M. Østergaard

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.

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors

Objectives To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. Methods ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Results Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.

Magnetic resonance imaging and bone scintigraphy in the differential diagnosis of unclassified arthritis

Objectives: To investigate the value in clinical practice of hand magnetic resonance imaging (MRI) and whole body bone scintigraphy in the differential diagnosis of patients with unclassified arthritis. Methods: 41 patients with arthritis (⩾2 swollen joints, >6 months’ duration) which remained unclassified despite conventional clinical, biochemical and radiographic (hands and feet) examinations were studied. Patients who fulfilled the ACR criteria for rheumatoid arthritis (RA) or had radiographic bone erosions were excluded. Contrast enhanced MRI of the wrist and metacarpophalangeal joints of the most symptomatic hand and whole body bone scintigraphy were performed. Two rheumatologists agreed on the most likely diagnosis and the patients were treated accordingly. A final diagnosis was made by another specialist review 2 years later. Results: Tentative diagnoses after MRI and bone scintigraphy were: RA (n = 13), osteoarthritis (n = 8), other inflammatory diseases (n = 11), arthralgias without inflammatory or degenerative origin (n = 9). Two years later 11 of 13 patients with an original tentative diagnosis of RA had fulfilled the ACR criteria while two were reclassified (one to psoriatic arthritis (RF negative + psoriasis); one to non-specific self-limiting arthritis). No patients classified as non-RA at baseline had fulfilled the ACR criteria after 2 years. The presence of MRI synovitis, MRI erosion and bone scintigraphic pattern compatible with RA showed 100% specificity for a diagnosis of RA at 2 year follow-up. Conclusions: In patients with arthritis unclassified despite conventional clinical, biochemical and radiographic examinations, MRI and scintigraphy allowed correct classification as RA or non-RA in 39 of 41 patients when fulfilment of ACR criteria 2 years later was considered the standard reference.

Intra-Articular Corticosteroids in Arthritic Disease

SummaryIntra-articular corticosteroid injections are widely used in aseptic arthritis, most often as a supplement to systemic anti-inflammatory therapy. Suppression of local joint inflammation by corticosteroids is rapid and pronounced, and may be achieved with only minor systemic effects; however, this suppression is usually only temporary. The original compound hydrocortisone acetate has been replaced by longer-acting preparations such as methylprednisolone acetate, tri-amcinolone acetonide and triamcinolone hexacetonide. In controlled studies, triamcinolone hexacetonide has proved most effective, providing clinical effect for a mean period up to several months. However, this compound frequently causes local tissue necrosis when injected outside a synovial cavity, and it should be used only by experienced clinicians.Indications for intra-articular corticosteroids include mono- or oligoarthritis in rheumatoid arthritis and other aseptic inflammatory joint diseases. Intra-articular corticosteroids are also used in osteoarthritis, but in controlled studies the effect is brief and transient.A number of potential adverse effects of intra-articular corticosteroids stress the importance of their judicious use. The risk of cartilage damage and progressive joint destruction is a controversial issue. The results of animal studies are ambiguous. Despite case reports of severe arthropathy, most studies on humans suggest that, when used appropriately, the beneficial effects of intra-articular corticosteroids exceed the harmful effects. Nevertheless, it is recommended that corticosteroid injections into the same joint should be limited, for instance to 1 injection every 6 weeks and no more than 3 to 4 in 1 year. Prior to intra-articular corticosteroid injections the indications and contraindications should always be considered. In particular, infection should be ruled out. Strict aseptic technique is essential to avoid iatrogenic septic arthritis.Correct intra-articular corticosteroid therapy is of great clinical value in the management of aseptic arthritic disease.

OP0165 Whole-body MRI for assessment of enthesitis in psoriatic arthritis, axial spondyloarthritis and healthy subjects – a comparison with 7 clinical enthesitis indices

