Safety and effectiveness of 6 months' etanercept monotherapy and combination therapy in Japanese patients with rheumatoid arthritis: effect of concomitant disease-modifying antirheumatic drugs.

OBJECTIVE: To assess real-world safety, tolerability, and effectiveness of etanercept monotherapy, etanercept plus methotrexate (MTX), or etanercept plus other disease-modifying antirheumatic drugs (DMARD) in Japanese patients with active rheumatoid arthritis (RA) despite previous treatment with DMARD. METHODS: In this 24-week, all-cases postmarketing surveillance study, adverse events (AE) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was assessed every 4 weeks using the 28-joint Disease Activity Score and the European League Against Rheumatism response criteria. RESULTS: Of 13,861 patients (81% women) in the analysis, 3616, 2506, and 7739, respectively, were classified into etanercept monotherapy (ETN-mono), etanercept plus DMARD other than MTX (ETN + DMARD), and etanercept plus MTX (ETN + MTX) groups. Rates of AE and serious AE (SAE) in the ETN + MTX group were lower than in other groups. Risk of SAE or serious infections was not significantly increased with higher versus lower MTX doses at baseline or with concomitant use of salazosulfapyridine or bucillamine in ETN + DMARD versus ETN-mono groups. A greater likelihood of achieving clinical remission was seen with ETN + MTX versus ETN-mono (OR 1.36; 95% CI, 1.16-1.60; p < 0.001). Higher MTX dose at baseline was associated with a higher remission rate (> 8 mg vs 0 to ≤ 4 mg, OR 1.47, 95% CI 1.07-2.00, p = 0.016; 6 to ≤ 8 mg vs 0 to ≤ 4 mg, OR 1.27, 95% CI 1.01-1.60, p = 0.038). CONCLUSION: Combination therapies with etanercept plus MTX or other DMARD were reasonably well tolerated, and ETN + MTX at higher doses was more effective than ETN-mono in Japanese patients with RA.

Osteoarthritis of the patella, lateral femoral condyle and posterior medial femoral condyle correlate with range of motion.

PURPOSE: The type of osteoarthritis and the degree of severity which causes restriction of knee range of motion (ROM) is still largely unknown. The objective of this study was to analyse the location and the degree of cartilage degeneration that affect knee range of motion and the connection, if any, between femorotibial angle (FTA) and knee ROM restriction. METHODS: Four hundreds and fifty-six knees in 230 subjects with knee osteoarthritis undergoing knee arthroplasty were included. Articular surface was divided into eight sections, and cartilage degeneration was evaluated macroscopically during the operation. Cartilage degeneration was classified into four grades based on the degree of exposure of subchondral bone. A Pearson correlation was conducted between FTA and knee flexion angle to determine whether high a degree of FTA caused knee flexion restriction. A logistic regression analysis was also conducted to detect the locations and levels of cartilage degeneration causing knee flexion restriction. RESULTS: No correlation was found between FTA and flexion angle (r = -0.08). Flexion angle was not restricted with increasing FTA. Logistic regression analysis showed significant correlation between restricted knee ROM and levels of knee cartilage degeneration in the patella (odds ratio (OR) = 1.77; P = 0.01), the lateral femoral condyle (OR = 1.62; P = 0.03) and the posterior medial femoral condyle (OR = 1.80; P = 0.03). CONCLUSION: For clinical relevance, soft tissue release and osteophyte resection around the patella, lateral femoral condyle and posterior medial femoral condyle might be indicated to obtain a higher degree of knee flexion angle.

Osteogenic effects of dedifferentiated fat cell transplantation in rabbit models of bone defect and ovariectomy-induced osteoporosis.

