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ObjectiveIn 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean-based and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the two sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria.MethodsWe used data from four randomised trials comparing biological disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0–10 cm) compared with the original threshold of 1 cm (Boolean1.0). We analysed agreement between the Boolean-based and index-based criteria (Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire (HAQ) score≤0.5) and radiographic non-progression.ResultsData from 2048 trial participants, 1101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared with Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8–4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes.ConclusionUsing the Boolean 2.0 criteria classifies, more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardising predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

Background: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET). Methods: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4–16 months). Improvement in peak VO 2 at follow-up was defined as ∆peak VO 2 ≥1.0 mL/(kg·min), stable peak VO 2 was defined as 0≤∆peak VO 2 2 was defined by ∆peak VO 2 Results: Baseline peak VO 2 >14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization ( P =0.002, P =0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance ( P =0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO 2 ( P 2 ( P P 2 had less advanced heart disease at baseline ( P =0.046). Conclusions: Our findings demonstrate that baseline peak VO 2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

ObjectivesThis study aimed to evaluate different patient global assessment (PGA) cut-offs required in the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean remission definition for their utility in rheumatoid arthritis (RA).MethodsWe used data from six randomised controlled trials in early and established RA. We increased the threshold for the 0–10 score for PGA gradually from 1 to 3 in steps of 0.5 (Boolean1.5 to Boolean3.0) and omitted PGA completely (BooleanX) at 6 and 12 months. Agreement with the index-based (Simplified Disease Activity Index (SDAI)) remission definition was analysed using kappa, recursive partitioning (classification and regression tree (CART)) and receiver operating characteristics. The impact of achieving each definition on functional and radiographic outcomes after 1 year was explored.ResultsData from 1680 patients with early RA and 920 patients with established RA were included. The proportion of patients achieving Boolean remission increased with higher thresholds for PGA from 12.4% to 19.7% in early and 5.9% to 12.3% in established RA at 6 months. Best agreement with SDAI remission occurred at PGA cut-offs of 1.5 and 2.0, while agreement decreased with higher PGA (CART: optimal agreement at PGA≤1.6 cm; sensitivity of PGA≤1.5 95%). Changing PGA thresholds at 6 months did not affect radiographic progression at 12 months (mean ꙙsmTSS for Boolean, 1.5, 2.0, 2.5, 3.0, BooleanX: 0.35±5.4, 0.38±5.14, 0.41±5.1, 0.37±4.9, 0.34±4.9, 0.27±4.7). However, the proportion attaining HAQ≤0.5 was 90.2%, 87.9%, 85.2%, 81.1%, 80.7% and 73.1% for the respective Boolean definitions.ConclusionIncreasing the PGA cut-off to 1.5 cm would provide high consistency between Boolean with the index-based remission; the integer cut-off of 2.0 cm performed similarly.

ObjectivesIdentification of trajectories of radiographic damage in rheumatoid arthritis (RA) by clustering patients according to the shape of their curve of Sharp-van der Heijde scores (SHSs) over time. Developing models to predict their progression cluster from baseline characteristics.MethodsPatient-level data over a 2-year period from five large randomised controlled trials on tumour necrosis factor inhibitors in RA were used. SHSs were clustered in a shape-respecting manner to identify distinct clusters of radiographic progression. Characteristics of patients within different progression clusters were compared at baseline and over time. Logistic regression models were developed to predict trajectory of radiographic progression using information at baseline.ResultsIn total, 1887 patients with 7738 X-rays were used for cluster analyses. We identified four distinct clusters with characteristic shapes of radiographic progression: one with a stable SHS over the whole 2-year period (C0/lowChange; 86%); one with relentless progression (C1/rise; 5.8%); one with decreasing SHS (C2/improvement; 6.9%); one going up and down (C3/bothWays; 1.4%) of the SHS. Robustness of clusters were confirmed using different clustering methods. Regression models identified disease duration, baseline C-reactive protein (CRP) and SHS and treatment status as predictors for cluster assignment.ConclusionsWe were able to identify and partly characterise four different clusters of radiographic progression over time in patients with RA, most remarkably one with relentless progression and another one with amelioration of joint damage over time, suggesting the existence of distinct patterns of joint damage accrual in RA.

Background Stringent remission criteria are crucial in rheumatoid arthritis (RA) assessment. Disease activity score in 28 joints (DAS28)-remission has not been included among American College of Rheumatology/European League Against Rheumatism definitions, because of its association with significant residual disease activity, partly due to high weighting of acute-phase reactants (APR). New, more stringent cut-points for DAS28-remission have recently been proposed that are suggested to reflect remission by clinical and simplified disease activity indices (clinical disease activity index (CDAI), simple disease activity index (SDAI)). However, their stringency in therapies directly influencing APR, like IL-6-blockers, has not been tested. We tested the new cut-points in patients with RA receiving tocilizumab. Methods We used data from randomised controlled trials of tocilizumab and evaluated patients in remission according to new DAS28-C-reactive protein (DAS-CRP) and DAS-erythrocyte sedimentation rate (DAS-ESR) cut-points (1.9 and 2.2). We assessed their disease activity state using the CDAI, SDAI and Boolean criteria and analysed their individual residual core set variables, like swollen joint counts (SJC28). Results About 50% of patients in DAS28-CRP-remission (

Heart failure with preserved ejection fraction (HFpEF) is among the most common forms of heart failure (HF). We aimed to investigate the prognostic significance of serum potassium levels and its interaction with type-2 diabetes mellitus in patients with HFpEF.Consecutive HFpEF patients were prospectively included in a registry study. The primary endpoint was a composite of cardiac death or HF hospitalization.363 HFpEF patients were enrolled (median age: 73.0 years; females: 70.3%). Median serum potassium (K+) was 4.3 mmol/L. A total of 128 (35.3%) patients had type-2 diabetes mellitus, of whom 92 were treated with oral anti-diabetic drugs and 35 with insulin. The study population was divided into two groups, according to their serum potassium levels. Significant differences between the groups were detected with regards to combined endpoint [n = 27 (61.4%) versus n = 87 (27.3%); p 0.0001]. Lower serum potassium levels were significantly associated with adverse outcome in the Cox proportional hazard analysis [hazard ratio (HR): 1.83; 95% confidence interval (CI) 1.14-2.94; p = 0.0118]. Further independent predictors of adverse outcome were a history of HF hospitalizations (HR: 2.77; 95% CI 1.82-4.21; p 0.0001), higher NT-pro BNP (HR: 1.93; 95% CI 1.82-4.21; p = 0.0084) as well as type-2 diabetes mellitus (HR: 1.57; 95% CI 1.05-2.34; p = 0.0027). Patients with diabetes and K+ ≤ 3.71 mmol/L faced the worst outcome as compared to the remainder of the group (p = 0.0001).In HFpEF patients, the combination of diabetes and low serum potassium levels are associated with an adverse outcome.

BackgroundRheumatoid arthritis (RA) is characterised by clinical joint swelling and elevation of acute phase reactant levels, typically measured by the C-reactive protein (CRP). Clinical and inflammatory responses are usually concordant, except for inhibition of IL-6, which often disproportionally reduces the CRP due to direct inhibition of its hepatic production. We investigated whether pre-treatment CRP is a useful marker that can guide a preferential treatment choice towards IL-6 inhibition.MethodsData of 1126 treatment courses with tocilizumab (TCZ; early RA), 250 courses of rituximab (RTX; established RA) and 249 courses of methotrexate (MTX; established RA) were analysed. We compared clinical disease activity index (CDAI) values and change along 24 weeks’ follow-up to CRP values at baseline or its early change. We validated the results using data from a separate TCZ trial in early RA.ResultsCRP levels in the TCZ group on average dropped by 74% within 4 weeks. Patients who attained CDAI remission at 24 weeks on TCZ had the highest baseline CRP levels while patients in high disease activity had the lowest; this association was reverse in the RTX and MTX groups. TCZ patients who achieved remission at 24 weeks showed the largest reductions of CRP levels by week 4 compared with those reaching higher disease activity states. Early CRP non-response was indicative of a risk of not achieving clinical treatment goals (p=0.038).ConclusionBaseline CRP appears to have a positive association with reaching the therapeutic target on TCZ treatment, but is a negative predictor for RTX and MTX. Patients on TCZ without an early CRP response have a lower chance of achieving remission. CRP and its early course may inform, to some extent, the estimation of potential therapeutic success in patients with RA.

Background Psoriatic arthritis (PsA) belongs to the group of the spondylarthropathies. It is associated with psoriasis and typically seronegative for autoantibodies. PsA disease activity can be measured using the Disease Activity in Psoriatic Arthritis (DAPSA) score which is based on both clinical (e.g., swollen joint count, SJC) and systemic (e.g., C-reactive protein, CRP) markers of inflammation. [1] However, the impact of clinical and systemic inflammation on structural progression is unclear. Objectives To determine the contribution of clinical and systemic inflammation on structural progression of patients with PsA. Methods In a secondary data analysis, we analyzed patient data from the IMPACT 2 trial of infliximab (INF) vs. placebo (PLC) in patients with established PsA (disease duration in years: INF: 7.5±7.8, PLC: 8.4±7.2). Concomitant methotrexate treatment was allowed but not mandatory in both treatment arms. [2] We obtained modified Sharp-van-der-Heijde scores from X-rays performed at baseline and after one year to compute radiographic progression. We further extracted levels of SJC and CRP and calculated time-averaged SJC (taSJC) and CRP (taCRP) values to reflect the clinical and systemic inflammation, respectively. In a multivariable binary logistic regression model, we assessed the impact of taSJC, taCRP, and their interaction, on structural progression. Next, we divided patients into different subgroups depending on their taSJC and taCRP levels into active (+) or inactive (-). We tested whether radiographic progression was different in taSJC+ vs. taSJC- and taCRP+ vs. taCRP- using the Mann-Whitney U test. Results 200 patients were enrolled in the IMPACT 2 trial (100 INF, 100 PLC). 151 patients were included in the analyses (76 PLC, 75 INF). Due to drop out or missing data, the remaining 49 patients were not considered for further analyses. Patients in the INF arm showed no radiographic progression (-1.16±3.96), while patients in the PLC arm showed little progression (0.74±2.98). We therefore focused on the 76 PLC patients. Despite the small overall progression, taSJC, taCRP, and their interaction were associated with radiographic progression (OR for taSJC: 1.24, CI 95%: 1.04-1.47, p=0.016; OR for taCRP: 6.08, CI 95%: 1.12-33.03, p=0.036; interaction term: p=0.097). Radiographic progression was higher in taSJC+ patients compared to taSJC- patients (1.05±3.21 and 0.56±2.30, respectively; p=0.016), as well as numerically higher without statistical significance in taCRP+ vs. taCRP- patients (1.14±3.23 and 0.05±2.37, respectively; p=0.532). Also, despite the limited power of subgroup analyses, there was evidence that SJC activity plays a role in CRP- patients (p=0.076), whereas CRP activity seems to be of less importance SJC- patients (p=0.643). Conclusion In patients with PsA, both clinical and systemic inflammation have impact on structural progression; in patients without systemic inflammation, clinical joint activity may still be considered as a risk factor for progression. References [1] Schoels M, Aletaha D, Funovits J, et al. Application of the DAREA/DAPSA score for assessment of disease activity in psoriatic arthritis. Ann Rheum Dis2010;69:1441–7. Doi:10.1136/ard.2009.122259 [2] Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis2005;64:1150–7. Doi:10.1136/ard.2004.032268 Disclosure of Interests Carina Borst: None declared, Farideh Alasti: None declared, Daniel Aletaha Grant/research support from: AbbVie, Bristol-Myers Squibb, and MSD, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB

