S. Verstappen

American College of Rheumatology/European League Against Rheumatism Provisional Definition of Remission in Rheumatoid Arthritis for Clinical Trials

OBJECTIVE Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patients RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3. CONCLUSION We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials

Objective Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. Methods A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. Results Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0–10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score–based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patients RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0–10 scale) are all ≤1, or (2) when the score on the Simplified Disease Activity Index is ≤3.3. Conclusion We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. The authors recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

External Beam Radiotherapy With Endocavitary Boost for Nasopharyngeal Cancer: Treatment Results and Late Toxicity After Extended Follow-Up

PURPOSE To evaluate the long-term outcome after treatment of nasopharyngeal carcinoma and assess late toxicity in a multidisciplinary clinic. METHODS AND MATERIALS A retrospective analysis of 117 patients treated for nasopharyngeal cancer in a single institute between 1985 and 2002 was performed. Fifty-one long-term survivors were evaluated for late toxicity by a multidisciplinary team comprising a radiation oncologist, otolaryngologist, neurologist, and oral and maxillofacial surgeon. RESULTS The 5-year local control rate for T1 to T2 and T3 to T4 tumors was 97% and 76%, respectively. Five-year disease-free survival and overall survival were 82% and 88% for Stage I to IIb disease and 46% and 52% for Stage III to IVb, respectively. Late morbidity evaluation revealed Radiation Therapy Oncology Group (RTOG) Grade III to IV toxicity in 71% of patients. A high incidence of cranial nerve palsies (47%) and mandibular osteolysis (82%) was found, although these complications had limited clinical impact. CONCLUSIONS The multidisciplinary late morbidity clinic revealed an unexpected high incidence of cranial nerve palsies and mandibular osteolysis and overall an RTOG Grade III to IV toxicity in 71% of patients treated for nasopharyngeal cancer. External beam radiotherapy with endocavitary brachytherapy produces excellent rates of local control for T1 to T2 tumors, but the high incidence of late toxicity suggests an overtreatment.

SAT0113 Common trajectories of HAQ disability progression over 15-years in the early rheumatoid arthritis study and the norfolk arthritis register

Background The Health Assessment Questionnaire (HAQ) is the most widely used measure of function in studies of inflammatory polyarthritis (IP) and its subset rheumatoid arthritis (RA). Previous research has suggested the mean HAQ over time is j-shaped with an initial improvement followed by an insidious decline. Few studies have attempted to identify distinct subgroups with common HAQ trajectories in IP and RA samples, or considered their validity across cohorts. Objectives To identify common trajectories of HAQ progression in two large prospective observational studies. Methods Data of two large inception cohorts, the Early Rheumatoid Arthritis Study (ERAS) and the Norfolk Arthritis Register (NOAR), were used. ERAS recruited patients with RA from 9 hospital clinics in England between 1986 and 1997: N=1460, mean age 55yrs, 66% female, mean symptom duration 8mths. NOAR is a primary care based inception cohort of early IP in Norwich, England. Patients recruited between 1990 and 1994 were included: N=1027, mean age 53yrs, 66% female, mean symptom duration 9mths. In both cohorts, disease activity and HAQ-scores are measured at baseline and at subsequent follow-up visits. To determine trajectories of HAQ progression over time, latent class growth models (LCGM) were applied to the datasets separately. Age, sex, baseline DAS, symptom duration, rheumatoid factor, and fulfillment of ACR criteria were included as predictors of class membership. Results In both cohorts a 4 class LCGM was selected as providing the best fit. The classes identified were similar in terms of the shape of the trajectories and distribution of patients between classes (see figure). Three classes exhibited a j-shaped trajectory. A fourth class experienced persistently high HAQ that increased early in the course of the disease. In both cohorts older age, female sex, longer symptom duration, fulfillment of ACR criteria and higher DAS were associated with increased likelihood of membership of classes with worse HAQ progression. Conclusions Four subgroups with common HAQ trajectories were derived from the ERAS and NOAR cohorts. That the subgroups identified were nearly identical supports their validity. Identifying distinct groups of patients at risk of poor functional outcome may help to target therapy to those most likely to benefit. Disclosure of Interest None Declared

FRI0041 The Prediction of Nonadherence to Methotrexate at Six Months in a Rheumatoid Arthritis Population