Background Tender entheses is a common disease manifestation in patients with psoriatic arthritis (PsA) and spondyloarthritis (SpA). Whole-body MRI (WBMRI) is a new imaging modality where patients are scanned from “head to toe” in one single scan. However, only few studies have investigated the ability of WBMRI to detect enthesitis in patients with PsA and SpA(1;2). Objectives The aim of this pilot study was to gain insight into the potential usefulness of WBMRI for detection of enthesitis in patients with PsA and SpA. Methods Patients with clinically active PsA, clinically active axial SpA and healthy subjects (HS) were included. All participants were examined for tenderness at 18 entheses (35 locations) included in the Berlin (3;4), Major (3;6), Gladman (5), Leeds (6), MASES (7), SPARCC (8) or IMPACT (9) enthesitis indices. The WBMRIs (3 tesla, T1-weighted pre- and post-contrast and STIR sequences with coronal orientation, slice thickness 4-6 mm) were anonymized and evaluated by an experienced musculoskeletal radiologist (IE). Enthesitis was scored as present, absent or not possible to evaluate. Results The PsA (n=20)/SpA (n=20)/HS (n=13) had a BASDAI of median (range) 48 (9-85)/54 (2-93)/2 (0-13) mm and DAS28: 4.35 (2.38-6.29)/3.38 (1.46-4.79)/NA. Evaluation of entheses on WBMRI was most often possible at the anterior superior iliac spine (94% of the 104 entheses), iliac crest (94%), and greater trochanter (GT) (92%), while evaluation was rarely possible at the insertion of plantar fascia into calcaneus (0%), 7th costochondral joint (2%), and patellar ligament at tibial tubercle (2%). Inflammation was frequently seen at GT (PsA/SpA: 64%/44%), Achilles tendon (36%/62%) and supraspinatus insertion on the humerus (SH) (28%/26%). There were no statistical significant associations between enthesitis on WBMRI and tender entheses assessed according to 7 enthesitis indices (see Table 1). On the level of the individual enthesis, the best agreement between clinical examination and MRI was found for the right ischial tuberosity (IT) (PsA/SpA: kappa 0.46; 0.40), left IT (SpA: 0.56), and left SH (SpA: 0.43). Table 1. The number (median (range)) of tender entheses (“Clinical”) and inflamed entheses on WBMRI according to 7 enthesitis indices PsA SpA HS Clinical WBMRI Clinical WBMRI Clinical WBMRI (n=20) (n=19) (n=20) (n=20) (n=13) (n=13) Berlin 2 (0-12) 2 (0-4) 3 (0-12) 2 (0-5) 0 (0-5) 2 (1-5) Major 3 (0-11) 1 (0-4) 2 (0-12) 2 (0-4) 0 (0-3) 2 (0-4) Gladman 2 (0-8) 1 (0-2) 0 (0-9) 2 (0-4) 0 (0-3) 0 (0-4) Leeds 1 (0-6) 0 (0-2) 0 (0-6) 1 (0-3) 0 (0-3) 1 (0-3) MASES 3 (0-12) 0 (0-3) 3 (0-13) 1 (0-4) 0 (0-4) 0 (0-2) SPARCC 5 (0-17) 1 (0-1) 2 (0-18) 2 (0-5) 1 (0-5) 1 (0-5) IMPACT 0 (0-4) 0 (0-2) 0 (0-4) 0 (0-2) 0 (0-2) 0 (0-2) All entheses 10 (0-33) 4 (0-6) 7 (0-35) 3 (0-8) 2 (0-14) 3 (1-8) Conclusions WBMRI is a new promising imaging modality for evaluation of entheses in patients with PsA and SpA. Future research should include optimization of image acquisition, e.g. positioning of hands and feet, slice thickness and slice orientation. References Althoff, ARD 2007. Weckbach, EuJRad 2011. Braun, Lancet 2002. Gladman, J Rheum 2007. Gladman, J Rheum 2004. Healy, AR 2008. Heuft-Dorenbosch, ARD 2003. Maksymowych, ARD 2009. Antoni, ARD 2005 Disclosure of Interest None Declared

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

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

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

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

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

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

OP0269 MRI of the spine for detection of new bone formation in ankylosing spondylitis: Does it offer any advantages over radiography?:

Background Radiographic assessment of new bone formation in the anterior vertebral corners of the cervical and lumbar spine is the current gold standard for detection of damage and disease progression in ankylosing spondylitis (AS). However, sensitivity to change is limited and radiography cannot assess the thoracic spine reliably. Standardization of terminology for MRI features indicative of new bone formation has been limited and it is unclear whether MRI might offer any advantages over radiography due to its visualization of the thoracic spine. Objectives To develop standardized definitions for features of new bone formation on MRI, to test the reliability of their detection in patients with AS, to compare this reliability with radiography, and to determine whether availability of radiographs enhances the reliability of detection on MRI. Methods We generated consensus definitions for bone spurs and ankylosis observed on sagittal images of T1-weighted MRI scans that included lesions at anterior and posterior vertebral corners as well as non-corner lesions in the disc space and lesions in the lateral segments of the thoracic and lumbar spine. A reference image set was generated that included examples of all these lesions as well as variations in normal anatomy. In the MRI-based score, bone spurs and ankylosis are assigned a score of 2 and 3, respectively. The first reading exercise assessed reliability for status and change scores for lesions detected on baseline and 2 year scans in 55 patients with AS by 3 readers scoring in known time sequence. Discrepant scans were reviewed extensively using radiography as a reference. The second exercise was conducted as follows by the same expert readers on 25 AS patients with baseline/2 year pairs of radiographs and MRI scans which were numbered independently from radiographs: 1. Assessment of radiographs alone for syndesmophytes and ankylosis. 2. Assessment of MRI scans alone for new bone. 3. Assessment of radiographs and MRI scans simultaneously. Reliability was assessed by intra-class correlation coefficient (ICC). Results ICC for 3 readers reading MRI scans in the first exercise were 0.79 and 0.23 for baseline status and 2 year change scores, respectively. In the second exercise, radiography was superior to MRI in reliably detecting new bone (Table 1). Simultaneous availability of radiographs enhanced the reliability of detecting new bone in the C spine by MRI but this was still inferior to radiography. ICC for detection of new bone in the thoracic spine by MRI was 0.48 and 0.36 for baseline status and 2-year change scores, respectively. Table 1 X-ray* X-ray vs MRI** MRI 1st READ* MRI 2nd READ* C spine ICC 0.95 0.67 0.50 0.77 T spine ICC NA NA 0.48 0.51 L spine ICC 0.91 0.75 0.75 0.77 *ICC (status) for 3 readers **Mean ICC for comparison of radiography and MRI. Conclusions Extensive standardization of MRI features, scoring methodology, and calibration of expert readers with radiography failed to show any major advantage of MRI over radiography in the reliable detection of new bone in the cervical and lumbar spine of patients with AS. Future efforts should focus on the methodology for assessment of the thoracic spine. Disclosure of Interest None Declared