Background:Joint damage is a defining feature of rheumatoid arthritis (RA), a major driver of functional impairment and of reduction of quality of life. Many factors are associated with damage accrual however, the course of structural damage of individual patients over time and factors associated with such trajectories have not been investigated.Objectives:Identification of trajectories of radiographic damage in RA by clustering patients according to the shape of their curve of Sharp-van der Heijde scores (SHS) over time. Developing models to predict their progression cluster from baseline characteristics.Methods:Patient-level data over a two-year period from 5 large randomized controlled trials on TNF-inhibitors in RA (ERA, PREMIER, TEMPO, GO-BEFORE and GO-FORWARD) were used. SHSs were clustered in a shape-respecting manner to identify distinct clusters of radiographic progression. Characteristics of patients within different progression clusters were compared at baseline and over time. Logistic regression models were developed to predict trajectory of radiographic progression using information at baseline.Results:In total 1887 patients with 7738 x-rays were used for cluster analyses. We identified 4 distinct clusters with characteristic shapes of radiographic progression: one with a stable SHS over the whole 2-year period (C0/lowChange; 86%); one with relentless progression (C1/rise; 5.8%); one with decreasing SHS (C2/improvement; 6.9%); and one going up and down (C3/bothWays; 1.4%) of the SHS. Robustness of clusters and shapes of progression over time were confirmed using different clustering methods and cut-offs to define radiographic progression (Figure 1). Regression models identified disease duration, baseline CRP and SHS and treatment status as predictors for cluster assignment (Table 1), showing good performance (PCC 87.5%; Nagelkerke r2 0.36).Conclusion:We were able to identify 4 different clusters of radiographic progression over time in patients with RA, most remarkably one with relentless progression and another one with amelioration of joint damage over time, suggesting the existence of distinct patterns of joint damage accrual in RA. The nature of the identified trajectories is mostly explained by inflammatory load, disease duration and especially type of treatment.Figure 1.Representations of the major three clusters of radiologic progression curves. (A) shows the curves of all patients with a SHS-range >= 10, colored by their cluster. Values between visits were linearly interpolated. Big dotted line is the median of particular cluster, thinner lines represent single patient values. Cluster C0 /lowChange are patients without enough variation in SHS to be seen as a curve, therefor not shown in the diagrams.Table 1.Simple logistic regression models to predict assignment to clusters of radiologic progression using information at baseline. Variables entered but not selected by a stepwise approach were: rheumatoid factor, age, gender, tender joint count;c0/low change vs:C1/rise ClusterC2/improve ClusterparametersOR95%CIOR95%CIX-ray Score1.021.01-1.031.031.02-1.03CRP (mg/dl)1.121.07-1.160.980.90-1.07Duration (years)0.870.80-0.951.091.05-1.12TreatmentCombinationREFREFREFREFcsDMARD4.982.88-8.630.050.01-0.23bDMARD Mono2.281.29-4.040.640.38-1.08Disclosure of Interests:Stephan Blüml Speakers bureau: Novartis, MSD, Abvie, Pfizer, Consultant of: MSD, Lilly, Novartis, Alexander Platzer: None declared, Farideh Alasti: None declared, Daniel Aletaha Speakers bureau: Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Consultant of: Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Grant/research support from: Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi, Josef S. Smolen Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO Pharma, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB., Consultant of: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO Pharma, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB., Grant/research support from: Dr Smolen received grants to his institution from Abbvie, AstraZeneca, Janssen, Lilly, Merck Sharpe & Dohme, Pfizer, and Roche, Helga Radner: None declared

Background:The notion that weather conditions may influence the symptoms and course of rheumatic and musculoskeletal diseases goes back to ancient times. However, despite the seemingly obvious relationship, previous studies assessing how meteorological variables affect pain and disease activity have yielded contradictory results.Objectives:To evaluate whether meteorological variables influence disease activity in patients with rheumatoid arthritis (RA).Methods:We assessed correlations between clinical measures of disease activity (pain, patient global assessment [PGA], tender- and swollen 28 joint counts [TJC and SJC]) and individual meteorological variables: temperature (temp.), effective (eff.) temperature, saturation vapor pressure (SVP), absolute humidity (AH), relative humidity (RH), dew point, vapor pressure (VP) and precipitation. Assessments documented in the Care for Rheumatoid Arthritis database of our institution were matched with these meteorological variables on a daily basis for a period of 12 years between 2005 and 2017 and analyzed utilizing generalized estimating equations. Patients with 11) disease activity based on the simplified disease activity index (SDAI).Results:A total of 461 patients with an average disease duration at first visit of 5.7±7.4 years, average age of 55.3±14.5 years and a mean SDAI of 22.1±12.7 were analyzed. Among patients with moderate or high disease activity, higher temp./eff. temp. and SVP were associated with lower pain, TJC and SJC (Figure 1); on the contrary, higher RH was associated with higher pain and higher SJC. In those in remission or low disease activity, higher RH, AH, VP or dew point were associated with lower PGA. Higher precipitation was associated with lower SJC.Figure 1.Association of meteorological parameters and clinical measures of disease activity. PGA: patient’s global assessment, SDAI: simplified disease activity index, SJC: swollen joint count, TJC: tender joint count. * p≤ 0.05, ** p≤ 0.01, *** p≤ 0.001Conclusion:In this large association study of meteorological parameters with RA, both temperature and humidity parameters were modestly inversely associated with pain, TJC and SJC.Disclosure of Interests:None declared

We would like to thank Dr Pethoe-Schramm and colleagues for their comment on our paper1 and the diligent assessment of the data we presented.2 The authors addressed each of our Figures sequentially and, therefore, it will be a pleasure to respond here accordingly. Before doing so, we would like to mention that in contrast to other studies, like the one by Wang et al 3 which we also referred to in our paper, we approached the analyses by using Clinical Disease Activity Index (CDAI) remission criteria (endorsed by ACR-EULAR for this purpose) rather than "remission" criteria by the Disease Activity Score using 28 joint counts (DAS28) .4 5 As often described, DAS28

Background:Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized through symmetric polyarthritis leading to joint destruction over time in many patients. Radiographic damage is an important outcome in RA clinical trials, most commonly assessed by conventional radiographs and quantified/reported by the modified total Sharp van der Heijde Score (mTSS). The mTSS is assessing erosive (ERO) changes as well as joint space narrowing (JSN; reflecting cartilage wasting) in the small joints of the hands and feet. While erosions are the hallmarks of RA, loss of cartilage has been reported to be highly relevant for functional limitations in RA. The sequence of occurrence of these events is not completely understood.Objectives:To investigate the time to radiographic progression and assess potential differences between time-to-JSN progression and time-to-ERO progression.Methods:Radiographs of RA patients from a large prospective clinical routine cohort were scored using the mTSS by one experienced reader (G.S.) unaware of the aim of this project. Time-to-JSN and time-to-ERO was estimated using survival analyses utilizing the Kaplan-Meier estimator. In additional analyses, patients were stratified based on JSN and/or ERO damage at baseline. Further, potential predictors (demographics, csDMARD/bDMARD treatment/combination therapy) of time-to-ERO and time-to-JSN were evaluated using Cox-regression techniques. All statistical analyses were conducted using SAS v9.4 (Cary, New York, USA).Results:We assessed 798 patients longitudinally for radiographic progression. JSN occurred significantly earlier than erosions (pFigure 1.Time to joint space narrowing and time to erosive damage (n=798).Figure 2.Time to JSN/ERO stratified by presence or absence of ERO/JSN at baseline.Conclusion:We identified a significantly shorter time to progression of JSN compared to ERO in this longitudinal cohort of RA patients. JSN remains an important radiographic outcome, as it is strongly associated with impairment of physical function. This calls for a stronger focus on cartilage damage in RA, and a stronger consideration of JSN in routine evaluation of RA radiographs in clinical practice.Disclosure of Interests:Andreas Kerschbaumer Paid instructor for: Celgene, Speakers bureau: Andreas Kerschbaumer has received lecture fees from Bristol-Myers Squibb, Gilead, Merck Sharp and Dohme and Pfizer., Farideh Alasti: None declared, Gabriela Supp: None declared, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche – grant/research support, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – consultant, Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – speaker, Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB

Despite modern therapeutics and treatment strategies, a subset of rheumatoid arthritis (RA) patients remains insufficiently responsive to multiple therapies. Here, we identify predictors of such refractory RA ("reRA").Patients from a longitudinal academic clinical database with reRA (defined as failing to reach the treatment target of at least low disease activity with ≥3 DMARD courses, including ≥1 biological, over a total of ≥18 months) were compared to patients who did respond within the first two treatments (treatment amenable RA, "taRA"). We performed logistic regression analysis to identify risk factors for refractory disease, and several sensitivity analyses concerning different potential definitions for reRA to confirm the robustness of the results; key findings were also validated in an independent community cohort.We enrolled 412 patients, of whom 70 were reRA and 102 taRA; 240 patients fulfilled neither definition. ReRA patients were more frequently female (92.9 vs. 70.6%, p 0.001), younger (44.37 vs. 51.14 years, p = 0.002), and had higher CDAI levels at first presentation (26.06 vs. 15.39, p 0.001). Treatment delay was significantly longer for reRA than for taRA (3.17 vs. 1.45 years, p = 0.001). In multivariable analyses, treatment delay, female gender and higher disease activity remained as independent predictors of refractory disease. Based on the identified predictors, we developed a matrix model for risk of future reRA.Our data identified delay to initial treatment, female gender and higher disease activity as important predictors of a later refractory course of RA. Delay of treatment initiation is the single most important modifiable risk factor of refractory disease.

