Toki Takemoto

Patient-reported outcomes as assessment tools and predictors of long-term prognosis: a 7-year follow-up study of patients with rheumatoid arthritis

Whether the Boolean‐based American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for rheumatoid arthritis (RA) including patient‐reported outcome measures (PROMs) for remission are strict for use in daily clinical practice is controversial. This study aimed to clarify the differences in the remission status defined by the criteria, including and excluding PROMs, and to identify the baseline predictors of long‐term prognosis using 7‐year follow‐up data.

Longterm Efficacy and Safety of Abatacept in Patients with Rheumatoid Arthritis Treated in Routine Clinical Practice: Effect of Concomitant Methotrexate after 24 Weeks

Objective. Our study aimed to evaluate the longterm efficacy and safety of abatacept (ABA), and to explore factors that increase its longterm efficacy in patients with rheumatoid arthritis (RA) treated in routine clinical practice. Methods. There were 231 participants with RA treated with ABA who were prospectively registered in a Japanese multicenter registry. They were followed up for at least 52 weeks. Results. Mean age of the patients was 64.3 years, mean disease duration was 12.1 years, mean 28-joint Disease Activity Score (DAS28)-C-reactive protein was 4.49, and 48.5% of patients were concomitantly treated with methotrexate (MTX). Overall retention rate of ABA was 77.1% at 52 weeks; 14.8% of patients discontinued because of inadequate response and 3.5% because of adverse events. The proportion of patients achieving DAS28-defined low disease activity (LDA) significantly increased from baseline to 52 weeks (7.3% to 43.8%, p < 0.01); 40.9% of patients who did not achieve LDA at 24 weeks had more than 1 categorical improvement in DAS28-defined disease activity at 52 weeks. Multivariate logistic regression revealed concomitant MTX use to be an independent predictor of the categorical improvement in DAS28-defined disease activity from 24 to 52 weeks (adjusted OR 3.124, p = 0.010). Conclusion. In routine clinical practice, ABA demonstrated satisfactory clinical efficacy and safety in patients with established RA for 52 weeks. The clinical efficacy of ABA increased with time even after 24 weeks, and this was strongly influenced by concomitant MTX use. Our study provides valuable real-world findings on the longterm management of RA with ABA.

Effects of Concomitant Methotrexate on Large Joint Replacement in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors: A Multicenter Retrospective Cohort Study in Japan

To determine the effects of concomitant methotrexate (MTX) on the incidence of large joint replacement resulting from the progression of large joint destruction in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors.

Disease activity early in treatment as a predictor of future low disease activity in RA patients treated with iguratimod

Objectives. This retrospective observational study aimed to examine the efficacy of iguratimod with and without concomitant methotrexate (MTX) and to estimate the adequate observational period for predicting low disease activity (LDA) achievement at 24 weeks in patients with rheumatoid arthritis (RA). Methods. All patients treated with iguratimod were registered in a Japanese multicenter registry. Multivariate analyses were performed to identify predictive factors for LDA achievement at 24 weeks. Receiver operating characteristic (ROC) curve analyses were performed to estimate the association of 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) at each time point with achievement of LDA at 24 weeks and determine a cut-off for DAS28-ESR. Results. A total of 123 patients were treated with iguratimod with (n = 65) or without (n = 58) MTX. Iguratimod therapy resulted in significant clinical improvement in both groups. Multivariate analysis revealed that DAS28-ESR at each time point was an independent significant predictor of LDA achievement at 24 weeks. Cut-off values of DAS28-ESR at 12 weeks based on ROC curves were 3.2 and 3.6 in patients with and without MTX, respectively. Conclusions. Iguratimod was effective in RA patients in clinical practice. Our results suggest that 12 weeks may be a sufficient period to judge the medium-term efficacy of iguratimod in patients treated with and without MTX.

Comparison of efficacy and safety of tacrolimus and methotrexate in combination with abatacept in patients with rheumatoid arthritis; a retrospective observational study in the TBC Registry.

