C. Gaujoux-Viala

Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts

Background A prolonged symptom or disease duration at treatment initiation is associated with unfavourable outcomes in rheumatoid arthritis (RA). It is unknown whether this relation is linear, referring to a common ‘the-earlier-the-better principle’, or whether a transient time frame in which the disease is more susceptible to treatment exists, referring to a ‘window of opportunity’. To elucidate this, we evaluated the shape of the associations of symptom duration with persistence of RA. Methods Patients with 1987 RA treated with disease modifying antirheumatic drugs (DMARDs) in the Leiden Early Arthritis Clinic (EAC, n=738) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n=533) were studied. Cox proportional hazards regression models using natural cubic splines were performed; the log-HR on DMARD-free sustained remission (the opposite of RA persistence) during 5-year follow-up was plotted against symptom duration. Discrimination was measured using time-dependent receiver operator characteristic curves. Subanalyses were performed stratified for the DMARDs used (methotrexate or other conventional DMARDs) and for anticitrullinated peptide antibody (ACPA). Results 11.5% (85/738) and 5.4% (29/533) of EAC and ESPOIR RA patients achieved DMARD-free sustained remission. In both cohorts and all analyses, the curves depicting the log-HRs on remission in relation to symptom duration were not linear. The symptom duration with optimal discriminative ability was 14.9 weeks (95% CI 12.3 to 16.0; area under the curve (AUC) 0.61) in the EAC and 19.1 weeks (95% CI 12.3 to 28.0; AUC 0.59) in ESPOIR. For ACPA-positive RA, this was 11.4 weeks (95% CI 7.7 to 79.0; AUC 0.56) and for ACPA-negative RA 15.0 weeks (95% CI 9.7 to 48.7; AUC 0.56). Conclusions The association between symptom duration and RA persistence is not linear, suggesting the presence of a confined period in which RA is more susceptible to treatment.

The effect on treatment response of fibromyalgic symptoms in early rheumatoid arthritis patients: results from the ESPOIR cohort

OBJECTIVE To evaluate whether patients with RA who belong to the spectrum of fibromyalgic RA (FRA) have an impaired response to treatment measured by traditional activity scores. METHODS Patients from the ESPOIR cohort were analysed. This prospective cohort included 813 patients with early arthritis not initially receiving DMARDs. Among the 697 patients who met RA classification criteria, we studied two groups, one with and the other without FRA. The following endpoints were compared at 6, 12 and 18 months using a mixed linear regression model: 28-joint DAS (DAS28), Simple Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and HAQ. In addition, attainment of low disease activity (LDA; DAS28 <3.2) and remission (DAS28 <2.6, SDAI <3.3, CDAI <2.8) at these time points was analysed. RESULTS Patients with FRA (n = 120) had higher DAS28, SDAI, CDAI and HAQ scores than patients with RA and no fibromyalgic characteristics (n = 548). DAS28 and other DASs started out higher in subjects with FRA, and while they improved to a similar extent to in the isolated RA group, they remained consistently higher among FRA patients. Achievement of LDA and remission was significantly less likely in subjects with FRA. CONCLUSION Patients with FRA and RA will have a similar response to treatment according to the decrease in indexes of disease activity, but may miss the target of remission or LDA.

Osteomyelitis in adults: an underrecognized clinical entity in immunocompetent hosts. A report of six cases.

OBJECTIVE Osteomyelitis is rare in adults and typically occurs in patients with risk factors such as sickle cell disease or immune deficiency. Cases in immunocompetent adults without sickle cell disease are extremely rare. The objective of this work was to describe the epidemiological, clinical, laboratory, and radiological features and the management of long-bone osteomyelitis in immunocompetent adults without sickle cell disease. METHODS We conducted a retrospective descriptive study of all immunocompetent adults without sickle cell disease who were admitted to our center between November 2002 and November 2008 for long-bone osteomyelitis. In all patients, the clinical symptoms started in adulthood, in the absence of a childhood history of osteomyelitis. RESULTS We identified six patients meeting our inclusion criteria over the 6-year study period. The causative microorganism was methicillin-susceptible Staphylococcus aureus in four patients and Salmonella in two patients (wild-type S. typhi and S. enterica, respectively). In each patient, there was a single focus of osteomyelitis and a single causative microorganism. The symptoms developed insidiously and lacked specificity. At presentation, the patients had moderate pain with or without a swelling. There was no fever initially in five patients, three of whom had major diagnostic delays as a result. Treatment associated antibiotics and surgery in all patients and the initial outcome was consistently favorable (median follow-up: 15 months; range: 8-72). CONCLUSION Osteomyelitis can occur even in immunocompetent adults. The protracted course and atypical presentation of osteomyelitis in immunocompetent adults may lead to major diagnostic delays.

