Junnosuke Ryu

Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis

Objectives: A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA). Methods: The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly. Results: Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. “Infections” or “respiratory disorders” were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab. Conclusion: This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.

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.

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.

Effectiveness and safety of tocilizumab: Postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan

Objective. An all-patient postmarketing surveillance program was conducted to evaluate the safety and effectiveness of tocilizumab (TCZ) for rheumatoid arthritis (RA) in the real-world clinical setting in Japan. Methods. Patients received 8 mg/kg TCZ every 4 weeks and were observed for 28 weeks. Data were collected on patient characteristics, and drug safety and effectiveness. Results. A total of 7901 patients were enrolled. Percentages of total and serious adverse events (AE) were 43.9% and 9.6%, respectively. The most common serious AE were infections (3.8%). Logistic regression analysis identified the following risk factors for the development of serious infection: age ≥ 65 years, disease duration ≥ 10 years, previous or concurrent respiratory disease, and concomitant corticosteroid dose > 5 mg/day (prednisolone equivalent). The incidence rate of serious infections in patients with ≥ 3 risk factors was 11.2%, compared with 1.2% for patients without risk factors. The Week 28 rates of 28-joint Disease Activity Score–erythrocyte sedimentation rate remission, Boolean remission, and European League Against Rheumatism (EULAR) Good Response were 47.6%, 15.1%, and 59.4%, respectively. Contributing factors for effectiveness were body weight ≥ 40 kg, less advanced RA, no previous biologics, no concomitant corticosteroids or nonsteroidal antiinflammatory drugs, and low disease activity at baseline. From the benefit-risk balance analysis, patients with a high probability of remission and a low probability of developing serious infection were most likely to have less advanced RA and to have not received biologics previously. Conclusion. These data confirm the safety and effectiveness of TCZ in patients with RA in the real-world clinical setting in Japan and identify factors that contribute to the successful use of TCZ for RA.

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

Abstract 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.

The prevalence of and factors related to calcium pyrophosphate dihydrate crystal deposition in the knee joint.

OBJECTIVES The purpose of this study was to reveal the accurate prevalence and related factors to the presence of calcium pyrophosphate dihydrate (CPPD) crystal deposition in cadaveric knee joints. DESIGN Controlled laboratory study. METHODS Six hundred and eight knees from 304 cadavers (332 male knees and 276 female knees, formalin fixed, Japanese anatomical specimens) were included in this study. The average age of the cadavers was 78.3 ± 10.7 years. Knees were macroscopically evaluated for the existence of CPPD, and the depth of cartilage degeneration of the femoro-tibial joint following the Outerbridges classification. CPPD crystal was confirmed under Fourier transform infrared spectroscopy (FTIR) analysis using light microscopy. Statistical analysis was performed to reveal the correlation between the occurrence of CPPD deposition in the knee joint and gender, age, and the depth of cartilage degeneration of the femoro-tibial joint. RESULTS The prevalence of grossly visible CPPD crystal was 13% (79 knees). In all of these knees, CPPD crystal was confirmed under FTIR analysis. Statistical analysis showed significant correlation between the occurrence of CPPD deposition and gender (P < 0.001), and depth of cartilage degeneration in the femoro-tibial joint (P < 0.001). In the cartilage degeneration positive knees (Over grade 3 in Outerbridges classification), average age of CPPD deposition knee was significantly higher than CPPD negative knees. CONCLUSIONS In this study, the prevalence of CPPD deposition disease was evaluated in a relatively large sample size of cadaveric knees. The prevalence of CPPD deposition disease was 13%, and was significantly correlated with the subjects age, gender, and severity of cartilage degeneration in the femoro-tibial joint.

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.

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.

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.

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.