H. Matsubara

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.

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.

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.

Predictors of biologic discontinuation due to insufficient response in patients with rheumatoid arthritis who achieved clinical remission with biologic treatment: A multicenter observational cohort study

Abstract Objective: This study aimed to investigate predictors of biologic discontinuation due to insufficient response as a surrogate for relapse in patients with rheumatoid arthritis (RA) who achieved clinical remission with biologic treatment. Methods: This study was performed based on data from a multicenter registry, and included 404 patients who achieved clinical remission within the first year of treatment with their first biologic. Cumulative retention rate of the first biologic was estimated using Kaplan–Meier curves, and the impact of patient characteristics on biologic discontinuation was assessed with Cox proportional hazards models. Results: During follow-up, 50 patients discontinued their first biologic due to insufficient response. Overall discontinuation rates due to insufficient response after achieving remission were 6%, 11%, and 19% at 1, 2, and 5 years, respectively. Multivariate analysis revealed that concomitant glucocorticoids at achieving remission [hazard ratio (HR): 3.80, 95% confidence interval (CI): 1.89–7.64)] and a higher level of C-reactive protein (CRP) at achieving remission (HR: 1.47 per 1 mg/dL, 95% CI: 1.09–1.99) independently predict discontinuation due to insufficient response after achieving remission. Conclusion: Patients with RA who achieved remission with concomitant glucocorticoid treatment and a higher level of CRP are at high risk of subsequent biologic discontinuation due to insufficient response.

THU0147 Drug Survival of Golimumab in Japanese Patients with Rheumatoid Arthritis Is Independent of Methotrexate and Prednisolone Concomitance: Results from The Multicenter Biologics Registry: Table 1.

Background When using biological agents, particularly tumor necrosis factor (TNF) inhibitors, in patients with rheumatoid arthritis (RA), the use of methotrexate (MTX) or prednisolone (PSL) can cause considerable problems for patients because they cause adverse events. Therefore, safety would be increased if MTX and PSL could be tapered or stopped. The objective of this report was to determine the drug retention rate of golimumab (GLM) in Japanese patients with RA and identify potential predictors associated with treatment discontinuation. Methods A prospective analysis was performed on 152 patients with RA who were treated with GLM in our multicenter biologics registry. We assessed the age, body weight, disease duration, use of pre-biological agents, Disease Activity Score 28-Erythrocyte Sedimentation Rate, and use and dose of MTX and PSL as baseline characteristics of the patients, and we compared cumulative survival among these factors. Results The overall 52 weeks drug survival rate of GLM was 71.6%. The patients with a body weight of <50 kg had a better drug survival rate than those with a body weight of >50kg (see Table). The use and dose of MTX and use of PSL did not show statistical differences in drug survival rate (see Table).Table 1. Characteristics of patients with RA receiving GLM at baseline Characteristic (unit) Group range (number) P value† Body weight (kg) <50 (41) 50–60 (54) 0.040* >60 (26) 0.010* Number of biologics used before GLM 0 (80) 0.363 1 (48) >1 (24) 0.015* DAS28-ESR <3.2 (14) 3.2–5.1 (48) 0.722 >5.1 (67) 0.589 MTX use negative (45) positive (103) 0.829 MTX dose (mg/w) <8 (30) 0.177 8 (32) 0.185 >8 (41) PSL use negative (74) positive (75) 0.520 †P value was calculated using log-rank test in each variable against its controls. *P value of <0.05 was considered to indicate statistical significance. Conclusions In daily practice, patients with RA taper or stop their MTX or PSL use while undergoing treatment with biological agents if their RA disease activities are low. On the other hand, MTX with biological agents, particularly TNF inhibitors, would produce better efficacy than higher dose. Our result indicates that Japanese patients with RA receiving GLM may be able to taper or stop MTX and PSL use, which could increase safety and raise the drug retention rate in these patients. These data would be of value in selecting biological agents for MTX-intolerant RA patients. Disclosure of Interest None declared

FRI0319 Drug Retention Rates of Biologic Monotherapies for Patients with Rheumatoid Arthritis in Daily Clinical Practice; Using Multicenter Registry in Japan

