Published papers

Rheumatoid arthritis (RA) is a multi-factorial disease characterized by chronic inflammation and destruction of multiple joints. To date, various biologic treatments for RA such as anti-tumor necrosis factor alpha antibodies have been developed; however, mechanisms underlying RA development remain unclear and targeted therapy for this condition has not been established. Here, we provide evidence that signal transducer and activator of transcription 3 (Stat3) promotes inflammation and joint erosion in a mouse model of arthritis. Stat3 global KO mice show early embryonic lethality; thus, we generated viable Stat3 conditional knockout adult mice and found that they were significantly resistant to collagen-induced arthritis (CIA), the most common RA model, compared with controls. We then used an in vitro culture system to screen ninety-six existing drugs to select Stat3 inhibitors and selected five candidate inhibitors. Among them, three significantly inhibited development of arthritis and joint erosion in CIA wild-type mice. These findings suggest that Stat3 inhibitors may serve as promising drugs for RA therapy.

BACKGROUND: Although femoral nerve block provides satisfactory analgesia after total knee arthroplasty (TKA), residual posterior knee pain may decrease patient satisfaction. We conducted a randomized controlled trial to clarify the efficacy of the sciatic nerve block (SNB) and local infiltration of analgesia with steroid (LIA) regarding postoperative analgesia after TKA, when administrated in addition to femoral nerve block (FNB). METHODS: Seventy-eight patients were randomly allocated to the two groups: concomitant administration of FNB and SNB or FNB and LIA. The outcome measures included post-operative pain, passive knee motion, C-reactive protein level, time to achieve rehabilitation goals, the Knee Society Score at the time of discharge, patient satisfaction level with anesthesia, length of hospital stay, surgical time, and complications related to local anesthesia. RESULTS: The patients in group SNB showed less pain than group LIA only on postoperative hours 0 and 3. Satisfactory postoperative analgesia after TKA was also achieved with LIA combined with FNB, while averting the risks associated with SNB. The influence on progress of rehabilitation and length of hospital stay was similar for both anesthesia techniques. CONCLUSIONS: The LIA offers a potentially safer alternative to SNB as an adjunct to FNB, particularly for patients who have risk factors for sciatic nerve injury.

PURPOSE: The flexion-extension axis (FEA) of the femur is substantially changed after mechanically aligned total knee arthroplasty (TKA) due to a discrepancy in bone cut thickness between the posterior and distal femoral regions. This study assessed the bony gap changes and FEA displacement caused by this problem in osteoarthritis patients. METHODS: The study enrolled 60 knees from 60 patients for whom primary TKA was planned due to medial knee osteoarthritis. All patients underwent computed tomography, and 3-dimensional (3D) bone models were reconstructed on 3D-planning software. Bone cuts of the distal femur and proximal tibia were simulated to be perpendicular to each mechanical axis. Bony gap change was computed as the difference in bone cut thickness between medial and lateral compartments. Each femoral condyle was assessed for potential FEA displacement, as the difference in bone cut thickness between posterior and distal femoral regions. RESULTS: The mean magnitude of bony gap discrepancy necessary for mediolateral balancing was 1.6 +/- 3.3 mm (range -7 to 8.2 mm) at 0 degrees extension and -0.2 +/- 2.6 mm (range -6.4 to 4.3 mm) at 90 degrees flexion. At least 2 mm of bony gap discrepancy at 0 degrees extension and 90 degrees flexion was found in 40 patients (67%) and 26 patients (43%), respectively. In terms of femoral bone cut, posterior bone cut thickness was significantly larger than distal bone cut thickness in the medial compartment (p < 0.001). Bony gap discrepancy between distal and posterior regions of the femoral condyle was >/=2 mm in 28 patients (47%). CONCLUSIONS: This study focused on two flaws of mechanically aligned TKA in OA patients. Substantial numbers of patients inevitably required >2 mm of medial collateral ligament release at 0 degrees extension and showed a bone cut discrepancy between distal and posterior regions, carrying a risk of FEA displacement and subsequent unnatural knee motions during knee extension and flexion. Level of evidence IV.

