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Background:Emerging evidence during the last two decades supports a pivotal role of Interleukin 6 (IL-6) in the pathogenesis of Systemic Sclerosis (SSc). Standard immunosuppressive agents are often inadequate to control disease activity in SSc patients and treatment failure of multiple regimens is frequent in real-world practice.Objectives:To examine the efficacy and safety of interleukin-6 receptor inhibition by tocilizumab in selected real-world patients with SSc.Methods:Twenty-one patients (20 women, 16 diffuse SSc, mean age: 52±10 years, mean disease duration: 6.4±3.7 years, all with negative rheumatoid factor and anti-cyclic citrullinated antibodies, none with overlap syndrome with RA) with active joint and skin involvement refractory to corticosteroids (n=21), methotrexate (n=17), cyclophosphamide (n=10), mycophenolate (n=7), rituximab (n=1), leflunomide (n=2), hydroxychloroquine (n=2), and hematopoietic stem cell transplantation (n=2) who received weekly tocilizumab (162 mg subcutaneously) in an academic center, were monitored prospectively. Changes in Eustar modified activity index (MAI), modified Rodnan skin score (mRSS), disease activity score (DAS)28, lung function tests (LFTs) and patient reported outcomes (PROs) were analyzed at one year of treatment and at the end of follow-up.Results:One patient discontinued tocilizumab after 3 months due to inefficacy. During the first year of treatment, 12 patients achieved low disease activity (mean MAI change -2.9±1.8, pConclusion:Tocilizumab was effective in refractory joint and skin involvement irrespective of SSc disease duration or subtype. Long-term retention rates and disease stabilization for most real-world patients suggest that tocilizumab might be a valuable choice for difficult-to-treat SSc.Table 1.Clinical and laboratory parameters and measures (mean ± SD) at baseline and after one year of treatment with tocilizumab in 20 patients with Systemic SclerosisBaseline1st yearchangepModified activity index4.9 ± 1.62.0± 1.2-2.9 ± 1.8mRSS 21.5 ± 9.5 14.6 ± 6.6-6.9 ± 5.9DAS28 5.3 ± 0.73.4 ± 0.6-1.9 ± 0.8FVC (% of predicted) 82 ± 19.5 79 ± 19.1-2.9 ± 12 0.389DLCO (% of predicted) 60.4 ± 16.361.1 ± 18.4 0.7 ± 12.3 0.844ESR (mm/1st hr)35.6 ± 17.212.9 ± 11.8 -22.8 ± 19.10.001CRP (mg/l)13.2 ± 12.51.2 ± 2.1 -12 ± 13.10.006SHAQ1.6 ± 0.81.0 ± 0.7 -0.6 ± 0.5VAS patient global score37.8 ± 16.860.5 ± 15.4 22.7 ± 20.3VAS physician global score33.4 ± 13.263.2 ± 13.9 29.8 ± 15.6mRSS: modified Rodnan skin score; DAS28: disease activity score 28; FVC: forced vital capacity; DLCO: diffusing lung capacity for carbon monoxide; ESR: erythrocyte sedimentation rate; CRP: c-reactive protein; SHAQ: scleroderma health assessment questionnaire; VAS: visual analogue scaleDisclosure of Interests:None declared

Background:Adiponectin is an adipokine with anti-inflammatory, anti-atherosclerotic and cardioprotective effects that also contributes to the pathogenesis of metabolic syndrome (MetS) [1]. MetS is frequently observed in patients with rheumatoid arthritis (RA), increasing the risk of cardiovascular (CV) morbidity and mortality in these patients [1-3]. A recent study of our group disclosed a short-term effect of anti-IL-6 therapy on serum levels of leptin (another adipokine with pro-inflammatory functions, related with MetS and CV disease) in RA patients [4]. Accordingly, it is plausible to think that such treatment may also have an effect in adiponectin levels.Objectives:To determine the short-term effect of the anti-IL-6 receptor tocilizumab (TCZ) administration on circulating adiponectin serum levels in patients with RA, as well as the potential association of adiponectin with demographic and clinical features of these patients.Methods:50 consecutive Spanish patients undergoing periodic treatment with TCZ who fulfilled the 2010 classification criteria for RA [5] were recruited. Adiponectin serum levels were assessed in samples obtained immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion) by a commercial Enzyme-Linked ImmunoSorbent Assay (ELISA) kit.Results:Similar serum levels of adiponectin were found following the TCZ infusion (mean ± standard deviation: 23.01 ± 18.58 µg/mL versus 22.35 ± 17.84 µg/mL, pre- and post-infusion, respectively, p=0.69). Additionally, there was a negative correlation between adiponectin basal levels and body mass index (r=-0.45, pConclusion:Our study suggests that anti-IL-6 therapy has no short-term effect on adiponectin serum levels in patients with RA. Furthermore, our results support that low adiponectin levels are associated with MetS features and, therefore, with CV disease in RA.References:[1]Biochem Pharmacol. 2019;165:196-206; [2] Clin Exp Rheumatol. 2008;26:596-603; [3] Mediators Inflamm. 2013;2013:710928; [4] Clin Exp Rheumatol 2020;38:1201-1205; [5] Arthritis Rheum. 2010;62:2569-2581.Acknowledgements:Personal funds:SR-M: RD16/0012/0009 (ISCIII-ERDF); VP-C: PREVAL 18/01 (IDIVAL); OG: GPC IN607B2019/10 (GAIN); RL-M: Miguel Servet type I programme CP16/00033 (ISCIII-ESF).Disclosure of Interests:Sara Remuzgo-Martínez: None declared, Verónica Pulito-Cueto: None declared, Fernanda Genre: None declared, Jaime Calvo: None declared, Elena Aurrecoechea: None declared, Irene Llorente: None declared, Ana Triguero-Martinez: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Javier Llorca: None declared, M E Ruiz: None declared, Natalia Rivera: None declared, Oreste Gualillo: None declared, Raquel López-Mejías: None declared, Santos Castañeda: None declared, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD.

