S. Hirabara

Hyaluronan inhibits TLR-4 dependent cathepsin K and matrix metalloproteinase 1 expression in human fibroblasts.

Rheumatoid synovial fibroblasts (RSF) are activated by toll-like receptor (TLR) signaling pathways during the pathogenesis of rheumatoid arthritis (RA). Cathepsin K is highly expressed by RSF, and is known to play a key role in the degradation of type I and type II collagen. Cathepsin K is considered to be implicated in the degradation of bone and cartilage in RA. Recent observations have shown that hyaluronan (HA) is an important inhibitor of inflammation. In the present study, we show that lipopolysaccharide (LPS) stimulation significantly increases cathepsin K expression by real-time PCR and western blotting analysis via a TLR-4 signaling pathway. Furthermore, we demonstrate that HA suppresses LPS-induced cathepsin K expression, which is dependent on CD44 but not intercellular adhesion molecule-1 (ICAM-1) interaction. We also show that HA suppresses LPS-induced matrix metalloproteinase-1 (MMP-1) expression, which is dependent on both CD44 and ICAM-1 interaction. We conclude that the anti-inflammatory effect of HA occurs through crosstalk between more than one HA receptor. Our study provides evidence for HA mediated suppression of LPS-induced cathepsin K and MMP-1 expression, supporting a protective effect of HA in RA.

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.

Drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors for rheumatoid arthritis in Japanese patients on low-dose methotrexate or without methotrexate

Abstract Objectives. The purpose of this study was to explore drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors (TNFi) in clinical practice in patients with rheumatoid arthritis (RA) on low-dose methotrexate (MTX) or without MTX. Methods. A total of 169 RA patients who had been withdrawn from first-course TNFi therapy and received a different TNFi or tocilizumab (TCZ) as a second biologic agent were selected from the Tsurumai Biologics Communication Registry, an observational cohort database. Retention rates of second biologic treatment were compared by the type of first TNFi and second biologic agents. Results. Eighty-six patients received first-course infliximab (IFX) or adalimumab (ADA) therapy, and 83 patients received first-course etanercept (ETN) therapy. The former group had a significantly higher retention rate (IFX, 81.1%; ADA, 83.3%) of the second biologic therapy compared to the latter (56.6%, p < 0.001, log-rank test). Drug retention rates of the second biologic agent after switching from IFX/ADA were significantly higher with ETN (90.0%) and TCZ (94.7%) than with ADA/IFX (59.3%). Drug retention rates of the second biologic agent after switching from ETN were significantly higher with TCZ (75.9%) than with ADA/IFX (46.3%). The differences were significant even after adjusting for baseline clinical variables using the Cox proportional hazards model. Conclusions. Drug retention rates of IFX and ADA after switching from the first TNFi were significantly lower compared to those of ETN and TCZ in patients on low-dose MTX or without MTX.

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.

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.

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.

Hyaluronan Inhibits Tlr-4-Dependent RANKL Expression in Human Rheumatoid Arthritis Synovial Fibroblasts

The Toll-like receptor (TLR) signaling pathway is activated in synovial fibroblast cells in patients with rheumatoid arthritis (RA). The receptor activator of nuclear factor-κB (RANK) and its ligand, RANKL, are key molecules involved in the differentiation of osteoclasts and joint destruction in RA. Hyaluronan (HA) is a major extracellular component and an important immune regulator. In this study, we show that lipopolysaccharide (LPS) stimulation significantly increases RANKL expression via a TLR-4 signaling pathway. We also demonstrate that HA suppresses LPS-induced RANKL expression, which is dependent on CD44, but not intercellular adhesion molecule-1 (ICAM-1). Our study provides evidence for HA-mediated suppression of TLR-4-dependent RANKL expression. This could present an alternative target for the treatment of destructed joint bones and cartilages in RA.

Hyaluronan Oligosaccharides Induce MMP-1 and -3 via Transcriptional Activation of NF-κB and p38 MAPK in Rheumatoid Synovial Fibroblasts.

Objective To explore the effect of hyaluronan oligosaccharides (HAoligos) on interactions between HA and its principal receptor, CD44, in rheumatoid synovial fibroblasts (RSFs) and matrix metalloproteinase (MMP) production. Methods RSFs were isolated from rheumatoid synovial tissue. HA distribution was visualized by immunocytochemistry. MMP-1 and MMP-3 induction was analyzed by real-time RT-PCR and immunoblotting. The interaction between HAoligos and their MMP-producing receptors was tested by blocking with anti-CD44 and anti-Toll-like receptor 4 (TLR-4). Phosphorylation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) was analyzed by immunoblotting. Results Endogenous HA decreased after treatment with HAoligos, while MMP-1 and MMP-3 expression increased in a dose-dependent manner. Pretreatment with anti-CD44 or anti-TLR-4 antibody significantly reduced the effect of HAoligos on MMP-1 and MMP-3 mRNA expression. NF-κB and p38 MAPK phosphorylation was enhanced by HAoligos pretreated with anti-TLR-4, and HAoligo-induced MMP production was blocked with an inhibitor of NF-κB and p38 MAPK pathways. Conclusions Disruptive changes in CD44-HA interactions by HAoligos enhanced MMP-1 and MMP-3 production via activation of NF-κB and p38 MAPK signaling pathways in RSFs.

