Takahiko Kurasawa

Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients—REACTION 52-week study

Objectives. To evaluate the effectiveness and safety of tocilizumab in RA patients in clinical practice. Methods. We observed 232 consecutive RA patients who began tocilizumab in three rheumatology centres in Japan for 52 weeks. Clinical, radiographic and functional status and safety were evaluated. Results. Mean age of the 232 patients was 59.1 years, mean duration of disease was 12.4 years and average DAS using the 28-joint count (DAS-28) was 5.6. Although 62.8% of the patients had been treated previously with anti-TNF biologics, clinical remission at Week 52 was achieved in 43.7%, radiographic non-progression in 62.8% and functional remission in 26.4%. Retention rate at Week 52 was 71.1%, and the same for those with or without previous anti-TNF treatment. Adverse drug reactions leading to tocilizumab discontinuation were observed in 15.5% of patients, the most frequent adverse drug reaction being pneumonia in eight cases. On multivariate logistic regression analysis, DAS-28, HAQ-disability index (HAQ-DI), concomitant MTX and concomitant glucocorticoids (GCs) were predictive variables for clinical remission at Week 52 of tocilizumab treatment. In particular, HAQ-DI was found to be a predictive variable for remission of all three types—clinical, radiographic and functional—at Week 52 of tocilizumab treatment. Conclusions. In daily clinical practice, tocilizumab exhibited excellent effectiveness in established RA patients, some of whom had failed to respond to previous anti-TNF treatment. Although further detailed safety findings are required, this study provides valuable real-world findings on the management of RA with tocilizumab.

Effect of interleukin-6 receptor inhibitor, tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors

Abstract Objectives. To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays. Methods. RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction. Results. Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ. Conclusion. TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR.

Clinical significance of cartilage biomarkers for monitoring structural joint damage in rheumatoid arthritis patients treated with anti-TNF therapy.

Purpose With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. Methods Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. Results Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. Conclusion The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3.

Infliximab and etanercept have distinct actions but similar effects on cytokine profiles in rheumatoid arthritis

OBJECTIVE Pro-inflammatory cytokines, especially TNFα, play a central role in the pathogenesis of rheumatoid arthritis (RA). The available TNF inhibitors are only slightly different from one another in terms of clinical efficacy, at least at the group level, but their structures and modes of action are not identical. Infliximab (IFX) and etanercept (ETN) differ in their ability to induce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in their ability to bind TNFβ. The purpose of our study was to elucidate the different cytokine pathways through which these two drugs enact their clinical efficacy. METHODS Serum from 44 RA patients treated with IFX and 24 patients treated with ETN was studied. All patients had been given these biologics at identical dosages and intervals for one year. The concentrations of 11 inflammatory cytokines and their receptors (IL-1β, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-12, TNFα, TNFβ, IFNγ, and GM-CSF) were measured at weeks 0, 22, and 54 using a high-sensitivity electro-chemiluminescence assay. Cytokine profiles were analyzed along with clinical efficacy. RESULTS IL-6 was significantly decreased in the ETN+MTX and IFX+MTX groups, although not in the ETN-only group; this change was consistent with changes in disease activity. IFNγ was gradually increased only in the non-remission subgroup of the IFX group, and not at all in the ETN group. TNFβ increased after starting IFX regardless of clinical efficacy. CONCLUSION IL-6 inhibition is a pathway affected by both IFX and ETN. In addition, IFNγ increase is a distinctive feature of the inefficacy of IFX.

