Kenya Terabe

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.

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.

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.

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.

SAT0138 The effectiveness of adalimumab concomitant with disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis

Background It has been defined that ADA monotherapy has only limited effectiveness compared to combination therapy with Methotrexate (MTX). On the other hand, MTX cannot be administered in some patients because of tolerability concern or their complications. It is inadequate to clarify the efficacy of ADA treatment concomitant with disease-modifying antirheumatic drugs (DMARDs) other than MTX in patients in whom MTX cannot be administered. Objectives The objective of this study was to investigate the effectiveness of ADA concomitant with DMARDs other than MTX in Japanese patients with RA. Methods All patients (n=175) who underwent ADA treatment between August 2008 and October 2009 at Tsurumai Biologics Communication Study Group’s institutes were enrolled. Patients were divided into three groups: (1) concomitant MTX (MTX group) (2) concomitant DMARDs other than MTX (DMARDs group) (3) monotherapy (mono group). Effectiveness end point was DAS28-ESR at 52 weeks. Kaplan-Meier analysis was used to estimate drug survival rates during first 52 weeks. Results In total, 136 (77,4%) were in MTX group, 20 (11.4%) were in DMARDs group and 19 (10.9%) were in mono group. The mean age was 58±14 years in MTX group, 61±13 in DMARDs group, 65±9 in mono group. The mean duration of disease was 12.9±10.9 years, 13.0±11.3, 17.2±11.1, respectively. In MTX group, mean dosage of MTX was 7.0±1.9 mg/weeks. In DMARDs group, the number of DMARDs types was 7 (Fig A). DAS28-ESR scores decreased from 4.84±1.18 at baseline to 3.27±1.29 at week 52 in MTX group (p<0.001 vs baseline), from 5.18±1.10 to 4.09±1.12 in DMARDs group (p<0.001 vs baseline) and from 6.06±0.95 to 5.21±1.61 in mono group (not significant vs baseline) (Fig B). Mean DAS28-ESR scores of patients in MTX and DMARDs groups were significantly greater than those of patients in mono group (MTX vs mono: p=0.002 DMARDs vs mono: p=0.04). Figure C shows the proportion of patients who achieved different disease statuses at 52 weeks in each group. The proportions of patients who still remains high disease activity in MTX and DMARDs group were less than that in mono group (MTX vs mono: p=0.001 DMARDs vs mono: p=0.004). The drug survival rates in MTX and DMARDs group were significantly higher than that in mono group (MTX vs mono: p=0.041 DMARDs vs mono: p=0.020) (Fig D). In the present study, effectiveness and drug survival rate were not significant difference between use of concomitant MTX with other DMARDs. We speculate that these results were caused from low dosage of MTX because the approved dosage of MTX is ≤8 mg/week according to the Japanese labeling at the time of the present study. Conclusions This study clearly confirmed the superior effectiveness of combination therapy with MTX and otherDMARDs over ADA monotherapy. Disclosure of Interest K. Terabe: None Declared, T. Kojima Speakers Bureau: Abbott Japan, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Parma, Pfizer Japan, Takeda Pharmaceutical, A. Kaneko: None Declared, Y. Hirano: None Declared, T. Fujibayashi: None Declared, Y. Hattori: None Declared, N. Ishiguro Speakers Bureau: Abbott Japan, Chugai Pharmaceutical, Daiichi Sankyo Pharmaceutical, Eisai, Mitsubishi Tanabe Parma, Pfizer Japan, Takeda Pharmaceutical

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.

The pericellular hyaluronan of articular chondrocytes

The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan-with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.

Longterm Retention Rate and Risk Factors for Adalimumab Discontinuation Due To Efficacy and Safety in Japanese Patients with Rheumatoid Arthritis: An Observational Cohort Study

Objective. To evaluate the rates of retention and discontinuation of adalimumab (ADA) due to efficacy and safety in Japanese patients with rheumatoid arthritis (RA). Methods. All patients with RA (n = 476) who were treated with ADA in the Tsurumai Biologics Communication Registry were enrolled. Results. The retention rate of ADA was 46% at 5 years. When focusing on insufficient efficacy, previous biologics use and high baseline disease activity were significant risk factors for up to 1 year. Methotrexate (MTX) use was a significantly low risk factor after 1 year of treatment. Conclusion. Concomitant MTX contributes to the longterm efficacy of ADA therapy.