Florian Schuch

Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study

Objective To prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial. Methods Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months. Results In this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003). Conclusions This randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA. Trial registration number 2009-015740-42.

Risk of infections in rheumatoid arthritis patients treated with tocilizumab

OBJECTIVES To investigate the occurrence and risk factors for infections in RA patients treated with tocilizumab. METHODS A cohort of all RA patients (n = 112) starting tocilizumab therapy between October 2008 and March 2010 in Northern Bavaria was screened for infections. Mild/moderate and severe infections were recorded. Multivariate logistic regression analysis was used to define risk factors for infection. RESULTS Overall, 26 patients developed infections [23.2%; 58.0/100 patient-years (py)], 18 of them were mild to moderate (16.1%, 40.1/100 py) and 8 were severe (17.9/100 py). Concomitant use of LEF and prednisone, high disease activity and previous therapy with rituximab were associated with the occurrence of mild/moderate infections. Severe infections were related to longer disease duration, exposure to more than three previous DMARDs and concomitant therapy with proton-pump inhibitors. CONCLUSION The rate of infection in RA patients treated with tocilizumab in clinical practice is higher than in the clinical trial populations. Increased attention should especially be given to patients with longer disease duration, previous exposure to multiple DMARDs, i.e. previous exposure to rituximab and those receiving concomitant LEF, prednisone or proton-pump inhibitor treatment.

Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment

Objective To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. Methods MBDA scores (scale 1–100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. Results Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA−/ACPA−, moderate in patients who were MBDA+/ACPA− (33.3%) and MBDA−ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). Conclusions MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. Trial registration number EudraCT 2009-015740-42.

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs

Objective To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. Methods Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0–1/10, 2–5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0–3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. Results Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0–1/10 reactivities) to 34% (2–5/10) and 55% (>5/10). With respect to specificity groups (0–3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. Conclusions The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. Trial registration number 2009-015740-42; Results.

Monotherapy with biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis

Current EULAR guidelines state that biologic DMARD (bDMARD) therapy should be administered in combination with MTX or other conventional synthetic (cs) DMARD in RA. Nonetheless, a third of patients for whom a bDMARD agent is prescribed take it in the absence of concurrent csDMARD therapy. While the reasons underlying the low uptake of bDMARD-csDMARD combination therapy in clinical practice have not been well delineated, they may include poor adherence, contraindication to csDMARD therapy and adverse effects, as well as csDMARD withdrawal following remission. The challenges surrounding bDMARD therapy and the benefit/risk ratio of biologic monotherapy when compared with combination with a csDMARD will be discussed. We will provide insights into these important issues, as well as reviewing the evidence base differentiating biologic agents and exploring therapeutic options for patients with rheumatoid arthritis for whom csDMARD therapy is contraindicated or discontinued.

AB1014 The Value of an Automated Ultrasound System in the Detection of Synovitis

Background The detection of joint swelling caused by synovitis is important for the diagnosis and assessment of inflammatory arthritis. Ultrasound (US) and MRI have proven to be more sensitive and reliable than physical examination, but a comprehensive examination of affected joints with these techniques is time consuming and expensive. The automated breast volume scanner (ABVS) was developed to acquire serial B-mode pictures of the female breast and these data can be analysed in all three dimensions. Objectives To analyse the value of automated grey scale B mode US employing the ABVS system in detecting synovitis of the finger joints compared to manual ultrasound and physical examination, using MRI as gold standard. Methods 19 consecutive patients suffering from rheumatoid (n=15) or psoriatic (n=4) arthritis with at least one swollen finger joint were included. Automated and manual US were conducted using the ACUSON S2000™. The ABVS transducer was equipped with a linear array used with a frequency of 11 MHz. Each automatic sweep of the scanner generated 15.4 x 16.8 x 2.5 cm volume data sets. The system was set to perform an automatic scanning time of 65 s per scan with a slice thickness of 0.5 mm. The dorsal and palmar side of each hand were scanned separately. Multiplanar reconstruction enabled examination of the images at multiple levels for the presence of synovitis. Results Automated US detected 12.0, manual ultrasound 14.2, MRI 13.4, and clinical examination 4.1 swollen joints on average, respectively, per patient. The inter-observer reliability of both assessors for automated and manual US, MRI, and physical examination, was 66.9%, 72.7%, 95.1%, and 88.9%, respectively. A double assessor detection of joint swelling with MRI was used as gold standard. For the other methods, single observer detection was chosen. 84.3% of the joints classified as positive on MRI were confirmed by automated ultrasound, 85.5% on manual US, and 36.0 on physical examination. This translated into a sensitivity of 83.5%, 85.5%, and 36.0% for the three methods, respectively. Conclusions Automated US is a simple and time sparing option for the effective detection of synovitis in patients with inflammatory arthritis. Disclosure of Interest R. Mueller: None declared, M. Gruenke: None declared, J. Wendler: None declared, F. Schuch: None declared, H.-P. Karina: None declared, I. Boettger: None declared, R. Jakobs Employee of: Siemens, H. Schulze-Koops: None declared, J. von Kempis: None declared DOI 10.1136/annrheumdis-2014-eular.2059

