Safety and effectiveness of abatacept in Japanese non-elderly and elderly patients with rheumatoid arthritis in an all-cases post-marketing surveillance.

Objectives: To investigate the safety, effectiveness, and risk-benefit balance of intravenous abatacept (ABA) in non-elderly (<65 years: NEG) and elderly (≥65 years: EG) rheumatoid arthritis patients. Methods: This sub-analysis of an all-cases postmarketing surveillance in Japan assessed safety in all enrolled patients and effectiveness in those with Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) measurements at ≥2 time points including baseline. Risk-benefit was evaluated based on infections and DAS28-CRP improvement >1.2. Results: The NEG and EG of the safety analysis set comprised 2,170 and 1,712 patients, respectively; corresponding 6-month ABA retention rates were 80.2% and 77.1%. The NEG had fewer adverse drug reactions (14.5% vs. 17.2%, p = .021) and infections (4.8% vs. 7.2%, p = .002) than the EG. DAS28-CRP changed similarly between groups. The proportion of patients with low-risk/high-benefit and high-risk/low-benefit were 33.1% and 6.9% (NEG) and 29.7% and 9.0% (EG). Low-risk/high-benefit patients were younger, had shorter disease duration and fewer comorbidities, and were with less use of oral glucocorticoid and prior biologics, more use of methotrexate and higher DAS28-CRP than high-risk/low-benefit patients at baseline. Conclusion: ABA was well tolerated and similarly efficacious in the EG and NEG. Identification of factors related to low-risk/high-benefit may aid appropriate patient selection.

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

OBJECTIVE: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). METHODS: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. RESULTS: Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. CONCLUSIONS: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.

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.

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.

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.

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.

Opinions of Japanese rheumatology physicians regarding clinical practice guidelines.

OBJECTIVE: To examine the views of rheumatology physicians concerning clinical practice guidelines in Japan, and changes to them following the dissemination of new guidelines for rheumatoid arthritis (RA) in 2004. DESIGN: Two cross-sectional questionnaire surveys, the first conducted before publication of new evidence-based RA clinical practice guidelines and the second conducted after implementation. SETTING: Rheumatology-focused practices in Japan. PARTICIPANTS: A random sample of physicians registered with the Japan Rheumatism Foundation who satisfied the registration criteria with regard to experience with RA care. RESULTS: The percentage of guideline users increased from 48 to 60% following publication of the new RA guidelines in 2004 (P < 0.01). The majority agreed that clinical practice guidelines support decision-making in practice, although the proportion of supportive responses decreased slightly in the second survey, from 83 to 77% (P < 0.01) for decision-making, while concern about restricting physician autonomy increased from 18 to 22% (P = 0.01). While only 39% of physicians felt that clinical practice guidelines would contribute to malpractice litigation, the proportion of physicians who were concerned that clinical practice guidelines would be used to bring legal action against providers was larger than that who expected they would defend providers (58 vs 30%, P < 0.001). CONCLUSIONS: Clinical practice guidelines are well accepted among Japanese rheumatology physicians, albeit that the proportion decreased slightly after the introduction of new guidelines. One reason for this may be concern about the use of the guidelines in malpractice litigation. To facilitate implementation, trends in physician support for the guidelines should be closely monitored.

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.

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.

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.

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.

Survivin expression levels as independent predictors of survival for osteosarcoma patients.

Survivin expression has been detected in various cancers and correlations have been recognized between the level of expression of this gene in tumors and prognosis. However, the aforementioned authors did not evaluate correlations between prognosis and survivin expression levels using surgically resected samples. In this study, we retrospectively investigated outcomes by examining the correlations between expression of this gene and clinicopathological parameters. Biopsy and resected specimens from which paraffin-embedded tissues could be extracted, were available from 16 patients in our hospital. We used the RT-PCR method and conducted a densitometric analysis to determine the ratio of survivin relative to h-GAPDH as an internal marker. Expression of survivin mRNA was detected in all samples. There was a significant negative correlation between survivin expression levels and duration of follow up, in months, using the Spearman's rank for the initial biopsy samples (rho=-0.775, p<0.01) and those obtained after chemotherapy (rho=-0.687, p<0.01). Moreover, Cox multivariate regression identified the survivin expression levels in both biopsy and post-chemotherapy samples as independent predictors of survival. We conclude that survivin levels in both initial biopsy and post-chemotherapy samples are useful prognostic indicators.

Clinical significance of a wide excision policy for sacrococcygeal chordoma.

