M.L. Hetland

Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study

Objective: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study. Methods: 160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76–104 ciclosporine/placebo-ciclosporine was tapered to zero. Results: American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p =  0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp–van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent. Conclusion: Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.

OP0168 Clinical response, drug survival and predictors thereof in 432 patients with ankylosing spondylitis switching anti tumor necrosis factor α therapy: Results from the danish nationwide danbio registry

Background Data on switching of biological treatment in patients with ankylosing spondylitis (AS) are limited. The Danish nationwide DANBIO registry now includes up to ten years of prospective follow up of patients with inflammatory arthritis treated with biologicals in routine care. Objectives To investigate reasons for switching, treatment response and drug adherence in patients with AS who switch tumor-necrosis-factor-alpha inhibitor (TNFi) treatment in routine clinical care. Methods AS patients treated with TNFi were identified in DANBIO. Disease activity, clinical response (50% or 20mm reduction in Bath AS Disease Activity Index, BASDAI), drug survival and predictors thereof were studied among patients receiving ≥2 different biological drugs. Results 1,436 AS patients (380 women, age 41 (33-50) years (median (IQR))) were identified. Among these, 432 patients (30%) switched to a second and 137 (10%) to a third biological drug during follow-up. Median (IQR) follow-up time was 2.6 (1.1-4.8) years. Switchers were more frequently women, had shorter disease duration and higher BASDAI, Functional Index (BASFI) and visual-analogue-scale (VAS) scores (global, pain, fatigue) compared to non-switchers when starting the first TNFi. The main reason for switching was lack of response (56% of switches from first to second TNFi). BAS- and VAS scores decreased significantly after 6 months’ treatment during the first, second and third treatment course. BASDAI scores at baseline vs. 6 months’ treatment were 56 (38-73) mm (median (IQR)) vs. 33 (16-59) mm (p=0.001) during the second treatment course and 64 (48-79) mm vs. 52 (28-63) mm (p=0.001) during the third. Median drug survival of the first, second and third TNFi was 3.1, 1.6 and 1.8 years respectively (p<0.001). After ∼2-years’ biological treatment, 52% of switchers and 63% of non-switchers (p=0.01) had achieved response (number needed to treat, NNT=1.9 and 1.6, respectively). Adherence was similar regardless of the reason for switching. Male gender and low BASFI predicted adherence to the second TNFi. Conclusions Nearly one third of AS patients in clinical practice switched biological treatment. The response rates and drug adherences were lower among switchers, however, half of switchers achieved clinical response. Male gender and low BASFI predicted response to the second TNFi. Irrespective of the reason for discontinuation of the first TNFi, switching to another TNFi should be considered. References Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years’ surveillance in the Danish nationwide DANBIO registry. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML. Ann Rheum Dis. 2010 Nov;69(11):2002-8. Disclosure of Interest B. Glintborg: None Declared, M. Østergaard Speakers Bureau: Abbott, Amgen, Bristol-Meyers Squibb, Centocor, Genmab, GlaxoSmithKline, Novo, Wyeth/Pfizer, Roche, Schering-Plough/MSD and UCB (less than

FRI0607 Effect of Methotrexate and Intra-Articular Betamethasone with or Without Additional Cyclosporine on Magnetic Resonance Imaging (MRI)-Determined Inflammatory and Destructive Changes in Very Early Rheumatoid Arthritis – Results from a 24-Months' Randomised Double Blind Placebo Controlled Trial

10,000 each), N. Krogh: None Declared, U. Tarp: None Declared, A. Loft Consultant for: Schering-Plough/MSD, UCB, Wyeth/Pfizer og Abbott, Speakers Bureau: Schering-Plough/MSD, UCB, Wyeth/Pfizer og Abbott, A. Hansen: None Declared, A. Schlemmer Speakers Bureau: MSD, Roche, V. Fana: None Declared, M. Kristensen: None Declared, H. Lindegaard Consultant for: Roche, H. Nordin: None Declared, C. Rasmussen Grant/Research support from: Wyeth/Pfizer, Abbott, Roche, L. Ejstrup: None Declared, P. Petersen: None Declared, N. Manilo: None Declared, D. Jensen: None Declared, M. Hetland Grant/Research support from: On behalf of DANBIO grants from Abbott, Bristol-Meyers Squibb, Roche, Schering-Plough/MSD, UCB-Nordic, and Wyeth/Pfizer (more than