Background:Previously, 12-week results of phase 2 clinical study of levilimab (LVL) in patients with active rheumatoid arthritis (RA) have been reported1. The study has met the primary endpoint at W12 confirming that treatment with LVL 162 mg SC + methotrexate (MTX) either QW or Q2W is superior to MTX alone in patients with RA and inadequate response to methotrexate (MTX-IR). Here we report 1-year efficacy and safety data in QW and Q2W arm of the study.Objectives:This study was aimed to assess the efficacy and safety of 2 dosing regimens of LVL in active MTX-IR RA subjects.Methods:This multicenter double-blind placebo-controlled study (NCT03455842) enrolled 105 MTX-IR subjects with active RA (ACR2010). The study design is outlined on Figure 1. Secondary endpoints for the open-label period included ACR20/50/70, LDA, remission rates, and DAS28-CRP(4), among others. The safety was evaluated up to W56.Figure 1.Study designResults:At W12 ACR20 was reached by 77.1% and 57.1% of subjects of QW and Q2W arms respectively. Within open-label (OLE) period further increase in clinical response degree was observed up to W52, more pronounced in ACR50 and even more in ACR70 / RA LDA and Remission rates (Table 1). Figure 1 summarizes the dynamic of DAS28-CRP(4) change throughout the study. QW regimen showed better efficacy results.Table 1.Efficacy results (full analysis set), n (%).QW + MTX(n = 35)Q2W + MTX(n = 35)p-valueACR20 W1227 (77.1)20 (57.1)0.07 W5232 (91.4)25 (71.4)0.03ACR50 W1218 (51.4)11 (31.4)0.09 W5226 (74.3)23 (65.7)0.43ACR70 W1210 (28.6)7 (20.0)0.40 W5223 (65.7)16 (45.7)0.09LDA (DAS28 20 (57.1)10 (28.6)0.02 W5229 (82.9)24 (68.6)0.16EULAR Remission W244 (11.4)2 (5.7)0.67 W5210 (28.6)10 (28.6)1.00Table 2 shows the main safety endpoints for the entire study (W0 – W56). The most common treatment related AEs (registered >5% of subjects) were laboratory abnormalities (neutrophil count decrease, ALT / AST increase, blood cholesterol/triglycerides increased). SAE occurred within the blinded study period were reported previously1. During OLE, starting from W12, four new serious AE (SAEs) were reported: 3 in LVL QW arm: haemorrhage (gr.3, unrelated), vaginal cyst (gr.3, unrelated) and keratitis (gr.2, unrelated); 1 in LVL Q2W arm: myocardial ischemia with cardiovascular insufficiency (gr.5, unrelated).Table 2.Safety results (full analysis set, W0 – W56), n (%).QW + MTX(n = 35)Q2W + MTX(n = 35)Any TEAEs/SAEs34 (97.1)29 (82.9)Any SAEs4 (11.4)2 (5.7)Any gr. 3-4 AEs16 (45.7)12 (34.3)Gr. 3-4 neutropenia4 (11.4)5 (14.3)AEs of special interest(ALT / AST high; Leucopenia / Neutropenia; Infections; Cholesterol/triglycerides high)28 (80.0)26 (74.3)Treatment discontinuation due to AE04 (11.3)Deaths02 (5.7) (unrelated)Conclusion:Within 1 year of treatment LVL + MTX showed sustained efficacy, with continuous clinical improvement in MTX-IR subjects with active RA. The safety profile of LVL was consistent with other IL6R inhibitors. LVL QW regimen was shown to be safe with better efficacy in terms of time and magnitude and was selected for phase 3 confirmatory clinical study.References:[1]http://dx.doi.org/10.1136/annrheumdis-2019-eular.7220Figure 2.Absolute DAS-28-CRP(4) change (median ± IQR, full analysis set)Disclosure of Interests:V Mazurov: None declared, Evgeniy Zotkin: None declared, Elena Ilivanova Grant/research support from: JSC BIOCAD, Tatyana Kropotina Grant/research support from: JSC BIOCAD, Tatyana Plaksina Grant/research support from: JSC BIOCAD, Olga Nesmeyanova Grant/research support from: JSC BIOCAD, Nikolaj Soroka Grant/research support from: JSC BIOCAD, Alena Kundzer: None declared, Anton Lutskii Employee of: JSC BIOCAD, Ekaterina Dokukina Employee of: JSC BIOCAD, Anna Eremeeva Employee of: JSC BIOCAD, Arina Zinkina-Orihan Employee of: JSC BIOCAD

Objectives To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. Methods In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. Results 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. Conclusion In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.

Serum C reactive protein (CRP) is generally elevated by infection. We encountered two patients with severe bacterial infections without increases in CRP. Patient 1: A 67-year-old man developed thoracic empyema by Escherichia coli and Streptococcus intermedius . His body temperature was 36.6°C, his leukocyte count was elevated (9960/μl) and he was negative for CRP (0.01 mg/dl). Despite antibiotic treatment, he died of respiratory failure. Patient 2: A 56-year-old woman developed multiple subcutaneous abscesses by Staphylococcus aureus . She had rheumatoid arthritis (RA) for 30 years and was treated with sodium aurothiomalate. Her body temperature was 37.4°C, and leukocyte count (5600/μl) and CRP (0.05 mg/dl) were not elevated. She recovered with antibiotics. Neither patient had a past history of severe bacterial infection. Since serum CRP is mainly controlled by interleukin (IL)-6,1 the lack of IL-6 function was suggested. Serum IL-6 was not detected by ELISA in either patient, although it is known to increase with severe infection.2 ,3 However, IL-6 production from peripheral blood monocytes with/without lipopolysaccharide stimulation was similar between Patient 1 and healthy controls (data not shown). Soluble IL-6 receptor (IL-6R) and IL-6 signal transducer (IL-6ST) serum levels were also …

Background and objectives B cells function as regulatory cells by producing inhibitory cytokines such as transforming growth factor β (TGF-β) and interleukin 10 (IL-10). Human CD25high B cells were shown to secrete higher levels of IL-10 versus CD25low B cells, suggesting this subset of cells to be immune-regulatory. Tocilizumab, a monoclonal antibody that acts as an IL-6R antagonist thus inhibiting IL-6 activity, and its autocrine growth activity on B cells is currently used for treatment of rheumatoid arthritis (RA). Following this treatment, one might expect a reduction in B cell activity status, and on the other hand increase of their regulatory properties. Methods Freshly purified B lymphocytes were isolated from 10 active RA patients, with inadequate response to methotrexate, at baseline and 3 months following add on tocilizumab. Clinical status was assessed by DAS 28 score and erythrocyte sedimentation rate (ESR). Using flow cytometry, B cells were stained for the expression of intracellular TGF-β, IL-10, membrane CD69, and MHC-II. These markers were assessed in primary (no-stimulated) CD25high B cells and expressed in MFI, with results given in mean ± SEM. Results Three months following initiation of tocilizumab, the expression of intracellular TGF-β in CD25high B cells was significantly increased (from 5.2 ± 2.3 at baseline to 8.1 ± 2.8; p Conclusions Our unique finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-β expression and the alteration in their activation status and APC properties in CD25high B cells, suggests that the induction/expansion of B regulatory cells may be one of the mechanisms by which tocilizumab may possibly produce its beneficial clinical effects.

