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Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.

Summary Background Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. Methods RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score ClinicalTrials.gov ( NCT02779114 ). Findings Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3–90·0) in the continue group, 58·6% (49·2–70·0) in the taper group, and 43·3% (34·6–55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69–5·40; p=0.0003) for the taper group and 4·34 (2·48–7·60; p Interpretation Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. Funding None.

Objective.To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)–tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission.Methods.The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 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 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83.Conclusion.Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.

Background:Due to better treatment strategies and higher remission rates the management of rheumatoid arthritis (RA) patients in sustained remission is of increasing interest (1). The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated the possibility to taper and stop disease modifying anti-rheumatic drugs (DMARDs).Objectives:To compare one-year remission and relapse rates in rheumatoid arthritis patients randomized to continued treatment, reduced treatment or gradual treatment withdrawal after stable remission under routine care.Methods:Primary data of the phase III, randomized, controlled RETRO trial in RA patients with stable conventional synthetic and/or biologic DMARD treatment in sustained (>6 months) DAS28-ESR remission (Results:316 RA patients in sustained remission were included, 303 were randomized (CONT: N=100; TAP: N=102; STOP: N=101) and 282 (93%) had complete data sets after 1 year (CONT:N=93; TAP: N=93; STOP: N=96; Table 1). After 1 year, 81.2%, 58.6%, 43.3% of patients, maintained their remission state over 1 year in the CONT, TAP and STOP arms, respectively (p=0.0004 with log rank test for trend; Figure 1). Hazard ratios for flare were 3.02 (95%CI 1.69 to 5.40) and 4.34 (95%CI 2.48 to 7.60) for the TAP and STOP arms. RA patients who flared were more likely to be female, have longer disease duration, RF/ACPA positivity and higher baseline DAS-28 scores with standardized mean differences >0.2. Serious adverse events were reported in 10.8%, 7.5%, and 13.5% in the CONT, TAP and STOP arms, respectively.Table 1.Baseline CharacteristicsGroupControlReduceReduce/StopOverallN939396282Age, mean(SD)55.9 (12.7)56.9 (13.0)56.5 (13.3)56.5 (13.0)Female, n (%)53 (57.0)57 (62.0)57 (59.4)167 (59.4)RF, n (%)52 (55.9)58 (62.4)52 (54.2)162 (57.4)ACPA, n (%)53 (57.0)50 (54.9)55 (57.3)158 (56.4)Disease duration, years, mean(SD)7.6 (6.9)7.8 (6.9)6.8 (8.1)7.4 (7.3)Remission duration, months, mean(SD)20.6 (18.0)16.5 (15.9)22.7 (30.4)20.0 (22.6)Biologics, n (%)39 (41.9)44 (47.3)39 (40.6)122 (43.3)Methotrexate, n (%)71 (76.3)67 (72.0)75 (78.1)213 (75.5)Other DMARDs, n (%)24 (25.8)20 (21.5)16 (16.7)60 (21.3)Glucocorticoids, n (%)27 (29.0)23 (24.7)17 (17.7)67 (23.8)CRP, mg/L, mean(SD)0.3 (0.3)0.5 (0.5)0.5 (0.6)0.4 (0.5)ESR, mm/h, mean(SD)11.3 (8.4)12.2 (8.8)13.0 (10.0)12.2 (9.1)Tender joint count, mean(SD)0.2 (0.6)0.0 (0.2)0.1 (0.3)0.1 (0.4)Swollen joint count, mean(SD)0.1 (0.3)0.1 (0.3)0.1 (0.4)0.1 (0.3)Physician VAS,mm, mean(SD)1.8 (4.2)2.6 (4.4)2.0 (3.9)2.1 (4.2)Patient VAS,mm, mean(SD)6.4 (9.0)5.5 (8.3)4.5 (8.4)5.5 (8.6)HAQ, standard, mean(SD)0.2 (0.4)0.2 (0.3)0.2 (0.4)0.2 (0.4)HAQ, alternative, mean(SD)0.2 (0.4)0.1 (0.3)0.2 (0.3)0.2 (0.3)DAS-28, mean(SD)1.7 (0.7)1.7 (0.6)1.7 (0.6)1.7 (0.6)SDAI, mean(SD)1.4 (1.5)1.4 (1.5)1.3 (1.3)1.3 (1.4)DAS-28 remission, n (%)91 (97.8)93 (100.0)95 (99.0)279 (98.9)SDAI remission, n (%)79 (87.8)79 (84.9)88 (92.6)246 (88.5)Boolean remission, n (%)69 (75.8)71 (76.3)76 (79.2)216 (77.1)Conclusion:This randomized controlled study shows that half of RA patients in sustained remission relapse when tapering/stopping their DMARDs. Presence of autoantibodies, higher baseline DAS28-ESR and female sex are predictors for flares.References:[1]Schett G et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis. 2016 Aug;75(8):1428-37.Disclosure of Interests:Melanie Hagen Speakers bureau: advisory boards, Koray Tascilar Speakers bureau: advisory board, Michaela Reiser: None declared, Larissa Valor: None declared, Judith Haschka Speakers bureau: advisory board, Arnd Kleyer Speakers bureau: advisory board, Axel Hueber Speakers bureau: advisory boards, Bernhard Manger Speakers bureau: advisory boards, Jayme Cobra Speakers bureau: advisory boards, Camille Figuereido Speakers bureau: advisory boards, Stephanie Finzel Speakers bureau: advisory boards, Hans-Peter Tony Speakers bureau: advisory boards, Joerg Wendler Speakers bureau: advisory boards, Stefan Kleinert Speakers bureau: advisory boards, Florian Schuch Speakers bureau: advisory boards, Monika Ronneberger: None declared, Martin Feuchtenberger Speakers bureau: advisory boards, Martin Fleck Speakers bureau: advisory boards, Karin Manger: None declared, Wolfgang Ochs: None declared, Matthias Schmitt-Haendle: None declared, Hanns-Martin Lorenz Speakers bureau: advisory boards, Rieke Alten Speakers bureau: advisory boards, Jörg Henes Speakers bureau: advisory boards, Klaus Krueger Speakers bureau: advisory boards, Jürgen Rech Speakers bureau: advisory boards, Georg Schett Speakers bureau: advisory boards.