Addition of another disease-modifying anti-rheumatic drug to methotrexate reduces the flare rate within 2 years after infliximab discontinuation in patients with rheumatoid arthritis: An open, randomized, controlled trial

Abstract Objectives. We examined whether the addition of another conventional disease-modifying anti-rheumatic drugs (DMARDs) to methotrexate (MTX) upon infliximab (IFX) discontinuation in well-controlled rheumatoid arthritis (RA) patients could suppress subsequent disease flare. Methods. RA patients maintaining DAS28-CRP (Disease Activity Score of 28 joints with C-reactive protein) scores < 2.6 for ≥ 6 months with IFX were randomized either to receive addition of bucillamine (BUC) to MTX (BUC + MTX group; n = 24) or not (MTX group; n = 31) upon discontinuing IFX. The primary endpoint was the flare rate within 2 years of IFX discontinuation. Results. Six patients discontinuing MTX during the study were excluded from analyses. Seventeen patients (63.0%) experienced flares in the MTX group, which was significantly reduced in the BUC + MTX group (31.8%; p = 0.045). Further, the flare rates differed significantly between remission and non-remission by a Boolean definition upon IFX discontinuation in the MTX group (40.0% vs. 91.7%, respectively; p = 0.014), but they were comparable in the BUC + MTX group. BUC treatment was interrupted in seven patients due to rash, proteinuria and incompliance. Conclusions. DMARDs combination therapy may be a better treatment strategy than MTX monotherapy for maintaining RA control after successful discontinuation of biological agents.

Successful treatment with tocilizumab monotherapy for Takayasu arteritis developing during infliximab therapy in a patient with ulcerative colitis

Abstract A 23-year-old female patient with ulcerative colitis (UC) who had been successfully treated with infliximab (IFX) plus 5-aminosalicylated acid (5-ASA) developed Takayasu arteritis (TAK). She refused to take glucocorticoids to treat TAK. IFX was discontinued, and 8 mg/kg of tocilizumab (TCZ) was added to 5-ASA. Her symptoms such as fever and chest pain disappeared within a week along with serum CRP. TCZ was administered every 2 weeks for 2 months and monthly thereafter. After 1-year treatment of TCZ monotherapy, arterial wall thickening also improved. In addition, UC has been in remission without any gastrointestinal symptoms. TCZ monotherapy is effective for TAK and might not compromise UC.

Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis

Abstract Objectives: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. Methods: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 – erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. Results: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. Conclusion: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

AB0431 Clinical Evaluation of Treat-to-Target Strategy-Based Management Using Shortening Interval Methods for Infliximab in Patients with Rheumatoid Arthritis

Background Treat-to-target (T2T) is a strategic approach to achieving remission or at least better control of disease activity, and is recommended in the clinical treatment of rheumatoid arthritis (RA). 1) In Japan, use of increased doses of infliximab (IFX) (up to 10mg/kg) or shortening of dosing interval (minimum every 4 weeks) has been approved since July 2009. Although the efficacy of increased doses of IFX has been reported 2,3), the efficacy and safety of shortening dosing intervals in T2T-based practice has not been clinically evaluated, despite its importance. Objectives To clarify the efficacy and safety of T2T strategy-based management with shortened intervals of IFX for RA. Methods Among 496 consecutive RA patients treated with IFX from August 2009 to December 2014, 124 patients were treated by T2T-based management by shortening intervals (six weeks or less) of IFX. Observation period was 12 months. Efficacy and safety were retrospectively and statistically evaluated using clinical information. Results In the shortening interval group, 83% were female. Mean age was 55 years, and mean disease duration was 88 months at IFX start. Average SDAI and concomitant methotrexate dose was 27.5 and 8.5 mg/week. During observation, interval was adjusted in 39.5% of patients whereas both interval and dose were adjusted in 61.5%. At 12 months, continuation rate after shortening of IFX was 63.7% and significant improvement in SDAI and HAQ-DI was confirmed (Figure 1). 44.2% of patients achieved remission, and disease activity was less than low in 86.6% in the SDAI category. In the shortening interval group without increased doses of IFX, continuation rate was 53.1% and 65.0% of patients achieved remission at 12 months. In contrast, the main causes of discontinuation were insufficient efficacy in 25 cases and adverse events in 9, including infusion reaction (5), pneumonia (3), and malignancy (1) in the shortening interval group. Conclusions Our consecutive cohort analysis concluded that T2T-based management by shortening intervals of IFX for active RA showed good efficacy and a good overall safety profile in clinical practice. This strategy is considered to be a useful option for the earlier achievement of remission. References Smolen JS et.al. Ann Rheum Dis. 2010;69(4):631-7. Takeuchi T et.al. Mod Rheumatol. 2009;19(5):478-87. Takeuchi T et.al. Ann Rheum Dis. 2012;71(9):1583-5. Disclosure of Interest T. Kurasawa: None declared, K. Suzuki Grant/research support from: Eisai Co.Ltd. and Bristol-Myers Squibb Company, H. Hanaoka Consultant for: Astrazeneca, Y. Kaneko Consultant for: Abbvie, Paid instructor for: Eisai Pharmaceutical, Chugai Pharmaceutical, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Speakers bureau: Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Janssen, UCB, H. Yasuoka Consultant for: Abbvie, N. Seta: None declared, K. Yamaoka Consultant for: Pfizer, Speakers bureau: Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithKline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma and Actelion Pharmaceuticals, H. Kameda Grant/research support from: Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company, Speakers bureau: Mitsubishi Tanabe Pharma Corporation, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd.,SymBio Pharmaceuticals Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Paid instructor for: Mitsubishi Tanabe Pharma Co., Eisai Co., Ltd., Abbivie GK, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co.,Ltd., Celtrion, Nipponkayaku Co.Ltd

