In vivo deep-flexion kinematics in patients with posterior-cruciate retaining and anterior-cruciate substituting total knee arthroplasty.

BACKGROUND: Posterior-cruciate ligament retaining total knee arthroplasty designs have long been used with excellent clinical success, but often have shown kinematics and flexion performance that are significantly different from the natural knee. The purpose of this study was to compare deep-flexion knee kinematics in patients with two types of posterior-cruciate ligament retaining total knee arthroplasty. METHODS: One group received a traditional curved symmetric articular configuration, and one group received a design incorporating a lateral compartment which constrains the lateral condyle to the antero-posterior center of the tibial plateau in extension, but allows translation in flexion--roughly approximating the role of the anterior cruciate ligament. In vivo kinematics were analyzed using three-dimensional model registration and plain radiographs of kneeling and squatting activities in 20 knees in 18 patients. FINDINGS: Knees with the anterior cruciate ligament substituting design exhibited greater flexion, femoral antero-posterior translation and tibial internal rotation. INTERPRETATION: Geometric features intended to improve knee flexion, including greater antero-posterior stability, a more posterior tibial sulcus, and reshaped femoral condyles, do provide measurable and significant differences in deep-flexion knee kinematics.

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.

Low disease activity state with corticosteroid may not represent 'true' low disease activity state in patients with rheumatoid arthritis.

OBJECTIVE: Corticosteroids constitute one of the most common treatments of RA. The purpose of this study is to investigate whether long-term corticosteroid use suppresses the progression of disability in RA patients with low disease activity state. METHODS: Data collected from a large observational cohort of RA patients at our institution were analysed for 214 RA patients whose disease activity score (DAS) 28 and HAQ were available consecutively from October 2000 to October 2004. All 214 patients had average DAS 28 <3.2, meaning only those who had well-controlled RA disease activity were chosen as subjects. The subjects were divided into steroid users who received continuous corticosteroids every month and non-steroid users who did not receive consecutive corticosteroids continuously every month. RESULTS: Fifty-five patients (25.7%) were corticosteroid users and 159 (74.3%) were non-users. Average prednisolone for the former group was 4.2 mg/day. No significant differences were observed among baseline variables and RA disease activity variables. However, for steroid users, HAQ progressively worsened with time and for non-steroid users, HAQ progressively improved. CONCLUSIONS: Although DAS 28 and other variables may suggest well-controlled RA disease activity, functional capacity of patients on low-dose corticosteroids deteriorated. Thus, low disease activity state with corticosteroid may not represent the 'true' low disease activity state. Along with the achievement of a low disease activity state, long-term efficacy, prognosis, and the quality of remission need to be also considered in the tight control of RA activity.

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.

Efficient management of rheumatoid arthritis significantly reduces long-term functional disability.

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.

What's in season for rheumatoid arthritis patients? Seasonal fluctuations in disease activity.

OBJECTIVES: To examine whether a seasonal fluctuation exists with rheumatoid arthritis (RA) activity and to analyse seasonal effects of varying components that express disease activity in RA patients. METHODS: A group of 1665 RA patients (mean age 57.2 yrs, mean disease duration 9.9 yrs) whose data were available for 10 consecutive phases from a large observational cohort study conducted at our institution from October 2000 to April 2005, bi-annually, were evaluated. Ten criteria were analysed to assess RA disease activity. RESULTS: All criteria revealed decrease in disease activity during fall and increase in disease activity during spring, except for the physician's global assessment of disease activity in which significant differences were not observed between the two seasons. CONCLUSIONS: We found definite seasonal differences in RA patients, both subjectively and objectively. RA disease activity was higher in spring and lower during fall. Seasonal changes may play an important role in evaluating disease activity of RA patients and should be taken into account when examining these patients.

Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan.

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.

Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population.

OBJECTIVE: The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is a member of the PTPs that negatively regulate T-cell activation. A missense single nucleotide polymorphism (SNP) in the PTPN22 gene known as R620W was recently reported to be associated with several autoimmune diseases including rheumatoid arthritis (RA). The association was confirmed repeatedly in the populations of North European ancestry. However, the SNP was reported to be non-polymorphic in the Asian populations. Because the gene confers an impact on autoimmune diseases, we attempt to explore an association between PTPN22 gene and RA in a Japanese population without restricting to the SNP, R620W. METHODS: We studied 1128 RA patients and 455 controls. In addition to the SNP, R620W, we selected eight testing SNPs spanning 45 kb over the PTPN22 gene using the International HapMap Project. Genotyping was performed using the TaqMan fluorogenic 5' nuclease assay. Associations between RA and each of the SNPs were estimated by the Fisher's exact test. Haplotype was constructed using the expectation-maximization algorithm. RESULTS: R620W was not polymorphic enough in both the patients and the controls, and was therefore excluded from further analysis. Each allele frequency for the eight other SNPs in both groups was compared and no association was detected. Haplotype analysis also revealed that PTPN22 gene was not associated with RA in a Japanese population. CONCLUSION: We found no association between PTPN22 and RA in a Japanese population. The result suggests that the PTPN22 gene is associated with RA only in a specific ethnic group.

Association between PADI4 and rheumatoid arthritis: a meta-analysis.