Background: Persistent drug-free remission of RA is a condition that is close to “cure” of the disease. However, long-term drug-free remission is considered to be rare and very challenging to reach. Also, little data are available that report how often persistent drug-free remission can be achieved and what kind of clinical characteristics are associated with such state. Objectives: To evaluate factors associated with persistent drug-free remission in patients with rheumatoid arthritis Methods: We analyzed the long-term observational follow-up phase of the randomized controlled RETRO (REduction of Therapy in RA Patients in Ongoing Remission) study on tapering and stopping of DMARDS in RA patients in stable remission (DAS28-ESR Results: All 141 patients being in the long-term observational follow-up phase of the RETRO study for at least 1 year were analyzed. Among them DMARDs were initially continued (Control, n=38), tapered (Taper, n=50) or stopped (Taper/Stop n=53). 19/141 patients were lost to follow-up and the worst case scenario was assumed that all of them did not reach persistent drug-free remission. Median time after study entry (Q1-Q3) was 69 (37-96) months as by December 2018. Overall number of patients in drug-free remission was 34/141 (24.1%), 10/38 (26%) in the control group, 6/50 (12%) in the taper group and 18/53 (34%) in the taper/stop group. After adjustment for baseline risk factors in the likelihood to reach persistent drug-free remission between the groups (OR:0.76, 95%CI: 0.29-1.99) was highly uncertain. Positive ACPA (OR: 3.38, 1.01 – 11.31) and erosive-state (3.05, 1.32 – 7.06) at baseline were associated with a lower likelihood to reach persistent drug-free remission. Conclusion: These data show that persistent drug-free remission can be reached in a subset of RA patients following a structured DMARD tapering approach after being in stable long-term DMARD control. References: [1] Haschka J, et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis. 2016 Jan;75(1):45-51. [2] Rech J, et al. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis 2016;75:1637-44. Disclosure of Interests: Larissa Valor: None declared, Melanie Hagen: None declared, Michaela Reiser: None declared, Arnd Kleyer Grant/research support from: Lilly, Consultant for: Lilly, Speakers bureau: Abbvie, Fabian Hartmann: None declared, Bernhard Manger: None declared, Georg Schett: None declared, Jurgen Rech Grant/research support from: Bristol-Myers Squibb and Celgene (greater than $10,000), Consultant for: Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Roche, Sanofi Aventis, and UCB (in total more than $10,000), Speakers bureau: Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Roche, Sanofi Aventis, and UCB (in total more than $10,000), Koray Tascilar: None declared