AB0036 Soluble CD83 Plasma Levels Are Associated with Disease Activity and Course of Disease in Early Rheumatoid Arthritis

10,000 each), Speakers Bureau: Abbott, Centocor, Roche, Schering-Plough/MSD, UCB-Nordic, and Wyeth/Pfizer (less than

SAT0079 Tumour Necrosis Factor Alpha Inhibitor Treatment Normalises Hand Bone Loss in a Minority of Rheumatoid Arthritis Patients Treated in Clinical Practice. Results from the Copenhagen Osteoarthritis Study and the Danbio Registry

10,000 each)

OP0256 ADAM17 And Galectin-9 are Critical Regulators of Local 4-1BB Activity and Disease Outcome in Rheumatoid Arthritis

Background MRI has been shown to be more sensitive than clinical examination and x-ray for detection of inflammatory and destructive joint changes in early rheumatoid arthritis (RA) and to discriminate between treatment arms in clinical trials using the semi-quantitative Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI scoring (RAMRIS) system. Objectives To investigate whether MRI-determined measures of disease activity and joint destruction were suppressed in very early RA patients following a treat-to-target strategy with methotrexate (MTX) and intraarticular (i.a.) betamethasone and to investigate whether concomitant cyclosporine (CYA) had an additional effect on MRI determined inflammatory and destructive findings over 2 years. Methods In the 2-year randomised, double-blind, multicentre, clinical, treat-to-target trial, CIMESTRA, 160 patients with early (<6 months) RA were treated with MTX, i.a. betamethasone and CYA/placebo CYA. 129 patients participated in the MRI substudy, and had contrast-enhanced MRIs at months 0, 6, 12 and 24 that covered the non-dominant wrist (wrist-only group) and if technically possible both wrist and metacarpophalangeal (MCP) joints (wrist+MCP group). MRIs were evaluated by an experienced radiologist blinded to patient identity, clinical and biochemical data but not to chronology, using the RAMRIS scoring system assessing inflammatory (osteitis, synovitis, tenosynovisits) and destructive (erosions, joint space narrowing) changes. Observed data, without any data imputations, are reported. Non-parametric statistics were used. A value of p<0.05 was considered statistically significant. Results MRI-results from the wrist-only group are shown in table 1. The data in the wrist+MCP group were overall similar (data not shown). No statistically significant differences between the treatment groups were observed in any MRI characteristics at baseline or at any follow-up time point. Both the wrist-only group and the wrist+MCP group showed significant reductions compared to baseline in osteitis, synovitis and tenosynovitis at 6 months (all parameters) and 12 and 24 months (synovitis and tenosynovitis). Statistically significant, but numerically low, increases in erosion and JSN scores from baseline to 6, 12 and 24 months were seen. Conclusions A treat-to-target strategy with MTX and i.a. betamethasone reduced MRI inflammatory findings significantly, with no additional effect of CYA, but minor structural damage progression was still observed. References Hetland ML, et al. 2006. Arthritis Rheum 54:1401-1409. Hetland ML, et al. 2009. Ann Rheum Dis 68:384-390. Disclosure of Interest None declared

Changes in multi-biomarker disease activity (MBDA) score correlate with changes in established disease activity measurements in patients with early RA from the opera study