We have previously reported that mature adipocyte-derived dedifferentiated fat (DFAT) cells have a high proliferative activity and the potential to differentiate into lineages of mesenchymal tissue similar to bone marrow mesenchymal stem cells (MSCs). In the present study, we examined the effects of autologous DFAT cell transplantation on bone regeneration in a rabbit bone defect model and an ovariectomy (OVX)-induced osteoporosis model. The formation of tissue-engineered bone (TEB) was observed when rabbit DFAT cells were loaded onto a ß-tricalcium phosphate (TCP)/collagen sponge and cultured in an osteogenic differentiation medium for 3 weeks. Autologous implantation of DFAT cell-mediated TEB constructs promoted bone regeneration in a rabbit tibial defect model. Regenerated bone tissue induced by transplantation of DFAT cell-mediated TEB constructs was histologically well differentiated and exhibited higher bone strength in a three-point bending test compared to that induced by the ß-TCP/collagen sponge alone. In OVX-induced osteoporosis model rabbits, DFAT cells were obtained with the osteogenic activity similar to cells from healthy rabbits. Intrabone marrow injection of autologous DFAT cells significantly increased the bone mineral density (BMD) at the injected site in the OVX rabbits. Transplanted DFAT cells remained mainly on the injection side of the bone marrow by at least 28 days after intrabone marrow injection and a part of them expressed osteocalcin. In conclusion, these results demonstrate that autologous implantation of DFAT cells contributed to bone regeneration in a rabbit bone defect model and an OVX-induced osteoporosis model. DFAT cells may be an attractive cell source for cell-based bone tissue engineering to treat nonunion fractures in all patients, including those with osteoporosis.

Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese postmarketing surveillance study.

Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor-α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P < 0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment.

Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis.

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2-5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs.

Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients.

OBJECTIVE: An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world. METHODS: This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. RESULTS: Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. CONCLUSIONS: Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.

Previous fracture surgery is a major risk factor of infection after total knee arthroplasty.

PURPOSE: Total knee arthroplasty (TKA) has been proven to be the most effective treatment for patients with severe joint disease. Although infection is not a frequent complication, it is certainly one of the most dreaded. The purpose of this study was to identify factors associated with infection after TKA. METHODS: Between 1995 and 2006, 2,022 primary TKAs in 1,146 patients were evaluated. Flexible Nichidai Knee (FNK) was used as a prothesis in all subjects. Twenty-four patient-specific data items were collected via chart review for each patient. Revision arthroplasty procedures and infected knees were excluded. The medical records were reviewed to extract the following information: age, gender, body mass index (BMI), preoperative C-reactive protein (CRP), preoperative erythrocyte sedimentation rate (ESR), preoperative total protein (TP), duration of surgery, operative blood loss, total blood loss, duration of surgical drain, duration of antibiotic prophylaxis, primary diagnoses, smoking, diabetes mellitus, steroid or disease modifying anti-rheumatic drugs (DMARDs) therapy, previous operation around the knee joint, previous arthroscopic surgery, previous non-arthroscopic surgery, previous high tibial osteotomy (HTO) or open reduction internal fixation (ORIF), remnants of previous internal fixation material, bone graft, patella replacement, and bone cement. RESULTS: The median age of the patients at the time of primary TKA was 72 (range, 26-91) years. The median follow-up period after primary TKA was 42 (range, 6-145) months. During the study period, 17 infected knee arthroplasties in 17 patients were identified. Previous history of ORIF, male gender, remnants of previous internal fixation material, and BMI showed significant correlation with postoperative infection. CONCLUSION: This study identified previous history of fracture and remnants of internal fixation as major risk factors of infection after TKA. For clinical relevance, surgeons should be aware of potential infection when performing TKA in patients with these risk factors and patients should be informed of the potential risks.

Postmarketing surveillance of safety and effectiveness of etanercept in Japanese patients with rheumatoid arthritis.

Our aim was to evaluate real-world safety and effectiveness in a 6-month postmarketing surveillance study covering all Japanese patients with rheumatoid arthritis (RA) who received etanercept during a 2-year period. Data for 13,894 patients (1334 sites) enrolled between March 2005 and April 2007 were collected. Adverse events (AEs) and serious adverse events (SAEs) were reported in 4336 (31.2%) and 857 (6.2%) patients, respectively. The most frequent AEs were injection site reactions (n = 610, 4.4%) and rash (n = 339, 2.4%), whereas pneumonia (n = 116, 0.8%) and interstitial lung disease (n = 77, 0.6%) were the most frequent SAEs. Significant improvement in the proportion of patients with a good European League Against Rheumatism (EULAR) response was observed from week 4 (17.6%) to week 24 (31.6%) (p < 0.001); 84.3% of patients had good or moderate EULAR responses at week 24. The percentage of patients achieving remission increased significantly from week 4 (9.3%) to week 24 (18.9%) (p < 0.001). Patients with early moderate RA were less likely to experience SAEs and were more likely to achieve remission compared with patients with more severe disease. The safety and effectiveness of etanercept was demonstrated in Japanese patients in one of the largest observational trials conducted thus far in RA patients treated with biologics.