THU0384 Classification of Systemic Lupus Erythematosus Patients by Expression Pattern of Immune and Disease-Associated Genes in Peripheral Blood

Background Gene expression analysis in SLE patients with peripheral blood have identified activated type I interferon signature by DNA microarray (1,2) and RNAseq (3). However, the link between detailed and comprehensive information at the molecular level and clinical manifestation and/or laboratory parameters remains unclear. In addition, it also remains unclear exactly how we should utilize this information for better understanding of pathophysiology in individual patient. Objectives Clarify the significant association between gene expression and clinical data and establish a means of classifying patients by expression patterns of immune and disease-associated genes. Methods Total RNA was purified from peripheral blood: 13 active SLE patients, 5 healthy controls (HC)). Quantitative gene expression data were collected by the latest high density DNA microarray (Human 8X60k ver.2.1, Agilent technologies) and analyzed by several bioinformatics methods. Results All patients were female and mean age was 45 years. Disease activity was high (SLEDAI: 16.5±7.5 (Mean ± SD). Differentially expressed gene analysis statistically identified 558 up-regulated and 289 down-regulated genes including non-coding RNA as compared with HC (P<0.05, t-test). Stratification analysis classified by presence or absence of renal involvement purified lupus nephritis associated 14 genes (10 up-regulated and 4 down-regulated) including RTKN2 although stratification by autoantibody, disease activity or treatment could not purify any gene. Next, we calculated the correlation between all gene expression data and 50 clinical parameters and identified that serum LDH and urine β2-microglobulin strongly associate with the overall change of gene expression whereas serum CRP, autoantibody and SLEDAI do not. These findings may suggest that LDH and β2-microglobulin but not CRP may reflect peripheral blood cell injury due to the activity of SLE. We further classified SLE patients and HCs by clustering analysis using gene lists: plasmablast (number of genes: 12, Figure), proteasome (55), and interferon (27) associated and SLE susceptibility (57) genes. Plasmablast, proteasome and interferon associated gene lists efficiently enriched SLE patients without precondition, however SLE susceptibility gene list did not. Conclusions Gene expression analysis focusing on its association to clinical data demonstrated that changes at the molecular level could reflect changes in clinical status of SLE patients. SLE patients had heterogeneous and unique characteristics from the aspect of immune associated gene expression. Our approach may aid physicians in determining treatment strategies for individual SLE patients. References Kirou KA et. al. Arthritis Rheum. 2004;50: 3958-67 Higgs BW et.al. Ann Rheum Dis. 2011;70: 2029-36 Suzuki K et.al. Ann Rheum Dis. 2014;73(suppl2): 347 Disclosure of Interest T. Kurasawa: None declared, K. Suzuki Grant/research support from: Eisai Co.Ltd. and Bristol-Myers Squibb Company, J. Kikuchi: None declared, F. Miyoshi Employee of: Mitsubishi Tanabe Pharma Corporation, A. Mogami Employee of: Mitsubishi Tanabe Pharma Corporation, S. Kojima Employee of: Mitsubishi Tanabe Pharma Corporation, Y. Hisada Employee of: Mitsubishi Tanabe Pharma Corporation, K. Yoshimoto: None declared, Y. Kaneko Consultant for: Abbvie, Paid instructor for: Eisai Pharmaceutical, Chugai Pharmaceutical, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Speakers bureau: Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Janssen, UCB, H. Yasuoka Paid instructor for: Abbvie, K. Yamaoka Consultant for: Pfizer, Speakers bureau: Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithKline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma and Actelion Pharmaceuticals, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd.,SymBio Pharmaceuticals Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Paid instructor for: Mitsubishi Tanabe Pharma Co., Eisai Co., Ltd., Abbivie GK, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co., Ltd., Celtrion, Nipponkayaku Co.Ltd