Background The immune modulatory dendritic cell (DC) marker CD83 has previously been associated with autoimmune diseases.1,2 Levels of soluble CD83 (sCD83) are elevated in RA synovial fluid3, however the relation to clinical outcome of RA remains unknown. We hypothesize that CD83 plays a central role in the inflammatory process and disease development in RA. Objectives To investigate the potential association of sCD83 with disease activity measures, treatment response and auto-antibody status in patients with early RA (eRA). Methods Plasma samples from eRA (n=88) randomized to conventional DMARD treatment with or without 12 months of additional adalimumab therapy (MTX+ADA and MTX+PLA, respectively) were randomly selected from the OPERA cohort.4 A commercial sandwich ELISA was used to quantify plasma levels of sCD83 in patients and in age- and gender-matched healthy volunteers (HV, n=43). Spearmans rank correlation coefficient between soluble CD83 plasma levels and measures of disease activity (tender joint count (TJC28,40), swollen joint count (SJC28,40), DAS28 and CRP), treatment response (ACR20,50,70,90) and auto-antibody status (IgM-RF and ACPA) was calculated. All results are expressed as median with interquartile range and compared by non-parametric statistics. Results At baseline, sCD83 in eRA was significantly higher than in HV plasma (168.5pg/ml (136.1pg/ml-203.5pg/ml) and 136.1pg/ml (116.9pg/ml-149.4pg/ml), respectively), p<0.0001. At 12 months follow-up sCD83 had decreased by approximately 10% (167.2 vs 151.2pg/ml, p=0006) in the MTX+PLA group while it remained unchanged in the MTX+ADA arm, (p=0.3). In MTX+ADA (n=43) group baseline sCD83 levels correlated with ACR50 at 6 and 24 months (ρ= -0.33, p=0.04 and ρ= -0.34, p=0.03, respectively) and ACR90 at 24 months (ρ= -0.37, p=0.02). In the MTX+PLA (n=45) group baseline sCD83 levels were found to correlate with TJC28 at 12 and 24 months (ρ= -0.30, p=0.05 and ρ= -0.43, p=0.003, respectively) and TJC40 at 24 months (ρ= -0.32, p=0.04). sCD83 showed no association with IgM-RF and ACPA positivity. Conclusions This study demonstrated that sCD83 levels were significantly elevated in eRA compared with HV. With additional adalimumab treatment, high sCD83 levels at baseline were sustained over time. A high sCD83 level at baseline was associated with changes in prospective disease activity parameters in both treatment groups, which points to a possible predictive value of sCD83 in eRA. References Eckhardt J. et al. Mucosal immunol. Jul 2014;7(4):1006–1018. Starke C. et al. Immunobiology. Nov 2013;218(11):1411–1415. Hock BD. et al. Tissue antigens. Jan 2006;67(1):57–60. Horslev-Petersen K. et al. Ann Rheum Dis. Apr 2014;73(4):654–661. Disclosure of Interest None declared

Patterns of MRI Bone Erosion in Rheumatoid Arthritis - Which Bones Are Most Frequently Involved and Show Most Change?

Background Rheumatoid arthritis (RA) is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) is measured by Digital X-ray Radiogrammetry (DXR) which has been proposed as an outcome measure for treatment effect in RA. A definition of increased HBL adjusted for age- and gender-related bone loss is lacking. Furthermore, it is unknown to which extent HBL is normalised in RA patients during treatment with tumour necrosis factor alpha inhibitors (TNF-I). Objectives To establish a reference material for HBL and to investigate whether HBL normalises in RA patients during TNF-I treatment in clinical practice. Methods Hand bone mass (DXR-BMD) was measured with DXR, a computerised method of estimating cortical bone mineral density in the diaphysis of the 2nd – 4th metacarpal bone in a reference population and a patient cohort. The reference population consisted of 1,533 men and 2618 women randomly selected from the urban county of Østerbro in Denmark who had hand x-rays performed in the cross-sectional Copenhagen Osteoarthritis Study. Linear regression analyses were used to calculate normal HBL (defined as the 95% Confidence Interval (95%CI) for the age-related mean changes in DXR-BMD between subsequent age-groups). The patient cohort was 135 patients from the DANBIO registry with hand x-rays obtained ∼2 years before start of TNF-I (pre-baseline, all patients treated with conventional synthethic Disease-Modifying Anti-Rheumatic Drugs (csDMARD)), at start of TNF-I (baseline) and ∼ 2 years after start of TNF-I (follow-up). Annual HBL during csDMARD and TNF-I treatment were calculated in individual patients and compared with the lower 95%CI of mean DXR-BMD change in the gender- and age-matched reference group to assess if increased HBL was present. Results Table 1 presents the HBL reference material. The 135 RA patients (85% women, 71% IgM-RF positive, median age 55 (range 23-84) years; median disease duration 5 (range 1-53) years) had a pre-baseline median DAS28 of 4.3 (range 1.6-6.9) and a baseline DAS28 of 5.3 (1.4-8.2). TNF-I treatment was infliximab (74%), etanercept (13%) or adalimumab (13%). At follow-up (DAS28 3.1 (1.4-7.7) 59% received the initial TNF-I, 27% had switched to another biological drug and 14% had withdrawn. Compared to the reference population, 84 (62%) patients had increased HBL during csDMARD treatment and 60 (44%) had during TNF-I treatment (p=0.10,Chi-Sq). In 42 patients who had elevated HBL during csDMARD treatment HBL was normalised during TNF-I. Eighteen patients had normal HBL during csDMARD treatment but increased HBL during treatment with TNF-I. Conclusions We have established a reference material for HBL in the general population and found significant age-related decreases in DXR-BMD in both men and women. Increased HBL was present in the majority of RA patients initiating TNF-I treatment in clinical practice and was normalised in only a minority of patients during treatment. Disclosure of Interest None declared