Objectives. Tacrolimus (TAC) and abatacept (ABT) inhibit T-cells via different mechanisms and, in combination, may be effective against rheumatoid arthritis. However, they may also disrupt normal immune functions. We compared the efficacy and safety of ABT administered to patients in combination with TAC, methotrexate (MTX), or other drugs. Methods. This was a retrospective multicenter study conducted to compare the efficacy and safety of ABT in 211 patients: the drug was administered together with TAC (ABT+ TAC group; 22 patients), MTX (ABT+ MTX group; 102 patients), or patients treated without concomitant MTX or TAC (ABT mono group; 87 patients). The disease activity, treatment continuation rate, and reason for discontinuation of treatment were investigated. Results. The retention rate at Week 24 was similar in the three groups. There were no cases of discontinuation related to the appearance of adverse events in the ABT+ TAC group. At Week 24, according to the European League Against Rheumatism response criteria, the “good” response rates were 33.3%, 13.4%, and 13.4% in the ABT+ TAC, ABT+ MTX, and ABT mono groups, respectively. Statistically significant decreases in various disease activity scores/indices were observed in all the groups as early as Week 4. Conclusions. Although the sample size was small, the results of this retrospective study suggest that the ABT+ TAC combination therapy has at least comparable safety and efficacy to those of the ABT+ MTX combination, and that it can thus be a useful option for patients who cannot take MTX.

Concomitant Methotrexate Protects Against Total Knee Arthroplasty in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors

Objective. To determine the effects of concomitant methotrexate (MTX) on the incidence of total knee arthroplasty (TKA) resulting from the progression of joint destruction in patients with rheumatoid arthritis (RA) during longterm treatment with tumor necrosis factor (TNF) inhibitors. Methods. A total of 155 patients with RA (310 knee joints) received TNF inhibitors at our institute between May 1, 2001, and May 31, 2008. A total of 111 symptomatic (tender and/or swollen) knee joints in 68 patients were retrospectively studied over the course of a minimum of 5 years of followup. The median (interquartile range) followup period was 8.1 (7.0–9.3) years. All data were analyzed using the knee joint as the statistical unit of analysis. TKA during treatment with TNF inhibitors was used as the outcome variable in predictive analyses. The cumulative incidence of TKA was compared by concomitant or no MTX use (MTX±). Results. There were 79 subjects (71%) who received concomitant MTX. According to Kaplan-Meier estimates, the cumulative incidence of TKA for the MTX+ group was significantly lower than that for the MTX− group (24% vs 45% at 5 yrs, respectively, p = 0.035). Multivariate analysis using the Cox proportional hazards model revealed that concomitant MTX (HR 0.44, 95% CI 0.22–0.89), Larsen grade (HR 2.93, 95% CI 1.94–4.41), and older age at baseline (HR 1.04, 95% CI 1.01–1.08) were independent predictors of TKA. Conclusion. Concomitant MTX reduces the incidence of TKA by 56% in patients with RA during longterm treatment with TNF inhibitors.

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.

AB0377 Differences in Baseline Predictive Factors for Remission at 52 Weeks by Concomitant MTX Use during Tocilizumab Treatment Using Propensity Score Matched Groups

Background In the treatment of rheumatoid arthritis, concomitant use of methotrexate (MTX) should be a critical factor for decision of treatment now. Tocilizumab, IL-6 receptor antibody has been reported to have good efficacy even without concomitant MTX in clinical trials and observational study. However, there is an important clinical question that concomitant MTX use could have any impacts on predictive factors of achievement of good clinical goal. Objectives To explore the differences in predictive factor for achievement of remission by concomitant MTX use during TCZ treatment. In observational study, it is important to match background of the patients for comparison. We used propensity score matching, which is useful statistical tool for comparison in clinical practice. Methods This study included 240 RA patients who received TCZ (concomitant MTX use: MTX(+) 117: no use: MTX(−) 123) in the multicenter observational cohort (Tsurumai Biologics Communication Registry; TBCR, 2827cases treated with biologics were registered until 2014). We prepared matched groups by concomitant MTX use using propensity score (matched factors, age, sex, previous biologics use, glucocorticoid use, Steinbrocker stage and class, disease duration, DAS28 at baseline). We determined the baseline predictive factors for remission (DAS28) at week 52 by the matched groups using multivariate logistic regression analysis. Especially, association of DAS28 at baseline to achievement of remission was compared using area under the curve (AUC) of ROC curve. Results Sixty-nine patients were matched between groups. Baseline characteristics were shown in Table 1. Rate of remission was 55.2% in MTX(+) group and 44.8% in MTX(−) group (p=0.39). Independent predictive factors at baseline for remission were disease duration [OR:0.90, 95%CI (0.83–0.97)] in MTX(+) group while DAS [OR:0.49, 95%CI (0.29–0.83)] in MTX(−) group based on multivariate analysis. We also showed significant difference in association of DAS at baseline to remission between groups using AUC of ROC curve (AUC 0.59 vs 0.73, Fig. 1). Interestingly, after matching baseline characteristics, achievement of remission in MTX(−) group depended on disease activity at baseline while that in MTX(+) group did not. The cut-off value of DAS28 at baseline for achievement of remission was 4.87 (sensitivity 0.61, specificity 0.84) in MTX(−) group. Conclusions There is significant difference in baseline predictive factors for good clinical results by concomitant MTX use during TCZ treatment. The results should be taken into consideration to predict clinical response in clinical practice. Disclosure of Interest T. Kojima Speakers bureau: Mitsubishi Tanabe Pharma, Takeda Pharma, Eisai Pharma, AbbVie, Bristol-Myers Squibb, and Pfizer, Janssenn Pharmaceutical Companies, Astellas Pharma and Chugai Pharma., S. Asai: None declared, N. Takahashi Speakers bureau: Abbvie Japan Co. Ltd, Eisai Co. Ltd, UCB Japan Co. Ltd, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Ltd, Pfizer Co. Ltd, Chugai Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., and Bristol-Myers Squibb Co. Ltd., Y. Yabe: None declared, Y. Hirano Speakers bureau: Abbvie Japan, Eisai, Mitsubishi Tanabe Pharma, Pfizer, Chugai Pharmaceutical, and Bristol-Myers Squibb., Y. Kanayama: None declared, A. Kaneko Speakers bureau: Mitsubishi Tanabe Pharma, Takeda Pharma, Eisai Pharma, Chugai Pharma, Abbott, Bristol-Myers Squibb, UCB, Janssen, and Pfizer, T. Takemoto: None declared, N. Asai: None declared, T. Watanabe: None declared, K. Funahashi: None declared, M. Hayashi: None declared, N. Ishiguro Grant/research support from: Daiichi Sankyo, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Taisho Toyama Pharmaceutical, Kaken Pharmaceutical, Eisai, Janssen Pharmaceutical, Bristol-Myers Squibb, AbbVie, Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Astellas Pharma, and Pfizer Japan, Speakers bureau: Daiichi Sankyo, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Taisho Toyama Pharmaceutical, Kaken Pharmaceutical, Eisai, Janssen Pharmaceutical, Bristol-Myers Squibb, AbbVie, Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Astellas Pharma, and Pfizer Japan