Efficacy and safety of biological DMARDs modulating B cells in primary Sjögren's syndrome: Systematic review and meta-analysis

OBJECTIVE In this review, we summarise the clinical efficacy and safety of B-cell targeted therapies for primary Sjögrens syndrome (pSS). METHODS A systematic literature review was conducted using databases including MEDLINE, EMBASE and Cochrane. Only articles reporting controlled or prospective studies of b-DMARDs modulating B cells in treatment of pSS were selected. The highest-quality studies were selected for meta-analysis. The primary outcome of interest was clinical efficacy at week 24 on fatigue, dryness, Schirmer test, salivary flow rate and the full ESSDAI score including biological domain. For the efficacy criteria used, the difference between rituximab and placebo groups was expressed as mean difference (MD). RESULTS Eighteen articles (13 of rituximab, 3 of belimumab, 1 of epratuzumab and 1 of baminercept) were identified for detailed evaluation. 4 controlled randomised trials of rituximab treatment vs. placebo involving 300 patients were included for quantitative analysis. No significant differences were observed between groups in the meta-analysis of mean improvements between baseline and week 24 in fatigue VAS [MD -3,24 95% CI (-30,21 to 23,72)], oral dryness VAS [MD -8,41 95% CI (-35,06 to 18,24)], salivary flow rate [MD 0,04 95% CI (-0,03 to 0,11)] and Schirmer test [MD 0,35 95% CI (-2,13 to 2,82)]. Rituximab was relatively safe compared to placebo. CONCLUSION Our review shows that rituximab is not effective in pSS with the designs and outcomes proposed in the trials. Controlled randomised trials are needed to prove the efficacy of belimumab and epratuzumab in this indication. The randomised controlled trial evaluating baminercept failed to achieve its primary endpoint.

The 2010 ACR/EULAR criteria are not sufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: Results from the Leiden-EAC and ESPOIR cohorts

OBJECTIVES The 2010 ACR/EULAR criteria were derived to classify rheumatoid arthritis (RA) earlier in time. Previous studies indeed observed that the 2010 criteria were fulfilled earlier than the 1987 criteria. This study determined whether the 2010 criteria perform equally in early classification of autoantibody-positive and autoantibody-negative RA. METHODS From the total Leiden-EAC (n = 3448) and ESPOIR (n = 813) RA patients who fulfilled the 1987 RA criteria at 1 year but not at presentation were selected (n = 463 and n = 53, respectively), as these patients were classified with delay with the 1987 criteria. These RA patients were studied on fulfilling the 2010 criteria at baseline (as 2010 positivity indicated that these RA patients were earlier identified) and these analyses were stratified for patients with and without anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Analyses were repeated for DMARD start within the first year as reference for RA (instead of fulfilling the 1987 criteria). RESULTS In the EAC, 75% of the selected RA patients did already fulfill the 2010 criteria at baseline. In ESPOIR this was 57%, indeed demonstrating early classification with the 2010 criteria. Among the selected autoantibody-positive RA patients of the EAC, 93% was already identified at baseline with the 2010 criteria. Within autoantibody-negative RA this was 51% (p < 0.001), indicating that 49% of autoantibody-negative RA patients were not early classified with the 2010 criteria. Similarly, within autoantibody-positive RA patients in ESPOIR 92% were 2010 positive at baseline, whereas this was only 25% within autoantibody-negative RA (p < 0.001), indicating that 75% of autoantibody-negative RA patients were not early classified with the 2010 criteria. Similar results were obtained when DMARD start was the reference for RA. CONCLUSIONS The 2010 criteria perform well in the early identification of autoantibody-positive RA, but autoantibody-negative RA patients are still frequently missed with these criteria. This implies that other diagnostics are required for ACPA-negative patients.