Background Several studies including our own RETRO study have shown that tapering or stopping disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible (1-3). However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Objectives Here we analysed the impact of tapering or stopping DMARD treatment on the physical function of RA patients, who were randomized into continuation, tapering or stopping DMARD treatment in the RETRO study. Methods RETRO is a multicentre, parallel-group phase 3 trial in which RA patients in stable DAS-28-ESR remission were randomized to (i) DMARD tapering, (ii) stopping DMARDs after a 24-week-taper or (iii) control strategy that continued DMARDS.1,2,3 HAQ and DAS-28 scores were measured at 0, 3, 6, 9 and 12 months.1,2 Functional worsening was defined as a HAQ increase of≥0.25. We calculated incidences of functional worsening (per 100 person-months) in each treatment group with 95% Poisson confidence intervals and plotted event-free survival by treatment arm. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with control, taper or taper/stop group as the predictor. Results 201 patients were analysed. In 44 patients functional worsening was observed. Incidence (95%CI) of functional worsening was in the control 1.48 (0.77-2.59), taper 1.74 (0.95-2.92) and taper/stop arm 1.96 (1.16-3.10). The incidences suggest higher probability of functional worsening in tapering and/or stopping DMARDs, however at the end of study, functional worsening was similar among the groups (Figure). Thus, in comparison to the control group, hazard ratio (HR) (95%CI) for functional worsening was 1.21 (0.56 -2.62) in the taper arm and 1.32 (0.76-2.60) in the taper/stop arm. Conclusion Point estimates and survival curves show that functional decline after tapering or stopping DMARDs in RA patients with stable remission is small. Although the incidence figures suggest a trend these results do not reject with good certainty the null hypothesis of no worsening in functional status. Reference [1] Haschka, J. et al. 2016; 2 Rech, J. et al. 2016; 3 Hagen, M. et al. 2018 Disclosure of Interests Marlene Stephan: None declared, Koray Tascilar: None declared, Melanie Hagen: None declared, Judith Haschka: None declared, Michaela Reiser: None declared, Fabian Hartmann: None declared, Arnd Kleyer Grant/research support from: Lilly, Consultant for: Lilly, Speakers bureau: Abbvie, Axel Hueber Grant/research support from: Novartis, Pfizer, Consultant for: Lilly, Speakers bureau: Lilly, Novartis, Janssen, Abbvie, Bernhard Manger: None declared, Camille Figuereido: None declared, Jayme Cobra: None declared, Hans-Peter Tony Consultant for: Eli Lilly and Company, Speakers bureau: Eli Lilly and Company, Stephanie Finzel: None declared, Stefan Kleinert Grant/research support from: Novartis, Consultant for: Novartis, UCB, Chugai, Celgene, Medac, Roche, Abbvie, Speakers bureau: Novartis, UCB, Chugai, Celgene, Medac, Roche, Abbvie, Joerg Wendler: None declared, Florian Schuch Consultant for: Celgene, Lilly, UCB, Roche, Sanofi-Aventis, Abbvie, Novartis, Speakers bureau: Celgene, Lilly, UCB, Roche, Sanofi-Aventis, Abbvie, Monika Ronneberger: None declared, Martin Feuchtenberger: None declared, Martin Fleck: None declared, Karin Manger: None declared, Wolfgang Ochs: None declared, Matthias Schmitt-Haendle: None declared, Hanns-Martin Lorenz: None declared, Hubert Nuesslein: None declared, Rieke Alten Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Jorg Henes: None declared, Klaus Krueger: None declared, Georg Schett: None declared, Jurgen Rech Grant/research support from: Bristol-Myers Squibb and Celgene (greater than $10,000), Consultant for: Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Roche, Sanofi Aventis, and UCB (in total more than $10,000), Speakers bureau: Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Roche, Sanofi Aventis, and UCB (in total more than $10,000)