AB0143 Identification of Aberrant Expression of 14-3-3 Zeta by Multiple-Quantitative Validation Methods in Patients with Rheumatoid Arthritis

Background The 14-3-3 proteins family consists of biologically essential protein kinases with multiple functions, such as in cell proliferation, differentiation, and cell cycle and functional regulation. It is evolutionally conserved and consists of 7 isoforms. Dysregulation of human 14-3-3 has been reported in several diseases such as neurologic disorders and cancers. Although aberrant up-regulation of 14-3-3 eta has been recently discovered in synovial fluid and serum in patients with rheumatoid arthritis (RA), little is known about the role of other family proteins. More interestingly, recent research showed that these proteins, including 14-3-3 zeta (YWHAZ), are activation-induced cytidine deaminase binding factors that work as essential elements in immunoglobulin class-switch DNA recombination [1]. Objectives To validate the presence of 14-3-3 zeta in blood and clarify its immuno-pathological role in RA Methods Peripheral blood samples obtained from untreated or methotrexate-naïve active RA patients who met either the 1987 and/or 2010 classification criteria and healthy individuals (HI) were enrolled. Total RNA was purified and relative mRNA expression was measured by quantitative PCR. Protein expression in peripheral mononuclear cells (PBMC) was evaluated by Western blotting. Further, intracellular expression was analyzed in a subpopulation by flow cytometry, and serum protein levels were measured by ELISA. Statistical correlation of expression with clinical indicators were analyzed. Results In whole blood, expression of 14-3-3 zeta mRNA in RA patients (n=30) was significantly (p=9.0E-07) up-regulated compared to HI (n=27). In PBMC also, Western blotting showed up-regulation of 14-3-3 zeta in RA patients (n=9), to a comparable degree to that of mRNA. On intracellular staining by flow cytometry in 41 RA patients and 13 HI, expression in whole blood from RA patients tended to be increased (average 1.7 times) in the percentage of positive cells (p=0.07). Interestingly, further subpopulation analysis showed a tendency to increased expression in CD20+ B cells only (p=0.07), but no increase in CD14+ or CD8+ cells. With regard to serum concentrations, the proportion of RA patients with a high concentration of 14-3-3 zeta (n=31) was higher than that of HI (n=13), while no correlation was seen with either titers of rheumatoid factors or anti-citrulinated antibodies, unlike the case with 14-3-3 eta. Conclusions We established different quantitation methods for 14-3-3 zeta in peripheral blood. Analysis showed up-regulation of 14-3-3 zeta in RA patients compared with HI. Aberrant expression of 14-3-3 proteins family, including eta and zeta, may link to B cell abnormalities in RA. References Zhenming Xu et.al. Nat Struct Mol Biol. 17(9):1124-35, 2010 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3949