SAT0069 The Validation about The Measurement of Joint Space Distance by Using Super Resolution Image and Curve Fitting Methods

Background Cartilage loss is irreversible progress, so physicians have to find the detection of joint space narrowing as early as possible. It is stated that physical disability in rheumatoid arthritis (RA) is associated with joint space narrowing rather than erosion [1], so early detection of progressive joint damage is the most important. But in DICOM which is the international standard for medical images, 1 pixel on radiographic images is 0.10 to 0.15 mm, so the detection of the change which is lower than that is impossible.To solve this problem, we previously developed new method measuring the joint space distance with the X-rays image which performed super-resolution image processing [2]. However, we did not validate the measured value by our methods. Objectives To validate the measurement of joint space distance by using super resolution image and curve fitting methods. We also evaluated whether the focus-film distance affected the measured value. Methods We producted phantom model (PM) of joint space that expressed metacarpophalangeal joint space 1mm by using 3D printer.The super-resolution images of PM with radiographs by using total variation regularization and shock filter were prepared (Fig. 1). We measured the distance of joint space by three methods, 1) conventional measurement; distance between two points, 2) measurement by using normal vector from the top of joint surface of phalanx bone, 3) measurement using joint space area calculated by integration method. Each method processed on MATLAB®. 2), 3) methods were processed by curve fitting method which create parabolic curve by choosing some points of joint surface.We measured the distance ten times to adjust the error of measurement.We took radiographs with the focus-film distance under conditions of 90cm, 100cm, 110 cm, respectively. Results Between the two points method, normal line method and integration method, the mean (standard deviation) of measured value under focus-film distance 90 cm was 1.033 (0.018), 0.964 (0.017), 0.939 (0.009), respectively. Under focus-film distance 100 cm, it was 0.963 (0.031), 0.969 (0.032) ,0.943 (0.025), respectively. Under focus-film distance 110 cm, it was 1.019 (0.026), 0.964 (0.018), 0.943 (0.015) , respectively. There were no significant differences with measured value between three methods under each focus-film distance. There were also no significant differences with each focus-film distance (Fig. 2). Conclusions The measured value was not affected by a difference of the focus-film distance between 90cm to 110cm.We obtained the measured value, 0.937 – 0.970 by two methods, which were equal to 1mm of PM.The standard deviation was less than 0.032mm. We validated the measurement accuracy of curve fitting methods. We suggested that the possibility of early detection with joint space narrowing in rheumatoid arthritis patients by using super resolution image and curve fitting methods. References Ann Rheum Dis. 2011 May;70(5):733–739. IEEE Global Conference on Consumer Electronics (GCCE2013) 2013;: 447 - 448 Disclosure of Interest K. Funahashi: 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 Speakers bureau: Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Eisai Pharma Corporation, Chugai Pharma Corporation,Abbott, Bristol-Myers Squibb and Pfizer, S. Asai: None declared, T. Takemoto: None declared, N. Asai: None declared, T. Watanabe: None declared, T. Goto: None declared, M. Shimizu: None declared, H. Kariya: 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

