Anette Jørgensen

Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial

Objectives An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months. Methods In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6–9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward. Results Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7–5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7–4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008<p<0.014, number-needed-to-treat: 4.0–5.4). Twelve months HAQ, SF12PCS and EQ-5D improvements were most pronounced in the adalimumab group. Treatments were well tolerated. Conclusions Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP<3.2 treatment target, but improved DAS28CRP, remission rates, function and quality of life in DMARD-naïve ERA.

Plasma Adiponectin in Patients with Active, Early, and Chronic Rheumatoid Arthritis Who Are Steroid- and Disease -Modifying Antirheumatic Drug-Naive Compared with Patients with Osteoarthritis and Controls

Objective. Rheumatoid arthritis (RA) is a systemic chronic inflammatory joint disease, whereas osteoarthritis (OA) is a local joint disease with low-level inflammatory activity. The pathogenic role of the adipocytokine adiponectin is largely unknown in these diseases. We hypothesized (1) that plasma adiponectin concentrations differ in healthy controls and patients with early disease-modifying antirheumatic drug (DMARD)-naive RA, chronic RA, and OA; (2) that changes in adiponectin are observed during methotrexate (MTX) treatment of chronic RA; and (3) that adiponectin correlates to disease activity measures in RA. Methods. Plasma adiponectin was analyzed with a validated in-house immunoassay. We measured adiponectin in healthy controls (n = 45) and patients with early DMARD-naive RA (n = 40), chronic RA (n = 74), and OA (n = 35). In a subgroup of patients with chronic RA (n = 31), the longitudinal effect of MTX treatment on adiponectin (Week 0 vs Week 28) was investigated. Results. Adiponectin differed significantly between healthy controls (mean 4.8 ± SD 2.7 mg/l) and the 3 groups, with 8.9 ± 4.8 mg/l in early RA, 11.6 ± 5.6 mg/l in chronic RA, and 14.1 ± 6.4 mg/l in OA. Longitudinally, MTX treatment increased adiponectin significantly from 9.7 ± 4.5 mg/l at Week 0 to 11.0 ± 4.5 mg/l at Week 28 in chronic RA. No correlations to disease activity measures were found. Conclusion. Both early DMARD-naive and chronic RA were associated with higher plasma adiponectin compared to healthy controls, but lower plasma adiponectin than OA. Adiponectin increased 13% during MTX treatment. In patients with RA and OA body mass index, age, sex, and disease activity measures failed to explain the findings.

A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial

Objectives To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. Methods In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. Results Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months’ follow-up, with mean change scores of −3.7 (median −3.0), −2.2 (−1) and −5.3 (−4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann–Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months’ follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001–0.002 and p=0.062–0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. Conclusions A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.

Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis

The pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) involves an abnormal chemokine regulation. The chemokine receptor CCR4 is necessary for T cell migration to the skin. We, therefore, studied if CCR4 and its ligand macrophage-derived chemokine (MDC/CCL22) could participate in spreading the disease between skin and joints by examining RA, PsA and osteoarthritis (OA) patients. In synovial fluid from RA and PsA patients we observed a significantly higher MDC/CCL22 level compared to OA patients. Additionally, the MDC/CCL22 protein was found to be elevated in RA and PsA plasma compared to OA and healthy volunteers. Flow cytometry revealed that most CD4(+)CCR4(+) lymphocytes also co-expressed CD45RO. Neither the MDC/CCL22 level nor the expression of CCR4 correlated to CRP. Immunohistochemistry of the RA and OA synovial membrane demonstrated CCR4 to be expressed by mononuclear cells and endothelial cells. Our results show that MDC/CCL22 is present within the synovial membrane of RA and OA patients and in high amount in the synovial fluid of patients with RA and PsA. This will enable migration of CCR4 expressing memory cells supporting that MDC/CCR4 could play a role in attracting skin specific memory T cells to the joints.

Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction: a 2-year investigator-initiated, double-blinded, randomised, controlled trial (OPERA)