Background Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are the most specific diagnostic markers of rheumatoid arthritis (RA). These antibodies are predominantly of the IgG (ACPA) or IgM (RF) isotype. Other subtypes of both antibodies – such as IgA – and other autoantibodies like RA33 have been repeatedly reported but their diagnostic value has still not been fully elucidated. Objectives To investigate the diagnostic value of IgA, IgG and IgM subtypes of RF, ACPA and RA33 antibodies in patients with RA and their potential predictive value regarding therapeutic response to methotrexate (MTX). Methods To determine the diagnostic specificity and sensitivity, sera from 290 RA patients (including 165 MTX starter), 261 disease controls and 100 healthy subjects were tested for the presence of IgA, IgG and IgM isotypes of RF, ACPA and RA33 by EliATM (Thermo Fisher Scientific). Cut-offs for prototype anti-RA33 (IgA, IgG and IgM) and the IgM-ACPA EliATM were calculated by Receiver Operating Characteristic (ROC) curve analysis against disease controls and healthy subjects. In addition, RF and ACPA had been routinely measured by nephelometry and the anti-CCP EliATM, respectively. Results The most specific antibodies were IgG and IgA-ACPA as well as IgG-RF, closely followed by IgG- and IgA-RA33 while IgM isotypes were found to be less specific. However, IgM-RF was the most sensitive isotype (65%) followed by IgG-ACPA (59.5%) and IgA-RF (50.7%). Other subtypes were less prevalent ranging from 35% (IgA-ACPA) to 6% (IgA-RA33). Concerning RA33 antibodies, 14 patients were positive for IgA- and 18 for IgG-RA33. Interestingly, the major RA33 subtype was IgM which was detected in 43 patients. However, in contrast to RF and ACPA the overlap between the RA33 isotypes was marginal. RA33 antibodies as well as IgA-RF and IgA-ACPA were found to increase the diagnostic sensitivity of serological testing since they were found also in 22% of seronegative patients. Moreover, analysing IgM-RF by EliATM proved more sensitive than RF measured by nephelometry which further reduced the number of seronegative patients. Thus, additional antibodies were detected in 30% of the seronegative population and, importantly, most patients had several antibodies, in contrast to disease controls which generally showed only one antibody species. The majority of antibody positive RA patients was found to be triple positive for RF, ACPA and either IgA-RF or IgA-ACPA. Among the 64 RA33 positive patients 48 were also positive for IgA-RF and/or IgA-ACPA (figure 1). Interestingly, we found high levels of IgM-RF (>124 IU/ml) to be associated with achieving a SDAI50 response to MTX (17 of 24 cases). Furthermore, also the presence of RA33 antibodies was associated with a MTX response as 50% of RA33 positive patients (n=32) achieved a SDAI50 response compared to 34% in the RA33 negative population (p=0.034). Conclusions Thus, increasing the number of antibodies in serological routine testing would provide valuable additional information allowing to better distinguish between RA and other rheumatic disorders also in patients negative in current routine diagnostics and may provide valuable additional information regarding the prediction of treatment responses. Disclosure of Interest D. Sieghart: None declared, A. Platzer: None declared, P. Studenic: None declared, F. Alasti: None declared, M. Grundhuber Employee of: Thermo Fisher Scientific, Phadia GmbH, S. Swiniarski Employee of: Thermo Fisher Scientific, Phadia GmbH, S. Blueml: None declared, H. Haslacher: None declared, J. Smolen: None declared, G. Steiner: None declared

Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are the most commonly used diagnostic markers of rheumatoid arthritis (RA). These antibodies are predominantly of the immunoglobulin (Ig) M (RF) or IgG (ACPA) isotype. Other subtypes of both antibodies—particularly IgA isotypes and other autoantibodies—such as RA33 antibodies—have been repeatedly reported but their diagnostic value has still not been fully elucidated. Here, we investigated the prevalence of IgA, IgG, and IgM subtypes of RF, ACPA, and RA33 antibodies in patients with RA. To determine the diagnostic specificity and sensitivity sera from 290 RA patients (165 early and 125 established disease), 261 disease controls and 100 healthy subjects were tested for the presence of IgA, IgG, and IgM isotypes of RF, ACPA, and RA33 by EliA™ platform (Phadia AB, Uppsala, Sweden). The most specific antibodies were IgG-ACPA, IgA-ACPA, and IgG-RF showing specificities >98%, closely followed by IgG- and IgA-RA33 while IgM subtypes were somewhat less specific, ranging from 95.8% (RA33) to 90% (RF). On the other hand, IgM-RF was the most sensitive subtype (65%) followed by IgG-ACPA (59.5%) and IgA-RF (50.7%). Other subtypes were less sensitive ranging from 35 (IgA-ACPA) to 6% (IgA-RA33). RA33 antibodies as well as IgA-RF and IgA-ACPA were found to increase the diagnostic sensitivity of serological testing since they were detected also in seronegative patients reducing their number from 109 to 85. Moreover, analyzing IgM-RF by EliA™ proved more sensitive than measuring RF by nephelometry and further reduced the number of seronegative patients to 76 individuals. Importantly, among antibody positive individuals, RA patients were found having significantly more antibodies (≥3) than disease controls which generally showed one or two antibody species. Thus, increasing the number of autoantibodies in serological routine testing provides valuable additional information allowing to better distinguish between RA and other rheumatic disorders, also in patients not showing antibodies in current routine diagnostics. In conclusion, testing for multiple autoantibody specificities increases the diagnostic power of autoimmune diagnostics and could further support physicians in clinical decision-making.

Background Treat-to-target (T2T) is a widely accepted management strategy for rheumatoid arthritis (RA) with a key decision point at 3 months after treatment initiation. At this time point, it remains unclear which patients will benefit from treatment adaptation or from continuation of existing treatment. Methods We performed a pooled analysis of patient-level clinical trial data of patients with RA. We used a diagnostic testing methodology and a probabilistic approach employing logistic regression to investigate which levels of response at 3 months can inform treatment decisions in regard to achieving the target at 6 months. Results To be at least 80% sensitive for achieving the low disease activity (LDA) target at 6 months, a change at 3 months in Simplified Disease Activity Index/Clinical Disease Activity Index (SDAI or CDAI) of 58% needs to be observed at 3 months. Higher changes are needed to sensitively predict remission (REM). Not reaching the (minor) SDAI 50% response level is afflicted with very low negative likelihood ratios (LRs) (0.28 for LDA and 0.07 for REM at 6 months). Experiencing (major) SDAI 85% response has substantial positive LRs of 9.2 for reaching LDA and 6.2 for reaching REM at 6 months. In logistic regression, the change at 3 months is significantly associated with reaching of the target at 6 months. Conclusions The 3-month time point is a critical decision point. Not achieving minor responses at 3 months makes reaching of the treatment target at 6 months highly unlikely, while reaching major responses is highly predictive of reaching the treatment target.

The Disease Activity Index for Psoriatic Arthritis (DAPSA) is a valid and discriminative tool. Definitions of disease activity states and therapeutic response are still missing. We derived such criteria for the DAPSA.We retrieved 30 patient profiles from an observational database including joint counts, patient pain and global activity ratings and C-reactive protein (CRP) and carried out a survey among experts to classify patients into remission (REM), low (LDA), moderate (MDA) or high (HDA) disease activity. Based on the distributions of DAPSA in each of these expert-assigned states we defined the cutpoints between groups. We performed similar analyses evaluating a clinical score (cDAPSA), omitting CRP. To define minor, moderate and major treatment response, we used Cohen's Kappa statistics and analysed agreement of DAPSA percentage change with ACR20/50/70-response in three randomised controlled trials.Our survey yielded a response rate of 75% (n=33). Mean DAPSA differed significantly between patients classified as REM, LDA, MDA or HDA (p0.001). Based on the distributions of DAPSA in these groups, we propose cut-off values of ≤4 for REM,4 and ≤14 for LDA,14 and ≤28 for MDA and28 for HDA. We observed best agreement with ACR20/50/70-response at DAPSA changes of 50/75/85%, reflecting minor, moderate and major improvement.The DAPSA constitutes a disease-specific, validated and feasible tool for PsA assessment. In this study, we provide criteria for disease activity states and treatment response. They are based on an international expert survey, and show good performance in clinical trials and observational data.

Background Sonographic assessment, measuring grey scale (GS) and power Doppler (PD) signals, is a sensitive tool for the evaluation of inflammatory joint activity in patients with rheumatoid arthritis (RA). We evaluated the persistence of PD and GS signals in previously clinically active RA joints that have reached a state of continuous clinical inactivity. Methods We performed sonographic imaging of 22 joints of the hands of patients with RA, selected all joints without clinical activity but showing ongoing sonographic signs of inflammation, and evaluated the time from last clinical joint activity. Results A total of 90 patients with RA with 1980 assessed joints were included in this study. When comparing the mean time from clinical swelling, we found a significantly longer period of clinical inactivity in joints showing low sonographic activity (mean±SD time from swelling of 4.1±3.2 vs 3.1±2.9 years for PD1 vs PD≥2, p=0.031 and 4.5±3.4 vs 3.3±3.2 years for GS1 vs GS≥2, p≤0.0001). Conclusions We conclude that subclinical joint activity is long-lasting in RA joints in clinical remission, but attenuates over time. The latter conclusion is based on the observed shorter time duration from last clinical activity for strong compared with weaker sonographic signals.

