Takuji Iwamoto

Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients

Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. In RA synovial tissue, the infiltrating cells such as macrophages, T cells, B cells and dendritic cells play important role in the pathogenesis of RA. Migration of leukocytes into the synovium is a regulated multi‐step process, involving interactions between leukocytes and endothelial cells, cellular adhesion molecules, as well as chemokines and chemokine receptors. Chemokines are small, chemoattractant cytokines which play key roles in the accumulation of inflammatory cells at the site of inflammation. It is known that synovial tissue and synovial fluid from RA patients contain increased concentrations of several chemokines, such as monocyte chemoattractant protein‐4 (MCP‐4)/CCL13, pulmonary and activation‐regulated chemokine (PARC)/CCL18, monokine induced by interferon‐γ (Mig)/CXCL9, stromal cell‐derived factor 1 (SDF‐1)/CXCL12, monocyte chemotactic protein 1 (MCP‐1)/CCL2, macrophage inflammatory protein 1α (MIP‐1α)/CCL3, and Fractalkine/CXC3CL1. Therefore, chemokines and chemokine‐receptors are considered to be important molecules in RA pathology.

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.

Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-α blockers: perioperative interruption of tumour necrosis factor-α blockers decreases complications?

OBJECTIVE TNF-alpha blockers reportedly increase the risk of complications in rheumatic patients following surgery. Whereas deep venous thrombosis (DVT) is a significant complication after orthopaedic surgery of the lower limbs, the risk for DVT in RA patients receiving TNF blockers remains unclear. The aim of this study was to identify complications that can be attributed to the use of TNF-alpha blocker therapy. METHODS In a retrospective 1:1 pair-matched case-control study, 64 anti-TNF-treated RA surgeries (TNF group) and 64 surgeries treated with conventional DMARDs (DMARDS group) were evaluated for surgical site infection (SSI), DVT and recurrence of arthritis (flare-up). Multivariate logistic regression analysis was performed to test the association of SSI or DVT with the putative risk factors. RESULTS Regression analysis identified the use of TNF blockers as a risk factor for SSI [P = 0.036; odds ratio (OR) = 21.80] and development of DVT (P = 0.03; OR = 2.83) after major orthopaedic surgery: 12.5% (8/64) of the patients in the TNF group had SSI, whereas 2% (1/64) of those in the DMARDs group had SSI. Fifty-one per cent (23/45) of the TNF group, but only 26% (12/45) of the DMARDs group was DVT positive. Flare-ups during the perioperative period were found in 17.2% (11/64) of all patients, and no delay in wound healing occurred in either group. CONCLUSIONS These data suggest that the use of TNF blockers is a likely cause of SSI and DVT development in RA patients following major orthopaedic surgery.

Decrease in orthopaedic operations, including total joint replacements, in patients with rheumatoid arthritis between 2001 and 2007: data from Japanese outpatients in a single institute-based large observational cohort (IORRA)

Several studies from different countries show that the rate of orthopaedic surgery has decreased for patients with rheumatoid arthritis (RA) in recent years. In Sweden, there was a decrease in RA-related lower limb surgical procedures between 1987 and 2001,1 and in RA-related upper limb surgery between 1998 and 2004.2 Denmark has reported a decrease in the incidence of total hip arthroplasties due to RA,3 and the number of total joint replacement (TJR) operations and synovectomies decreased in the Norwegian population from 1994 to 2004.4 Japan has also reported the declining use of synovectomy surgery for patients with RA.5 These changes may reflect trends in disease severity, management and health outcomes in each country. Meanwhile, Sokka et al reported that the rate of TJR …

Raised monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebrospinal fluid of patients with neuropsychiatric lupus

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.

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.