Reconstruction of the knee extensor mechanism in patients with a malignant bone tumor of the proximal tibia.

PURPOSE: Reconstruction of the knee extensor mechanism after the excision of a malignant bone tumor is often difficult, particularly if the tumor is located in the proximal tibia. We developed a novel method to reconstruct the knee extensor mechanism using autologous fasciae, and subsequently evaluated the efficacy of this method. METHODS: We examined the studied reconstruction method, range of motion, extension lag, knee extensor strength, and functional evaluation of three patients with a malignant bone tumor in the proximal tibia. All three patients underwent reconstruction of the knee extensor mechanism by our method. RESULTS: All patients experienced satisfactory outcomes with regard to the above-mentioned parameters. The functional evaluation scores in the three patients were 90%, 95%, and 95% (mean, 90%). CONCLUSION: In this analysis of our recently devised reconstruction method, the follow-up duration was short and only three patients were investigated. However, if appropriate patients are carefully selected for this procedure, long-term outcomes associated with new technique may be better than those associated with other methods of the knee extensor reconstruction.

Bactericidal effect of photodynamic therapy using Na-pheophorbide a: evaluation of adequate light source.

OBJECTIVE: To evaluate the efficacy of photodynamic therapy (PDT) against methicillin resistant-Staphylococcus aureus (MRSA) by selecting different light sources for irradiation and combining them with the photosensitizer Na-Pheophorbide a (Na-Phde a). BACKGROUND: The treatment of drug-resistant bacterial infection is a serious issue. Recently, as a new clinical approach against septic arthritis, an experimental in vivo and in vitro model for the inactivation of MRSA by PDT using the photosensitizer Na-Phde a has been developed. MATERIALS AND METHODS: Na-Phde a solution (280 micromol/L) was mixed with MRSA strain bacterial inoculum. After 60 minutes, light was irradiated for 30 minutes using the following light sources: GaA1p semiconductor laser (300 mW, 670 nm), halogen lamp (75 W), xenon lamp (300 W) and fluorescent lamp (27 W). Bacterial growth was evaluated after 24 hours incubation in a blood agar culture. RESULTS: The semiconductor laser and halogen lamp groups showed perfect bactericidal effects after PDT. The xenon lamp and fluorescent lamp groups showed partial bactericidal effects. CONCLUSIONS: The results of this experiment showed that PDT using the combination of Na-Phde a with a semiconductor laser or halogen lamp showed a better bactericidal performance than with xenon or fluorescent lamps. These findings indicated that PDT using Na-Phde a could be a useful treatment for septic arthritis and soft tissue infection.

Unilateral developments of osteoarthritis and Charcot's joint in a patient with neurofibromatosis.

BACKGROUND: Precise mechanism of developing neuropathic arthropathy known as Charcot's joint is not fully understood. CASE REPORT: A 55-year-old Japanese woman with neurofibromatosis-1 complained of right gonalgia in December 2001. Physical examination revealed a huge tumor in the right lower leg without signs of inflammation. Laboratory findings were unremarkable. Radiographic examination disclosed the presence of osteoarthropathy in the right knee joint. In contrast, radiologic findings of the right foot and ankle were compatible with neuropathic arthropathy. Further investigations could not reveal abnormal findings in the nervous system. To improve patient's quality of life, partial resection of the tumor was performed. The resected tissues were compatible with neurofibromatosis without malignant transformation. The patient newly noticed pains in the right ankle and tarsal joints one year after the operation. Restricted mobility and insufficient blood supply in the right knee arising from the huge tumor might accelerate development of osteoarthropathy through malnutrition of the chondrocytes. Because the patient did not experience the arthralgia before the operation, the tumor might damage the peripheral nerves unabling to receive afferent signals from such joints resulting in neuropathic arthropathy. CONCLUSIONS: The damaged peripheral nerves might be contributory to developing or accelerating neuropathic arthropathy.

Postmarketing surveillance of the safety and effectiveness of etanercept in Japan.

