Daizo Kato

Study protocol of a multicenter registry of patients with rheumatoid arthritis starting biologic therapy in Japan: Tsurumai Biologics Communication Registry (TBCR) Study

Biologic agents have proven to be effective against rheumatoid arthritis (RA) in clinical trials and post-marketing surveillance (PMS) studies. However, limited follow-up periods and strict criteria for recruitment might lead to an underestimation of adverse events. To document the long-term course of patients with RA treated with biologics in clinical settings, we established the Tsurumai Biologics Communication Registry (TBCR). First, we retrospectively collected data of patients registered for any biologic PMS study or clinical trial at participating institutes. Thus far, thirteen institutes have joined the registry and 860 patients have been identified. Comparing baseline characteristics by age and initiation year of biologics, young patients had significantly less joint damage and dysfunction and a higher dose of concomitant methotrexate (MTX) compared to older patients. Older age and functional class were significantly related to the incidence of adverse events that resulted in discontinuation of the 1st biologic treatment. The TBCR is in its initial stages, and information on all patients newly starting biologic therapy at participating institutes is being collected prospectively. Differences in baseline characteristics by age and initiation year of biologics need to be carefully evaluated in order to report on drug-related survival and long-term prognosis, using follow-up data in the near future.

A selective estrogen receptor modulator inhibits tumor necrosis factor-α-induced apoptosis through the ERK1/2 signaling pathway in human chondrocytes

Tumor necrosis factor α (TNF-α) is a pleiotropic cytokine mediating inflammatory as well as cell death activities, and is thought to induce chondrocytic chondrolysis in inflammatory and degenerative joint diseases. Selective estrogen receptor modulators (SERMs), such as raloxifene, which are commonly used in clinical settings act as estrogen agonists or antagonists. It is assumed that estrogens have a potential role in cartilage protection; however, the precise molecular mechanism for the protective effects of estrogens is unclear. This study was designed to examine whether raloxifene inhibits TNF-α-induced apoptosis in human chondrocytes and to clarify the mechanisms involved. We also investigated the signaling pathways responsible for the anti-apoptotic effect of raloxifene. Apoptosis in chondrocytes was determined by DNA fragmentation assay and caspase-3 activation. Raloxifene significantly inhibited TNF-α-induced caspase-3 activation and cell DNA fragmentation levels in chondrocytes. The inhibitory effect of raloxifene was abolished by the estrogen receptor antagonist ICI 182,780. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates apoptosis, acting as an apoptotic or anti-apoptotic signal. TNF-α-induced apoptosis was significantly enhanced by the ERK1/2 pathway inhibitor PD98059. Raloxifene stimulated a further increase in ERK1/2 phosphorylation in TNF-α-treated chondrocytes. Furthermore, the anti-apoptotic effects of raloxifene were inhibited by PD98059. In addition, the anti-apoptotic effects of raloxifene were completely abolished in ERK1/2 siRNA-treated chondrocytes. These results suggest that raloxifene prevents caspase-3-dependent apoptosis induced by TNF-α in human chondrocytes by activating estrogen receptors and the ERK1/2 signaling pathway.

Importance of methotrexate therapy concomitant with tocilizumab treatment in achieving better clinical outcomes for rheumatoid arthritis patients with high disease activity: an observational cohort study

OBJECTIVE The purpose of this study was to identify the effects of concomitant use of MTX and baseline characteristics for remission in the treatment of RA with tocilizumab (TCZ) in daily clinical practice. METHODS A total of 240 RA patients who received TCZ were selected from the multicentre Tsurumai Biologics Communication Registry. Predictive baseline factors for remission [28-item DAS (DAS28) < 2.6] at 52 weeks were determined by logistic regression analysis. To confirm whether the associations varied by the level of baseline disease activity, we also assessed the model including the interaction term (each baseline variable × DAS28). RESULTS In total, 49.3% of the study participants used MTX with TCZ. Even after controlling for the baseline DAS28, shorter disease duration (≤3 year) [odds ratio (OR) 3.58 (95% CI 1.81, 7.07)], less structural damage [Steinbroker stage ≤II, OR 2.33 (95% CI 1.32, 4.12)] and concomitant prednisolone use [OR 0.38 (95% CI 0.21, 0.68)] showed significant predictive values for remission. Concomitant MTX use failed to show a significant association with remission, whereas a significant interaction was observed among concomitant MTX use × DAS28 (P = 0.006). In patients with high baseline disease activity (DAS28 > 5.1), concomitant MTX use was associated with increased odds for remission [adjusted OR for all baseline variables 2.54 (95% CI 1.11, 5.83)], while no association was indicated between them in patients with low to moderate baseline disease activity (DAS28 ≤ 5.1). CONCLUSION Concomitant MTX use is an important component of TCZ treatment for RA patients with high disease activity.