Introduction Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are important diagnostic tools in rheumatoid arthritis (RA). These antibodies are predominantly of the IgM (RF) or IgG (ACPA) isotype. Other isotypes of both antibodies – like IgA – and other antibodies – like anti-RA33, which is directed to the nuclear antigen hnRNP-A2 – have been repeatedly reported but their diagnostic and prognostic value has still not been fully elucidated. Objectives Here we investigated (i) the prevalence of IgA-RF and IgA-ACPA as well as isotypes IgA, IgG and IgM of anti-RA33 antibody in patients with RA and (ii) their predictive value regarding therapeutic response to methotrexate (MTX). Methods Sera from 290 RA patients, 261 disease controls and 100 healthy subjects were tested for the presence of RF, ACPA and anti-RA33 IgG/A/M isotypes by EliATM (Thermo Fisher Scientific). RF and ACPA were routinely measured by nephelometry and the anti-CCP EliATM, respectively. For finding associations with American College of Rheumatology (ACR)20 and simplified disease activity score (SDAI)50 therapeutic responses, an inception cohort of 165 RA patients was analysed. Results Diagnostic specificity of antibodies was at least 95%. 185 (63.4%) of 290 RA patients tested positive for at least one routine marker (RF or ACPA) while 107 were negative for both antibodies (seronegative). Among these, 24 (8.2%) patients tested positive for IgG/A/M anti-RA33 and/or IgA-RF/ACPA. To determine the prognostic value regarding therapeutic responses a cross-validated combined model with an accuracy of 77% and an estimated p-value (k=10) of 0.00034 showed high levels (>133 IU/ml) of IgM-RF to be associated with a favourable response to methotrexate (MTX). In case of low or no RF, the presence of IgG-RA33 antibody on the one hand, and the absence of IgA-ACPA on the other hand was associated with a favourable response. Conclusions Thus, these data suggest that determination of multiple antibodies increases the diagnostic power of serological testing and may be a feasible tool for the prediction of MTX response especially in combined models. Disclosure of interest D. Sieghart: None declared, A. Platzer: None declared, F. Alasti: None declared, P. Studenic: None declared, M. Grundhuber Employee of: Thermo Fisher Scientific – Phadia GmbH, S. Swiniarski Employee of: Thermo Fisher Scientific – Phadia GmbH, S. Blueml: None declared, T. Perkmann: None declared, J. Smolen: None declared, G. Steiner: None declared

Introduction The synovium demonstrates a distinct cellular structure with a densely packed synovial lining layer that sits on top of a loosely organised sublining layer. In rheumatoid arthritis (RA), this tissue hosts the inflammatory reaction and undergoes drastic structural changes. We hypothesise that this inflammatory remodelling results in tissue dysfunction, thereby perpetuating the inflammatory process. To explore the relationship between tissue structure and function, we use a 3D human synovial organoid culture system to model healthy and diseased synovium. Methods FLS from RA patients were resuspended in Matrigel and cultured as 3D organoids for an extended period of time. This allows FLS to re-establish a synovial tissue-like structure. To mimic inflammation, 3D synovial organoids were challenged with TNF. A re-stimulation experiment was designed in which synovial organoids were exposed to TNF for 10 days, followed by a 3 day wash out phase. Thereafter, the organoids were re-stimulated with TNF. To prevent TNF-driven remodelling, Marimastat, a broad MMP inhibitor, was added during the first TNF stimulation. For selected experiments, synovial tissue-like structure was assessed by HE staining in paraffin embedded sections of synovial organoids. qPCR and RNA Seq were used in gene expression profiling. IL-6, IL-8 and MMP3 protein production was determined by ELISA. Results TNF-stimulated synovial organoids demonstrated lining layer hyperplasia and cellular condensation in the sublining layer. After TNF-stimulation, gene expression of MMP1, MMP3 and IL-6 and protein production of IL-6, IL-8 and MMP3 was upregulated. Upon re-stimulation of synovial organoids with TNF, protein levels of IL-6, IL-8 and MMP3 were significantly increased when compared to previous stimulations. In order to explore whether this effect is due to TNF-induced structural changes, tissue remodelling was blocked using Marimastat. IL-6 protein level was reduced in 21%. To further explore the increased TNF response upon re-stimulation, epigenetic mechanisms are currently being tested. Conclusions TNF stimulation has a direct effetc in synovial organoids function and structure. TNF-driven tissue remodelling is associated with an increased in IL-6, IL-8 and MMP3 expression response upon re-stimulation. Inhibition of TNF-induced remodelling partially prevents this effect. Additional epigenetic mechanisms may account for tissue memory. Disclosure of interest None declared

Background In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. Methods In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0–2 tender joints, and an acute-phase reactant within the normal range. Results Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p

Background Rheumatoid arthritis is a chronic form of inflammatory arthritis that is thought to have an early stage or reversibility with effective therapy (“window of opportunity”). Objectives In the present study, we explored the effects of induction therapy with anti-TNFα antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. Methods In an investigator-initiated, double-blind, randomized, placebo-controlled, multi-center trial, patients with synovitis of 12–16 weeks duration in at least 2 joints underwent one year of treatment with IFX in combination with MTX, MTX monotherapy or PL randomized in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart including week 54) with remission defined as no swollen joints, 0 - 2 tender joints and a C-reactive protein (CRP) level within the normal range ( Results See Table 1. 90 patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX+MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL (Table). This difference was statistically significant for all three groups (p Conclusions These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared to MTX alone, suggesting the existence of a window of opportunity where intensive treatment can alter the disease evolution Disclosure of Interest T. Stamm Grant/research support from: For all authors: DINORA was partly funded by a grant from Janssen (previously Centocor). TS: AbbVie, Consultant for: AbbVie, Novartis, Speakers bureau: AbbVie, Janssen, MSD, Novartis and Roche, K. Machold: None declared, D. Aletaha Grant/research support from: AbbVie, Pfizer, Grunenthal, Merck Medac, UCB, Mitsubishi/Tanabe, Janssen and Roche, Consultant for: AbbVie, Pfizer, Grunenthal, Merck Medac, UCB, Mitsubishi/Tanabe, Janssen and Roche, F. Alasti: None declared, P. Lipsky Consultant for: Janssen, EMD Serono, Astra Zeneca, UCB, Roche, Celgene, Sanofi and Horizon, but none of them relates to the content of this manuscript, D. Pisetsky: None declared, R. Landewe Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB and Wyeth, Consultant for: Abbott/AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Celgene, Janssen (formerly Centocor), Galapagos, Glaxo-Smith-Kline, Novartis, Novo-Nordisk, Merck, Pfizer, Roche, Schering-Plough, TiGenix, UCB and Wyeth, Employee of: RL is director of Rheumatology Consultancy BV which is a registered company under Dutch law., Speakers bureau: Abbott/AbbVie, Amgen, Bristol Myers Squibb, Janssen (formerly Centocor), Merck, Pfizer, Roche, Schering-Plough, UCB and Wyeth, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boeringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB, Employee of: DH is director of Imaging Rheumatology bv., A. Sepriano: None declared, M. Aringer Grant/research support from: MA9s institution is clinical trial site for AbbVie, Astra Zeneca, Boehringer Ingelheim, Novartis, Pfizer and Roche., Consultant for: AbbVie, Astra Zeneca, BMS, Chugai, GSK, Hexal, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and UCB, Speakers bureau: AbbVie, Astra Zeneca, BMS, Chugai, GSK, Hexal, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and UCB, D. Boumpas: None declared, G. Burmester Grant/research support from: AbbVie, BMS, UCB and Roche, Speakers bureau: MSD, UCB and Roche, M. Cutolo Grant/research support from: BMS, Horizon, Actelion, Celgene and MSD, Speakers bureau: Biogen, Mundipharm, Pfizer and Menarini, W. Ebener Consultant for: Novartis and Abbvie, W. Graninger: None declared, T. Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boeringher, Takeda, Epirus and Eli Lilly, G. Schett Speakers bureau: BMS, Celgene, Chugai, Lilly, Roche and UCB, H. Schulze-Koops Speakers bureau: AbbVie, Actelion, AstraZeneca, Biogen International, Boehringer Ingelheim, BMS, Celgene, Celltrion, Chugai, Cinfa Biotech, GSK, Hospira, Janssen-Cilag, Lilly, MSD, Medac, Merck, Mundipharma, Novartis, Pfizer, Hexal Sandoz, Roche and UCB, P. P. Tak Employee of: PPT has become an employee of GlaxoSmithKline. GSK has not been involved in this study., F. Breedveld: None declared, J. Smolen Grant/research support from: Abbvie, Lilly, MSD, Pfizer and Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Boehringer-Ingelheim, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB

Background Studies evaluating weather sensitivity among patients with rheumatoid arthritis (RA) have yielded conflicting results. Objectives To evaluate whether patients with RA exhibit sensitivity to outside temperature. Methods We assessed correlation between mean daily temperature and self-reported pain (by visual analogue scale), and patient9s global assessment of disease activity (PGA). Assessments documented in the RA database of our department as well as the average temperature obtained from the Central Institute for Meteorology and Geodynamics, were matched on a daily basis for a period of 10 years between 2005 and 2015 and analyzed using generalized estimating equation (GEE) and a mixed model analysis (MM). Patients with Results A total of 399 patients with RA (average disease duration at first visit: 6.0±7.6 years, average age: 57.7±13.9 years, 82% female, mean CDAI 19.7±11.5, 59.9% rheumatoid factor positive) were analyzed. Lower temperatures correlated significantly with higher pain levels (estimate: -0.07, p=0.021) in GEE, however the effect size was very small. When we performed MM with temperature as independent variable and VAS pain or PGA as dependent variable, the majority of patients showed no sensitivity to temperature, however 22% of patients were significantly sensitive to cold temperature with an estimate of -0.29 (p Conclusions Our results indicate that a subgroup of patients with RA show significant sensitivity to cold temperature, and that these patients are characterized by higher pain and PGA levels at lower daily temperatures. These aspects may have to be taken into account in longitudinal analyses of disease activity of RA. Disclosure of Interest None declared

