Taisuke Tomatsu

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.

Arthroscopic Synovectomy of the Elbow in Rheumatoid Arthritis

Background: The purpose of this study was to investigate the results of arthroscopic synovectomy for the treatment of elbows affected by rheumatoid arthritis.Methods: Arthroscopic synovectomy was performed on twenty-nine elbows (twenty-seven patients) between 1984 and 1996. Twenty-one elbows (twenty patients), followed for a minimum of forty-two months, were evaluated clinically with use of the Mayo elbow performance score and radiographic findings. The mean duration of follow-up was ninety-seven months. With use of the system of Larsen et al., we classified all elbows into three groupsæGrades 1 and 2, Grade 3, and Grade 4æaccording to the preoperative radiographic findings. These groups were then compared.Results: The mean Mayo elbow performance score improved from 48.3 points preoperatively to 77.5 points (an excellent result in two elbows, a good result in thirteen, a fair result in six, and a poor result in none) at two years after the operation and 69.8 points (an excellent result in two elbows, a good result in seven, a fair result in seven, and a poor result in five) at the final follow-up evaluation. The mean score for pain improved from 9.3 points preoperatively to 31.4 points at two years after the operation and 27.9 points at the final follow-up evaluation. Clinically apparent synovitis recurred in five of the twenty-one elbows, and two of the five required total elbow arthroplasty. Among the three groups, only elbows with Larsen Grade-1 or 2 arthritis had a favorable long-term result with regard to total function. The postoperative results were unsatisfactory for Larsen Grade-4 elbows.Conclusions: Arthroscopic synovectomy in an elbow affected by rheumatoid arthritis is a reliable procedure that can alleviate pain. Our results suggest that one of the most favorable indications for arthroscopic synovectomy is a preoperative radiographic rating of Grade 1 or 2.

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.

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.

Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population

AbstractProgrammed cell death 1 (PDCD1) is a necessary negative regulator to maintain peripheral tolerance and is a key molecule in the development of autoimmune diseases. Although PDCD1 gene polymorphisms and haplotypes were reported to be associated with rheumatoid arthritis (RA), replication studies later on showed conflicting results. Here, we analyzed the association of PDCD1 with RA using a large series of Japanese RA patients and population-based controls. DNA samples were obtained from 1,504 RA patients and 449 sex-matched controls. All samples were genotyped for three SNPs on PDCD1 (PD-1.1, PD-1.3 and PD-1.5) using the TaqMan fluorogenic 5′ nuclease assay. Chi-square testing was performed for a case-control study, and the PENHAPLO program was used for haplotype estimation. We could not observe any significant association of PD-1.1 or PD-1.5 polymorphisms between RA. PD-1.3, which was reported to be involved in susceptibility to RA in patients of European descent, was non-polymorphic in the Japanese population. We conclude that polymorphisms in the PDCD1 gene analyzed here are not associated with RA in a Japanese population.

The Influence of Sex on Patients with Rheumatoid Arthritis in a Large Observational Cohort

Objective. To compare the sex differences of various components of rheumatoid arthritis (RA). Methods. Data of 4823 patients from a large observational cohort study were analyzed. Remarkable differences were noted between the sexes, and overall, women had significantly higher disease activity. Results. When variables were adjusted using sex, age, and duration, Health Assessment Questionnaire, rather than Disease Activity Score, contributed most to sex difference. Further analysis showed evidence that progression of disability was approximately 3 times more rapid in female patients compared to male patients. Conclusion. Women overall have higher RA disease activity and are prone to greater and faster progression of disability over time.

MHC2TA is associated with rheumatoid arthritis in Japanese patients

Many diseases have increased expression of both major histocompatibility complex (MHC) class I and II molecules, and in particular the class II genes in the human leucocyte antigen region in particular are known to influence many chronic inflammatory diseases. Recently, a −168A→G polymorphism (rs3087456) in the type III promoter of MHC2TA, which has a pivotal role in MHC class II regulation, was found to be associated with increased susceptibility to rheumatoid arthritis in a Swedish population.1 However, most replication studies in other populations did not reproduce this finding, except a Spanish study.2–6 The purpose of this study was to see if the reported association could be observed in a Japanese population. DNA samples were …

Declining use of synovectomy surgery for patients with rheumatoid arthritis in Japan

Several studies from different countries suggest that the rates of orthopaedic surgery have decreased for patients with rheumatoid arthritis (RA) in recent years. From the Rochester Epidemiology Project, there was a reduction in the overall rates for all types of joint-related surgery inpatients.1 The California State Hospitalization Database for 1983–2001 reported a decrease in the rate of total knee arthroplasty for patients with RA.2 From Scandinavian countries, there was a decrease of RA-related surgical procedures to the lower limbs in Swedish patients between 1987 and 2001,3 from Denmark a decrease in the incidence rate of total hip arthroplasties due to RA was reported,4 …

A role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis

We studied the role of monocyte chemoattractant (MCP)‐4/CCL13 in the pathogenesis of rheumatoid arthritis (RA). MCP‐4 was highly expressed in cartilage from RA patients. Interferon‐γ significantly stimulated MCP‐4/CCL13 production in human chondrocytes, and this effect was enhanced in combination with interleukin‐1β or tumor necrosis factor‐α. MCP‐4/CCL13 induces the phosphorylation of extracellular signal‐regulated kinase in fibroblast‐like synoviocytes and activates cell proliferation, and PD98059 completely inhibits these effects. These data suggest that interferon‐γ in combination with interleukin‐1β/tumor necrosis factor‐α activates the production of MCP‐4/CCL13 from chondrocytes in RA joints, and that secreted MCP‐4/CCL13 enhances fibroblast‐like synoviocyte proliferation by activating the extracellular signal‐regulated kinase mitogen‐activated protein kinase cascade.

Risk factors associated with incident fractures in Japanese men with rheumatoid arthritis: a prospective observational cohort study

There are limited data in the literature concerning risk factors for incident fractures in men with rheumatoid arthritis (RA). We evaluated the association between potential risk factors and incident clinical fractures in male Japanese patients with RA. A total of 1050 male patients with RA were enrolled in a prospective, observational cohort study from 2000 to 2005. Participants were followed from 6 to 66 months (median follow-up, 48.7 months) and classified into three groups according to their incident fracture status from baseline: no new fracture, any new nonvertebral fracture, and new clinical vertebral fracture. The associations of potential risk factors were analyzed by Cox proportional hazards models. During follow-up, 30 patients (2.9%) developed a new nonvertebral fracture or a vertebral fracture. The baseline age, history of total knee replacement (TKR), and serum C-reactive protein (CRP) levels were associated with any nonvertebral fracture [baseline age: hazard ratio (HR), 1.08, 95% confidence interval (CI), 1.03–1.14; history of TKR: HR 6.02, 95% CI 1.19–30.42; and CRP: HR 0.60, 95% CI 0.38–0.95]. The baseline Japanese health assessment questionnaire (HAQ) score and daily dose of prednisolone were also associated with the incidence of clinical vertebral fractures (HR 7.74, 95% CI 2.10–28.48, and HR 1.28, 95% CI 1.14–1.45, respectively). Older age, history of TKR, and low serum CRP levels appear to be associated with any incident nonvertebral fracture in Japanese men with RA. High HAQ disability score and baseline doses of daily prednisolone may correlate with incident clinical vertebral fracture in Japanese men with RA.