vascularity and infiltration of lymphoid cells among the vessels. Marked plasma cell infiltration and lymphoid follicle formation were found in one synovial tissue sample. There was no evidence of infection or vasculitis. These findings suggest that the histopathological characteristics of synovial tissue in Behçet's disease may have a wide range, some of which may even resemble the synovial tissue of rheumatoid arthritis.

A new culture system to study the metabolism of the intervertebral disc in vitro.

STUDY DESIGN: This study determined whether entrapment of a rabbit intervertebral disc in alginate gel helped to promote the retention of normal metabolic activities by the nucleus pulposus and anulus fibrosus in tissue culture. OBJECTIVES: To establish an in vitro culture system to study the metabolism of the intervertebral disc as a whole integral organ. SUMMARY OF BACKGROUND DATA: In vitro studies of the metabolism of intervertebral discs have been scarce because of the difficulties involved in maintaining the integrity of the tissues, especially that of the nucleus pulposus, in culture medium. METHODS: Rabbit intervertebral discs were embedded in alginate gel and maintained in culture for as long as 1 month. At weekly intervals, experiments were performed to measure the rate of proteoglycan synthesis and to characterize proteoglycans newly synthesized by cells in the anulus fibrosus and nucleus pulposus. In addition, at these same time intervals, the contents of sulfated proteoglycans, antigenic keratan sulfate, hyaluronan, and collagen in these two intervertebral disc tissues were measured to evaluate tissue integrity. Intervertebral discs cultured in medium alone were used as controls and analyzed in parallel. RESULTS: The anulus fibrosus and nucleus pulposus of intervertebral discs cultured in alginate gel sustained a higher rate of proteoglycan synthesis and maintained a higher content of extracellular matrix components than the respective controls at all times. CONCLUSIONS: This new alginate tissue culture system should prove useful for studying the metabolism of whole intervertebral discs.

Elastase from polymorphonuclear leukocyte in articular cartilage and synovial fluids of patients with rheumatoid arthritis.

Objective was to study the significance and the mechanism of action of elastase from polymorphonuclear leukocyte (PMN elastase) in patients with rheumatoid arthritis (RA). The experiments conducted consisted of two phases. Firstly, articular cartilage and synovia from 8 patients with RA undergoing total knee replacement were obtained, and the gelatinolytic enzyme activity was extracted with 2M guanidine hydrochloride. The gelatinolytic activity of each tissue was measured to confirm that the activity was due to PMN elastase by using an antihuman leukocyte elastase antibody. Secondly, the levels of PMN elastase-alpha 1 proteinase inhibitor complex (EIC) in the blood and synovial fluid of 170 patients with RA were measured by immunoassay. The results were as follows: 1. Gelatinolytic activity was shown to be mainly due to PMN elastase, and found to be highest in cartilage and synovia in RA joints. 2. The EIC levels in plasma of RA patients were significantly higher than those in gout and osteoarthritis (OA), and the EIC levels increased according to the stage of articular cartilage destruction. Moreover, the EIC levels in synovial fluid of RA patients were higher compared to those of OA patients. The activity of PMN elastase was elevated in destructive joints of RA. With the progression of articular cartilage destruction, EIC levels in plasma of RA patients increased as well. We suggest that PMN elastase may play a significant role in RA disease.

[Arthritic manifestations in ulcerative colitis].

Ulcerative colitis (UC) is commonly associated with peripheral joint disease which correlates with the activity and extent of the inflammatory bowel disorder. They are generally divided into three clinical categories; peripheral arthritis, spondylitis, and sacroiliitis. The arthritis is usually pauciarticular, generally asymmetric, transient, and nondestructive. However, the peripheral arthritis becomes chronic and destructive in some cases. Rheumatoid arthritis has been reported to be seldom associated with UC. Inflammatory joint disease is considered an enteropathic arthritis if the gastrointestinal tract is directly involved in the pathogenesis. The occurrence of rheumatologic manifestations in UC is reviewed in this paper.

[Osteoporosis in collagen diseases].

The pathogenesis of osteoporosis in patients with rheumatic diseases, especially rheumatoid arthritis (RA), is poorly understood. The duration of the disease, the severity of the inflammatory process, gender, age, steroid therapy and menopause have been suggested as risk factors for osteoporosis in patients with RA. Although these factors may contribute to the development of osteoporosis, the influence of one specific factor is difficult to evaluate. It is said that the treatment with steroids has a deleterious effect on bone turnover, but this effect has been controversial. The dose margin of prednisone that will lead to osteoporosis is not known but has been estimated to be 10 mg per day. Fractures and stress fractures in patients with RA are probably much more common. Further study concerning osteoporosis in rheumatic diseases is necessary.

An arthroscopic check valve release improves knee intrameniscal cyst symptoms in adolescent: a case report.

Intrameniscal cysts begin with the flow of synovial fluid from a meniscal tear in one direction, enlarging probably as a result of an on-and-off valve mechanism of the tear flap. The current available literature focuses primarily on the necessity for surgery, however a large meniscus resection to remove cysts may place an additional burden on menisci, leading ultimately to knee joint degenerative changes. In this article, we present a rare case of intrameniscal cysts with an isolated horizontal meniscal tear in an adolescent, and describe a new arthroscopic procedure for treating this type of intrameniscal cyst. We performed arthroscopic partial release of the meniscal tear check-valve mechanism, preventing further intrameniscal cyst expansion. The patient's clinical symptoms improved, and this procedure may also be useful in treating intrameniscal cysts with an isolated horizontal meniscal tear and can be considered as an option to preserve meniscal function and minimize degenerative arthritis in young athletes.