Background In general, drug retention rate reflects the effectiveness and tolerability of the drug. In Japan, seven biological agents have been approved for the treatment of rheumatoid arthritis (RA). There is few data comparing the retention rates between biological monotherapies for RA patients in daily clinical practice. Objectives The purpose of this study is to compare the drug retention rates of three biological monotherapies with different target molecules, etanercept (ETN), tocilizumab (TCZ), abatacept (ABT). Methods We collected the data from the patients who started monotherapies with ETN, TCZ, ABT as first-biologics since 2008 and registered in the multicenter, large cohort of RA patients (Tsurumai Biologics Communication Registry; TBCR). We surveyed the following information: demographic data, disease activity (DAS28-CRP) at the baseline of each biological treatment. Drug retention rates were calculated by the Kaplan-Meier analysis and compared using the log-rank test among groups. We investigated drug retention rates for discontinuation due to insufficient effectiveness (IE) and adverse events (AE). To compare risks of drug discontinuation due to IE and AE for patients treated with these biological agents, the Cox proportional hazard model was applied. Results We analyzed 279 patients of 2072 patients registered in TBCR until March 2011 (141 patients in the ETN group, 63 patients in the TCZ group, 75 patients in the ABT group). The mean follow up time was 25.7 months. Table shows baseline characteristics of the groups (Table). The patients in the ABT group were older compared with other groups. Cumulative incidence rate for discontinuation due to insufficient effectiveness was significantly lower in the TCZ group (p=0.019, Fig.1A). Cumulative incidence rate for discontinuation due to adverse events was significantly lower in the ABT group (p=0.007, Fig.1B). Compared with TCZ group, the use of ABT was significantly associated with a lower risk of discontinuation due to AE (HR 0.081; 95% CI 0.009 to 0.737). Conclusions We demonstrated that TCZ monotherapy had a lower discontinuation rate due to IE and that ABT monotherapy had a lower discontinuation rate due to AE. Disclosure of Interest H. Matsubara: None declared, T. Kojima Speakers bureau: abbvie Japan, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical, N. Ishiguro Speakers bureau: abbvie Japan, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical DOI 10.1136/annrheumdis-2014-eular.5755

FRI0282 Predictive Factors for Suppressing Progression of Cervical Lesions in Patients with Rheumatoid Arthritis Receiving Infliximab Treatment from Japanese Tbcr

Background Cervical lesions are known to occur at high frequency as a complication of rheumatoid arthritis (RA). Treatment with Anti-TNFα agents are more clinically effective than the DMARDs that were in use previously, in particular, with their efficacy in suppressing joint destruction having been emphasized. However, most clinical studies on the efficacy of biological agents in suppressing joint destruction in the hands and feet. Therefore, we reported the efficacy of infliximab (IFX) for suppressing the progression of RA cervical lesions at ACR2009, EULAR 2010, 11, 12 and 13. Objectives To investigate to determine predictive factors for suppressing radiographic progression of cervical lesions with RA receiving IFX treatment. Methods We used IFX for treating 604 Japanese patients with active RA who fulfilled the ACR criteria in 1987. The final study cohort of 67 patients received continuous IFX treatment for 3 years from Tsurumai Biologics Communication Registry (TBCR). For evaluation of cervical lesions, the atlanto-dental interval (ADI), the space available for the spinal cord (SAC), and the Ranawat value were measured by plain lateral radiographs in the flexion position, at initiation, 1, 2 and 3year. Results The group of patients included 9 males and 58 females. The mean age was 54.0±12.6 years; disease duration was 10.6±9.4 years; and methotrexate dose was 7.4±1.7 mg/week. Clinical findings related to RA were as follows: swollen and tender joint count, 7.0±5.2, 8.0±5.7; patients global assessment, 55.7±22.9mm; CRP, 3.4±2.0mg/dL; ESR, 53.4±29.2mm/h; DAS28 5.53±1.20; and MMP3, 363.4±331.3ng/mL; ADI, 3.5±1.7mm; SAC, 18.2±2.5mm; Ranawat value, 14.4±2.2mm and TSS, 60.9±51.4. When progression was defined as a change of 1 mm or more in one of the radiographic cervical lesion parameters for 3 years, the numbers of patients, who showed progression in ADI, SAC and Ranewat value were 25 (37%), 22 (33%), and 23 (34%), respectively, and the number who showed progression in at least one of these three parameters was 31 (46%). In order to determine predictive factors for suppressing progression of cervical lesions, We used Mann-Whitney U-test and ROC analysis between 36 non-progressive and 31 progressive patients. The factors which showed the significant difference were as follows: disease duration: 8.3±8.3 and 13.2±10.0 years (p=0.017); ADI: 3.0±1.4 and 4.0±2.0 mm (p=0.039); SAC 19.3±2.2 and 17.0±2.2 mm (p<0.001); Ranawat value: 15.1±1.5 and 13.6±2.6 mm (p=0.014); TSS at initiation: 49.3±50.0 and 74.3±50.3 mm (p=0.027); DAS at 3Y: 2.80±0.86 and 3.50±1.00 (p=0.002); average MMP3: 98.0±92.6 and 125.2±75.1 ng/ml (p=0.030); average DAS: 2.83±0.81 and 3.47±0.77 (p=0.001) and ΔTSS for 3 years: 0.68±0.71 and 1.73±1.04/y (p<0.001). The factors which showed the AUC0.7 were SAC at initiation, DAS at 3Y, average DAS for 3 years and ΔTSS (AUC=0.774, 0.721, 0.727 and 0.798). Also each cut-off value were 18.0, 2.70, 2.56 and 1.33 by Youden index method. Conclusions Early treatment, sustained remission and lower ΔTSS were important factors to suppress the progression of RA cervical lesions. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2685

FRI0075 Etanercept treatment for the elderly patients with rheumatoid arthritis; using multicenter registry in japan