Background:Today approximately 50 percent of patients with RA reach sustained remission. In a specific subset of RA patients in stable remission, biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) may be successfully tapered. However, it remains challenging to predict the patients’ individual flare risk. As we have recently shown, machine learning based on extensive clinical and laboratory data could be used to estimate individual flare risk [1].Objectives:In this study we aimed to investigate the performance of machine learning models trained with variables that are typically (1) immediately available to a physician during patient visits (clinical and demographic variables without laboratory values and composite disease activity scores), (2) theoretically available to patients at home and (3) available to payers in large health-system databases.Methods:Longitudinal clinical data of RA patients on bDMARDs from the first interim analysis of the phase-3, multicentre, randomised, open, prospective, controlled, parallel-group RETRO study (EudraCT number 2009-015740-42) was used [2] to build a predictive model for estimating the flare probability within 3 months from the current patient visit. A flare was defined as a DAS-28 ESR score over 2.6. Four different models (log. regression, random forest, k-NN and naïve Bayes) were trained which output the flare probability at each patient visit. These probabilities were used as an input for a stacking logistic regression meta-classifier [3]. The final model performance expressed as the AUROC was assessed using nested cross-validation [4]. We applied this method to three variable subsets (physician, patient, payer, Table 1).Table 1.List of variables used in three subsets:Variable / RolePhysicianPatientPayerGender (m/f)xxxDisease duration (years)xxxMethotrexate co-use (yes/no)xxxOther DMARDs co-use (yes/no)xxxDrug ATC codexxxIV-administration (yes/no)xxxDose percentagexxxAgexxxBody mass indexxxxDose percentage changexxxSwollen joint countxTender joint countxVAS_GH (pat. global disease activity)xxHAQ (health assessment questionnaire)xxSmoking status (yes/no/ex)xxAlcohol consumption (yes/no)xxPrevious flares (yes/no)xResults:Data from 135 follow-ups of 41 patients were used. The measured AUROC of the best performing model using all RETRO variables was 0.802 (95%CI 0.717 – 0.887) [1]. When a subset based on demographic and clinical variables is used that is available to a physician immediately during a patient visit the AUROC drops about 5 percent points. When only variables theoretically available to patients at home are used, the performance drops about 10 percent points comparing to the original model. Similar observation holds for the variable subset typically available to payers (Figure 1).Conclusion:This study shows that predictive models for flares have the potential to support physicians in making decisions immediately during the patient visit, even though laboratory values and respective activity scores are not yet available. In the future, machine learning applications may allow fast and reliable decisions on flare prediction in RA patients. These data can guide decisions about DMARD tapering at in real time during the physician-patient contact and allow to reduce costs not only by selective treatment tapering but also by sparing additional laboratory examinations.References:[1] Vodencarevic A. et al. Arthritis Rheumatol. 2019; 71[2] Haschka J et al. Ann Rheum Dis 2016; 75:45-51.[3] Tang J et al. CRC Press 2015; 498-500[4] Cawley GC et al. J Mach Learn Res 2010; 11:2079-2107Disclosure of Interests:Asmir Vodencarevic Shareholder of: Siemens Healthcare GmbH. Siemens Healthcare GmbH is a medical technology company (NOT a pharmaceutical company)., Employee of: Siemens Healthcare GmbH. Siemens Healthcare GmbH is a medical technology company (NOT a pharmaceutical company)., Koray Tascilar: None declared, Fabian Hartmann: None declared, Michaela Reiser: None declared, Sara Bayat Speakers bureau: Novartis, Johannes Knitza Grant/research support from: Research Grant: Novartis, Larissa Valor: None declared, Melanie Hagen: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis,Abbvie, Speakers bureau: Novartis, Lilly, Marcus Zimmermann-Rittereiser Shareholder of: Siemens Healthcare GmbH. Siemens Healthcare GmbH is a medical technology company (NOT a pharmaceutical company)., Employee of: Siemens Healthcare GmbH. Siemens Healthcare GmbH is a medical technology company (NOT a pharmaceutical company)., Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly

Background DAS28-ESR is the most widely used instrument to assess remission in rheumatoid arthritis (RA) patients. Nonetheless, substantial residual disease activity can be present in RA patients fullfilling DAS28-ESR remission. Therefore, more stringent criteria for remission have been developed. While it is known that patients can fulfil DAS28-ESR but fail ACR/EULAR Boolean remission criteria, the existence of the reverse is less known. Objectives To test the possibility to loose DAS28-ESR remission while staying in ACR/EULAR remission in patients with RA Methods Data were obtained from the prospective randomised RETRO study (EudraCT: 2009–015740–42), which recruits RA patients in stable remission. Remission was assessed by the following instruments every three months: DAS28-ESR, DAS28-CRP, CDAI, SDAI, PAS, and ACR/EULAR criteria. In the group of patients, escaping DAS28-ESR remission, but fulfilling ACR/EULAR Boolean remission, the individual components of DAS28-ESR were analysed that determined their escape from remission. Results 142 patients analysed, which were all in DAS28-ESR remission at baseline. Of them, 140 (98.59%) were in DAS-CRP-remission, 131 (92.25%) in CDAI-remission, 130 (91.55%) in SDAI-remission, 109 (76.76%) in ACR/EULAR remission and 66 (46.48%) in PAS-remission. We analysed upon the 1 year follow up those patients loosing DAS28-ESR remission over time: 58 patients lost DAS-ESR remission at least once during the 4 follow-up visits. Surprisingly, 24% (3 months), 36% (6 months), 24% (9 months) and 28% (12 months) of the patients still fulfilled the Boolean remission criteria. The only plausible reason for failing DAS28-ESR remission but staying in ACR/EULAR remission is an isolated elevation of the ESR, not accompanied by increased signs and symptoms of disease. Indeed all patients loosing DAS28-ESR remission but staying in ACR/EULAR Boolean remission had an elevated ESR equal or higher than 15 mm. However, if DAS28 scores were calculated by C-reactive protein in the same patients, they all fulfilled remission criteria. Conclusions DAS28-ESR remission can be missed even if a patient fulfils the more stringent ACR/EULAR Boolean remission criteria. The reason for this remarkable constellation is an elevated erythrocyte sedimentation rate without any clinical symptoms. Hence, isolated elevations of erythrocyte sedimentation rate should be seen critical. These data show the limitations of individual instruments to assess remission in RA and show that interpretations of the erythrocyte sedimentation rate need to be done in the clinical context Disclosure of Interest None declared

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 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

Background Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as one third of patients do not respond adequately to TNFi. Objectives We investigated whether brain activity associated to arthritis measured by functional magnetic resonance imaging (fMRI) can function as a predictor of response to TNFiin RA patients. Methods This is an interim analysis of the first 50 patients of the PreCePRA trial, a multi-center, double-blind, placebo-controlled fMRI trial on patients with RA. [1] [2] Active RA patients failing csDMARDs with a DAS28-ESR >3.2 and at least three tender and/or swollen joints received a baseline brain BOLD fMRI scan upon joint compression at screening. Patients werethen randomized into a 12-week double-blinded treatment phase with placebo (arm 1) or 200mg certolizumab-pegol eow (arm 2; fMRI Bold signal>2000 voxel i.e. 2cm3, arm 3; fMRI Bold signal Results In 31 patients (responders) baseline signal volume i.e. sum of significantly coupled voxels after the FDR thresholding was significatly higher compared to 19 patients (non-responders) (p Conclusions Based on this interim analysis we conclude that high BOLD volumes in fMRI, indicating high-level brain representation of pain in arthritis. These data represent the first encouring signal of the PreCePRA brain fMRI study supporting the concept that increased RA-related brain activity is related to response to TNFi. References Rech, J., et al., Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis. Arthritis Rheum, 2013.65(2): p. 325–33. Hess, A., et al., Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A, 2011.108(9): p. 3731–6. Disclosure of Interest None declared

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 ( 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

ObjectiveTo 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.MethodsImmune 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.ResultsPatients 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.ConclusionsThe 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 number2009-015740-42; Results.

ObjectiveTo 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.MethodsMBDA 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.ResultsModerate-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%).ConclusionsMBDA 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 numberEudraCT 2009-015740-42.