Background Clazakizumab (CLZ) is a potent, neutralizing anti-interleukin-6 (IL-6) monoclonal antibody currently in development for RA. The Phase IIb study described herein evaluated the efficacy and safety of subcutaneous (SC) CLZ with or without MTX in patients with moderate-to-severe RA and an inadequate response to MTX in a randomized, comparator-controlled, double-blind study.1 Objectives To compare the change from baseline at Weeks 12 and 24, and the proportion of patients achieving minimal clinically important differences (MCID) at Week 24, in patient-reported outcomes (PROs) on treatment with CLZ with and without MTX vs MTX alone. Methods This was a post hoc analysis of data from the Phase IIb study. Patients were randomized equally to receive either CLZ 25, 100, or 200 mg with MTX, CLZ 100 or 200 mg monotherapy, or MTX alone every 4 weeks or adalimumab with MTX every 2 weeks. PROs assessed included the Health Assessment Questionnaire-Disability Index (HAQ-DI); fatigue (visual analogue scale [VAS]), pain (VAS), Patient Global Assessment (PGA) of disease activity (VAS); and the physical component summary (PCS) and mental component summary (MCS) of the Short Form 36-item questionnaire (SF-36). HAQ-DI was previously reported.1 Analyses were conducted on the modified intent-to-treat population comprising all randomized patients who received at least one dose of study medication. MCIDs for each PRO were based on criteria from the literature. An analysis of covariance was conducted with treatment as a factor and baseline scores as covariates. In cases where patients received rescue medication, or with missing data, a last observation carried forward approach was used. Results Overall, 418 patients were randomized. Compared with MTX alone, treatment with CLZ with or without MTX (at all doses) resulted in greater mean changes from baseline, and higher proportions of patients achieving an MCID on each of the PROs assessed at Week 24, except MCS (Table). ![Figure][1] Conclusions Treatment with clazakizumab with or without MTX resulted in improvements in multiple PROs and a greater proportion of patients achieved MCID on these PROs compared with MTX alone in patients with RA with an inadequate response to MTX. References 1. Weinblatt M et al. Arthritis Rheum 2013;65(10):S735–36. Disclosure of Interest E. Alemao Shareholder of: BMS, Employee of: BMS, S. Joo Shareholder of: BMS, Employee of: BMS, S. Banerjee Shareholder of: BMS, Employee of: BMS, P. Emery Grant/research support: AbbVie, BMS, Merck, Pfizer, Roche, Consultant for: AbbVie, BMS, Merck, Pfizer, Roche, Takeda, M. Weinblatt Grant/research support: BMS, Crescendo Bioscience, UCB, Consultant for: BMS, Crescendo Bioscience, UCB, AbbVie, Roche, Janssen, G. L'Italien Shareholder of: BMS, Employee of: BMS DOI 10.1136/annrheumdis-2014-eular.1515 [1]: pending:yes

Background Many reports have been published in recent years on the usefulness of anti-cytokine therapy in AA amyloidosis in rheumatic disease but, to date, no reports have been published that directly compare the utility of TNF inhibition to that of IL-6 inhibition. Objectives We retrospectively compared the efficacy and safety of tocilizumab (TCZ) and anti-TNF therapy (TNF) in AA amyloidosis in rheumatic disease at our hospital. Methods Of the 42 patients studied who were receiving anti-cytokine agents, 31 were receiving a single agent, 10 were receiving 2 agents, and 1 was receiving 3 agents. The patients were divided into 2 groups, a TCZ group (22 patients) and a TNF group (32 patients, 20 of whom received etanercept, 10 infliximab, and 2 adalimumab), and the two groups were compared using the following parameters: (1) treatment retention rate (Kaplan-Meier method) and reasons for withdrawing, (2) SAA profile (mcg/dl, median), (3) change in the eGFR (ml/min/1.73 m2, median), (4) proteinuria profile, and (5) severe gastrointestinal lesions. Results In the TCZ group, the 1-year retention rate was 90.4%; the 5-year retention rate was 90.4% as well. Two of the 22 patients withdrew, both due to adverse reactions (lower gastrointestinal perforation and cellulitis of the lower leg). In the 32 patients in the TNF group, the 1-year retention rate was 69.0% and the 5-year retention rate was 34.3%. The 14 patients who withdrew did so due to: primary non-response (2 patients), secondary non-response (7 patients), adverse reactions (5 patients [cancer (2 patients; esophageal cancer, malignant lymphoma], hypersensitivity vasculitis [1 patient], lower gastrointestinal perforation [1 patient], COP pattern IP). The retention rate was significantly higher in the TCZ group (log-rank test: p=0.0154). The SAA fell from 219.2 mcg/dl at treatment initiation to 5.0 mcg/dl at the last observation in the TCZ group and from 143.6 mcg/dl at treatment initiation to 38.1 mcg/dl at the last observation in the TNF group, and therefore decreased significantly more in the TCZ group (p=0.0194) (median observation period: 22.5 months in the TCZ group and 21.0 months in the TNF group). The eGFR increased from 41.6 ml/min/1.73 m2 at treatment initiation to 50.7 ml/min/1.73 m2 at the last observation in the TCZ group and decreased from 76.3 ml/min/1.73 m2 at treatment initiation to 67.4 ml/min/1.73 m2 at the last observation in the TNF group. Therefore, although TCZ treatment was initiated at a more advanced stage, significant improvement in renal function was obtained (p=0.0062). In the TCZ group, proteinuria was found in 13 patients at treatment initiation and, at the last observation, 9 had turned negative (median observation period: 31 months). In the TNF group, proteinuria was found in 3 patients, and 1 patient turned negative (median observation period: 10 months). Severe gastrointestinal lesions were found in 1 patient in the TCZ group and 3 patients in the TNF group. Conclusions We found that TCZ offered greater clinical utility than TNF in AA amyloidosis in rheumatic disease. References Y. Okuda et al. Arthritis Rheum. 54:2997-3000, 2006 D. Kishida, Y. Okuda et al. Mod Rheumatol. 21:215-218, 2011 Y Okuda et al. Challenges of Rheumatology INTECH. 155-168, 2011 Disclosure of Interest Y. Okuda Grant/Research support from: the Intractable Disease Division of the Ministry of Health and Welfare of Japan, a Research Committee for Amyloidosis in Japan, M. Ohnishi: None Declared, K. Takasugi: None Declared