Background Unfortunately, response to Methotrexate (MTX) is not universal and nonadherence may partially explain poor response, therefore identification of patients who are likely to be nonadherent prior to MTX commencement would present an early opportunity to intervene and optimise treatment response. Objectives 1)To evaluate adherence to MTX over the first six months 2)To identify potential predictors of nonadherence. Methods Patients were recruited to the Rheumatoid Arthritis Medication Study (RAMS). This is a UK multicentre prospective cohort of incident MTX users with a diagnosis of RA. At baseline, clinical history, disease activity scores (DAS28), disease duration, Health Assessment Questionnaire (HAQ), visual analogue scales (VAS) general well-being, pain and fatigue, demographic, alcohol and smoking data are collected. Patients completed The Beliefs about Medicines Questionnaire (BMQ), Brief Illness Perceptions Questionnaire (BIPQ), Hospital Anxiety and Depression Scale (HADS). Adherence was measured during the first 6 months after MTX commencement using a patient completed weekly MTX diary, including missed doses and reasons. Proportional adherence was calculated as the percentage of weeks patients took MTX as directed. Nonadherence was defined as ≥1 dose missed against medical advice. Baseline variables with a near significant association with adherence in univariate logistic regression analysis (defined as p<0.2) were entered into a backwards stepwise logistic regression to identify independent factors associated with nonadherence. Results Of the total 1014 eligible patients recruited between 31/08/08 and 01/09/14, 661 (65%) returned a 6-month diary. Comparison of baseline characteristics showed diary returners were younger, less deprived, and had lower disease activity than those who did not return a diary. Patients included in this study were on average 60.2 (13.0) yrs old, had a median DAS28 score of 4.4 [3.4-5.3] and 68% were female. Overall 156/594 (26.2%) reported nonadherence (≥1 nonadherent week), although proportional mean adherence was high (97%). Of the 438 who were adherent 17% were medically advised to miss ≥1 dose. Reasons for nonadherence (%nonadherent patients) included; feeling unwell (38%), side effects (33%), no reason (18%), forgot (14%), drug holiday (11%), changed dose (7%), ran out (6%), delayed commencement (5%) & lack of effect (1.5%). Higher tender joint count (OR 1.032 95%CI:1.007-1.056), fatigue (OR 1.097 95%CI 1.026-1.172), higher concerns (OR 1.133 95%CI:1.037-1.238) and emotional distress (OR 1.069 95%CI:1.002-1.140) attributed to RA and lower mood at baseline predicted nonadherence at six months. 12 baseline variables were entered into multivariate analysis (Table 1), and a higher fatigue score (OR 1.071 95%CI:0.996-1.151) and higher concerns attributed to RA (OR 1.113 95%CI:1.013-1.223) associated with nonadherence (ROC analysis AUC=0.6027). Conclusions Initial adherence to MTX amongst diary returners was high, higher than previously reported. Further exploration of the way higher RA concern, a modifiable component of the self regulation model of illness, is influencing patient nonadherence may provide insight into early interventions to optimise patient adherence. Disclosure of Interest None declared

OP0126 Early and sustained remission is associated with improved survival in patients with inflammatory polyarthritis: Results from the norfolk arthritis register