THU0078 Effects of Concomitant Methotrexate on the Long-Term Outcome of Knee Joint Destruction in Patients with Rheumatoid Arthritis Treated with Tumour Necrosis Factor Inhibitors

Background Various tumour necrosis factor (TNF) inhibitors in combination with methotrexate (MTX) have been shown to be significantly superior to monotherapies of each agent in inhibiting radiographic progression of small joints in patients with rheumatoid arthritis (RA). Damage to large joints, especially weight-bearing joints such as the knee, has a larger impact on functional disability than damage to small joints. Accordingly, the evaluation of large weight-bearing joints is important when assessing the efficacy of drug therapy for RA, as is the evaluation of small joints. It is also important to evaluate the long-term inhibitory effect of drug therapy on joint damage. Given that total joint arthroplasty is a common procedure for treating damaged large joints, it can serve as a surrogate for the long-term outcome of large joint destruction in patients with RA. Objectives This study aimed to determine the effects of concomitant MTX on the incidence of total knee arthroplasty (TKA) resulting from the progression of joint destruction in patients with RA during long-term treatment with TNF inhibitors. Methods A total of 155 RA patients (310 knee joints) received TNF inhibitors at our institute between May 1, 2005 and May 31, 2008. A total of 111 symptomatic (tender and/or swollen) knee joints in 68 patients were retrospectively studied over the course of a minimum of five years of follow-up. The median (IQR) follow-up period was 8.1 (7.0-9.3) years. All data were analysed using the knee joint as the statistical unit of analysis. TKA during treatment with TNF inhibitors was used as the outcome variable in predictive analyses. The cumulative incidence of TKA was compared by concomitant or no MTX use (MTX (+/-)). Results Subjects were predominantly female (86%), and had a median age of 54 years, disease duration of 8 years and DAS28-CRP of 5.6 at initiation of TNF inhibitors. Based on the Larsen grade of knee joints, 5 joints were categorized as grade 0, 24 as grade I, 26 as grade II, 31 as grade III, 25 as grade IV, and 0 as grade V. Of all subjects, 79 (71%) received concomitant MTX. A total of 33 knee joints underwent TKA during treatment with TNF inhibitors. According to Kaplan-Meier estimates, the incidence of TKA for the MTX (+) group was significantly lower than that for the MTX (-) group (P=0.035) (Fig. 1). Previous studies reported that age and joint damage existing at baseline was a risk factor for the progression of large joint destruction in patients with RA treated with TNF inhibitors. Interestingly, multivariate analysis using the Cox proportional hazards model revealed that concomitant MTX predicted TKA (hazard ratio: 0.44, 95% confidence interval: 0.22 to 0.89) independently of age and joint damage at baseline (Table 1). Conclusions Concomitant MTX effectively reduces the incidence of TKA in patients with RA during long-term treatment with TNF inhibitors, regardless of age and pre-existing joint damage. Our findings suggest that TNF inhibitors should be used preferentially in combination with MTX to inhibit the progression of large joint destruction as well as small joint destruction, and also strongly support recent EULAR recommendations to commence MTX with all bDMARDs. Disclosure of Interest S. Asai Speakers bureau: Eisai Pharma Corporation, N. Takahashi: None declared, K. Funahashi: None declared, Y. Yoshioka: None declared, T. Takemoto: None declared, K. Terabe: None declared, N. Asai: None declared, N. Ishiguro Grant/research support from: Daiichi Sankyo, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Taisho Toyama Pharmaceutical, Kaken Pharmaceutical, Eisai, Janssen Pharmaceutical, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Astellas Pharma, and Pfizer Japan., Speakers bureau: Daiichi Sankyo, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Taisho Toyama Pharmaceutical, Kaken Pharmaceutical, Eisai, Janssen Pharmaceutical, Bristol-Myers Squibb, Abbott Japan, Chugai Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Astellas Pharma, and Pfizer Japan., T. Kojima Grant/research support from: Takeda Pharma Corporation, Janssen Pharmaceutical, and Astellas Pharma Corporation., Speakers bureau: Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Eisai Pharma Corporation, Abbvie, Bristol-Myers Squibb, Pfizer, Chugai Pharma Corporation, Janssen Pharmaceutical, and Astellas Pharma Corporation