Background Patients with rheumatoid arthritis (RA) have a high risk of osteoporosis and osteoporotic fracture. In primary osteoporosis (either high bone turnover osteoporosis [type I] or low bone turnover osteoporosis [type II]), bone loss is induced by an imbalance of bone metabolism: bone resorption dominates bone formation. However, it is not fully understood how RA affects bone metabolism or if bone metabolism is improved by blockade of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Objectives We aimed to examine change in the balance between bone resorption markers and bone formation markers in inflammation, and how it is affected by blockade of IL-6 or TNF-α, using a mouse model of collagen-induced arthritis (CIA). Methods CIA in DBA/1J mice was triggered by intradermal injection of bovine type II collagen on day 0 and 21. Mice were injected with anti-mouse IL-6 receptor antibody (MR16-1) intraperitoneally on days 0 and 21. On the other hand, TNF receptor-Fc (TNFR-Fc) was given intraperitoneally 3 times per week from the first immunization. Serum and urine were sampled on days 14 (before swelling), 35 (peak of swelling), and 54 (after swelling subsides). Urinary bone resorption markers (DPD: deoxypyridinoline, CTX: collagen type 1 cross-linked C-telopeptide) and serum bone formation markers (P1NP: procollagen type 1 N-terminal propeptide, OC: osteocalcin) were measured by ELISA. The lumbar spine was excised on day 56, and trabecular bone volume (BV/TV) was analysed by micro-computed tomography (μCT). Results In CIA mice, lumbar spine BV/TV on day 56 had significantly declined by 62.1% compared with non-immunized mice. Both MR16-1 and TNFR-Fc significantly suppressed development of arthritis compared with untreated CIA mice. In MR16-1-treated mice, lumbar spine BV/TV was significantly increased to 1.44 times that of untreated CIA mice; TNFR-Fc also increased BV/TV (1.13 times), but not significantly. On days 35 and 54, CTX and DPD levels were significantly higher in CIA mice than in non-immunized mice. OC level in CIA mice was significantly lowered on day 14. On day 35, OC had recovered to the level in non-immunized mice; however, P1NP was significantly lower. In MR16-1-treated mice, bone resorption markers were significantly lower on days 35 (CTX) and 54 (CTX and DPD) than in untreated CIA mice, and bone formation markers were significantly higher on days 14 (P1NP) and 35 (P1NP and OC). Moreover, bone formation markers were higher on day 35 than in non-immunized mice. In TNFR-Fc-treated mice, on the other hand, although bone resorption markers on days 35 (CTX) and 54 (DPD) were significantly decreased, bone formation marker levels were similar to those of untreated CIA mice. Conclusions We demonstrated that CIA induced severe bone loss by an imbalance of bone metabolism, not only increasing bone resorption but also suppressing bone formation. Moreover, our results indicated that both IL-6 and TNF play an important role in increasing bone resorption, but that only IL-6 played a crucial role in decreasing bone formation. Our findings provide evidence that anti-IL-6 receptor antibody would have a beneficial effect on systemic osteoporosis in RA patients. Disclosure of Interest None Declared

Background Studies have demonstrated the clinical efficacy of tocilizumab, a humanized anti-IL-6 receptor (R) antibody (Ab), in patients with rheumatoid arthritis (RA). The rational for blocking IL-6 in this disease mainly lays on the pro-inflammatory role of this cytokine in the disease. Moreover, IL-6 acts as a “pivot”, determining whether an immune response is dominated by regulatory CD4 + Foxp3 + T cells or Th17 effector T cells. However, only few works have studied the consequences of anti-IL-6R treatment on Tregs cells and only focuses on their frequency. Objectives In this study, we hypothesized that IL-6 inhibition led to Tregs modifications in RA models given that (i) anti-IL6R is therapeutic in RA and its models by inhibiting Th17 cells, and (ii) IL-6 plays a determining role in inducing Th17 when present, or Tregs when it is absent. Our objective was thus to elucidate anti-IL-6R mode of action in RA models by studying the consequences of this treatment on Tregs phenotype and biological activity. Methods Mice with collagen-induced arthritis were treated by MR16-1 (a rat anti-mouse IL-6 receptor monoclonal Ab provided by Chugai Pharmaceutical Co. LTD, Japan) and the evolution of Tregs (defined as CD4 + FoxP3 + ) during arthritis course was assessed at key time points (day 9-17-28 and 43 after CIA induction) by studying their number, frequency and phenotype (expression of GITR, ICOS, Helios, CD62L, CTLA-4 and CD39) in lymph nodes (LN) and spleen by flow cytometry. Finally, the immunosuppressive activity of the Treg cells on CFSE-labeled CD4+ CD25- T effector (Teff) cells proliferation was also studied. Numerical analysis of Th17 and Th1 cells was also performed at the same times by flow cytometry. Results Clinical evaluation of arthritides in mice treated with anti-mouse IL-6R mAb showed, as expected, a less severe disease as compared to control Ig treated mice. A decreased Teff/Tregs ratio overtime were observed in the LN of MR16-1 treated mice. Tregs phenotype was modified in treated mice mostly at day 17, with a decreased frequency of Tregs expressing CD62L or Helios (spleen) but an enhanced intensity of CD39 expression on Tregs (spleen and LN) and increased frequency of CD39+ Tregs (LN). No modification in ICOS, GITR and CTLA-4 were observed on Tregs at any time in any compartments. Lastly, the immunosuppressive activity of the Treg cells on Teff cells proliferation was not modified, suggesting that Tregs immunosuppression activity was probably due to another mechanism. Conclusions Tregs are modified by anti-IL-6R treatment in CIA, that could result in an enhanced peripheral generation of Tregs (Helios down regulation), an increased Tregs activation (CD39+ upregulation) and a better capacity to leave the secondary lymphoid organs and to migrate within the inflammatory joint (decreased CD62L down regulation). All together, thisstudy shows that inhibition of IL-6 in CIA also acts by modifying Tregs state. Disclosure of Interest None Declared