Background Remission has become an achievable goal when treating patients with inflammatory polyarthritis (IP) and its subset rheumatoid arthritis. Previous studies suggest that early and sustained remission prevents long-term disability in patients with IP. Whether the achievement of the status of remission may also affect survival needs to be investigated. Objectives To estimate the relationship between clinical remission and overall survival in an inception cohort of patients with IP. Methods Consecutive patients with early IP from a primary-care based inception cohort, recruited between 1990 and 1994 (first cohort) and between 2000 and 2004 (second cohort), were eligible for this study. Patients were assessed yearly after inclusion by a research nurse and flagged with the national UK death register. Baseline assessment included a 51 tender and swollen joint count (JC), the HAQ-score; blood was collected to determine CRP, RF and ACPA. The 51- tender and swollen JC were also assessed at 1, 2 and 3 yr after registration. Remission was defined as the absence of clinically detectable joint inflammation (swollen 51-JC=0 and tender 51-JC=0). Only patients with at least 3 years of follow-up were included in the present study. Different variables for remission were evaluated: ever remission, number of assessments in remission and time of first remission within the first 3 years. All-cause death was the main outcome of this study. Censoring was set at 1st May 2011. The relationship between remission and mortality was analysed using the Cox proportional hazard regression model (start-date of survival was set at 3 yrs after inclusion). Multivariate analyses were applied to adjust for pre-specified relevant predictors, including demographics, cohort, baseline disease activity and severity, and cumulative treatment variables. Multiple imputation of predictors was used to optimize available information. The results are shown as hazard ratios (HR) and 95%CI. Results A total of 2,769 patients were eligible for the analyses, 1,604 from the first and 1,165 from the second cohort, with a median follow-up of 105 months. 578 subjects died during the observation time. 962/2,589 (37.2%) fulfilled the predefined 51-JC remission criteria at least once within the first 3 yrs. Having been in remission at least once within the first 3 years of follow-up was associated with a significant better survival: crude HR [95%CI] 0.81 [0.67, 0.96] and adjusted HR [95%CI] 0.80 [0.66, 0.96]. The number of times in remission was also associated with a significantly decreased risk of all-cause mortality: per each additional time spent in remission crude HR [95%CI] was 0.90 [0.82, 0.99] and adjusted HR [95%CI] was 0.90 [0.81, 0.99]. Looking at the effect of time lag until the first remission, those patients who were in remission 1 year after the first assessment had the greatest reduction in mortality risk compared to patients who never achieved remission within the first 3 years (adjusted HR 0.61 [0.43, 0.87]), while no significant association was found for patients who achieved remission at a later time point, i.e. at second (adjusted HR [95%CI] 0.80 [0.60, 1.07]) and third year (HR [95%CI] 0.97 [0.72, 1.32]). Conclusions Early remission and sustained remission are associated with a decreased all-cause mortality in patients with IP. Disclosure of Interest None Declared

THU0667 Disease, work and personal related factors associated with presenteeism in patients with rheumatoid arthritis: results from the national rheumatoid arthritis society survey (NRAS)

Background At-work productivity loss (i.e. presenteeism) is a major problem for patients with rheumatoid arthritis (RA) and employers and could be a marker of long-term absenteeism. To develop interventions to prevent presenteeism, a better understanding of which factors are associated with presenteeism is needed. Objectives To assess the association between disease and work related factors with presenteeism. Methods A large survey about employment amongst patients with RA was conducted in the UK using an online platform and inviting NRAS members and non-members to participate. Patients completed the multi-item Workplace Activity Limitation Scale (WALS; range 0–36 worst score), a measure of presenteeism. Other job related questions included: occupation (NS-SEC coding), job demand questions, help from colleagues (categorised into: always/often, sometimes, rarely/never) and a patient acceptable state questionnaire about work (PASS). Patients also completed the disease specific RAID questionnaire (score 0–10=worst score). Univariable and multivariable linear regression analyses were performed to assess the association between the disease and job related factors and presenteeism, adjusting for age and gender. Results 891 respondents were in paid work at the time of the survey (51.5% working for others, 33.1% self-employed and 15.4% on temporary sick leave). The majority of participants were women (91.5%) and 4.9% were aged 16–30, 69.2% 31–54% and 25.8% aged 55–74 years. Over half (51.5%) had a higher managerial, administrative or professional occupations, 33.1% an intermediate occupation, and 15.4% a routine/manual occupation. Mean (SD) RAID score was 5.2 (2.2). 58.2% rated their current job performance somewhat/much worse than before the onset of their arthritis. In univariable regression analyses greater disease activity, less control, lower support from colleagues and being in a unacceptable disease state (PASS) were associated with higher levels of presenteeism. In multivariable analysis, disease activity, ability to influence work and a unacceptable disease state remained statistically significantly associated with presenteeism.Abstract THU0667 – Table 1 Conclusions In this large national survey in patients with RA we found that not only disease activity, but also having control, especially the flexibility to influence work and take breaks when needed, were associated with levels of presenteeism. Preventing presenteeism should therefore be aimed at managing the disease, but also toward adapting work circumstances and finding the right balance between work requirements and personal needs. Disclosure of Interest None declared