THU0432 Impact of Comorbidities on Measuring Indirect Utility by the SF-6D or the EQ-5D in Rheumatoid Arthritis: an Analysis of 962 Patients Enrolled in Comedra

Background Many patients with rheumatoid arthritis (RA) have several chronic co-occuring disorders (comorbidities). There is an inverse relationship between comorbidy and health-related quality of life (HRQoL). Because indirect utility measurement involves HRQoL, comorbidities probably affect utility assessment. Objectives We investigated the impact of comorbidities on the measure of utility with 2 indirect utility measures widely used to calculate quality-adjusted life-years (QALYs), SF-6D and EQ-5D, in patients with rheumatoid arthritis (RA). Methods 962 patients of COMEDRA, a French multicentric clinical trial involving patients with stable RA, were included in the study. Comorbidities assessed were chronic obstructive pulmonary disease, diabetes, hypertension, obesity, cardio-vascular diseases, stroke, hypercholesterolemia, renal insufficiency and osteoporosis. Bio-clinical variables were also recorded (activity by DAS28, function by HAQ score, Rheumatoid Arthritis Impact of Disease score ...). Two separate linear regression models, using the number of comorbidities and the different categories of comorbidities, were fitted to determine predictors of utility scores. Results For the 962 patients included (mean age ± SD =57.7±11.1 years, 79% women), the mean SF-6D utility score was 0.67±0.12 (range: 0.357, 1), and the mean EQ-5D utility score was 0.64±0.27 (range: -0.416, 1). The mean number of comorbidities was 1.02±0.95 and 40.6% of patients have 1 comorbidity, 19.3%, 2 comorbidities and 7%, ≥3 comorbidities. In the first multivariate model, for each additional comorbidity (range 0–5) the mean SF-6D utility score decreased of 0.007 point (p<0.0001) and the mean EQ-5D utility score decreased of 0.028 point (p<0.0001). In the second model, including comorbidities by categories, no comorbidity predicted significantly low utility score. In both regression models a worsened function (increased HAQ score) significantly decreased the EQ-5D utility score and a worsened mental state (increased mental component of RAID score) significantly decreased the SF-6D utility score. The number of comorbidities explained <1% of the variance in utility scores (partial R-square=0.0097 for EQ-5D and 0.003 for SF-6D), whereas the HAQ score explained 51.2% of the variance in EQ-5D utility score in both models and the mental state explained 38,2% of the variance in SF-6D utility score. Conclusions Compared to greater negative effect of functional impairment for EQ-5D and mental state for SF-6D, the number of comorbidities has a negative but relatively marginal impact on indirect utility scores in RA. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5794

FRI0131 The 2010 acr/eular criteria are insufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: results from the leiden-eac and espoir cohorts

Background The 2010-ACR/EULAR criteria were derived to classify RA earlier in time. Previous studies indeed observed that the 2010-criteria were fulfilled earlier than the 1987-criteria. This study determined whether the 2010-criteria perform equally in the early detection of autoantibody-positive and autoantibody-negative RA. Objectives To compare the performance of the 2010-criteria between autoantibody-positive and autoantibody-negative RA within two different early arthritis cohorts. Methods From the total Leiden-EAC (n=3448) and ESPOIR (n=813) RA-patients who fulfilled the 1987-RA criteria at 1-year but not at presentation were selected (n=515 and n=53, respectively). These RA-patients were studied on the presence of ACPA and RF, and on fulfilling the 2010-criteria at baseline, as 2010-positivity indicated that these RA-patients were earlier identified. Results In the EAC, 67% of the selected RA-patients did already fulfil the 2010-criteria at baseline. In ESPOIR this was 57%, indeed demonstrating early classification with the 2010-criteria. Among the selected autoantibody-positive RA-patients of the EAC, 85% was identified at baseline already with the 2010-criteria. Within autoantibody-negative RA this was 45% (p<0.001). Similarly within autoantibody-positive RA-patients in ESPOIR 92% was 2010-positive at baseline, whereas this was only 25% within autoantibody-negative RA (p<0.001). Conclusions The 2010-criteria perform well in the early identification of autoantibody-positive RA, but autoantibody-negative RA-patients are still frequently missed with these criteria. As it has been demonstrated that early treatment initiation is beneficial for the outcome of ACPA-negative RA as well, other diagnostics are required for the early identification of ACPA-negative RA. Disclosure of Interest None declared