OBJECTIVE: Postmarketing surveillance (PMS) was conducted evaluating safety and effectiveness of etanercept (ETN; Enbrel) in Japan, following all patients with rheumatoid arthritis (RA) during the conditional approval period of ETN. METHODS: Registration of patients from 1,334 medical sites was conducted between March 2005 and April 2007. Patients were followed for 24 weeks; data regarding patients' background, safety, and effectiveness was recorded centrally. Adverse events (AE) and adverse drug reactions (ADR) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was measured using the Disease Activity Score 28 (DAS28). RESULTS: Of 14,369 patients registered, data collection and evaluation for 7,091 patients by March 2006 is reported. At least 1 AE was observed for 2,173 patients (30.6%); 60% of AE occurred within 8 weeks of starting ETN. Most frequent AE were injection site reaction (n = 377, 5.3%) and rash (n = 228, 3.2%). Serious AE occurred in 403 patients (5.7%); most frequent were pneumonia (n = 59, 0.8%) and interstitial lung disease (n = 42, 0.6%). Pneumonia was the most common specifically important ADR (n = 102, 1.4%). Mean baseline DAS28 was 6.0, which reduced to 4.4 within 4 weeks, and to 3.9 within 24 weeks. The proportion of patients having good or moderate EULAR response measured by DAS28 was 84.1% at Week 24. Effectiveness rates were more favorable in patients concomitantly using methotrexate. Good or moderate EULAR response rate among patients switched from infliximab was 84.9%. CONCLUSION: This extensive observational trial, including all patients with RA in Japan taking ETN, found ETN to be both effective and well tolerated by Japanese patients with RA. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00503503.

Analysis and results of dissociation of the polyethylene liner in the Harris-Galante I acetabular component.

The Harris-Galante I modular acetabular components (Zimmer, Warsaw, Ind) were most widely used in the 1980s in primary and revision total hip arthroplasty. We assessed 76 primary total hip arthroplasties performed using Harris-Galante I modular acetabular components. Dissociation of the polyethylene liner occurred in 5 patients and required revision surgery. None of the 76 hips had fractures of the metal locking tines on the metal shell. Liner dissociation was attributed to fatigue fracture of the polyethylene, a result of a gap between the liner and the metal shell. The thin polyethylene liner rim aggravated failure. The revision technique was to cement the polyethylene liner into the well-fixed Harris-Galante metal shell. The average follow-up observation period after revision surgery was 6.4 years; and there was no recurrence of dissociation, which supports the use of our revision technique.

Effects of fibronectin on osteoinductive capability of fresh iliac bone marrow aspirate in posterolateral spinal fusion in rabbits.

STUDY DESIGN: A rabbit model of posterolateral intertransverse process spine arthrodesis was used. OBJECTIVE: To assess the osteogenic potential of hydroxyapatite (HA) sticks soaked with marrow and resultant strength in spinal fusion and effects of various biologic agents, in particular fibronectin (FN) on the strength. SUMMARY OF BACKGROUND DATA: Mesenchymal stem cells (MSCs) contained in marrow can differentiate into cells constituting bone, cartilage, muscles and fat. Unlike autogenous bone grafts, prosthetic bone grafts combined with marrow have failed to attain adequate strength of new bone even if they are used with marrow. METHODS: Porous HA sticks were used as a vehicle for new bone growth in spinal fusion. In experiment 1, rabbits received 2 HA sticks each with or without iliac marrow into the dorsal subcutaneous muscle. The sticks were explanted 6 weeks after surgery and tested mechanically and histologically. In experiment 2, 6 groups of animals underwent spinal fusions with 6 different bone grafts, either autogenous or prosthetic, and the local osteoinductive activity and mechanical strength of the fusion were evaluated. RESULTS: In experiment 1, the HA sticks implanted with marrow showed histologically more active osteogenesis and were mechanically stronger than those implanted alone. The increase in mechanical strength was significantly higher in the former group. In experiment 2, the spinal fusion with autogenous iliac bone was significantly stronger and more elastic than those with autogenous local bone and HA sticks with or without marrow (P < 0.05). The spinal fusion with HA sticks soaked with FN and marrow was significantly stronger than that with HA sticks soaked with marrow. The local osteogenesis after the fusion with HA sticks soaked with FN and marrow was more active than that with HA sticks plus marrow and HA stick plus FN. CONCLUSION: The impregnation of marrow into HA sticks produced histologically demonstrable active osteogenesis, possibly due to MSCs incorporated into the sticks. In the group receiving HA sticks soaked with FNand marrow, both osteogenesis and strength were increased to levels comparable to those achieved by spinal fusion with autogenous iliac bone grafts. It can be expected that the additional use of FN, which increases incorporation of MSCs into HA, will improve osteogenesis and hence the strength of the fusion.