Alexithymia, Depression, Inflammation, and Pain in Patients With Rheumatoid Arthritis

We previously reported that depression and inflammation have independent effects on pain severity in patients with rheumatoid arthritis (RA). Alexithymia is a personality trait characterized by deficits in cognitive processing and regulation of emotions. A broad association between alexithymia and various health problems has been suggested, including depression, inflammation, and pain. The objective of this study was to examine the independent influence of alexithymia on pain perception and its relationship to depression and inflammation.

Longterm Retention Rate and Risk Factor for Discontinuation Due to Insufficient Efficacy and Adverse Events in Japanese Patients with Rheumatoid Arthritis Receiving Etanercept Therapy

Objective. Assessing retention rate and risk factor for drug discontinuation is important for drug evaluation. We examined a 3-year retention rate and the risk factor for discontinuation due to insufficient efficacy (IE) and adverse events (AE) in Japanese patients with rheumatoid arthritis (RA) who are receiving etanercept (ETN). Methods. Data were collected from 588 patients treated with ETN as a first biologic from the Tsurumai Biologics Communication Registry. Baseline characteristics for the incidence of both IE and AE were analyzed using the Cox proportional-hazards regression model. Patients were divided into groups based on age and concomitant methotrexate (MTX). Drug retention rates were calculated using the Kaplan-Meier method and compared among groups using the log-rank test. Results. ETN monotherapy without concomitant MTX [MTX(–)] was significantly related to a higher incidence of discontinuation due to IE [hazard ratio (HR) = 2.226, 95% CI 1.363–3.634]. Older age and MTX(–) were significantly related to a higher incidence of discontinuation due to AE [HR = 1.040, 1.746, 95% CI 1.020–1.060, 1.103–2.763, respectively]. The MTX(–)/≥ 65 years group had the lowest retention rate (p < 0.001). The discontinuation rate due to IE was lower in the MTX(+)/< 65 years group compared to < 65 years/MTX(–), ≥ 65 years/MTX(–) group (p = 0.006, p < 0.001, respectively). The discontinuation rate due to AE was highest in the MTX(–)/≥ 65 years group (p < 0.001). Conclusion. Our findings suggest that the risk of discontinuation due to IE was high in the patients who did not use concomitant MTX and that the risk of discontinuation due to AE was high in elderly patients who did not use concomitant MTX.

The first point prevalence survey of health care–associated infection and antimicrobial use in a Japanese university hospital: A pilot study

BACKGROUND Point prevalence surveys (PPSs) in Japanese hospitals have not yet been reported. The purpose of this pilot PPS study was to evaluate the epidemiology of health care-associated infections (HAIs) and antimicrobial use in a Japanese tertiary university hospital. METHODS A 1-day, cross-sectional PPS was performed at a Japanese university hospital. Data on demographics, active HAIs, and antimicrobial use of all inpatients were collected using a data collection form. RESULTS Of 841 patients, 85 (10.1%) had 90 active HAIs, and 308 patients (36.6%) were administered 494 antimicrobials. Among the 90 HAIs and 58 pathogens, the most frequent infection and isolated pathogen were pneumonia (20.0%) and Enterobacteriaceae (27.6%), respectively. Of the 118 antimicrobials used for treatment of HAIs, carbapenems were the most frequently administered category of antimicrobials (22.9%). In regard to antimicrobials for surgical prophylaxis, 37 of 119 (31.1%) were administered to patients on postoperative day 3 or later, and 48 of 119 (40.3%) were administered orally. CONCLUSIONS The incidence of HAIs is higher than in other developed countries. The social and medical situation in Japan may affect patient demographics, active HAIs, and antimicrobial use. Multicenter PPSs are necessary to uncover the real epidemiology of HAIs and antimicrobial use in Japan.

Pneumococcal polyarticular septic arthritis after a single infusion of infliximab in a rheumatoid arthritis patient: a case report.

IntroductionWe present a case of Streptococcus pneumoniae polyarticular septic arthritis in a patient with rheumatoid arthritis receiving a single infusion of infliximab.Case presentationA 38-year-old Japanese man with a 5-year history of seronegative rheumatoid arthritis had previously received sulphasalazine and methotrexate therapies and was on regular low-dose prednisolone therapy. Despite these treatments, his disease activity remained high and infliximab was introduced in addition to methotrexate, prednisolone, and folic acid. However, he was admitted to hospital with a fever of 40.6°C, chills, and polyarthralgia eight days after the first infusion of infliximab. His joints were swollen, painful, and warm. Laboratory data showed marked acute inflammation. He was diagnosed with bacterial septic polyarthritis, and emergency surgical joint lavage and drainage was performed at the knees along with needle aspiration and lavage of the ankles and right wrist. He was then given intravenous antibiotic therapy for 31 days. He made a good recovery and was discharged on day 37.ConclusionsWe believe this is the first reported case of severe pneumococcal septic arthritis requiring hospitalization in a patient treated with infliximab. S. pneumonia is now a well-recognized but uncommon cause of polyarticular septic arthritis that can lead to cessation of therapy, as in our patients case.