THU0189 One-year treatment retention after a nationwide non-medical switch from originator to biosimilar etanercept in 2,061 patients with inflammatory arthritis followed in the danbio registry

Background In rheumatoid arthritis (RA) 4-1BB (TNFSFR9) is believed to be involved in the continued T cell activation within the inflamed joint. 4-1BB binds to 4-1BB ligand (4-1BBL) generating local clonal expansion and accumulation of antigen-specific effector-type T cells. Galectin-9 (Gal-9) is upregulated at site of inflammation and has recently been suggested to be a restricting factor for the inflammatory signal of 4-1BB. ADAM17 (TACE) has previously been linked to RA and inflammation. It is a sheddase with a broad substrate specificity although it is best know for its involvement in TNFα release by being the main sheddase of proTNFα. Objectives To determine the role of the interplay between 4-1BB, ADAM17 and Gal-9 in RA. Methods 4-1BB and Gal-9 expression was studied in paired peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMCs) by flow cytometry in chronic RA (cRA), and in PBMCs from healthy volunteers (HV). 4-1BBL, Gal-9, and TNFα were used to stimulate SFMCs. Surface plasmon resonance analysis was performed with human recombinant proteins 4-1BB, 4-1BBL, and Gal-9. Transfected HEK293 cells expressing 4-1BB were established to investigate potential sheddases of 4-1BB. Soluble 4-1BB was measured by ELISA in plasma from treatment naïve early RA (eRA) patients obtained at treatment initiation (the OPERA regimen, n=96)1. Results In chronic RA (cRA), the percentage of T cells expressing 4-1BB was significantly higher in SFMCs compared with PBMCs and in cRA PBMCs compared with HV PBMCs (both p<0.01). After TNFα stimulation of SFMCs the percentage of 4-1BB-positive T cells doubled (p<0.05). Stimulation of RA SFMC cultures with 4-1BBL only increased the TNFα production when combined with Gal-9, confirming that Gal-9 is pivotal for the function of 4-1BB in RA (p<0.05). When HEK293 cells expressing 4-1BB were incubated with PMA, the level of s4-1BB doublet (p<0.05). The role of ADAM17 in this process, was confirmed by RNAi mediated ADAM17 knockdown, which decreased the shedding of 4-1BB to the level of control and mock-transfected cells (p<0.05). The plasma concentration of s4-1BB was significantly elevated in eRA patients at baseline compared with HV (P<0.01). Baseline s4-1BB associated with baseline SJ40 and DAS28CRP at 24 months (both p<0.05)). Furthermore, the ability to sustain high s4-1BB plasma levels correlated with progression in TSS after 12 month (ρ =0.25, p=0.02). Conclusions ADAM17 induces 4-1BB shedding in RA and is connected to TNFα metabolism. Gal-9 is pivotal for the local function of 4-1BB in RA. Furthermore, high plasma levels of s4-1BB are associated with number of swollen joints, but also with a good prognosis measured by DAS28CRP and TSS. 4-1BB metabolism thereby plays a central role in the delicate network of pro- and anti-inflammatory factors in RA. References Hørslev-Petersen et al. Ann rheum Dis. 2013 Disclosure of Interest None declared