SAT0110 Trajectories of functional disability in patients with early inflammatory polyarthritis and moderate disease activity: results from the early rheumatoid arthritis network and norfolk arthritis register

Background A large group of patients with inflammatory polyarthritis (IP), and its subset rheumatoid arthritis (RA), have moderate disease activity, despite disease modifying therapy. Identifying patients with moderate disease who are likely to have subsequent high disability may prompt different treatment strategies for these patients. Objectives To identify common trajectories of disability progression in patients with moderate disease in two large prospective observational studies. Methods The Early Rheumatoid Arthritis Network (ERAN) recruited 1236 patients with RA (<36 months symptoms) from 23 centres in England from 2002-11. The Norfolk Arthritis Register (NOAR) recruited 1054 IP patients (<24 months symptoms) from Norfolk, England, from 2000-8. At baseline and subsequent follow-ups, functional disability was assessed using the Health Assessment Questionnaire (HAQ). Included patients scored ≥3.2 and <5.1 on the Disease Activity Score (DAS28) at either baseline, year 1 or year 2, and had previously received csDMARDS (NERAN=605; NNOAR=407). Latent class growth models (LCGMs) were used to identify HAQ trajectories independently in each cohort. Age, sex, fulfilment of ACR RA criteria, symptom duration, DMARDs at baseline, and baseline DAS28 were included as predictors of trajectory group membership using multinomial logistic regression. Results Baseline characteristics of the cohorts were similar (ERAN vs NOAR: mean age = 57 vs 56 years; female = 70% vs 69%; met ACR criteria = 88% vs 77%; mean DAS28 = 4.7 vs 4.2). For both cohorts, LCGM analysis indicated 4 subgroups provided best fit (Bayesian Information Criterion), with similar shaped trajectories (figure 1). Multinomial logistic regression indicated that older age (ERAN & NOAR, p<0.005), female gender (ERAN & NOAR, p<0.01), meeting ACR criteria (NOAR only, p<0.05), use of DMARD (ERAN & NOAR, p<0.01), and baseline DAS28 (ERAN & NOAR, p<0.005) were related to an increased likelihood of being in a subgroup with higher disability (vs. lowest disability subgroup). Conclusions Four disability trajectories were observed in both the ERAN and NOAR cohort of patients with moderate disease activity. Patients on a worse trajectory who may benefit from more intensive treatment could potentially be identified earlier in the disease the group of patients with moderate disease activity. Reference: [1] This research was funded by Arthritis Research UK. Disclosure of Interest: None declared

THU0078 Moderate Alcohol Consumption Is Not Associated with Serum Liver Abnormalities in Patients with Rheumatoid Arthritis Taking Methotrexate: Data from The Clinical Practice Research Database (CPRD)

Background Methotrexate (MTX) is the most commonly prescribed disease modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Patients taking MTX are advised to restrict their alcohol consumption because of a theoretical hepatotoxic interaction between alcohol and MTX. However data are limited to support this advice. Objectives To quantify the association between alcohol consumption and abnormal serum liver function tests (LFTs) in patients with RA taking MTX, using routinely collected clinical data. Methods Patients with RA in the Clinical Practice Research Database (CPRD) starting MTX between 1987 and 2011 were studied. Patients were included if they had alcohol consumption details recorded in CPRD and ≥6 LFTs per year, indicating adequate monitoring. Patients were grouped by reported weekly alcohol consumption. Crude rates of abnormal LFTs (defined as alanine transaminase or aspartate aminotransferase level ≥3 times the upper limit of normal) per 1000 person-years follow up were calculated. Cox proportional hazards models described the association between alcohol consumed and development of abnormal LFTs whilst taking MTX univariately, then adjusting for age and gender. Patients were censored at time of first abnormal LFT, death or the end of follow up (31/12/2011). Results 8801 patients were included in the study, 6285 (71%) female, mean age (SD) was 58 (14) years. There were 241 abnormal LFTs in 38000 person-years follow up. There was no difference in rates of abnormal LFTs between drinkers and non-drinkers, adjusted hazard ratio (HR) (95% confidence interval (CI)) 1.12 (0.82–1.51). Crude rates of abnormal LFTs appeared to increase with increasing levels alcohol consumption (table 1); similarly when treated as a continuous variable, each increased unit of alcohol consumed was associated with a higher risk of abnormal LFTs, adjusted HR (95%CI) 1.01 (1.00–1.02). In the adjusted Cox model, moderate alcohol consumption (≤14 units per week) was not associated with a statistically significant risk of developing abnormal LFTs (table 1). There was a non-significant trend to higher HR with higher levels of alcohol consumption, however power was limited in the patients consuming >14 units per week. Units of alcohol per week Number of events§† Crude rate (95% CI) Hazard ratio (95% CI) Hazard ratio (95% CI) Per 1000 person years Univariate Age & gender adjusted 0 24 5.58 (3.74–8.33) ref ref 1–7 83 5.57 (4.49–6.91) 1.01 (064–1.58) 1.02 (0.65–1.60) 8–14 23 5.99 (3.98–9.01) 1.07 (0.60–1.89) 1.15 (0.65–2.06) 15–21 11 7.58 (4.20–13.68) 1.36 (0.67–2.78) 1.59 (0.76–3.30) 21–28 3 8.61 (2.78–26.70) 1.51 (0.46–5.03) 1.91 (0.56–6.47) >28 6 9.05 (4.07–20.15) 1.60 (0.66–3.92) 1.92 (0.76–4.89) §Event=abnormal LFT. †Not all patients who were defined as drinkers/non-drinkers had alcohol consumption defined in units. Conclusions In patients with RA taking MTX, increasing alcohol consumption is associated with an increased risk of developing abnormal LFTs. The clinical importance of this increased risk may be small when drinking ≤14 units per week. Disclosure of Interest None declared

