Yutaka Yoshioka

Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and chronic inflammation, which lead to the progressive destruction of cartilage and bone in the joints. Numerous studies have reported that administrations of various types of MSCs improve arthritis symptoms in animal models, by paracrine mechanisms. However, the therapeutic effects of the secreted factors alone, without the cell graft, have been uncertain. Here, we show that a single intravenous administration of serum-free conditioned medium (CM) from human deciduous dental pulp stem cells (SHED-CM) into anti-collagen type II antibody-induced arthritis (CAIA), a mouse model of rheumatoid arthritis (RA), markedly improved the arthritis symptoms and joint destruction. The therapeutic efficacy of SHED-CM was associated with an induction of anti-inflammatory M2 macrophages in the CAIA joints and the abrogation of RANKL expression. SHED-CM specifically depleted of an M2 macrophage inducer, the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9), exhibited a reduced ability to induce M2-related gene expression and attenuate CAIA. SHED-CM also inhibited the RANKL-induced osteoclastogenesis in vitro. Collectively, our findings suggest that SHED-CM provides multifaceted therapeutic effects for treating CAIA, including the ED-Siglec-9-dependent induction of M2 macrophage polarization and inhibition of osteoclastogenesis. Thus, SHED-CM may represent a novel anti-inflammatory and reparative therapy for RA.

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.

Use of a 12-week observational period for predicting low disease activity at 52 weeks in RA patients treated with abatacept: a retrospective observational study based on data from a Japanese multicentre registry study

OBJECTIVE Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. METHODS Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). RESULTS Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). CONCLUSION Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.

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.

Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages

BackgroundThe aim of this study was to assess the effects of soluble sialic acid-binding immunoglobulin-type lectin (sSiglec)-9 on joint inflammation and destruction in a murine collagen-induced arthritis (CIA) model and in monolayer cultures of murine macrophages (RAW264.7 cells and peritoneal macrophages) and fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis.MethodsDBA/1J mice were immunized with type II collagen. Effects of sSiglec-9 were evaluated using a physiologic arthritis score, histological analysis, serum tumor necrosis factor (TNF)-α concentration, and the proportion of forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. In vivo biofluorescence imaging was used to assess the distribution of sSiglec-9. Levels of M1 (TNF-α, interleukin [IL]-6, and inducible nitric oxide synthase) and M2 (CD206, Arginase-1, and IL-10) macrophage markers and phosphorylation of intracellular signaling molecules were examined in macrophages, and levels of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 were examined in FLS.ResultssSiglec-9 significantly suppressed the clinical and histological incidence and severity of arthritis. The proportion of Foxp3-positive Treg cells significantly improved and serum TNF-α concentration decreased in vivo. Although sSiglec-9 reduced the expression of M1 markers in macrophages, it did not affect the expression of M2 markers and MMPs in FLS. Nuclear factor (NF)-kB p65 phosphorylation was attenuated by sSiglec-9, and chemical blockade of the NF-kB pathway reduced M1 marker expression in RAW264.7 cells.ConclusionsIn this study, we have demonstrated the therapeutic effects of sSiglec-9 in a murine CIA model. The mechanism underlying these effects involves the suppression of M1 proinflammatory macrophages by inhibiting the NF-kB pathway. sSiglec-9 may provide a novel therapeutic option for patients with rheumatoid arthritis refractory to currently available drugs.

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

AB0466 The Outcome of Tocilizumab Treatment with Achievement of Glucocorticoids Withdrawal Against Rheumatoid Arthritis for 24 Months from TBC Registry

Background It is stated that low-dose glucocorticoids (GCs) should be considered as part of the initial treatment strategy with rheumatoid arthritis (RA), but should be tapered as rapidly as clinically feasible in overarching principles with EULAR recommendations 2013 [1]. Objectives To assess treatment outcome tapering glucocorticoids (GCs) in accordance with EULAR recommendations 2013 with Tocilizumab (TCZ) treatment for 24 months by using multi-center registry for the treatment of RA with biologics in Japan (Tsurumai Biologics Communication Registry; TBCR) [2]. Methods 276 RA patients treated with TCZ for at least 24 months in Nagoya University Hospital and 12 affiliated institutes (TBCR Study Group) were enrolled in this study. We compared three groups which are TCZ treatment without GCs at the baseline (n=95), with stopping GCs by 24 months (n=78) and with persistence of GCs for 24 months (n=103). Difference in baseline characteristics was summarized in Table.1. We assessed disease activity with DAS28-ESR, retention rate of drug continuity with Kaplan-Meier method for 24 months and the proportion of achievement with low disease activity and remission on DAS28-ESR. The last observation carried forward (LOCF) method was used in each analysis. Results In GCs(-) group, GCs withdrawal group and GCs continuation group, the values of DAS28-ESR at the baseline were 5.39, 5.57, 5.77, respectively. Although each group significantly improved in DAS28-ESR, it is significantly different in the three groups at 24 months by one-way ANOVA (Fig. 1). The continuation rate of TCZ treatment associated with inadequate response (IR) and adverse events (AEs) was significant difference between GCs withdrawal group and GCs continuation group (Log-rank test: p=0.007; IR p=0.006; AEs) (Fig. 2). The two years continuation rate associated with IR is 88.0, 95.8, 82.6% in each group. The proportion of achievement with low disease activity and remission on DAS28-ESR is 65.5, 67.1, 45.1% in each group at 24 months (Fig.3). Conclusions We confirmed that the good outcome of TCZ treatment by stopping GCs with effectiveness and safety. References Ann Rheum Dis. 2014 Mar;73(3):492-509. Mod Rheumatol. 2012 Jun;22(3):339-45. Disclosure of Interest K. Funahashi Speakers bureau: Abbvie Japan Co. Ltd, Eisai Co. Ltd, UCB Japan Co. Ltd, Mitsubishi Tanabe Pharma, 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, 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 PharmaceuticalCo. Ltd, Janssen Pharmaceutical K.K., and Bristol-Myers Squibb Co. Ltd., S. Asai: None declared, Y. Yoshioka: None declared, T. Takemoto: None declared, K. Terabe: None declared, N. Asai: None declared, Y. Yabe: 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.