Objectives To study clinical and radiographic outcomes after withdrawing 1 years adalimumab induction therapy for early rheumatoid arthritis (eRA) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy (NCT00660647). Methods Disease-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate (20 mg/week) and intra-articular triamcinolone (20 mg/ml) for 2 years. In addition, they were randomised to receive placebo adalimumab (DMARD group, n=91) or adalimumab (40 mg/every other week) (DMARD+adalimumab group, n=89) during the first year. Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months. During year 2, synthetic DMARDs continued. Adalimumab was (re)initiated if active disease reoccurred. Clinical response, remission, disability, quality of life and radiographic changes were assessed. Results One year after adalimumab withdrawal, treatment profiles and clinical responses did not differ between groups. In the DMARD/DMARD+adalimumab groups, the median 2-year methotrexate dose was 20/20 mg/week (p=0.45), triple DMARD therapy had been initiated in 33/27 patients (p=0.49), adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg (p=0.15). The treatment target (disease activity score, 4 variables, C-reactive protein (DAS28CRP) ≤3.2 or DAS28>3.2 without swollen joints) was achieved at all visits in ≥85% of patients in year 2; remission rates were DAS28CRP<2.6:69%/66%; Clinical Disease Activity Index ≤2.8:55%/57%; Simplified Disease Activity Index <3.3:54%/49%; American College of Rheumatology/European League against Rheumatism (28 joints):44%/45% (p=0.66–1.00). Radiographic progression (Δtotal Sharp score/year) was similar 1.31/0.53 (p=0.12). Erosive progression (Δerosion score (ES)/year) was year 1:0.57/0.06 (p=0.02); year 2:0.38/0.05 (p=0.005). Proportion of patients without erosive progression (ΔES≤0) was year 1: 59%/76% (p=0.03); year 2:64%/79% (p=0.04). Conclusions An aggressive triamcinolone and synthetic DMARD treat-to-target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy. ES progression was slightly less during and following adalimumab induction therapy. Trial registration number NCT00660647.

Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post-hoc study of the OPERA trial

Objectives: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial. Method: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year. Results: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01–1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96–1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003). Conclusion: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.

FRI0535 Hand Bone Loss in Early Rheumatoid Arthritis Is Independent of Adalimumab Treatment. A Substudy of The Optimized Treatment Algorithm in Early RA (Opera) Trial

Background Rheumatoid arthritis (RA) is characterised by progressive destruction of joint bone and loss of periarticular bone mineral. Hand bone loss (HBL) measured by Digital X-ray Radiogrammetry (DXR) has been proposed as a sensitive outcome measure for treatment effect and as a potential predictor of subsequent radiographic progression in RA patients. Objectives To investigate the effect of adding adalimumab to a methotrexate and intra-articular triamcinolone treat-to-target strategy on one-year HBL (HBLone-year) in early RA and to determine if HBL6months is associated with radiographic progression after two years. Methods In a clinical trial (OPERA) of 180 treatment-naive early RA patients (1), bone mineral density (BMD) was estimated from hand radiographs with Digital X-ray radiogrammetry (DXR) at baseline, after 6 months (n=90) and 12 months (n=70) of follow-up. Baseline and two-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL6months (0–6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (ΔTotal Sharp/van der Heijde Score (TSS) as dependent variable) and logistic (+/− radiographic progression (ΔTSS>0) as dependent variable) regression analyses. Variables with p<0.10 were included in multivariable models. Results In 70 patients with available HBLone-year data, HBLone-year was median (InterQuartileRange (IQR)) -1.9 (-3.3; -0.26 mg/cm2) in the placebo-group and -1.8 (-3.6; 0.06) mg/cm2 in the adalimumab-group, p=0.98,Mann Whitney. Increased HBL (compared to general population reference values (2)) was found in 26/37 and 23/33 patients in the placebo- and adalimumab-groups, Chi-sq=0.99. In 90 patients with HBL6months data and two-year radiographic data, HBL6months was independently associated with ΔTSS after two years (β=-0.086 (95% Confidence Interval= -0.15; -0.025) TSS unit/mg/cm2 increase,p=0.006), and borderline associated with presence of radiographic progression (ΔTSS>0) (OR 0.96 (0.92–1.0), p=0.10). Conclusions In early RA, adding adalimumab to a methotrexate-based treat-to-target strategy had no impact on HBLone-year, which was increased in both treatment groups. HBL6months was independently associated with ΔTSS after two years. References Hørslev-Petersen et al. Ann Rheum Dis. 2015 doi: 10.1136/annrheumdis-2015-208166. Ørnbjerg LM et al. [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). Disclosure of Interest L. Ørnbjerg: None declared, M. Østergaard Grant/research support from: Abbvie, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Pfizer, Roche, UCB, Celgene, Sanofi, Regeneron, Novartis, T. Jensen: None declared, K. Hørslev-Petersen Grant/research support from: Abbvie, Meda, Roche, K. Stengaard-Pedersen Grant/research support from: Meda, Abbvie, Roche, Speakers bureau: UCB, Pfizer, P. Junker: None declared, T. Ellingsen: None declared, P. Ahlquist: None declared, H. Lindegaard Grant/research support from: Boehringer Ingelheim, A. Linauskas: None declared, A. Schlemmer Grant/research support from: Abbvie, Roche, MSD, M. Dam: None declared, I. Hansen: None declared, T. Lottenburger: None declared, C. Ammitzbøll: None declared, A. Jørgensen: None declared, S. Krintel: None declared, J. Raun: None declared, M. Hetland: None declared

FRI0148 Remission rates increase substantially by adding adalimumab to methotrexate and intra-articular glucocorticoid in patients with early rheumatoid arthritis - 1-year results of investigator-initiated, double-blinded randomized clinical trial (OPERA)