Background It is an ongoing matter of research, whether the natural course of rheumatoid arthritis (RA) can be altered by an early intervention, a concept historically referred to as the “window of opportunity” (1). So far, only short-term disease activity outcomes have been investigated (e.g. “remission off drugs”), which are, however, inherently affected by the unknown rate of underlying rate self-limiting disease. It is unclear, whether among those, who eventually develop RA, the disease course is really affected by the timing of their initial treatment. Objectives To explore whether the long-term course of RA is different according to the delay of initial treatment. Methods Based on a longitudinal observational dataset, we initially identified a group of patients with an observed refractory disease, we defined presenting with ongoing moderate or high disease activity (by the Simplified Disease Activity Index, SDAI), despite at least three courses of DMARDs, of which at least on course was a biological compound. To ensure that sufficient time had been allowed for the previous treatments to be exert their non-effects, we also required these patients to have total treatment time of at least 18 months in accordance with treat to target strategy (3 x 6 months). We identified 399 patients with a treatment time of at least 18 months. 48 patients were excluded despite fulfilling the disease activity criteria, because they haven9t experienced enough treatment courses, or had received a biological compound yet, to claim refractory disease as per our criteria above. We could include 69 refractory and 282 non-refractory patients in our analyses and then performed logistic regression analysis to assess the effects of different characteristics at baseline, including disease duration, on becoming refractory. Results By comparing patient characteristics (Table 1), more of the patients, who later will become refractory, are female (94.2% Vs 73.4%, p>0.001), have higher baseline disease activity (SDAI of 25.5 vs 17.7, p The multivariable logistic regression model confirmed that a longer delay of first treatment is independently afflicted with a higher probability of a refractory disease course at a later stage. This model was adjusted for disease activity at baseline and gender (p Conclusions Our data suggest that delay to initial treatment in RA affects the long-term course of RA. Earlier treatment initiation thus may change the severity of RA. References van Nies, J.A., et al., What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis, 2014. 73(5): p. 861–70. Disclosure of Interest None declared

Background Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are important diagnostic markers in rheumatoid arthritis (RA). These antibodies are predominantly of the IgM (RF) or IgG (ACPA) isotype. The added diagnostic and prognostic value of IgA autoantibodies is being debated. Objectives To determine the prevalence of IgA-RF and IgA-ACPA in patients with RA and to investigate their potential predictive value regarding response to treatment with methotrexate (MTX) and TNF inhibitors. Methods A total of 255 patients were tested for the presence of IgA-RF, IgA-ACPA and IgG-ACPA by EliA® (Thermo Fisher Scientific); IgM-RF was measured by nephelometry. Therapeutic responses to MTX and TNF blocking biologicals were calculated in an inception cohort (n=104) who had started their DMARD therapy at our clinic. To define therapeutic responses simplified disease activity index (SDAI) 50 and American College of Rheumatology (ACR) 20 responses were calculated. Results Among the 255 patients tested 125 (49%) had at least one type of IgA autoantibody: 114 (44.7%) were found to be IgA-RF positive and of these 10.5% were negative for IgM-RF and 5.2% were double negative for both IgM-RF and IgG-ACPA; thus, in these patients IgA-RF was the only detectable antibody. IgA-ACPA were detected in 79 (31%) patients and apart from one exception all of them had also IgG-ACPA. Remarkably, the percentage of patients showing a SDAI50 response to TNF inhibitors was significantly lower in patients positive for IgA-RF and/or IgA-ACPA (p Conclusions While the added diagnostic value of IgA antibody measurement was moderate, IgA-RF and particularly IgA-ACPA appear to be associated with poorer therapeutic responses to TNF inhibitory biological drugs and therefore may help in further stratification of RA patients and therapeutic decision making. Disclosure of Interest None declared

Objectives In PsA management, remission and low disease activity represent preferential treatment targets. We aimed at evaluating the predictive value and clinical use of initial therapeutic response for subsequent achievement of these targets. Methods Based on data of 216 patients enrolled in a randomized controlled trial of golimumab (GO-REVEAL), we performed diagnostic testing analyses using 3- and 6-month disease activity as tests for treatment outcomes to understand the implications of early response. In regression analyses, we estimated the probabilities for achieving at least LDA. Disease activity was measured by the disease activity index for PsA (DAPSA). Results Three-month DAPSA levels were excellent tests for disease activity at 6 months (and at 1 year), with areas under the receiver operating characteristic curves of 0.92 (and 0.88, respectively). The estimated probability for 6-month LDA could be quantified as

Background The synovial membrane is a distinctly organised tissue structure. During the course of rheumatoid arthritis (RA), the synovium becomes hyperplastic and demonstrates thickening of the lining layer and cellular condensation at the sublining layer. Using a three-dimensional synovial organ culture system, we explore cellular mechanisms of synovial tissue formation and inflammatory remodelling. Materials and methods Fibroblast-like synoviocytes (FLS) derived from patients with RA were cultured in 3D micromasses. To mimic synovial inflammation, micromasses were challenged with TNF. For histological analyses, micromasses were embedded in paraffin, sections were stained with haematoxylin and eosin; Ki67 labelling was performed to identify proliferating cells. 3D confocal micrographs were analysed using Imaris Bitplane software. mRNA levels for various genes expressed in FLS were determined by qPCR. Results Synovial micromasses demonstrated thickening of the lining layer over time. When stimulated with TNF, hyperplasia of the lining layer and cellular aggregation at the sublining layer was observed. In order to identify the origin of cells contributing to the thickening of the lining layer, proliferation studies were conducted. Intriguingly, in the early phase of the culture period, the percentage of proliferating cells in the lining layer was higher when compared to the sublining layer. This proliferative activity, however, was no longer present in the late phase, after the lining layer was established. In the presence of TNF, an increased number of proliferating cells at the lining layer was maintained for an extended period of time, consistent with higher rates of cellular proliferation at the synovial lining in sections of RA synovial tissues when compared to OA. qPCR data indicate that MMP1, MMP3, and IL-6 are differentially expressed during the early phase and the mature phase of the culture period. By contrast, lubricin, cadherin-11, CCL20, and STAT1 were not differentially expressed. Conclusions The three-dimensional FLS micromass culture reveals spontaneous cellular organisation that strikingly resembles the lining/sublining architecture of the synovium. This process involves FLS proliferation as well as expression of genes that allow for tissue remodelling. In inflammatory conditions similar cellular programs are re-activated resulting in synovial lining hyperplasia and a pannus-like condensed mass of cells.

Background/objective Progression of joint damage is linked to disease activity. This link is dissociated upon treatment with tumour necrosis factor (TNF)- or IL-6-inhibitors plus methotrexate (MTX). It is hitherto unknown if this may also be true for therapies targeting B-cells. We thus evaluated if rituximab (RTX) therapy inhibits joint damage irrespective of its effects on disease activity. Methods We used a random 90% sample of data from two arms of the IMAGE trial comprising patients with active early rheumatoid arthritis (RA) receiving MTX (n=188) or MTX+RTX 1000 mg (n=204). Patients were divided into low, moderate and high disease activity at one year of treatment by simplified disease activity index (low disease activity (LDA), moderate disease activity (MDA), high disease activity (HDA)), or by swollen joint count (SJC) or C reactive protein (CRP) tertiles. Progression of damage by the Genant modified total Sharp score (TGSS) was compared between therapies (Kruskal-Wallis, Wilcoxon tests) for each of these subgroups. Results In patients treated with MTX, 1-year progression of TGSS In LDA, MDA and HDA was 0.40±0.88, 1.04±1.73, and 1.31±3.02, respectively. In contrast, on RTX+MTX, TGSS progression was 0.38±1.07, 0.39±1.28, and −0.05±0.44, respectively (for MDA and HDA the progression of TGSS was significantly lower in the combined group than in the MTX group: p=0.003 and p=0.05, respectively). Additional analyses (tertiles of SJC, CRP, and matching for disease activity) confirmed the primary analysis. Conclusions In early RA, progression of joint damage increases with increasing disease activity on MTX. RTX plus MTX retards damage independently of its effects on disease activity, since even in HDA destruction is halted, contrasting MTX monotherapy. This indicates that beyond cytokine blockade (TNF- and IL-6 inhibitors), also cell-directed therapy (anti-CD20 antibody) conveys profound anti-destructive effects and dissociates the link between disease activity and joint damage.

BackgroundRheumatoid factor (RF) is prototypic for rheumatoid arthritis (RA) and serves diagnostic and prognostic purposes. RF is associated with joint destruction, but the role of disease activity as a potential mediator of these effects has not been clearly elucidated yet.ObjectiveTo investigate if higher radiographic progression (Sharp score, ΔTSS) in RF+ patients is dependent or independent of disease activity.MethodsThe authors performed a cross-sectional multivariate analysis at baseline and a matched cohort study in patients from five RA clinical trials. The authors pooled methotrexate treatment arms and compared ΔTSS in RF+ and RF− patients before and after matching for other associated variables.ResultsAmong 686 patients, 124 were RF− and 562 RF+, 343 having high (>160 U/ml) RF. ΔTSS was 1.03±5.83, 3.23±8.10 and 3.58±8.18 (pConclusionsThe data reveal that damage progression in seropositive RA patients is related to higher levels of disease activity and to independent effects of RF, particularly on bone damage. This calls for consideration of RF status irrespective of disease activity.