PURPOSE: Surgical treatment of sacrococcygeal chordoma is very difficult and the recurrence rate is high. We investigated the outcomes of wide excision in 12 sacrococcygeal chordoma patients treated between 1983 and 2003. METHODS: The 12 patients underwent primary wide excision. The conventional procedure was wide excision employing a chisel and airtome for sacral tumours, and in 1997 a new threadwire saw procedure was introduced. All 12 patients were included in a retrospective analysis of tumour- and treatment-related variables, and outcomes. RESULTS: Six patients underwent surgery with a combined anterior-posterior approach at the cephalad sacral border. In 12 patients, 11 lesions were broadly excised, and in the 1 remaining patient the intralesional margin showed tumour contamination due to a fracture macroscopically. The latter patient received post-operative radiation therapy, but suffered a recurrence 8.0 years later. Three patients died before final follow-up: one from subsequent metastases, two elderly patients from complications. For the 10 chordoma patients, i.e. excluding the two who died due to complications, the 5, 10 and 20 years recurrence rates were 100, 66.7 and 66.7%, respectively. For the 12 patients, overall 5, 10 and 20 years survival rates were 83.3, 55.6 and 55.6%, respectively. CONCLUSIONS: Our results suggest that large chordoma should be widely excised, using a modified threadwire saw, with a combination of anterior-posterior procedures.

New meniscus repair by an all-inside knot suture technique.

The indications for the all-inside knot suture technique include tears in the red-red zone or red-white zone in the meniscus, and a horizontal tear, a vertical tear, and a peripheral tear. First, find an appropriate place for a suture insertion site with a Kateran needle or a spinal needle. Make sure it exits beyond the tear in the meniscus. Once the insertion site is chosen, a suture is passed into and through the joint. The suture is slowly pulled back. You should be able to feel the tip of the suture come out of the joint capsule. If you want to make a vertical suture to suture the tear, move the suture vertically apex. Then insert the suture back into the joint through the capsule. Make sure the suture stays inside the joint. Find and grab the suture with a punch inserted from the clear cannula. Pull the suture out of the joint through the clear cannula with the punch. Tighten the knot with a knot pusher. Then confirm the stability of the sutured site with the probe. Our all-inside knot suture technique can be performed arthroscopically, allowing reliable repair of the torn meniscus.

[Surgical treatment of rheumatoid arthritis based on EBM].

Even though the advancement of pharmacotherapy, the maintenance treatment to keep the function of degenerated and destructed joint on rheumatoid arthritis and the surgical treatment for joint reconstruction are very important to prevent the patients from being bedridden and to keep the quality of life. The adaptation of operation varies among disease stage and site of bone destruction. Missing the chance of operation, it becomes impossible to perform surgical treatment. So it is important to consult with specialist finding proper opportunity.

Correlation between the histological grade of chondrosarcoma and the expression of MMPs, ADAMTSs and TIMPs.

BACKGROUND: The malignant degree of human chondrosarcoma can be difficult to determine using only histological findings. We, therefore, assessed the expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAM) with thrombospondin motifs (ADAMTSs) and tissue inhibitor of metalloproteinases (TIMPs) in chondrosarcoma and ascertained the relationships to histological degree of malignancy and prognosis. MATERIALS AND METHODS: In 28 chondrosarcoma cases, immunostaining was performed using antibodies against MMP 2, 3, 7, 9, 13, ADAMTS 4, 5 and TIMP 1, 2, 3. RESULTS: The chondrosarcoma were classified into groups of 7, 15 and 6 cases based on histologically malignant grade I, II and III, respectively. All target proteins were expressed in chondrosarcoma. Positive correlations (p < 0.05) existed between immunostaining scores and histological grades for all proteins except MMP 9, with strong correlations (p < 0.01) for MMPs 2, 3 and 13, both ADAMTSs and all 3 TIMPs. No correlation existed between prognosis and immunostaining scores. CONCLUSION: These target proteins could, thus, indicate the degree of malignancy in human chondrosarcoma.

Patellar dislocation: arthroscopic patellar stabilization with anchor sutures.

There are many procedures to treat recurrent patellar subluxations and dislocations. Most of these procedures are open repairs for acute conditions or open reconstructions for chronic conditions, and both surgeries need large skin incisions. Although there are many arthroscopic procedures for meniscal and ligament injuries, there are very few arthroscopic procedures described for patellofemoral instability. In this report, we describe a new arthroscopic method to stabilize the patella for acute dislocation. Our technique includes an arthroscopic lateral release and a medial structure repair. We suggest that this procedure is minimally invasive and easier than traditional open procedures. Moreover, this may prevent patients from developing chronic instability of the patellofemoral joint.