Background Magnetic resonance imaging (MRI) is a useful tool for evaluating disease activity and therapeutic efficacy in rheumatoid arthritis (RA). Magnetic resonance imaging (MRI) allows a highly accurate detection of synovitis, bone edema, and erosions, constituting the ideal instrument for the evaluation of treatment response. Objectives The aim of this study was to assess the disease activity in rheumatoid arthritis (RA) patients treated with the anti-interleukin 6 (anti-IL 6) receptor antibody tocilizumab in terms of responsiveness at a six months to disease activity and ability to predict structural damage at six month and one year. Methods A cohort of patients with RA (n=22) treated with tocilizumab were included in the study. All patients were evaluated clinically including disease activity score 28 (DAS28) andby low field dedicated MRI (dominant handand wrist) at initiation of treatment with anti-IL 6 receptorantibody agents and after 6 months. The MRI images were scored using the Outcome Measures in Rheumatology Clinical Trials RAMRI score (OMERACT RAMRIS). Conventional radiography for both hands and wrists and foot was performed at baseline 6 and at 12 months. Responsiveness was assessed by standardized response means (SRM). Areas under the curve (AUC) for measures at baseline, and 6 months were correlated with DAS28-ESRand structural damage at six month. Results Among the laboratory and clinical parameters, DAS28-ESR was the most responsive with a large effect size of SRM. Baseline DAS28 was superior to 3.2 in all patients (ranging from 4.8 up to 7.8). At 6 months, 16 patients have responded, however without having achieved clinical remission, as DAS28 was still above 2.6. MRI showed that synovitis was reduced in 13 patients to a score of 1, bone edema was slightly reduced (8% of reduction), and erosive score was unchanged. Structural damage progressions for radiography and MR erosion were correlated with AUC of MR bone erosion.Thus Despite persistent low disease activity, patients treated with tocilitumab had stable RAMRIS erosive scores over 6 months. Conclusions In the evaluation of disease activity in RA patients in the first few months after starting anti-IL 6 receptor antibody tocilizumab treatment, the MRI RAMRIS score of the hand is responsive and predictive of structural damage progression at 6 months. Disclosure of Interest None Declared

Background Glucocorticoids (GCs) such as prednisolone (PSL) and dexamethasone (DEX) are the main therapies used for chronic inflammatory diseases. GCs are potent and effective, but induce many side-effects such as osteoporosis, making it important to reduce dose. Some patients have difficulty tapering off GCs because of GC resistance. In Rheumatoid arthritis (RA), about 30% of patients fail to show good response to GCs [1,2]. Pro-inflammatory cytokines such as IL-6 are reportedly involved in GC resistance [3]. However, the influence of IL-6 inhibition on steroid action has not been fully examined. Objectives To investigate with a mouse arthritis model whether IL-6 regulates both anti-inflammatory effects and side-effects of GCs. Methods 1) A collagen-induced arthritis (CIA) model was used: mice were immunized intradermally with bovine type II collagen, and 21 days later (Day 21) were given a booster injection. From Day 21 mice were treated intraperitoneally with 3 or 6 mg/kg PSL five times a week (PSL3 group; PSL6 group) or 8 mg of anti-mouse IL-6R monoclonal antibody as an IL-6 inhibitor once on Day 21 (anti-IL-6R group). Other mice were given a combination of the two from Day 21 (PSL3+anti-IL-6R group; PSL6+anti-IL-6R group). Clinical symptoms of arthritis were evaluated by observation and expressed as a score of 0–4 for each limb. Lumbar vertebral BMD was measured with DXA to assess side effects of PSL. 2) Synovial cells from CIA mice and mouse osteoblastic cell line MC3T3-E1 were pretreated with 100 ng/mL of IL-6. After medium replacement, cells were stimulated by 1 μM of DEX for another 3 or 24 h. After culture, to evaluate inflammatory response in synovial cells, expression levels of cyclooxygenase (COX)-2 mRNA were examined by real-time PCR and the influence of IL-6 on DEX-induced nuclear translocation of glucocorticoid receptor (GR) were examined by western blotting. To evaluate osteogenic response in MC3T3-E1 cells, expression levels of osteocalcin (OC) mRNA were determined by real-time PCR. Results 1) PSL dose-dependently reduced arthritis score in the CIA model on the peak of arthritis (Day 33). PSL3+anti-IL-6R improved clinical symptoms significantly more than PSL3 alone on Day 33 although anti-IL-6R alone was ineffective against swelling when administered on Day 21. A significant decrease in lumbar vertebra BMD by CIA was confirmed. Interestingly, PSL6 alone produced the same degree of arthritis improvement as PSL3+anti-IL-6R, but lumbar vertebral BMD was higher in the PSL3+anti-IL-6R group than in the PSL6 group. 2) To explore how anti-IL-6R could improve these effects of PSL, we examined the influence of IL-6 on DEX activity in vitro . COX-2 expression was clearly suppressed by DEX, but IL-6 pretreatment attenuated the inhibitory effect of DEX, and IL-6 pretreatment inhibited GR nuclear translocation in synovial cells. On the other hand, OC expression was suppressed by DEX, and IL-6 pretreatment enhanced this inhibitory effect of DEX in MC3T3-E1 cells. Conclusions Anti-IL-6R augmented the anti-inflammatory effect of GCs via recovery of nuclear translocation of GR repressed by IL-6, and improved side-effects via a pathway independent of GR nuclear translocation. Anti-IL-6R might be a drug which makes GC tapering possible. References Scand J Rheumatol. 2007;36:167-71 Arthritis Rheum. 1995;38:334-42 Proc Natl Acad Sci U S A. 2012;109:5995-9 Disclosure of Interest None Declared