BackgroundRecently, disease activity states were developed for the Disease Activity index for PSoriatic Arthritis (DAPSA). Here, we assess if different DAPSA disease activity states are associated with different degrees of functional impairment and different extents of joint damage progression in patients with psoriatic arthritis (PsA).MethodsWe used data from two pivotal trials of tumour necrosis factor (TNF) inhibitors in PsA (IMPACT II and GO-REVEAL) and identified patients in DAPSA remission (REM, ≤4), and low, moderate or high disease activity (LDA, ≤14; MDA, ≤28; HDA, >28) at 6 months. Across these groups we compared the functional scores (Health Assessment Questionnaire Disability Index, HAQ and physical component scale of the Short Form-36, PCS), and 1-year structural progression (PsA-modified Sharp/van der Heijde Score).ResultsWe identified 310 from GO-REVEAL and 130 from IMPACT II, with a mean (SD) baseline DAPSA of 48.8 (26.4) and 44.6 (17.9), respectively. HAQ scores increased across patients groups in the four DAPSA disease activity states, while PCS decreased (pConclusionsDisease activity states of the PsA specific DAPSA score are highly valid for future use as endpoints in clinical trials or as targets in clinical practice.Trial registration numbersIMPACT 2: NCT02152254; GO-REVEAL: NCT00265096.

Objectives Clinical joint activity is a strong predictor of joint damage in rheumatoid arthritis (RA), but progression of damage might increase despite clinical inactivity of the respective joint (silent progression). The aim of this study was to evaluate the prevalence of silent joint progression, but particularly on the patient level and to investigate the duration of clinical inactivity as a marker for non-progression on the joint level. Methods 279 patients with RA with any radiographic progression over an observational period of 3–5 years were included. We obtained radiographic and clinical data of 22 hand/finger joints over a period of at least 3 years. Prevalence of silent progression and associations of clinical joint activity and radiographic progression were evaluated. Results 120 (43.0%) of the patients showed radiographic progression in at least one of their joints without any signs of clinical activity in that respective joint. In only 7 (5.8%) patients, such silent joint progression would go undetected, as the remainder had other joints with clinical activity, either with (n=84; 70.0%) or without (n=29; 24.2%) accompanying radiographic progression. Also, the risk of silent progression decreases with duration of clinical activity. Conclusions Silent progression of a joint without accompanying apparent clinical activity in any other joint of a patient was very rare, and would therefore be most likely detected by the assessment of the patient. Thus, full clinical remission is an excellent marker of structural stability in patients with RA, and the maintenance of this state reduces the risk of progression even further.

Introduction Although the prognostic value of rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPAs) in patients with rheumatoid arthritis (RA) is well established, their association with RA disease activity remains unclear. Here, we investigate this association in a large study using data from clinical trials. Methods We used baseline data from four recent randomized controlled clinical trials of RA. We investigated individual and composite measures of disease activity. The relationship of RF and ACPAs with these measures was investigated by using stratified analysis (comparing four groups of patients according to the presence or absence of RF and ACPAs) and matched analysis (disease activity levels compared between patients negative and patients highly positive for one autoantibody who were matched for levels of the other autoantibody as well as for age, gender, and duration of RA). Results A total of 2118 patients were analysed in the different cohorts. In the stratified analysis, RF+ patients, regardless of ACPA status, had the highest levels of disease activity, whereas ACPA+ patients had disease activity that was similar to or lower than that of ACPA− patients, both in the presence and in the absence of RF. When matched for ACPA levels, patients with highly positive RF had significantly higher disease activity for all composite indices compared with patients who were RF− (P = 0.0067), whereas ACPA-highly-positive and ACPA-negative patients matched for RF levels had similar disease activity, again even with the tendency toward lower disease activity for ACPA+ patients (P = 0.054). Conclusion The data presented suggest that the presence of RF has a clear association with higher levels of disease activity but that the presence of ACPAs has not and even appears to be associated with lower disease activity. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0736-9) contains supplementary material, which is available to authorized users.

Background In previous studies it has been indicated that functional measures are less responsive in patients with established or late rheumatoid arthritis (RA) as compared with early RA, potentially because chronic irreversible functional damage is present. Therefore, they may not be useful as disease activity measures. We aimed to investigate whether this is specific to functional measures, or if it similarly also relates to other typical RA disease activity measures. Methods We performed a pooled analysis of patient level clinical trial data of patients with RA. We investigated the effects of duration of RA on the responsiveness of all RA core set measures by using logistic regression analysis. We performed a number of sensitivity analyses to support our findings. Results The probability of response in functional scores decreased from ∼60% in early disease to ∼30% in established/late disease (p=0.0023). No other core set variable or composite index behaved in this way. The effect of chronicity solely on functional responses was confirmed in all sensitivity analyses, particularly also when joint damage was used as a surrogate of chronicity, responsiveness decreased from >60% in patients with little structural damage to Conclusions Physical function is among the most important outcomes of RA, but in contrast with other core set measures it is not a reliable measure for disease activity.

Objectives To evaluate whether meteorological parameters influence disease activity in patients with rheumatoid arthritis (RA). Methods We assessed correlations between individual meteorological variables and clinical measures of disease activity: clinical disease activity index (CDAI), self-reported pain (by visual analogue scale), tender- and swollen 28 joint counts (TJC and SJC). Assessments documented in our RA database as well as the average temperature and relative humidity, obtained from the Central Institute for Meteorology and Geodynamics, were matched on a daily basis for a period of 10 years between 2005 and 2015, and analyzed using generalized estimating equations (longitudinal data analysis). Results A total of 1437 patients with RA (average disease duration at first visit: 4.88±8.63 years; 77% female, mean CDAI 17.8±11.7, mean time in study: 75 month, mean number of visits during study period: 19) were analyzed. Higher temperature and lower humidity were significantly associated with lower CDAI (p=0.0002, and p=0.0332, respectively). Regarding pain, the effects of temperature showed an interaction with humidity: while lower temperatures were associated with higher pain levels at the low and middle tertile of relative humidity, they corresponded to a lower pain level at the high tertile of relative humidity. Temperature showed a significantly negative correlation with TJC (p Conclusions In this largest association study of meteorological parameters with RA specific outcomes both temperature and relative humidity were shown to have significant effects on disease activity. Individual measures of disease activity and pain correlated either with temperature or humidity, while the composite CDAI measure correlated with both meteorological variables. These aspects may have to be taken into account in longitudinal analyses of disease activity of RA. Disclosure of Interest None declared

Objectives To produce ultrasound (US) consensus-based definitions of cartilage change in rheumatoid arthritis (RA) and assess its intraobserver and interobserver reliability in a web-based exercise. Methods We conducted a Delphi study on US defined cartilage change and a proposed semiquantitative (SQ) US scoring system for cartilage change in RA. A written Delphi questionnaire was developed based on a systematic literature review and expert international consensus and was distributed via consecutive written questionnaires by email to a group 35 rheumatologists from 17 countries with experience in musculoskeletal US. Taskforce members performed US B mode examination of the metacarpal cartilage in metacarpophalangeal joints 2–5 in RA patients and the images were collected in an electronic database. A reference image atlas of cartilage changes was developed for scoring 123 anonymized images including 25 duplicate images. These were sent to the participants who independently scored the images. Intraobserver reliability was assessed by Cohen9s kappa and interobserver reliability by Fleiss9 kappa. Results Group agreement (76–100%) was reached for 6 statements concerning: i) MSUS definition and assessment of normal hyaline cartilage, ii) elementary cartilage lesions in MSUS and iii) grading of elementary cartilage lesions in patients with RA in a two-round Delphi consensus process. A three-grade SQ (0–2) scoring system (grade 0, normal cartilage; grade 1, minimal change: blurring of outer and/or subchondral margin, focal thinning or incomplete loss of homogeneity of echostructure; grade 2, severe: diffuse thinning or complete loss of homogeneity of echostructure) was agreed for scoring cartilage damage in RA. Both intra- and inter-observer reliability were good (κ value of 0.87 and 0.64 respectively). Conclusions This study demonstrates that US is a reliable tool for evaluating cartilage in RA and strongly supports the use of a new reliable semiquantitative MSUS scoring system for cartilage change. Disclosure of Interest None declared

Background The Disease Activity index for PSoriatic Arthritis (DAPSA) was developed and validated. It is a composite measure of swollen and tender joint counts, patient global and pain assessment and an acute phase reactant. Recently, also DAPSA disease activity states were developed using clinical trial data and observational data (1). However, the validity of these states in regards to important outcomes of the disease has not yet been determined. Objectives To assess if different DAPSA disease activity states are associated with different degrees of functional impairment and/or different extents of joint damage progression in patients with psoriatic arthritis (PsA). Methods We used data from two pivotal trials of TNF-inhibitors in PsA, the IMPACT II (n=134) and the GO-REVEAL (n=313) trials. At 4 months, we identified patient in DAPSA remission (REM, ≤4), low disease activity (LDA, ≤14), moderate disease activity (MDA, ≤28), and high disease activity (HDA, >28). We then determined the rate of structural progression (defined as Sharp van der Heijde, SvdH, score increase of >0, >0.5, and >1 point from baseline to end of year 1) across these four disease activity groups. We also correlated DAPSA levels at 4 months with changes in SvdH change scores from baseline to year 1. We also studied functional construct validity of the DAPSA states by assessing median scores of the Health Assessment Questionnaire Disability Index (HAQ; GO-REVEAL study only), and of the physical component scale of the Short Form-36 (PCS, SF-36; IMPACT II study only), across the different DAPSA states at 6 months. Results We identified 313 from GO-REVEAL and 134 from IMPACT II, with a mean (SD) baseline DAPSA of 44.7 (17.8) and 48.7 (26.3). The probability of progression according to different DAPSA scores is depicted in panel A of the Figure, separately for three cutpoints of progression. For all three analyses, the link between DAPSA and the probability of progression was significant (progression >0: p=0.039; progression >0.5 and >1.0: p=0.0001 for both). This association was also seen when we compared patients in the four disease activity states at four months for their actual rate of progression, e.g., the proportion of patients with progression of >1 over one year was 3.7% among DAPSA remitters and 15.1% among patients with DAPSA HDA (p=0.0004). We also confirmed functional construct validity by using HAQ scores in one trial (GO-REVEAL), and the SF-36 PCS in the other (IMPACT II). As can be seen in panel B of the Figure, the HAQ and PCS scores across the four groups were highly significantly different (p Conclusions The definition of traditional disease activity states on the scale of the DAPSA, a PsA specific disease activity instrument, shows high validity against important constructs in PsA. This is important, and validates these DAPSA endpoints for future use in clinical trials, or as targets in clinical practice. References Schoels M et al. Ann Rheum Dis. 2015 Aug 12. [Epub ahead of print] Acknowledgement We thank Janssen/Centocor for providing data from their trials for the current analysis. Disclosure of Interest None declared