FRI0098 Elevated multi-biomarker disease activity (MBDA) predicts relapses in ra patients in sustained remission tapering tumour necrosis factor inhibitor therapy- results from the randomized controlled retro study

Background Tumor necrosis factor inhibitors (TNFi) are the most frequently used bDMARDs in RA patients. TNFi induces remission in a substantial numbers of patients. Once remission, particularly sustained remission is achieved the question arises whether TNFi can be successfully tapered. To date biomarkers, which can help to predict if TNFi can be tapered or stopped, remain to be developed. Objectives To test whether residual subclinical inflammation assessed by multi-biomarker disease activity (MBDA) predicts the risk of disease relapse after tapering or stopping TNFi treatment in RA patients in sustained remission. Methods Sub-analysis of TNFi treated patients of the RETRO study, a randomized-controlled study in RA patients in sustained (>6 month) DAS28 remission comparing 3 different DMARD treatment strategies (continuation of full dose, 50% dose tapering, stopping after 50% dose tapering). Patients were followed over one year for the occurrence of relapses as defined by leaving DAS28-ESR remission (>2.6 units) (1). Vectra-DA tests were done in the baseline samples of all patients included into the RETRO study. MBDA score was calculated according to previously defined algorithms with low MDBA score defined as <30 units and moderate to high scores as ≥30 units (2). Results Of the 151 patients included in the RETRO study, 42 received TNFi treatment (mean age: 56 ys, 25 (60%) females, 78% concomitant csDMARDs; 69% ACPA/RF positive. Baseline demographic and disease specific characteristics of these patients were comparable to the non-TNFi treated patients of the RETRO study. 26/42 patients (62%) had low MBDA scores at baseline, while 16/42 (38%) had moderate/high scores. Relapse rates were significantly (chi square p=0.016) lower in RA patients with low MBDA scores (N=8 of 26; 31%) than in those with moderate/high scores (N=11 of 16; 69%) (Figure; left graph). When separately analyzing only patients tapering TNFi (N=29), relapse rates were moderate in RA patients with low MBDA scores (N=6 of 16; 37%) but high in those with moderate/high scores (N=10 of 13; 77%) (chi square p=0.015) (Figure; right graph). Conclusions These data show that the majority of RA patients in sustained clinical remission with low MBDA scores can successfully taper TNFi. In contrast tapering cannot be recommended in patients with moderate to high MBDA scores, as relapse rates are high in these patients. References Haschka J et al. Ann Rheum Dis 2016,75;45–51. Curtis JR et al. Arthritis Care Res 2012;64:1794–803. Disclosure of Interest None declared

OP0249 Multi-biomarker disease activity and autoantibody status lead to cost effective tapering algorithms in rheumatoid arthritis patients in sustained remission

Background Achieving remission is the ultimate treatment goal in patients with rheumatoid arthritis (RA). With the development and wider use of highly effective disease modifying anti-rheumatic drugs (DMARD) about half of RA patients reach the disease remission state (1), raising the question about tapering or stopping anti-rheumatic treatment and appropriate predictors (2). Objectives To analyse the effect of a risk-stratified DMARD tapering algorithm based on multiple-biomarker disease activity (MBDA) score and anti-citrullinated protein (ACPA) status for successful DMARD tapering and treatment cost reduction in RA patients in sustained remission enrolled in the prospective randomized controlled RETRO study (3,4). Methods MBDA scores and ACPA status were determined in the baseline samples of 146 patients in sustained remission. Patients either continued DMARDs (arm1), tapered dose by 50% (arm 2) or stopped DMARDs after tapering (arm 3) for one year according to the RETRO study protocol. Direct treatment costs (including testing costs at baseline) were evaluated every three months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. Results RA patients with a low MBDA score (<30) and negative ACPA showed lowest relapse risk (19%). With either single positivity for ACPA or moderate/high MBDA scores (≥30) relapse risk increased and was high in double-positive patients (61%). In MBDA negative (<30) and MBDA single-positive (≥30) groups, DMARD tapering appears feasible. Considering only patients that did not flare, costs for synthetic and biologic DMARDs in the MBDA-negative and single-positive groups (n=41) would have been 123.751,29€ for full-dose treatment over one year. Tapering and stopping DMARDs in this low-risk relapse groups allowed a reduction of 92.821,50€ (-75%) of DMARD costs. Average reduction of DMARD costs per patient were 2.350,08€ in the double negative (MBDA- /ACPA-) and single negative (MBDA- /ACPA+) group and 1.761,43€ in the MBDA single positive (MBDA+ /ACPA-) group. Conclusions Combining MBDA score and ACPA status allows risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD. Given that previous data of the RETRO have shown that patients relapsing after tapering their DMARDs respond well to their reintroduction, a stratified tapering and stopping of DMARDs is not only a cost economic but also clinically feasible strategy. References Aga AB et al. Ann Rheum Dis. 2013;74:381–8. Schett G et al. Ann Rheum Dis. 2016 Aug;75(8):1428–373. Haschka J et al, Ann Rheum Dis. 2016;75:45–51. Rech J et al, Ann Rheum Dis. 2015; Oct. 19. Disclosure of Interest None declared