Background ALX-0061 is a monovalent IL-6R targeting Nanobody. It inhibits signalling via soluble and membrane IL-6R. PK/PD modelling resulted in a condensed study design, combining single ascending dose (SAD), multiple ascending dose (MAD) and clinical proof-of-concept using PK, biomarker and clinical readouts as decision tools. Objectives MAD: To determine the efficacy and safety of 24 weeks of dosing in patients with RA and to investigate the tolerance, PK, PD and immunogenicity after multiple dosing with ALX-0061. Methods Multicentre, randomised, double-blind, placebo controlled, dose escalation, Phase I/II study in patients with active RA on stable MTX therapy. MAD: In the first 12 weeks patients received placebo or ALX-0061 IV infusion at 1 or 3 mg/kg Q4W, or 6 mg/kg Q8W. In the second 12 weeks, patients with insufficient EULAR response were allowed to rollover (placebo) or to intensify dosing to enrich the safety and efficacy population. Results Thirty-seven patients with active RA from 6 sites in CEE started at 1 mg/kg (10 patients), 3 mg/kg (11 patients), 6 mg/kg (10 patients) or placebo (6 patients). 31 patients continued on ALX-0061 in the 2 nd 12 weeks with only 4 changing their dosing regimen and 3 rolling over from placebo. The patients initiated on ALX-0061 had a median duration of disease of 5.7 years, median age of 53 years and median BMI of 26 kg/m 2 and moderate-to-severe disease activity (median DAS28 score 4.7; median VAS patient score 49). ALX-0061 was well tolerated for up to 24 weeks. Clinically relevant neutropenia was absent as well as serious infections. Clinically significant signals in lipids were not observed. No anti-drug antibodies were detected. After 24 weeks of treatment, a total of 18 patients (58%) on ALX-0061 achieved DAS28 remission, of which 8 achieved Boolean remission. All DAS28 components contributed evenly and onset of remission occurred as early as week 2 for certain patients. Clinically meaningful improvements for bone oedema were observed and the global RAMRIS scores showed no worsening after 24 weeks. Conclusions The use of modelling enabled a rational study design with 3 biologically effective dose levels. In patients with active RA, rapid and strong effects on the IL-6 pathway were observed and associated with a strong clinical response. Clinically significant improvement of disease activity occurred fast and almost 60% of patients achieved state of remission at the end of 24 weeks. The treatment was well tolerated at all doses and the improvement of signs and symptoms was accompanied by a reduction in bone oedema and absence of radiographic disease progression. Disclosure of Interest J.-B. Holz Shareholder of: Ablynx, Employee of: Ablynx, L. Sargentini-Maier Shareholder of: Ablynx, Employee of: Ablynx, S. De Bruyn Shareholder of: Ablynx, Employee of: Ablynx, B. Gachalyi: None Declared, I. Udvaros: None Declared, B. Rojkovich: None Declared, S. Bruk: None Declared, P. Sramek: None Declared, M. Korkosz: None Declared, K. Krause: None Declared, P. Schoen Shareholder of: Ablynx, Employee of: Ablynx, J. D’Artois Shareholder of: Ablynx, Employee of: Ablynx, K. Verschueren Shareholder of: Ablynx, Employee of: Ablynx, W. Willems Shareholder of: Ablynx, Employee of: Ablynx, K. De Swert Shareholder of: Ablynx, Employee of: Ablynx, G. Arold: None Declared

Background Sirukumab (formerly named CNTO136) is a human mAb that binds with high affinity to the cytokine IL-6. In the proof of concept part (Part A) of this multicenter, randomized, double blind, PBO controlled, phase 2 study, 100mg sirukumab SC injections q2w were generally well tolerated and efficacious Objectives The phase 2 dose-ranging Part B was initiated after Part A to determine efficacious and safe sirukumab dose regimens. Methods In Part B, pts with active RA despite MTX were randomized equally to: (1) PBO q2wk at wks 0–10, then sirukumab 100 mg q2wk at wks12–24; (2) sirukumab 100 mg q2wk at wks 0–24; (3) sirukumab 100 mg q4wk at wks 0–24; (4) sirukumab 50 mg q4wk at wks 0–24; or (5) sirukumab 25 mg q4wk at wks 0–24. As reported previously, the primary endpoint (ACR50 response at wk 12) was achieved by the 100 mg q2wk and 50 mg q4wk doses. We now report specific changes observed through wk12 in the Health Assessment Questionnaire disability index (HAQ-DI), the physical component summary (PCS) score of the Short Form-36 (SF-36) scales, and individual ACR core components other than HAQ-DI. Two improvement thresholds (≥0.25 and ≥0.30) were used to define HAQ-DI response. Clinical response was assessed using the Disease Activity Score (employing 28 joints and C-reactive protein, DAS28-CRP) and Clinical Disease Activity Index (CDAI). The study was only powered for the primary endpoint. An intent-to-treat analysis of pts according to original treatment assignments was conducted, with imputation of missing data by carrying forward the last observation and treatment failure rules for non-responders. Results In Part B, 151 pts were randomized and treated. At baseline, mean age: 53±11 yrs, mean weight: 69±15 kg, mean DAS28 (CRP): 5.9±0.9, and median serum CRP: 1.7 mg/dL. Mean baseline HAQ-DI scores (1.54±0.64) were comparable between treatment groups; mean SF-36 PCS score (31.55±7.78) was notably below the general population norm. At wk12, a higher proportion of pts achieved HAQ-DI response, significantly greater improvement in HAQ-DI was observed in the combined sirukumab group (mean±sd: 0.42±0.53) compared to PBO (0.15±0.56) (p=0.012). No apparent sirukumab dose response was observed. HAQ-DI response was observed as early as wk2 and increased over time through wk24 in all 5 treatment groups. At wk12, greater improvement in SF-36 PCS score was observed in the combined sirukumab group compared with PBO (p=0.038). Also, statistically significant improvement in the combined sirukumab group vs. PBO was observed for each of the ACR core components, except for tender joint count, which trended toward improvement (p=0.06). Pain (p=0.010), physician global (p=0.005), and CRP (p Conclusions In this Phase 2 study of patients with active RA despite MTX therapy, sirukumab in combination with MTX, improved physical function as well as reduced multiple other signs and symptoms of RA. Disclosure of Interest B. Hsu: None Declared, C.-F. Chiou: None Declared, S. Sheng Employee of: Janssen Research & Development, LLC, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study

Background Th17 cells play an important role in many animal models of autoimmune arthritis. However, pathophysiological roles of Th17 cells in patients with rheumatoid arthritis (RA), as well as the impact of RA treatment on Th17 population in those patients have not been elucidated. Recently, CD161, a C-type lectin-like receptor, has been described as a cell surface marker of human Th17 cells. Objectives To examine whether Th17 population is altered by the presence of RA and the treatment for it, we investigated the percentage of CD4+CD161+CD45RO+CCR6+ cells (defined as human Th17) in total CD4+ T cells in peripheral blood from healthy adults (HA) and patients with RA stratified by treatments. Methods Peripheral blood was collected from 81 RA patients and 17 HA. The mean (±SD) age of RA patients was 55.6±14.4 years, with the mean disease duration of 6.2±7.0 years. Among a total of 81 RA patients, 7 patients have not been treated with any DMARDs or biologics until the blood isolation, while 19 patients were receiving DMARDs alone, 29 receiving TNF inhibitors, and 26 receiving tocilizumab (TCZ). Four-color flow cytometry was used to analyze the surface phenotype of freshly isolated peripheral blood. Results The mean (±SD) values of DAS28-ESR in untreated RA patients, those with DMARDs, TNF inhibiters and TCZ were 4.68±0.89, 4.98±1.01, 2.72±0.94, 2.16±0.94, respectively. The mean percentages of Th17 in CD4+ T cells were not significantly different between RA patients (5.8%) and HA (4.8%). However, the percentage of patients with high Th17 rate (defined as above the mean+2SD value in HA) was 0% in HA and 23% in RA patients, respectively. Among RA patients, the mean percentage of Th17 in CD4+ T cells in untreated patients was 8.3% (range: 6.0-12.6%), which was significantly higher than that in any treatment groups (DMARDs alone, TNF inhibitors or TCZ; p 100 U/ml), which was significantly greater than that in the remaining patients (16.7%; p Conclusions Th17 ratio in peripheral blood CD4+ T cells may be determined by autoantibody profiles and the undergoing treatment status in patients with RA. Although clinical efficacy of anti-IL-6 and anti-TNF therapies seemed to be comparable in this study, these treatments showed different effects on Th17 cells in peripheral blood of RA patients. Disclosure of Interest None Declared