AB0379 Tapering or Stopping of Methotrexate in Non-Tumor Necrosis Factor Therapy (Tocilizumab and Abatacept) in Patients with Rheumatoid Arthritis

Background Non-tumor necrosis factor (TNF) agents, such as tocilizumab (TCZ) and abatacept (ABT), were widely used in the treatment of rheumatoid arthritis (RA). It seems that non-TNF agents are slightly different from anti-TNF agents in respect to dependency on methotrexate (MTX). Although MTX is a very important concomitant drug in anti-TNF therapy, MTX may not be so in non-TNF therapy for majority of patients. MTX have many severe adverse events (AE) such as interstitial pneumonia, severe infection, and myelosuppression. Tapering or stopping of MTX have been tried in our institute to avoid AE of MTX when RA patients treated with non-TNF agents reached at sustained remission. We report the preliminary results of MTX tapering in non-TNF therapy in this study. Objectives This retrospective study evaluated tapering or stopping of MTX in non-TNF therapy (TCZ and ABT) and impact of it to RA treatment in clinical practice. Methods 27 RA patients who initiated TCZ or ABT with concomitant MTX and continued non-TNF agents for 2 years were used. Time-course of disease activity (DAS28-CRP and CDAI), arthritis marker (serum MMP-3), activity of daily living (mHAQ), joint destruction (ΔmTSS per a year) and tapering concomitant drug (MTX and prednisolone) were investigated. MTX was tapered depending on physicians decisions and stopped if possible. Results 20 females and 7 males with mean age of 60 years were used in this study. Mean RA duration was 11.8 years. TCZ was continued for 2 years in 16 cases and ABT in 11 cases. MTX of mean dosage of 9.0mg/week (4.0–16.0 mg/w) was prescribed in all patients at baseline. Mean DAS28-CRP was 4.57 at baseline, 2.26 at 1 year and 2.00 at 2 years. There were significant decreases not only from baseline to 1 years (p<0.0001) but also from 1 year to 2 years (p=0.04). Significant decrease and sustainment were also observed in CDAI, serum MMP-3 and mHAQ) (Fig. 1). Although ΔmTSS at baseline was )10.0, it was significantly improved to 1.5 from baseline to 1 year (p=0.0001) and to 0.5 from 1 year to 2 years (p<0.0001). Mean MTX dosage was significantly decreased from 9.0mg/w at baseline to 4.8mg/w at 1 year (p=0.0003) and to 2.9mg/w at 2 years (p<0.0001). There was a significant difference of MTX dosage between at 1 year and 2 years (p=0.049). Although MTX was concomitant in all patients at baseline, it was used in only 66.7% at 1 year and only 40.7% at 2 year. Mean PSL was also tapered from 3.5mg/day at baseline to 1.2mg/d at 2 years (Fig. 2). Similar trends were observed in both patients treated with TCZ and ABT. Conclusions This study suggested that concomitant MTX may be tapered or stopped in RA patients treated with TCZ or ABT and reached to sustained remission without worsening disease activity and joint destruction. Information of prospective large studies was necessary in the future. Disclosure of Interest None declared

AB0480 Clinical Efficacy of TNF Inhibitors and Abatacept in Japanese Rheumatoid Arthritis Patients Switching from Tocilizumab

Background Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, was approved in 2008 for use in clinical practice in Japan. The efficacy of tocilizumab in treating rheumatoid arthritis (RA) has been demonstrated in several clinical trials as well as in clinical practice. Given the high efficacy and safety, few patients switch from tocilizumab to other drugs, and limited studies have been reported in this regard. Controversy exists as to whether tumor necrosis factor inhibitors (TNFi) or abatacept should be selected when switching from tocilizumab. Objectives The aim of this study was to compare the clinical efficacy of two classes of biologics, TNFi and abatacept, after switching from tocilizumab therapy. Methods We performed a retrospective multicenter study of 40 RA patients who underwent 52-week biologic therapy after switching from tocilizumab therapy (Tsurumai Biologic Communication Registry). Patients were divided into two groups based on the biologic they switched to: TNFi (n=18) and abatacept (n=22). Changes in clinical parameters were examined at 0, 24, and 52 weeks after the switch: tender joint count (TJC) and swollen joint count (SJC) on 28 joints, general health on a visual analog scale (GH-VAS), and serum C-reactive protein (CRP) levels. Disease activity was evaluated at each time point using the 28-joint disease activity score with CRP (DAS28-CRP), as well as the clinical disease activity index (CDAI), which included data from the above-mentioned disease parameters. Results Patients at baseline had a mean age of 60.3 years, mean disease duration of 12.1 years, and mean DAS28-CRP of 5.1. There was no significant difference between the two classes of drugs at baseline, except in disease durations and oral steroid use (%). Retention rates for TNFi and abatacept treatment at 52 weeks were 78.6% and 80.1%, respectively (Figure 1). Discontinuation due to all unfavorable causes did not significantly differ between the two in hazard ratio-based evaluations (Table 1). DAS28-CRP levels were lower with TNFi compared to abatacept at 24 weeks (TNFi, 3.52; abatacept, 4.12, p=0.033), but no difference was found at 52 weeks (TNFi, 3.55; abatacept, 3.94, p=0.135) (Figure 2). Percentages of subsequent low disease activity of CDAI for TNFi and abatacept were 46.2%, and 22.2%, respectively. Conclusions This study is the first to compare the clinical efficacy of two different classes of biologics (TNFi and abatacept) after switching from tocilizumab using a multicenter registry system. Our results show that TNFi and abatacept are both effective, with no significant differences. When switching from tocilizumab, the characteristics of each drug should be considered to make an appropriate choice for each patient. References Nishimoto N, et al. Ann Rheum Dis. 2009;68(10):1580-4. Kojima T, et al. Mod Rheumatol. 2012;22(3):370-5. Yamanaka H, et al. Mod Rheumatol. 2011;21(2):122-33. Disclosure of Interest None declared