Background In the CIMESTRA Study patients with early rheumatoid arthritis (RA) were treated with methotrexate (MTX) and intra-articular glucocorticoid. This led to results comparable to biological trials with 34%/28% of pts in DAS28/ACR remission after 1 year (1,2). Objectives We studied if addition of adalimumab (ADA) to the CIMESTRA strategy is of further therapeutic benefit. Methods DMARD naïve early RA patients with disease duration <6 months (n=180) were randomized 1:1 to MTX 7.5 mg weekly + ADA 40 mg eow or MTX + placeboADA (PLA). MTX was increased to 20 mg/week within two months. Treatment target was low disease activity (DAS28(CRP) <3.2). Injections of triamcinolone were given into swollen joints (max. 4 joints/4 ml/visit). Oral prednisolone was not allowed. Sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added if DAS28(CRP) >3.2 after three months. Efficacy was assessed by DAS28(CRP), CDAI, SDAI and ACR/EULAR Boolean remission criteria. Primary analysis was by ITT with last observation carried forward. Completer analysis and ITT without imputations gave similar results (not shown). Values are medians (5%/95% percentiles) or percentage. We used Mann-Whitney or Pearson’s chi-square tests. Results Baseline characteristics were similar between MTX+PLA/MTX+ADA groups: Women: 69%/63%; age: 54.4/56.2 years; disease duration: 83/84 days; anti-CCP positive: 70%/60%; IgM-RF positive: 74%/70%; DAS28(CRP): 5.6/5.5; HAQ: 1.0/1.1 (all NS). Triple therapy was added in 25/17 patients (p=0.25). Treatment target was reached in 46%/58% (MTX+PLA/MTX+ADA) at 1 month, 63%/73% (2 months), 70%/76% (3 months), and 76%/80% (12 months) (NS between groups at all time points). However, in the MTX+ADA group significantly more patients achieved rapid and sustained clinical remission as assessed by DAS28, CDAI, SDAI and ACR/EULAR remission criteria (table). Number needed to treat (NNT) with ADA to achieve remission in one extra patient at 1 year was 4 to 5.9 depending on remission criteria. MTX+PLACEBO MTX+ADALIMUMAB P Number of patients included /completers 91/80 89/81 – Methotrexate (mg/week) 12 months 20 (7/25) 20 (7.5/20) 0.33 Triamcinolone (ml) cumulated 0–12 months 7 (2/17.8) 5.4 (1.8/16.6) 0.084 DAS28(CRP) 1 month 3.4 (1.8–5.9) 2.6 (1.7–5.1) 0.003 DAS28(CRP)≤2.6; 1 month 29% 48% 0.010 ΔDAS28 (CRP) 0–1 month –1.9 (–0.3/–3.8) –2.6 (–0.8/–4.7) 0.0011 DAS28(CRP) 12 months 2.6 (1.7/4.7) 2.0 (1.7/5.2) 0.0088 DAS28(CRP)≤2.6; 12 months 49% 74% 0.0011 CDAI ≤2,8; 12 months 41% 61% 0.011 SDAI ≤3.3; 12 months 40% 63% 0.0028 ACR/EULAR (28 joints) remission; 12 months 31% 48% 0.0241 ACR/EULAR (40 joints) remission; 12 months 27% 47% 0.0098 Conclusions Low disease activity was achieved by

Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year

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Levels of lectin pathway proteins in plasma and synovial fluid of rheumatoid arthritis and osteoarthritis

80% in both groups, but remission rates increased considerably by adding adalimumab to methotrexate and intraarticular glucocorticoid injections in DMARD naïve patients with early RA. References Hetland et al: Arthritis Rheum 2006;54:1401-09. Hetland et al: Ann Rheum Dis 2008;67:815-22. Disclosure of Interest K. Hørslev-Petersen Grant/Research support from: Abbott, M. Hetland Grant/Research support from: Abbott, Bristol-Meyers Squibb, Roche, Schering-Plough/MSD, UCB-Nordic, and Wyeth/Pfizer, Speakers Bureau: Abbott, Centocor, Roche,Schering-Plough/MSD, UCB-Nordic, and Wyeth/Pfizer, P. Junker: None Declared, J. Pødenphant: None Declared, T. Ellingsen: None Declared, P. Ahlquist: None Declared, H. Lindegaard Speakers Bureau: Roche, A. Linauskas: None Declared, A. Schlemmer Speakers Bureau: MSD, Roche, M. Dam: None Declared, I. Hansen: None Declared, H. Horn: None Declared, A. Jørgensen: None Declared, S. Krintel: None Declared, J. Raun: None Declared, C. Ammitzbøll: None Declared, J. Johansen: None Declared, M. Østergaard Grant/Research support from: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genmab, Glaxo-Smith-Kline, Mundipharma, Novo, Pfizer, Roche, Schering-Plough, UCB and Wyeth., Speakers Bureau: Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genmab, Glaxo-Smith-Kline, Mundipharma, Novo, Pfizer, Roche, Schering-Plough, UCB and Wyeth., K. Stengaard-Pedersen Grant/Research support from: Abbott