Background In the last years the development of new anti-rheumatic drugs based on the current state of knowledge with respect to pathogenic mechanisms involved in RA and especially in RA-related bone destruction was pursued. At this point, one therapeutic target represents IL-6 which is presumed to aggravate local inflammatory reaction by augmenting inflammatory cell infiltration. Consequently, the inhibition of IL-6 has proven beneficial for RA patients as documented by recent data. IL-6 inhibition causes early and sustained decrease in acute-phase response markers (ESR and serum CRP), limiting the sensitivity of such serologic markers for assessment of the degree of activity of the underlying autoimmune process responsible for RA. Due to this limitation, clinical, serology-independent disease activity scores (CDAI) were developed for more accurate evaluation of the course of the disease during treatment with biologics, particularly, anti-IL-6R agents. Assuming that the autoimmune process might evolve on a subclinical level, we have decided to add a perfusion-based additional functional MRI tool to the already established morphologic MR imaging information in order to more confidently objectify all disease-related abnormalities of articular or tendon synovium and bone marrow. Objectives Evaluation of response to anti-IL-6 receptor antibody Tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) 4, 12 and 24 weeks after treatment initiation using morphology- and perfusion-based MRI parameters in comparison to serologic biomarkers (C-reactive protein [CRP]) and clinical assessment scores (DAS-28-ESR and CDAI). Methods Nine patients (2 men, 7 women; 48.0 ± 12.6 years) with longstanding active RA and prior ineffective treatments (including anti-TNF agents) were initially enrolled. MRI protocol included T2w SE, T1w and a fat-suppressed dynamic T1w sequence. Data evaluation followed modified OMERACT-RAMRIS recommendations. Additionally, DCE-MRI parameter maps (k-trans, Ve and Vp), noise corrected relative enhancement (RE) at 52 seconds and the rate of early enhancement (REE) were calculated. Results DAS-28-ESR decreased significantly at 4, 12 and 24 weeks post-treatment whereas the decrease of CDAI reached significance solely at week 12. The strong decrease of ESR was statistical significant after week 12 and 24. None of the morphological and functional MRI parameters presented significant changes at 4 and 12 weeks while synovial volume, RE and REE significantly decreased at week 24. Although statistically not significant, semi-quantitative parameters showed a stronger decrease of MRI parameters in the responder-group after 12 weeks of treatment with TCZ. Conclusions Semi-quantitative perfusion-derived MRI parameters might detect response of RA to TCZ therapy more accurately in comparison to morphology-based MRI scores (RAMRIS) except for synovial volume measurements. Clinical scores (DAS-28-ESR) and laboratory measurements (ESR) showed a significant decrease already after 4 and 12 weeks, respectively, but this change was similar among responders and non-responders. Disclosure of Interest None Declared

Objectives To determine the efficacy and safety of SC sirukumab (SRM) dose regimens & to describe PK & PD in active RA pts in a Ph2 dose-ranging Part B study. Methods Pts w/ active RA despite MTX were randomized: (1) PBO q2w at wks 0–10, then SRM 100mg q2w at wks 12–24; (2) SRM 100mg q2w at wks 0–24; (3) SRM 100mg q4w at wks 0–24; (4) SRM 50mg q4w at wks 0–24; or (5) SRM 25mg q4w at wks 0–24. Primary endpt ACR50 at wk12, compared btw each active grp vs PBO. Key secondary endpts: change from baseline (BL) in DAS28 (CRP) at wk12, serum SRM PK, & % change from BL in serum CRP at wk2. Results In Part B, 151 pts were randomized & treated. 85% female, 60% Caucasian, 21% Japanese. At BL, mean age:53±11yrs, mean weight:69±15kg, mean DAS28 (CRP):5.9±0.9, & median serum CRP:1.7mg/dL. 26 (87%) PBO pts crossed over to SRM 100mg q2w at wk12. At wk12, SRM sig improved ACR50 (overall p=0.010) & sig decreased DAS28 (p 80% from BL w/ SRM at wk2 & remained suppressed thru wk24. Thru wk38, AEs occurred more often w/ SRM than PBO (81 vs 67%), including minor infections/infestations (31 vs 13%), GI disorders (19 vs 10%), & injection site reactions (16 vs 3%). Leukopenia (19, 13% [1 NCI Gr 3]), neutropenia (5, 3% [3 Gr 3]), thrombocytopenia (3, 2% [1 Gr 3, 1 Gr 4]), & lymphopenia (2, 1%, [1 Gr 3, 1 Gr 4]) were reported w/ SRM. ALT (8 Gr 3, 7%) & AST (1 Gr 3, 1%) elevations not associated w/ increased bilirubin; & sustained increase from BL starting at wk2 in total cholesterol (mean SRM vs PBO: 19%±17% vs -5%±12%) & LDL (20%±20% vs -4%±22%) were seen w/ SRM. These lab abnormalities occurred w/o dose relationship or short term clinical sequelae. SAEs were more common w/ PBO (4, 13%) than SRM (13, 9%); majority were infections. 1 pt died of unrelated brain aneurysm. 4/136 (3%; 2 100mg q4w, 2 PBO→100mg q2w) evaluable pts had antibodies to SRM thru wk38; 3 of these pts were ACR50 responders at wk24, 0 had injection site reactions. Conclusions SRM was efficacious & generally well tolerated. SRM PK were linear over SC regimens ranging from 25 to 100mg. Disclosure of Interest B. Hsu Employee of: Janssen Research & Development, LLC, S. Sheng Employee of: Janssen Research & Development, LLC, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study