BACKGROUND: The aims of the present study were to investigate the factors affecting one-leg standing (OLS) time in patients with end-stage knee osteoarthritis (OA) and to clarify the age-related recovery process following total knee arthroplasty (TKA) in the early postoperative period. METHODS: A total of 80 knees of 40 patients with knee OA were enrolled. They were asked to perform relaxed standing on one leg for as long as possible. First, OLS time was measured. Second, age, body mass index, knee flexion angle during (KFA) OLS, femorotibial angle (FTA) during OLS, and a visual analogue scale (VAS) for pain were evaluated. Multiple regression analysis was done to identify the factors affecting OLS time. In addition, the recovery process was compared between older and younger patients after TKA. RESULTS: A larger KFA during OLS, older age, and larger FTA were significantly associated with shorter OLS time. After TKA, postoperative OLS time in older patients did not improve significantly by postoperative day 20, while the time in younger patients improved significantly from postoperative day 19. CONCLUSIONS: Even if subjective knee pain and KFA during OLS improved, longer rehabilitation was required to improve OLS time in older patients in the early postoperative period.

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.

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that affects 0.5-1% of the population. RA causes progressive joint destruction that leads to the restriction of activities of daily living and deterioration of quality of life. Although the pathogenesis of RA has not yet been fully elucidated, it is considered to be a complex, multifarious disease that is influenced by both genetic and environmental factors. Genetic influences that contribute to RA susceptibility have been demonstrated both in studies of twins and families, as well as in genome-wide linkage scans, and it is estimated that genetic factors are responsible for 50-60% of the risk of developing RA. Thus, environmental factors may explain the remaining risk of developing RA. A large variety of environmental factors such as infectious agents, smoking, sex hormones, pregnancy etc. have been extensively studied previously. Understanding of how these factors contribute to the development of RA may lead to the better understanding of pathogenesis of RA.

OBJECTIVE: STAT4 encodes a transcriptional factor that transmits signals induced by several key cytokines, and it might be a key molecule in the development of autoimmune diseases. Recently, a STAT4 haplotype was reported to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in Caucasian populations. This was replicated in a Korean RA population. Interestingly, the degree of risk of RA susceptibility with the STAT4 haplotype was similar in the Caucasian and Korean populations. The present study was undertaken to investigate the effect of STAT4 on susceptibility to RA and SLE in the Japanese. METHODS: We performed an association study using 3 independent Japanese RA case-control populations (total 3,567 cases and 2,199 controls) and 3 independent Japanese SLE populations (total 591 cases). All samples were genotyped using the TaqMan fluorogenic 5' nuclease assay for single-nucleotide polymorphism (SNP) rs7574865, which tags the susceptibility haplotype. The association of the SNP with disease susceptibility in each case-control study was calculated using Fisher's exact test, and the results were combined, using the Mantel-Haenszel method, to obtain combined odds ratios (ORs). RESULTS: We observed a significant association of the STAT4 polymorphism with susceptibility to both RA and SLE. The combined ORs for RA and SLE, respectively, were 1.27 (P = 8.4 x 10(-9)) and 1.61 (P = 2.1 x 10(-11)) for allele frequency distribution; these ORs were quite similar to those previously observed in the Caucasian population. CONCLUSION: We conclude that STAT4 is associated with RA and SLE in the Japanese. Our results indicate that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups.

We present two rheumatoid arthritis (RA) patients suffering from disturbances of the symphysis pubis. Radiography revealed one with pelvic ring disruption with symphysis pubis diastasis, and the other with osteolysis at both pubic rami and disruption of the superior aspect of the symphysis pubis. Both cases had received long-term corticosteroid therapy, including pulse therapy. We recommend reducing the corticosteroid dose to prevent disturbances of the symphysis pubis especially in RA patients on long-term steroid therapy.