Background In Japan, the treatments for the patients with rheumatoid arthritis using etanercept (ETN) started since 2005. We should carefully treat especially in elderly patients, who have relatively high risk associated with the treatment. Now, mid, and long term follow up data for the efficacy and safety of the treatment of RA with ETN in clinical practice should be needed. Objectives The aims of this study are to investigate the trends and safety of ETN treatment especially in elderly patients. Methods We collected the data from the patients who started ETN treatment as first-biologics since 2005 and registered in the multicenter, large cohort of RA patients (Tsurumai Biologics Communication Registry; TBCR). We surveyed the following information: demographic data, disease activity (DAS28-CRP) at the initiation of ETN, current treatment status (discontinuation of treatment with ETN and its reason). Drug survival rate was determined by Kaplan-Meier method, comparing by age (tertile values), MTX use, and by DAS28-CRP (tertile values) at the initiation of ETN. Cumulative incidence rate of adverse events was determined in the same way. Results We analyzed 683 ETN cases of 1574 cases registered in TBCR until 2010. The mean follow up time was 26.8 months. Mean of age and disease duration was 55.9 years old and 11.0 years, respectively. The rate of concomitant MTX use was 79.6%, 69.5%, 50.0% (young age:≤51, middle age: 52-64, old age: 65≤, respectively). Drug survival rate was significantly lower in old age and no MTX use group (p<0.001, Fig. 1 and 2). In old age group, disease activity at baseline had no significant effect on drug survival rate (Fig. 3). The cumulative incidence rate of adverse events was significantly higher in old age and no MTX use group (p<0.001, Fig. 4). Conclusions In clinical practice, some elderly patients may not use MTX because of complications. We showed that incidence rate of adverse events was high in those patients. We should treat more carefully the elderly patients who don’t use concomitant MTX. Disclosure of Interest H. Matsubara: None Declared, T. Kojima Speakers Bureau: Abbott Japan, Chugai,Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical, N. Takahashi: None Declared, K. Funahashi: None Declared, D. Kato: None Declared, Y. Hattori: None Declared, N. Ishiguro Speakers Bureau: Abbott Japan, Chugai,Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical

THU0124 Importance of monitoring of C-reactive protein level to predict achievement of better clinical outcome during treatment with tocilizumab in patients with rheumatoid arthritis

Background Biologics have molecular target such as cytokine and its receptor. It should be critical for maximizing its clinical response how biologics completely inhibit signalling of the target cytokines. However, it is difficult to know whether administered biologics inhibit the target molecules completely or not. Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor. Interestingly, IL-6 directly stimulates the expression of C-reactive protein (CRP). Objectives We studied clinical results of TCZ for 52 weeks based on normalization of CRP level during treatment, which could be a possible index of adequate dose of TCZ for each patient. Methods All RA patients (n=122) who underwent TCZ treatment between May 2008 and September 2009 at Nagoya University Hospital and 12 other institutes (Tsurumai Biologics Communication Study Group) were enrolled in this study. Demographic data at baseline and the following parameters of disease activity (tender joint count (TJC) and swollen joint count (SJC) on 28 joints, patient global assessment (VAS), ESR, and serum CRP and MMP-3 levels during 52 weeks. We divided the patients into three groups based on the time of normalization of CRP levels (4 weeks; group A, N=78, 4-12 weeks; group B, N=28, positive CRP at 12 weeks; group C, N=16). We compared clinical results including remission rate at 52 weeks using the 2011 definition of remission (Boolean approach) as well as DAS28-ESR among these three groups. Results Mean (SD) of age, disease duration and DAS28-ESR were 57 (13) years old, 10.5 (8.5) years and 5.8 (1.4),respectively. 61% of the patients had history of previous TNF-failure. 39% of the patients were treated with concomitant MTX. Patients in group C had higher disease activity (SJC, TJC, CRP, DAS28-ESR) than those in group A and B at baseline. We found that, at 52 weeks, patients in group A and B achieved significantly higher rate of DAS-remission (48.6%), SJC≤1, and TJC≤1 than those in group C (Fig.1 and 2). Especially, VAS as well as MMP-3 was significantly improved in patients in group A and B but not those in group C at all (Fig. 3). Patients in group A and B had more normal level of MMP-3 than those in group C. Multivariate logistic analysis including concomitant MTX, previous use of TNF inhibitor, disease duration, clearly showed lower CRP (cut-off, 2.13 mg/dl, determined by ROC analysis) was independent factor for achieve normal CRP level until 12 w. Conclusions In this study, we clearly showed that patients with normalization of CRP level at 12 weeks, which could be related to adequate dose of TCZ for complete inhibition of IL-6 signalling for each patient, achieved better clinical results. Disclosure of Interest T. Kojima Speakers Bureau: Abbott Japan, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical, K. Funahashi: None Declared, N. Takahashi: None Declared, D. Kato: None Declared, H. Matsubara: None Declared, Y. Hattori: None Declared, Y. Yabe: None Declared, N. Ishiguro Speakers Bureau: Abbott Japan, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Pfizer Japan, Takeda Pharmaceutical