Objectives To assess remission rates from a phase 2 study of sirukumab, a human monoclonal antibody against the cytokine interleukin-6 (formerly named CNTO 136), using the new provisional 2011 ACR/EULAR rheumatoid arthritis (RA) remission criteria. Methods In the dose-ranging part of a 2-part, multicenter, randomized, double blind, placebo controlled, phase 2 study, pts with active RA despite methotrexate (MTX) were randomized equally to receive SC injections of placebo q2w at wks 0-10 and sirukumab 100 mg q2w at wks 12-24 (n=30), sirukumab 100 mg q2w at wks 0-24 (n=30), sirukumab 100 mg q4w at wks 0-24 (n=30), sirukumab 50 mg q4w at wks 0-24 (n=30), or sirukumab 25 mg q4w at wks 0-24 (n=31). RA remission rates were prospectively assessed using the DAS28 (CRP) remission criteria and retrospectively assessed using the 2011 ACR/EULAR remission criteria (Boolean-and SDAI-based) at wks 12, 24, and 38. The 2011 ACR/EULAR remission criteria used in this study were: Boolean-based (68-joint TJC ≤1, 66-joint SJC ≤1, CRP ≤1 mg/dL, PGA ≤1 on a 1-10 cm VAS), index-based (SDAI score [ie, 28-joint TJC + 28-joint SJC + PGA + physician’s global assessment + CRP mg/dL] ≤3.3). Results At wk 12 (pre-crossover), more pts were in remission with sirukumab than with placebo according to both Boolean- and SDAI-based ACR/EULAR criteria (2% vs 0% and 6% vs 3%, Table). The percentage of pts in remission according to all 3 criteria increased to a peak at wk 24 in the sirukumab 100 mg q2w and q4w treatment groups and remained higher than wk-12 rates at wk 38, 14 wks after the last dose of sirukumab. Pts who received sirukumab 100 mg q2w throughout the study achieved the highest remission rates according to all 3 remission criteria at all time points, including a statistically significant difference compared with placebo according to DAS28 remission criteria at wk 12 (20% vs 0%, p=0.024) and Boolean-based ACR/EULAR remission in 4/30 (13%) pts and SDAI-based ACR/EULAR remission in 7/30 (23%) pts at both wk 24 and wk 38. As expected, the more stringent 2011 ACR/EULAR remission criteria resulted in generally lower remission rates than the DAS28 remission criteria at all time points. Lower remission rates were seen for all groups at all time points with the Boolean-based vs the SDAI-based definition. Conclusions Higher remission rates according to both the 2011 ACR/EULAR and the DAS28 (CRP) criteria were achieved with sirukumab at SC dose regimens ranging from 25-100 mg q2w-q4w compared with placebo. After placebo crossover to sirukumab, all groups achieved increasing remission rates over time with continued sirukumab treatment. The highest sirukumab dose regimen (100 mg q2w) achieved the highest remission rates. The 2011 ACR/EULAR criteria were more stringent than the DAS28 (CRP) criteria; and the Boolean-based definition was more stringent than the SDAI-based definition. Disclosure of Interest B. Hsu Employee of: Janssen Research & Development, LLC, S. Sheng Employee of: Janssen Research & Development, LLC, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study

Background It is reported that, compared with non-obese patients, obese Rheumatoid arthritis (RA) patients experience worsening of symptoms [1] and do not respond as well to TNF inhibitors [2, 3]. The main reason is thought to be that in obesity many adipokines such as IL-6 and TNF-α are produced from hypertrophied adipocytes and infiltrating macrophages, resulting in exacerbation of inflammation. However, the efficacy of IL-6 inhibition has not yet been fully examined. Objectives The purpose of this study was to investigate the difference in response to IL-6 inhibition and to TNF inhibition in therapy for arthritis with obesity, using a mouse model of arthritis. Methods 1) To prepare a collagen-induced arthritis (CIA) model, mice fed a normal diet (non-obese mice) and mice fed a high-fat diet (obese mice; relative body weight: 125%) were immunized intradermally with bovine type II collagen, and 21 days later (Day 21) once again given a booster injection. We used anti-IL-6 receptor antibody (anti-IL-6R) as an IL-6 inhibitor and TNFR-Fc as a TNF inhibitor. Anti-IL-6R was intraperitoneally administered at a dose of 8 mg twice (Day 0 and 21). TNFR-Fc was intraperitoneally administered at doses of 1 mg three times a week from Day 0. Clinical symptoms of arthritis were evaluated by observation and expressed as an arthritis score on a scale of 0–4 for each limb. IL-6, TNF-α, and macrophage marker F4/80 mRNA expressions in hind limbs of mice immediately before primary immunization were measured by real-time PCR. 2) The mouse macrophage cell line RAW264.7 was cultured with 10 ng/mL of IL-6 or TNF-α for 24 h. After culture, to evaluate the inflammatory response, expression levels of monocyte chemoattractant protein (MCP)-1 and cyclooxygenase (COX)-2 mRNA were determined by real-time PCR. Results 1) Arthritis scores were relatively higher (but not significantly) in obese mice than in non-obese mice on the peak of arthritis (Day 33). Furthermore, the anti-arthritic effect of TNFR-Fc was lower in obese mice than in non-obese mice(inhibition ratio: 54% vs. 64%). Interestingly, the anti-arthritic effect of anti-IL-6R was higher in obese mice (inhibition ratio: 87% vs. 62%). Moreover, in non-arthritic control mice, the expression levels of IL-6, TNF-α and F4/80 were higher in hind limbs of obese mice than in non-obese mice. 2) To explore the roles of anti-IL-6R and TNFR-Fc, we next examined the influence of IL-6 or TNF-α activity in RAW264.7 cells. The expressions of MCP-1 and COX-2 were dramatically increased by IL-6 but not by TNF-α. Conclusions We demonstrated that the anti-arthritis effect of TNFR-Fc was reduced by obesity, as is also shown in clinical reports, and that the anti-arthritis effect of anti-IL-6R was increased by obesity in this mouse model. One reason might be that obesity promotes macrophage infiltration and IL-6 is prominently involved in the inflammatory response of macrophages in mice. It goes without saying that it is essential for every patient to reduce excess weight because of its association with risk of developing other diseases such as cardiovascular disease and diabetes. However, anti-IL-6R has the potential to be useful in the treatment of all RA patients, even those who are obese. References Arthritis Care Res (Hoboken). 2013; 94: 78-87 Arthritis Rheum. 2011; 63: 359-64 Arthritis Care Res (Hoboken). 2013; 94: 94-100 Disclosure of Interest None Declared