Background The presence of rheumatoid factor (RF) is associated with progression of joint damage in patients with rheumatoid arthritis (RA). RF levels may change during the course of therapy1, but it is not clear, if such changes also reflect a change in prognosis of RA. Objectives Here, we aimed to investigate whether fluctuation of RF levels is an independent marker of progression of RA. Methods We identified 239 RA outpatients based on classifiable RA by the 2010 ACR/EULAR classification criteria, the presence of at least two available radiographs of hands and feet (2–4 years apart), the availability of repeated measurements of RF (at least two/year), and positive initial RF levels (≥50 IU/ml; for the possibility of fluctuation). Radiographic images were scored using the modified Sharp/van der Heijde (SvH) method. A total of 375 radiographic intervals could be included, since some of the patients had more than one included observation periods. Logistic regression analysis was used to examine the effect of fluctuating RF levels (expressed as standard deviation of all RF measurements between the two radiographs) on significant damage progression (defined by an average increase of ≥3 on the SvH score per year); results were adjusted for mean RF levels over time, disease activity (expressed as Simplified Disease Activity Index – SDAI), percentage time on biologics and already existing radiographic damage. Results Mean (SD) RF levels were 351.4 (618.7) IU/ml at baseline and 253.7 (424.2) IU/ml at the time of the second radiograph (p Univariate logistic regression showed a clear association of higher standard deviations of RF levels with radiographic progression (p=0.015). When adjusting this effect for mean RF levels, disease activity (time-integrated levels of SDAI), percentage time on biologics and already existing radiographic damage, the association of standard deviation of RF levels on radiographic progression was lost (p=0.087), whereas disease activity (p When adjusting for each of these predictors individually, the association remained unchanged when tested against time on biologics only (p=0.016), or pre-existing damage only (p=0.048). Even adjusting for mean RF levels only left a significant independent association (p=0.032), while the mean RF levels were not significant (p=0.146). Only when adjusted for time-integrated disease activity, standard deviation of RF lost significance on the association with radiographic progression (p=0.126; Table). Conclusions Fluctuations of RF levels are associated with radiographic progression in RA. This effect is independent of mean RF levels over time, but seems to be associated with, or a consequence of, disease activity. Further studies need to explore the direction of causality of these observations. References Serological changes in the course of traditional and biological disease modifying therapy of rheumatoid arthritis. Bohler C et al. Ann Rheum Dis, 2013 Feb;72(2):241–4. Disclosure of Interest None declared

Background Treatment options for rheumatoid arthritis (RA) patients are manifold, but methotrexate (MTX) and leflunomide categorized as DMARDs of first choice in treating rheumatoid arthritis patients. Methotrexate accumulates in patients with impaired kidney function and should therefore be used cautiously. At the same time, such accumulation may also lead to an increased effectiveness. Objectives To investigate the effects of methotrexate dose and kidney function on effectiveness, using patients treated with leflunomide as the control group. Methods We identified patients starting either MTX or leflunomide treatment, who had clinical and laboratory follow up for at least 6 month out of a longitudinal observational database. By using multivariable regression analyses, we tested whether creatinine or glomerular filtration rate (GFR) besides baseline SDAI were associated with observed Simplified Disease Activity (SDAI) response. Results 200 patients receiving MTX (74% female, Median (IQR): GFR=77 (67-90), SDAI=14 (7-23.1), 59% rheumatoid factor positive) and 46 receiving Leflunomide (89% female, Median (IQR): GFR=67 (61-81), SDAI=12 (6-18.6), 59% rheumatoid factor positive) were identified in our longitudinal observational database for analyses. Regression analyses in the MTX cohort showed that after adjusting for MTX dose higher creatinine was associated with higher SDAI response after 6 month of treatment (p=0.002). Analogously, in a separate analysis lower GFR was also significantly associated with larger clinical improvement (p=0.013) (Figure). In patients treated with leflunomide creatinine as well as GFR was not associated with SDAI change after 6 month of treatment (p=0.254). Conclusions Impaired kidney function is a risk factor for MTX accumulation and associated toxicity, at the same time, higher treatment responses in these patients indicate increased clinical benefit in these patients. This could also indicate room for higher doses in patients with normal kidney function, which is historically limited to 25mg/week. Disclosure of Interest None declared

Background The last decade brought major advances in treatment choices for rheumatoid arthritis (RA) patients. The first choice in the treatment of RA patients is methotrexate (MTX) with a rapid step up to alternative conventional disease modifying antirheumatic drugs (DMARDs) or biologicals according to established treatment algorithms. Following these strategies, treatment retention can be seen as a surrogate marker for treatment response in clinical practice. Objectives We aimed to identify patient or treatment characteristics or comorbidities that are associated with treatment retention in an observational cohort of RA patients. Methods We identified patients starting DMARD treatment for RA patients from a longitudinal observational database. We considered the first 6 sequential treatments in our analysis, because the number of patients with >6 treatment was small. We used a two step forward conditional Cox regression model. In the first step we tested clinical variables and the impact of the sequence of the treatment as well as DMARD category (eg. csDMARD monotreatment, Non-TNFi biological DMARD, etc); and in the second step we tested the effects of comorbidities using hemoglobin levels, leukocyte counts, serum creatinine and glomerular filtration rate (GFR), alanin-aminotransferase (ALT) and gamma-glutamyl-transferase (GGT) as additional predictors. We finally repeated the analyses using only patients of an inception cohort. Results 695 patients were identified in our longitudinal observational database for analyses: 78% female; mean ± SD disease duration: 4.7±7.9 years; CDAI: 17.6±11.1; age: 54.3±12.9; 61% rheumatoid factor positive). The inception cohort comprised 260 patients starting their first DMARD: 74% female; disease duration: 0.09±0.46 years; CDAI: 17.6±10.9; age: 54.3±13.5; 56% rheumatoid factor positive. In analyses of the inception group we found that CDAI, age and treatment segment function as clinical predictors for treatment retention. Function, rheumatoid factor status, anti-citrullinated antibody or disease duration did not contribute significantly in explaining the outcome. The more previous treatments the patient had received, the higher the disease activity, and the younger the patient, the higher the risk for discontinuation of therapy. Considering comorbidities in step 2, only ALT could add significantly in step 2 of the analysis, with higher ALT levels being associated with lower risk of treatment discontinuation (Table 1). Whether the high baseline ALT is a consequence of chronic use of pain killers needs to be explored. In this case, the subjective benefit of DMARDs may also contribute to longer retention. When using the complete cohort the same clinical variables were found significant. Concerning laboratory surrogates of comorbidities, only higher hemoglobin levels were associated with a lower risk of treatment discontinuation (Table 1). ALT did not associate with treatment retention in the complete cohort. Conclusions Patients on their first DMARD treatment show higher retention rates than on subsequent treatments, independent of DMARD category. Anemia is an important independent risk factor of DMARD discontinuation. Disclosure of Interest None declared

Objectives To investigate the associations of rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPA) with rheumatoid arthritis (RA) disease activity. Methods We used baseline data from four recent randomized controlled clinical trials of RA (one in early RA patients on rituximab, RTX; three on golimumab, GOL, in early and established populations). The effects of RF and ACPA on individual and composite measures of disease activity were investigated by using stratified analysis and a matched analysis. Results A total of 2118 patients were analysed in the four studies. In both, the RTX and the pooled GOL cohorts, RF+ patients, regardless of ACPA status, had the highest levels of baseline disease activity, while ACPA+ patients had similar or lower disease activity than ACPA- patients, regardless of RF status (See Figure, using Simplified Disease Acitivty Index, SDAI). When patients from the RTX trial were matched for the levels of ACPA, as well as for age, gender, and duration of RA (n=29), SDAI levels were 49.3±14.5 in the presence of high positive RF, and 42.3±12.7 in patients who were RF negative; this was the opposite for ACPA in patients matched for RF levels and the same covariates: high positive ACPA: 45.8±14.8; ACPA negative: 53.1±16.5 (p=0.025). These trends were supported in the respective analyses in the pooled GOL trials (RF high vs. neg.: SDAI of 36.8 vs. 33.1; ACPA high vs. neg.: 37.0 vs. 39.5), although the difference did not reach statistical significance. Figure. Simplified Disease Activity Index at baseline of the rituximab trial (left panel) or the pooled golimumab trials (right panel) by groups of RF/ACPA status. Conclusions The data suggest that the presence of RF rather than ACPA is related to higher disease activity. When matched for RF levels, ACPA had little influence on disease activity, if at all, with the tendency towards lower disease activity for ACPA+ patients. Acknowledgements We thank Roche and Janssen for providing anonymised patient level data from their clinical trials. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4396