Massive mediastinal cryptococcosis in a young immunocompetent patient

Pulmonary cryptococcosis with lymph node involvement is relatively rare in immunocompetent patients. We report a case of pulmonary cryptococcosis with massive mediastinal lymphadenopathy in an immunocompetent young patient. In this report, a 17‐year‐old boy presented with high‐grade fever and persistent cough. Chest X‐ray and computed tomography showed massive mediastinal lymphadenopathy. Endobronchial ultrasound‐guided transbronchial needle aspiration revealed histological evidence of cryptococcal lymphadenitis. He was treated with liposomal amphotericin B plus flucytosine followed by fluconazole and recovered.

SAT0118 The Clinical Outcome of Abatacept Treatment in Biologic NaÏVe Patients with Rheumatoid Arthritis in Multi-Center Clinical Practice

Background The 2008 American College of Rheumatology Recommendations has been updated last year, abatacept (ABT) has become available as the first biologic agent for patients with established RA1. The efficacy and safety of ABT in biologic naïve patients has been reported in clinical trials, but still uncertain in clinical practice. Objectives We studied the clinical outcome of ABT treatment for 52 weeks in patients without previous biologic history (Naïve group) and with previous biologic treatment (Switch group). We assessed whether the history of previous biologic treatment had any impact on the ABT clinical efficacy in RA. Methods All RA patients who underwent ABT treatment for longer than 52 weeks (n=156) at Nagoya University Hospital and 12 other institutes (Tsurumai Biologics Communications registry : TBCR study group) were enrolled in this study. We compared disease activities using DAS28 CRP between Naïve group (n=71) and Switch group (n=85). Furthermore, EULAR response criteria and drug retention rate at 52 weeks were evaluated. The last observation carried forward (LOCF) method was used in each analysis. Results In the baseline characteristics data, there was no significant difference between Naïve and Switch group, except for age (65.1 and 61.9 years old), disease duration (10.4 and 12.6 years) and prednisolone user (38.5 and 61.5%). Disease activities were significantly decreased at 4 weeks in both groups, and further decreasing were observed continuously (Fig. 1). At 52 weeks, the percentage of the patients who achieved low disease activity (DAS28 < 2.7) in Naïve group (47.8%) was apparently higher than that in Switch group (23.8%) (Fig.2). EULAR response rate was 75.3% in Naïve group (good 36.2%, moderate 39.1%), while 47.5% in Switch group (good 17.5%, moderate 30.0%). Drug retention rate at 52 weeks was 81.7% in Naïve group and 71.8% in Switch group (Fig 3). Image/graph Conclusions Although the clinical efficacy of ABT was demonstrated in patients with the history of biologics treatment, the responsiveness to ABT was superior in the biologic naïve patients. Our data suggest that ABT is useful in biologic naïve patients in clinical practice. References Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis care & research. 2012;64:625-39. Disclosure of Interest M. Hanabayashi: None Declared, T. Kojima Speakers bureau: Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Eisai Pharma Corporation, Chugai Pharma Corporation, Abbott, Bristol-Myers Squibb and Pfizer., N. Takahashi: None Declared, K. Funahashi: None Declared, D. Kato: None Declared, Y. Hattori: None Declared, N. Ishiguro Speakers bureau: Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Eisai Pharma Corporation, Chugai Pharma Corporation, Abbott, Bristol-Myers Squibb and Pfizer.

Active surveillance in response to the identification of a single carbapenemase-producing Escherichia coli at a Japanese university hospital

This report described the experience of active surveillance culture implemented in response to the identification of a single carbapenemase-producing Escherichia coli in a Japanese university hospital. It revealed a horizontal transmission event and an additional asymptomatic carrier of carbapenemase-producing Escherichia coli with unique drug susceptibility and resistance gene profiles. Early implementation of active surveillance culture as a part of multifaceted infection control measures appeared to be useful to control further transmission of carbapenemase-producing Escherichia coli even in the low endemic facility. Further investigations on the timing and usefulness of active surveillance culture in the control of carbapenemase-producing Enterobacteriaceae would be warranted.