AB0189 Anti-Modified Protein Antibody Response Pattern Influences The Risk for Disease Relapse in Rheumatoid Arthritis Patients Tapering Disease Modifying Anti-Rheumatic Drugs

Background Autoimmunity is still present in rheumatoid arthritis patients in sustained disease remission. In the absence of inflammation the pattern of autoimmunity against post-translationally modified proteins could potentially impact the course of disease of rheumatoid arthritis patients, espepcially their risk to experience relapse of disease when disease modifying anti-rheumatic drugs (DMARDs) are tapered or stopped Objectives To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in rheumatoid arthritis (RA) patients in sustained remission and to test whether its composition influences the risk for disease relapse when tapering DMARD therapy. Methods Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0–1/10, 2–5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0 to 3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. Results Patient varied in their anti-modified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed sub-specificities. Relapse risk significantly (p=0.011) increased from 18% (0–1/10 reactivities) to 34% (2–5/10) and 55% (>5/10). With respect to specificity groups (0 to 3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. Conclusions The data suggest that the pattern of anti-modified protein antibody response determines the risk of disease relapse in RA patients tapering DMARD therapy. Disclosure of Interest C. Figueiredo: None declared, H. Bang Employee of: Organtec Diagnostica, J. Cobra: None declared, M. Englbrecht: None declared, A. Hueber: None declared, J. Haschka: None declared, B. Manger: None declared, A. Kleyer: None declared, M. Reiser: None declared, S. Finzel: None declared, H.-P. Tony: None declared, S. Kleinert: None declared, J. Wendler: None declared, F. Schuch: None declared, M. Ronneberger: None declared, M. Feuchtenberger: None declared, M. Fleck: None declared, K. Manger: None declared, W. Ochs: None declared, M. Schmitt-Haendle: None declared, H.-M. Lorenz: None declared, H. Nuesslein: None declared, R. Alten: None declared, J. Henes: None declared, K. Krueger: None declared, J. Rech: None declared, G. Schett: None declared

Effects of Concomitant Conventional and Previous Biological Disease Modifying Anti-Rheumatic Drugs Treatment on the Efficacy of Tocilizumab to Induce Remission in Patients with Rheumatoid Arthritis An Observational Real-Life Study

Objectives: To investigate remission rates in rheumatoid arthritis patients exposed to tocilizumab treatment in real life clinical practice and to test whether concomitant conventional and previous biological disease modifying anti-rheumatic drugs treatment affects the efficacy of tocilizumab to reach remission. Methods: Between January 2009 and December 2012 disease activity was analyzed in 272 rheumatoid arthritis patients exposed to tocilizumab at the onset of treatment and sequentially thereafter, i.e. every four weeks at the time of infusion. Aside from demographic and disease-specific variables, previous and concomitant conventional and biologic disease modifying anti-rheumatic drugs therapy was documented in all patients. Multivariate logistic regression analyses were conducted to identify factors influencing Disease Activity Score 28 remission and attrition to tocilizumab treatment. Results: 219 (80.5%) of all patients were female. Mean Age was 55.48 ± 13.23 years and our patients had mean disease duration of 12.48 ± 9.30 years. Disease Activity Score 28 significantly decreased from 5.00 ± 1.52 at baseline to 3.09 ± 1.49 at the latest infusion. Mean treatment period was 58.28 ± 43.95 weeks. A total of 101 patients (42.8%) achieved Disease Activity Score 28 remission, which was significantly associated to the length of tocilizumab exposure. Achievement of Disease Activity Score 28 remission was independent from the concomitant use of conventional disease modifying anti-rheumatic drugs. Previous exposure to tumour necrosis factor inhibitors but not rituximab significantly reduced the likelihood to achieve Disease Activity Score 28 remission. Two logistic regression analyses revealed baseline disease activity and duration of tocilizumab therapy as independent factors for Disease Activity Score 28 remission, whereas age and concomitant methotrexate therapy were linked to attrition to tocilizumab treatment. Conclusion: Remission rates found in this observational study are comparable to those of randomized controlled trials and those of big post-marketing surveillance studies. Remission rates of rheumatoid arthritis patients treated with tocilizumab in clinical practice are not influenced by concomitant disease modifying anti-rheumatic drugs use. Previous exposure to tumour necrosis factor inhibitors but not to rituximab decreases the chance to reach remission with tocilizumab.