Background Today’s therapeutic targets in rheumatoid arthritis (RA) are remission or low disease activity, but it was shown that joint damage may continue to progress despite these favourable clinical states.[1][1];[2][2] While progression of joint damage is related to joint swelling,[3][3];[4][4] radiographic damage may progress even without evidence of clinical synovitis, at least in early RA.[5][5] Objectives To evaluate the frequency of radiographic progression in clinically persistently inactive joints of patients with established RA. Methods We included 80 random RA patients (mean disease duration: 7.32±9.78 yrs.) with radiographic progression (increase≥1) by the Sharp van der Heijde (SvdH) score over an observational period of at least three to a maximum five years. To conform with the records of clinical joint assessment, we only considered radiographic progression in any of the 22 hand/finger joints (10 proximal interphalangeal joints[PIP], 10 metacarpophalangeal joints[MCP], and the 2 wrists), but excluded the feet (not assessed by the 28 joint count). Clinical data on individual joints (swelling and tenderness) from each clinical visit performed between one year prior to the baseline x-ray until the time of the x-ray endpoint were collected from the patient charts. We evaluated whether there are joints showing radiographic progression despite clinical inactivity and compared them to progressing joints that were clinically active. Further, patients with radiographic progression in clinically inactive joints were compared to those with clinical activity. Results The mean±SD time between x-rays was 3.51±0.41 yrs and the mean number of clinical visits per patient was 16.3±4.32. A total of 104 (5.9%) of the 1760 evaluated joints showed progression in erosions and 206 (12.8%) worsened in joint space narrowing (JSN). Of all joints with progression in erosions, 30 (28.8%) were never swollen during the observation period (in 19 patients), 16 (53.3%) were never swollen in the total patient history, and only 7 (6.7%) never showed any activity also by tenderness. In the total patient population, progression was higher in joints with clinical swelling (during the observation period) compared to joints without swelling (2.36±1.7 vs 1.76±1.62). The number of visits with swelling correlated to a low but significant extent with the rate of radiographic progression (r=0.13; p 90% when including ever clinically active joints since onset of disease. Conclusions Only 7% of joints with radiographic progression in patients with established RA show consistent lack of clinical activity, and these joints show a low degree of progression. Thus, radiographic progression despite lacking clinical activity is a negligible event on the joint level. Clinical joint involvement is decisive for progression of joint damage and continues to be a highly predictive outcome measure for monitoring patients with RA. 1. Aletaha D et al. Arthritis Rheum 2009; 60(5):1242-1249. 2. Molenaar ET et al. Arthritis Rheum 2004; 50(1):36-42. 3. Aletaha D et al. Ann Rheum Dis 2011; 70(11):1975-1980. 4. van Riel PL et al. J Rheumatol 1995; 22(9):1797-1799. 5. Klarenbeek NB et al. Ann Rheum Dis 2010; 69(12):2107-2113. Disclosure of Interest None Declared [1]: #p-8 [2]: #p-9 [3]: #p-10 [4]: #p-11 [5]: #p-12

Background The presence of rheumatoid factor (RF) is prototypic for rheumatoid arthritis (RA) and serves diagnostic and prognostic purposes. RF is associated with joint damage, but it is not clear if this is only due to its effects on disease activity or whether there are also independent effects. Objectives We investigated whether the higher radiographic progression (change in total Sharp score, ΔTSS) seen in RF positive patients is dependent or independent of higher levels of disease activity, or both. Methods We used methotrexate treatment arms from five different RA trials and compared ΔTSS in RF negative and RF high positive patients before and after matching for other prognostically important variables. The high positive positive group was selected to achieve a clear contrast in RF levels despite matching for other variables, and was defined as being above the median of all positives. We used Wilcoxon test for statistical comparison, and a number of sensitivity analyses to see if the results were robust. Results Among 687 patients, 124 (18.1%) were RF negative, 562 (81.9%) RF positive, and 343 (50.0%) high positive (RF>160 U/ml). One year ΔTSS was 1.03±5.83, 3.23±8.10 and 3.58±8.18 (p Conclusions Our data indicate that damage progression in seropositive RA patients is partly related to higher levels of disease activity, but partly also to independent effects of RF, particularly on bone damage. This identifies RF as an important independent risk factor for structural damage, and calls for an even more consequent pursuit of disease activity targets in seropositive RA patients. Disclosure of Interest None Declared

Background Remission has been proposed as the therapeutic target in RA. Physical function, on the other hand, is one of the major outcomes in RA predicting work disability, health care resource utilisation and mortality. It is currently still unclear what the minimum duration of remission is that would improve functional capacity to the best possible degree. Objectives To investigate the course of functional status assessed by health assessment questionnaire (HAQ) in RA patients with sustained clinical remission (REM) for at least 6 months. Methods We were provided a random 80-90% data sample of RA patients enrolled in recent clinical trials (ASPIRE, ATTRACT, DE019, ERA, Leflunomide, PREMIER, and TEMPO; n=4362) by the respective sponsors. We identified patients, who at some point during the trials achieved REM by the Disease Activity Score using 28 joint counts and C-reactive protein (DAS28-CRP ≤2.6) or Simplified Disease Activity Index (SDAI ≤3.3), and who maintained it in all subsequent visits throughout at least 6 months.We obtained HAQ scores during these 6 month REM periods, and were thus able to investigate the course of physical function over time in sustained REM using the Wilcoxon test. In additional analyses, patients with a HAQ=0 at REM entry were excluded as they had a priori no chance to show improvement during sustained REM. Results Out of 4362 patients we identified 605 patients in sustained remission by DAS28-CRP (mean duration of REM 38.8±25.1 weeks), and 385 patients by SDAI (mean duration 37.2±23.7 weeks). There were no significant differences in baseline characteristics between these two groups. A significant decrease of HAQ over time was found over the first 6 months in REM by DAS28-CRP (mean±SD HAQ monthly from baseline to month 6: 0.25±0.4 to 0.22±0.38 to 0.22±0.39 to 0.21±0.38 to 0.20±0.37 to 0.18±0.31 to 0.16±0.32) or SDAI (0.17±0.3 to 0.16±0.32 to 0.15±0.3 to 0.14±0.29 to 0.13±0.29 to 0.13±0.26 to 0.11±0.27) with significantly (p Conclusions Functional capacity is significantly improving when remission is reached, but continues to improve if remission is sustained. The stringency of the remission criteria determines how quickly patients in remission achieve their best possible functional improvement. Disclosure of Interest H. Radner: None Declared, F. Alasti: None Declared, J. Smolen Consultant for: Abbott, Amgen, Centocor, Pfizer and Sanofi, D. Aletaha Consultant for: Abbott, Amgen, Centocor, Pfizer and Sanofi

Background Autoantibodies are a hallmark of RA. Since many years ACPA are regarded as more specific than RF for diagnostic and prognostic utility. These data are not unequivocal and most of them have come from observational studies. While it is known for long that RF+ patients have more active and severe disease than RF-, it is not clear if this is due to RF, ACPA or both in the light of the large (>80%) overlap of RF and ACPA and the above controversy. Objectives To compare the extent of disease activity in RF+ and/or ACPA+ patients to understand the impact of these autoantibodies on disease activity of RA. Methods We were kindly provided patient level data from a multicenter randomized controlled trial comparing methotrexate (MTX) and rituximab plus MTX in early ( 1 . Core set variables and levels of RF (by nephelometry) and ACPA (by ELISA) were available. For the purpose of this analysis, we focused on baseline data and pooled the patients of all 3 treatment groups. Following subgroups were formed: RF-/ACPA- (n=64); RF+/ACPA+ (n=611); RF+/ACPA- (n=40); RF-/ACPA+ (n=29). We compared disease activity variables and indices (disease activity score, DAS28; simplified and clinical disease activity index, SDAI, CDAI) across these groups using Kruskal Wallis test for overall assessment, and Wilcoxon test for subsequent pairwise comparisons. A focus of the latter was comparing the RF+/ACPA- and RF-/ACPA+ populations. Results At baseline, DAS28 was 6.9, 7.1, 7.1 and 6.6, respectively, and SDAI 47.8, 49.8, 53.1, 42.3, and significantly different among the groups. By both scores, the lowest values were seen for the RF-/ACPA+ population, significantly lower than in the RF+/ACPA- group (p=0.014 for DAS28, and p=0.004 for SDAI). Similar data were seen for CDAI, swollen and tender joint counts, while for ESR and CRP there was a similar numerical trend(Table). Interestingly, RF+/ACPA+ patients tended to have slightly lower activity than RF+/ACPA-, and higher than RF-/ACPA+. Importantly, similar findings were made for the baseline values of each of the trial arms when assessed individually (not shown). Conclusions The data suggest that RF may contribute more strongly to disease activity than ACPA. While they can only be hypothesis generating, confirmation in other trial databases could shed new light on the prognostic value of ACPA compared to RF. Acknowledgment. We thank Roche for kindly providing the data for this study. References Tak, P.P. et al. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis 70, 39-46 (2011). Disclosure of Interest J. Smolen Grant/Research support from: Roche, Consultant for: Roche, F. Alasti: None Declared, D. Aletaha Consultant for: Roche

Background Progression of joint damage as measured radiographically is a hallmark of rheumatoid arthritis (RA), and its reduction a key claim for traditional and novel antirheumatic drugs. Data from clinical trials may be interpreted to indicate that the observed progression of RA (in comparator groups of clinical trials) has decreased over the past two decades. 1 Although these observations mainly stem from clinical trials, it has been hypothesized that RA may have become a less destructive disease. Objectives To evaluate the frequency as well as the level of radiographic progression in real life routine RA patients in the 21 st century. Methods RA patients of our outpatient clinic, who had two x-rays performed over a three to five year interval between the years 2000 and 2012 were included. X-rays of the hands and feet were scored according to the Sharp van der Heijde (SvdH; range 0-448) method. 2 Clinical and demographic data were collected from the patients’ charts. Disease activity was assessed using the clinical disease activity index (CDAI-average over time). Patients were separated into three periods of time (2000-2004, 2005-2008, 2009-2012) and the annual radiographic progression was calculated based on the observed progression in these periods. The mean number of joints with radiographic progression per patient, as well as the mean grade of progression per joint (erosion/joint space narrowing, JSN) were evaluated. Lack of progression was defined as no progression in total SvdH. Results Of the 444 patients included (mean duration of RA 7.4±9.4 years, 56.2% rheumatoid factor positive, 62.0% ACPA positive), 406 (91.4%) showed radiographic progression over a mean of 3.8±0.6 years. In all progressors we found no difference in rates of total radiographic progression, erosion score, or JSN, the three different time periods (Table 1). Conclusions Only a minority of patients did not progress structurally over three to five years. The temporal trend analysis indicates that on the background of similar average disease activity and mixed treatment, the overall annual progression was constant during the last decade. However, in general progression of joint damage was low. References Rahman MU et al. Ann Rheum Dis 2011; 70(9):1631-1640. van der Heijde D. J Rheumatol 1999; 26(3):743-745. Disclosure of Interest None Declared