SAT0009 Investigation of Differential Methylation as A Potential Biomarker of Methotrexate Response in Patients with Rheumatoid Arthritis

Background Methotrexate (MTX) is the first-line disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). By two years of treatment only 55% of patients remain on the drug, implying that many do not respond adequately or experience adverse effects (1,2). Therefore, identifying blood-based biomarkers that predict treatment response is an important research priority. DNA methylation is an epigenetic marker that modifies but does not alter DNA sequence, and should be considered for evaluation as potential biomarkers for treatment response. The mechanisms of action of MTX are unclear. However, it is thought that MTX promotes adenosine release and interferes with the intracellular methyl donor status leading to DNA hypomethylation (3). Objectives To identify differential DNA methylation signatures in whole blood, which may act as biomarkers predictive of response to MTX in patients with RA. Methods Epigenome-wide DNA methylation levels were measured using the HumanMethylation450 BeadChip (Illumina) in whole blood-derived DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study (RAMS), a one year observational study including patients with RA starting MTX for the first time, who had EULAR good response (n=36) or EULAR poor response (n=36) to MTX. DNA was taken from blood samples pre-treatment and following four weeks on therapy. Response was determined at six months using the DAS28 score. Differentially methylated positions (DMPs) were identified using linear regression, adjusting for gender, age, cell composition, and baseline DAS28 score. Results Although no probe reached study-wide significance, 16 DMPs suggestive loci were associated with MTX response in the pre-treatment samples (arbitrary p<10–4), including a DMP close to the IL6R gene (cg15633035, p=5.24x10–5). At four weeks, 20 DMPs were associated with response, with no overlap with the DMPs reported in the pre-treatment sample. In good responders, 10 DMPs were differentially methylated between pre-treatment and four week samples. In poor responders, 17 DMPs were differentially methylated between time-points. There was no overlap of DMPs between good and poor responders Conclusions These preliminary results suggest DNA methylation may provide a useful source of biomarkers of MTX response and now require replication in an independent dataset. Furthermore, investigation of differential methylation between baseline and four weeks reveals the potential of DNA methylation in pharmacodynamic modelling of MTX response. Further analysis is being conducted and significant findings will be validated in the total RAMS population using pyrosequencing. References Barrera P et al, Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis. Rheumatology. 2002 Apr;41(4):430–9 Verstappen SMM, et al, Prediction of response and adverse events to methotrexate treatment in patients with rheumatoid arthritis. Int. J. Clin. Rheu. 2012;7(5):559–567 Kim Y, et al, DNA hypomethylation in inflammatory arthritis: reversal with methotrexate. J. Lab. Clin. Med. 1996;128:165–172 Disclosure of Interest None declared