Our aim was to determine whether the use of infliximab for rheumatoid arthritis (RA) patients is associated with an increased rate of postoperative complications. In this study we evaluated the serum concentration of infliximab to study the influence of autologous blood donation (AB donation) in patients who were administered infliximab and underwent total knee replacement (TKR). We examined five RA patients. Infliximab combined with methotrexate was administered at 3 mg/kg every 8 weeks for all patients. We carried out the TKR operation in the middle of the 8-week interval in which infliximab was administered. The AB donation consisted of 400 ml pooled AB drawn at one point 2 weeks following the final administration of infliximab. Serum infliximab levels were measured using an enzyme-linked immunosorbent assay. Mean serum infliximab levels were 5.46 +/- 5.62 microg/ml 2 weeks after the final administration of infliximab, 2.02 +/- 1.66 microg/ml just before the operation, and 1.48 +/- 1.31 microg/ml 1 day post operation. Moreover, the mean serum level in an autologous blood bag sampled just before AB donation was 5.02 +/- 4.79 microg/ml. This study indicated the serum level of infliximab in the stored blood remained at almost the same level as the collected autologous blood. However, even after autotransfusion those levels were decreased compared with levels measured just before the operation. Therefore, we conclude that there is little influence of AB donation on the risks of infliximab.

Castleman's disease (CD), diffuse idiopathic skeletal hyperostosis (DISH), and ossification of the posterior longitudinal ligament of the spine (OPLL) are three different entities. Castleman's disease displaying a variety of calcifications in the abdomen and/or pelvis has been reported in some papers. However, there were no reports suggesting an association between CD and ossification/calcification in spine and joints. So far, there has been no case report regarding the coexistence of these diseases in the literature. Herein, we detail a 75-year-old man suffering from CD who demonstrated the features of DISH with coexisting features of OPLL. The cardinal symptoms such as fatigue, high fever, and swollen glands in this case were reduced by corticosteroid therapy. However, it is possible to produce actual symptoms of ossifying/calcified diathesis of entheses and ligaments as a consequence, like the pathology of calcification found in the region of the spleen. In this paper, we describe this patient in order to discuss the association of these diseases.

We report the unique occurrence and treatment of spontaneous multiple insufficiency fractures after sepsis in a patient with rheumatoid arthritis (RA). The patient was a 53-year-old woman with a 13-year history of RA. Her disease activity was not influenced by a disease-modifying antirheumatic drug (DMARD) regimen that included bucillamine, D-penicillamine, gold, sulfasalazine, and methotrexate. Due to an increased disease activity, her DMARD treatment regimen was changed to leflunomide. She had also undergone corticosteroid therapy with prednisolone ranging from 10 to 15 mg daily over the previous 8 years. She first presented with a wound infection at the surgical site of resection arthroplasty on her left foot, which had caused hematogenous dissemination that led to pelvic abscess and sepsis. For the next 2 years, she experienced multiple insufficiency fractures in parts of the ilium, sacral body, sacral ala, three thoraco-lumbar vertebral bodies (T12, L1, and L2), and subcapital femoral neck without low energy trauma. Postmenopausal osteoporosis, pelvic abscess, sepsis, decreasing daily activity, high RA disease activity, and high-load corticosteroid therapy were considered to be the causes of these fractures. Nonspecific symptoms such as low back pain and fever delayed diagnosis, which may have led to secondary fractures. Although her course after treatment was satisfactory during the study period, we recommend taking repetitive radiographs to detect insufficiency fracture for RA patients with continuing pain and reducing the corticosteroid dose to prevent infection and fracture.

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-gamma significantly stimulated MCP-4/CCL13 production in human chondrocytes, and this effect was enhanced in combination with interleukin-1beta or tumor necrosis factor-alpha. 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-gamma in combination with interleukin-1beta/tumor necrosis factor-alpha 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.