Corrective Osteotomy for Volarly Malunited Distal Radius Fracture

PURPOSE To retrospectively analyze consecutive cases with opening wedge corrective osteotomy of the volarly malunited distal radius with iliac bone graft, including preoperative and postoperative comparison of symptoms, visual analog scale (VAS), Japanese Society for Surgery of the Hand version of the Disabilities of the Arm, Shoulder, and Hand (DASH-JSSH) questionnaires, radiographic indices, clinical results as evaluated by modified Mayo wrist score, and complications. METHODS Subjects were 28 patients with volarly malunited distal radius fracture treated by transverse opening wedge osteotomy with oblique iliac bone graft. Preoperative symptoms included wrist deformity, weakness of grip strength, and marked restriction of supination range. Postoperative symptoms, radiographic parameters, clinical results, and complications were analyzed at an average of 25 months of follow-up. We also analyzed the union period of the radius in younger patients (< or =45 years old) and older patients (>45 years old). RESULTS Mean preoperative visual analog scale was 45, improving significantly to 3 postoperatively. Range of wrist motion improved in all 28 patients, with supination range improving from 16 degrees preoperatively to 80 degrees postoperatively. Mean preoperative DASH-JSSH score was 55, improving to 9 postoperatively. Radiography revealed that volar tilt improved from 32 degrees preoperatively to 10 degrees postoperatively, and radial inclination increased from 17 degrees to 21 degrees . Preoperative ulnar variance of +5.9 mm was corrected to -0.1 mm postoperatively. All 28 wrists demonstrated bony union at the osteotomy site after an average of 52 days (younger patients, 51 days; older patients, 54 days). No complications, significant radiographic correction loss, or nonunion were seen after at least 2 years of follow-up. Modified Mayo wrist score was excellent in 16 patients, good in 10 patients, and fair in 2 patients. CONCLUSIONS Opening wedge osteotomy for volarly malunited distal radius fracture restored bony configuration of the distal radius, decreased pain, and improved grip strength and range of wrist motion, particularly for forearm supination. No complications or noteworthy correction loss were noted after surgery, even in older patients. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic IV.

Recent trends in orthopedic surgery performed in Japan for rheumatoid arthritis

The aim of this report was to review the use of orthopedic surgeries performed to manage rheumatoid arthritis (RA). Our review of studies published in English indicates that there has been a decrease in RA-associated surgeries in Western countries. Improvements in medical treatment may partly explain the reduction in numbers of orthopedic joint surgeries, which also suggests a worldwide trend toward improved long-term outcomes. However, the results of our multicenter study in Japan indicate that the number of RA-associated operations has not decreased, and that the numbers of operations performed annually have been relatively stable from 1998 to 2008. Although there definitely has been a decline in the numbers of synovectomy surgeries, the numbers of operations on the upper limbs and foot arthroplasties have increased. With the trend toward milder disease because of improved medical treatment, we speculate that RA patients may want and need better function for the activities of daily living. The combination of medical treatment and surgical intervention is thought to improve outcomes in RA patients who will develop joint destruction. Additional studies, including analyses of RA databases containing long-term data on a variety of surgical interventions, are needed.

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.

Three-dimensional anthropometric analysis of the glenohumeral joint in a normal Japanese population

BACKGROUND An understanding of normal glenohumeral geometry is important for anatomical reconstruction in shoulder arthroplasty. Unfortunately, the details of the glenohumeral joint in Asian populations have not been sufficiently evaluated. The purpose of this study was to evaluate the 3-dimensional geometry of the glenohumeral joint in the normal Japanese population and to clarify its morphologic features. METHODS Anthropometric analysis of the glenohumeral joint was performed using computed tomography scans of 160 normal shoulders from healthy Japanese volunteers. The glenohumeral dimensions and orientation were analyzed 3-dimensionally. Sex differences and correlations between sides and among the respective parameters in the glenohumeral dimensions were evaluated. RESULTS The normal Japanese humeral head has an average width of 41.4 mm, thickness of 13.2 mm, diameter of 42.9 mm, retroversion of 32°, and inclination of 135°. The glenoid has an average height of 31.5 mm, width of 23.1 mm, diameter of 62.0 mm, retroversion of 0°, and inferior inclination of 2°. The values of the glenohumeral dimensions were uniform in men and women, and the humeral head and glenoid were larger in men than in women. The glenohumeral size was well correlated between the 2 sides, and there were direct correlations among the heights, humeral length, humeral head size, and glenoid size. CONCLUSIONS The present study revealed the glenohumeral geometry in the normal Japanese population. The present results would be useful to determine the size of implants and to improve the design of shoulder prostheses that reflect the normal anatomy of the Asian glenohumeral joint.