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)

Background Achieving remission is the most important 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 a state of disease remission, raising the question about tapering or stopping anti-rheumatic treatment. Objectives To assess the effect of a controlled DMARD tapering regimen on treatment costs and work productivity in RA patients in remission Methods 101 RA patients in sustained remission (DAS28 Results In RA patients treated with conventional DMARDs, baseline quarterly treatment costs of 154€ remained stable in arm 1 (156€), while decreasing to 81€ in arm 2 and 75€ in arm 3. In patients treated with biologic DMARDs quarterly treatment costs were 5708€ at baseline. They remained stable in arm1 (5533€) and decreased to 2855€ in arm 2 and 2668€ in arm 3. Overall DMARD costs were reduced by 327.292€ within one year, while outcome was very good with patients either remaining in remission or immediately regaining remission when exposed to original DMARD regimen after relapse. Conclusions Controlled tapering of DMARD treatment leads to effective reduction of treatment costs in RA patients in sustained remission. References ) Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study.Haschka J, Englbrecht M, Hueber AJ, Manger B, Kleyer A, Reiser M, Finzel S, Tony HP, Kleinert S, Feuchtenberger M, Fleck M, Manger K, Ochs W, Schmitt-Haendle M, Wendler J, Schuch F, Ronneberger M, Lorenz HM, Nuesslein H, Alten R, Demary W, Henes J, Schett G, Rech J. Ann Rheum Dis. 2016 Jan;75(1):45–51. doi: 10.1136/annrheumdis-2014-206439. Epub 2015 Feb 6. Disclosure of Interest None declared

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

Background Due to improved therapeutic management a steadily increasing number of rheumatoid arthritis (RA) patients reach stable remission of disease. Data on withdrawal of medication after sustained remission are limited, though it is important for economic and safety reasons. The RETRO study represents a real-life study addressing different strategies of reduction of DMARD therapy in RA patients in stable disease remission. Objectives To prospectively analyze the risk for disease relapses in rheumatoid arthritis (RA) patients in sustained remission, either continuing, tapering, or stopping disease modifying anti-rheumatic drugs (DMARD). Methods RETRO is a phase 3, multicenter, randomized, controlled, open, prospective, parallel-group trial (EudraCT Number: 2009-015740-42). Patients, fulfilling the ACR/EULAR2010 criteria for RA were enrolled into the study if they were in clinical remission (DAS28-ESR 2.6) the original therapy was restarted. Results 101 patients (61.4% females, 60% ACPA positive, 63% RF positive; 37.6% biologic therapy, 80.2% MTX, 7.9% other DMARDs) finished the one year endpoint: 38 patients in arm 1 (age 55.8±13.9y, disease duration 6.8±5.9y, remission 20.9±16.7mo), 36 patients in arm 2 (age 54.1±13.1y, disease duration 8.6±7.7y, remission 14.5±12.7mo) and 27 patients in arm 3 (age 54.8±12.3y, disease duration 5.6±7.0y, remission 17.6±19.5mo). Of 101 patients, 66.3% were still in remission at 12 mo. Significantly more patients flared in reduction arm 2 (38.9%, c2(1)=5.0, p=0.036) and arm 3 (51.9%, c2(1)=9.6, p=0.003) compared to control arm 1 (15.8%), while there was no significant difference between the two reduction arms (c2(1)=1.1, p=0.443). With multivariate logistic regression ACPA positivity (p=0.03) and treatment reduction (arm2 p=0.01, arm3 p=0.003) were detected as predictors for flares. Conclusions This study is a prospective real life treatment strategy study investigating the effect of reduction and discontinuation of DMARD therapy in RA patients in stable remission. Presence of ACPA but not RF was the only predictor for recurrence of disease. Disclosure of Interest None declared

19 young healthy subjects were subjected to parabolic rollercoaster flight. A horizontal luminous line was seen by the subjects in a headfixed goggle device. During the hypergravic phases of parabolic flight the luminous line seemed to rotate into and during the hypogravic phase against the direction of static head tilt. Ocular counter rotation and activity of the neck position receptors cannot explain these subjective rotations. We conclude that information from the otolith system, converging with visual information within the brain, dislocated the headfixed visual target line. While the retinal image of the luminous line remains unchanged, loading and unloading the otoliths in parabolic flight changes the sensation of self tilt into object tilt, hereby subjectively rotating visual targets such as the luminous line.