The minimum influences for murine normal joint tissue by novel bactericidal treatment and photodynamic therapy using na-pheophorbide a for septic arthritis.

OBJECTIVE: In this study, we examined the effect of photodynamic therapy (PDT) using Na-pheophorbide a (Na-Phde a) on normal joint tissue. BACKGROUND DATA: The treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious issue. Recently, an experimental in vivo and in vitro model for the inactivation of MRSA by PDT using a photosensitizer, Na-Phde a, has been developed. MATERIALS AND METHODS: The knee joints of mice were injected with 560 or 280 micromol/L of Na-Phde a. Thirty minutes after injection, percutaneous laser irradiation was applied for 5 min using a semiconductor laser (power: 125 mW; wavelength: 664 nm; total energy: 12 J/cm2). The joint perimeter and body weight of the treated mice were monitored, and histological evaluation was also done. RESULTS: Joint swelling was observed up to 3 wk after PDT (p < 0.05). On histology 1 wk post-PDT, the treated knees were found to have inflammatory changes, primarily in synovial tissue. Eight weeks after PDT, the synovitis was no longer present. No significant effects were observed on cartilage, bone marrow, or menisci. CONCLUSIONS: The results of this experiment showed that PDT with Na-Phde a induced arthritis for a short time after treatment. However, this arthritis was reversible, and the PDT did not appear to induce osteoarthritic changes in normal joint tissue. These findings indicate that PDT using Na-Phde a caused minimal but reversible changes in joint tissue, suggesting that it would be a safe and useful treatment for bacterial septic arthritis.

Current state of extendable prostheses for the lower limb in Japan.

With the cooperation of the Japanese Musculoskeletal Oncology Group (JMOG), we conducted a questionnaire survey to assess the status of extendable prosthesis use after resection of malignant bone tumors in children. The subjects were 28 patients (mean age, 10.1 years). Osteosarcoma was the most frequent tumor, and all patients had undergone preoperative chemotherapy and wide resection. The prosthesis was the Growing Kotz-type in 26 patients. The mean predicted leg length discrepancy was 67.7mm, mean stem diameter 10mm, mean number of elongations 2.1, and mean total elongation 35.4mm. Infection was observed in one patient with a mean functional assessment of 75%. In Japan, extendable prostheses, as represented by the Growing Kotz-type, provide a useful limb reconstruction method, with a minimum of major complications and with good function of the affected limb. However, a long-term follow-up survey is necessary.

A comparative study for wide excision of malignant tumors distal to S2.

BACKGROUND AND AIM: We conducted a retrospective study comparing 5 patients (Group A) who underwent posterior excision of tumors distal to S2 using a modified threadwire saw (MT-saw) with 5 similar patients (Group B) who underwent tumor excision using chisels and airtomes. PATIENTS AND METHODS: The data of 10 patients were obtained from intra-operative records. A flexible silver guide probe connected to an MT-saw by a suture thread was devised for use in osteotomy passing through the S1 sacral canal in the lateral sacrum. Operative time, blood loss and excisional margins were compared between the two groups. RESULTS: Group A had a shorter average operative time (2 hours 24 minutes) and smaller average blood loss (2,124.6 ml) than Group B. In Group A, one patient incurred an S1 nerve root injury, and all patients had wide histological margins. In Group B, one patient had an S1 nerve root injury and another tumor contamination due to a fracture. CONCLUSION: The MT-saw greatly facilitated lateral sacral osteotomy and reduced the risk of tumor cell spread, permitting faster, safer excision with a wider margin.

Longitudinal osteotomy of lateral sacrum for malignant iliac tumor using modified threadwire saw.

A longitudinal osteotomy of lateral sacrum for malignant iliac tumors using modified threadwire saw is conducted. This procedure issignificantly wide, rapid and safe.