OBJECTIVE: Polymorphisms and haplotypes of the peptidylarginine deiminase type 4 gene (PADI4) have been reported to be associated with rheumatoid arthritis (RA) in a Japanese population. However, subsequent replication studies showed conflicting results. The aim of this study was to determine whether meta-analysis would prove the existence of the association. METHODS: PubMed was searched using the term 'PADI4' for articles from the publication of the first study to December 2005. Replication studies that tested the association between PADI4 and RA were reviewed for meta-analysis. The Breslow-Day test for homogeneity across the studies was calculated. The Mantel-Haenszel procedure was used to pool odds ratios (OR) with 95% confidence intervals (CI) to evaluate the association. RESULTS: Six replication studies, one from Japan and five from Europe and North America, fulfilled the selection criteria for inclusion in the meta-analysis. Homogeneity was confirmed across the replication studies. The common OR was 1.14 (95% CI = 1.07-1.21) for allelic distribution. The association was confirmed when only five replication studies in the European descent populations were combined (P = 0.0096, common OR = 1.10). CONCLUSIONS: Our meta-analysis showed a positive association between PADI4 and RA not only in the Japanese population but also in populations of European descent.

Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis.

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.

Monocyte chemoattractant protein-4 (MCP-4)/CCL13 is highly expressed in cartilage from patients with rheumatoid arthritis.

OBJECTIVES: To study the role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 in the pathogenesis of rheumatoid arthritis (RA), we analysed the expression of MCP-4/CCL13 in chondrocytes, synovial fluid and serum from patients with RA and investigated the effect of MCP-4/CCL13 on the proliferation of synovial cells. METHODS: Human articular cartilage specimens were obtained from joints from RA and osteoarthritis (OA) patients and normal joints (controls). Transcript levels of MCP-4 in cartilage were determined by real-time polymerase chain reaction. Protein levels were measured by enzyme-linked immunoassay. Cultured fibroblast-like synoviocytes (FLS) were treated with various concentrations of recombinant MCP-4/CCL13 protein, and cell proliferation was evaluated with a viability assay. RESULTS: The gene expression of MCP-4 was significantly higher in cartilage from RA patients than in that from OA patients (P = 0.00902) and in normal cartilage (P = 0.00902). The concentration of MCP-4/CCL13 protein in serum from RA patients (mean 94.7 +/- 37.6 pg/ml) was significantly higher than in serum from OA patients (mean 49.2 +/- 31.2 pg/ml, P = 0.0051) and controls (mean 32.6 +/- 23.9 pg/ml, P = 0.0001). The concentration of MCP-4/CCL13 protein in synovial fluid from RA patients (mean 247.2 +/- 161.2 pg/ml) was also significantly higher than in that from OA patients (mean 29.6 +/- 50.5 pg/ml, P = 0.000019). Moreover, MCP-4/CCL13 enhanced the proliferation of FLS in a dose-dependent manner. CONCLUSIONS: MCP-4/CCL13 is highly expressed in RA joints at the mRNA and protein levels. Our results suggest that MCP-4/CCL13 is secreted from chondrocytes and activates the proliferation of rheumatoid synovial cells, thereby leading to joint destruction in RA.

Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients.

OBJECTIVE: To elucidate the direct role of human T cells in the induction of osteoclastogenesis in rheumatoid arthritis (RA), by studying human monocytes and the pathogenetic roles of receptor activator of nuclear factor kappaB ligand (RANKL), RANK, and osteoprotegerin (OPG). METHODS: Synovial tissue obtained at total knee replacement was stained immunohistologically using anti-RANKL, CD3, and CD4 antibodies. Synovial fluid was obtained from patients with RA, osteoarthritis (OA), gout, or trauma. Concentrations of the soluble form of RANKL (sRANKL) and OPG in the synovial fluid were measured by enzyme-linked immunosorbent assay. Activated T cells from peripheral blood mononuclear cells (PBMC) of healthy volunteers were cultured with human monocytes from PBMC. RESULTS: Immunostaining of the synovial tissue of RA patients demonstrated that RANKL-positive cells were detected in a subset of fibroblast-like synoviocytes and infiltrating mononuclear cells. Double immunostaining revealed that RANKL-positive cells were detected in a subset of CD3+ cells and CD4+ cells. An increased concentration of sRANKL and a decreased concentration of OPG were detected in synovial fluid from RA patients. The ratio of the concentration of sRANKL to that of OPG was significantly higher in synovial fluid of RA patients than in synovial fluid of patients with OA or gout. The activated T cells expressing RANKL induced osteoclastogenesis from autologous peripheral monocytes. The role of RANKL in this osteoclastogenetic process was confirmed by dose-dependent inhibition by OPG. CONCLUSION: The present study is the first to demonstrate osteoclastogenesis using human-derived T cells and monocytes. In addition, the present findings suggest that excess production of RANKL by activated T cells increases the level of sRANKL in synovial fluid and may contribute to osteoclastic bone resorption in RA patients.

[A questionnaire-based survey on the Internet concerning optimal timing for knee surgery in a patient with rheumatoid arthritis].

To investigate the differences between orthopedists and internists in indications for surgical management in patients with rheumatoid arthritis (RA), a questionnaire-based survey was performed on the Internet with the presentation of a case of progressive RA along with serial X-ray films of the knee. Ninety-three doctors (43 orthopedists and 50 internists, average age: 49.2 years) answered the questionnaire. Most of the doctors who viewed the X-ray film showing Larsen's grade IV chose that as the optimal time for total knee arthroplasty. No difference was noted in their choice between orthopedists and internists. Opinions varied widely, however, among younger doctors, but there was agreement among older doctors, suggesting the effect of the study and experience. On the other hand, some doctors recommended arthroscopic synovectomy for knees in the earlier stages of RA, but others did not recommend the arthroscopic surgery itself. Although this new methodology might include possible biases, we believe it should be considered in the research of rheumatology.