FRI0561 Safety of denosumab in post-menopausal osteoporosis and in cancer: a systematic review and meta-analysis

Background Denosumab is a RANK ligand antibody (1) used for the treatment of post-menopausal osteoporosis (OP) and prevention of bone metastases complications (2,3). Objectives The aim of this meta-analysis was to assess the safety of Denosumab. Methods Data sources included MEDLINE, EMBASE, Cochrane Library, and recent abstracts from ACR and EULAR congresses were searched until March 2016. Randomized controlled trials comparing the safety of Denosumab to placebo or bisphosphonates (BP) in postmenopausal OP and in cancer (either cancer with bone metastases or with hormone therapy) were selected. Data were extracted by one investigator, confirmed by another, and pooled in meta-analysis using Review Manager software (Cochrane collaboration). Results 6136 articles were of potential interest, and 19 met the inclusion criteria. 7 articles compared the safety of Denosumab to BP in post-menopausal OP. There was no significant difference when comparing Denosumab with bisphosphonates in any adverse events (AAE) (RR=0.98, 95% CI=0.95–1.01) serious adverse event (SAE) (RR=1.04, 95% CI=0.81–1.33). Regarding Denosumab versus placebo in post-menopausal OP, 7 studies were included and there was no significant difference in AAE (RR=0.98, 95% CI=0.94–1.01), SAE (RR=1.03, 95% CI=0.96–1.11), however cellulitis was more frequently found with Denosumab (RR=8.03, 95% CI=1.44–44.79). No cases of osteonecrosis of the jaw (ONJ) had been reported. 5 articles were pooled to compare Denosumab with BP in patients with bone metastases and no significant difference was found in AAE (RR=0.99, 95% CI=0.98–1.00), SAE (RR=0.99, 95% CI=0.95–1.03), and ONJ (RR=1.40, 95% CI=0.92–2.13). 4 articles were selected concerning patients treated with placebo or Denosumab in breast and prostate cancer without bone metastases. Although no significant difference was found in AAE (RR 1.01, 95% CI=0.99–1.03), use of Denosumab was associated with a significantly increased risk of hypocalcemia (RR 5.20, 95% CI=1.34–20.13) and of cholecystitis (RR 3.43, 95% CI=1.01–11.69). Conclusions In post-menopausal OP, Denosumab had a relatively good safety profile although significantly more cellulitis occurred when compared with placebo. For patient with cancer, Denosumab was associated with more hypocalcemia and cholecystitis than placebo. References Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res Off J Am Soc Bone Miner Res. 2009;24(1):153–61. Lipton A, Fizazi K, Stopeck AT, Henry DH, Smith MR, Shore N, et al. Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur J Cancer Oxf Engl 1990. 2016;53:75–83. Disclosure of Interest None declared

FRI0355 Development of a Patient Version of the Recommendations of the French Society of Rheumatology for Managing Rheumatoid Arthritis

Background The French Society of Rheumatology developed recently recommendations for the management of rheumatoid arthritis (RA) for a target population of health professionals [1]. Points emphasized in the 3 overarching principles and the 15 recommendations include shared decision making, treatment targets, tight control, first and second line disease-modifying drugs, biologics, glucocorticoids and dealing with remission. Patients are naturally very much impacted by management recommendations, in the context of shared decision-making. Objectives To extend the cooperation between rheumatologists and patients, by translating the recommendations into a language that can be easily understood by patients. Methods At the instigation of a patient association, 3 French patients with RA, 3 physicians who had initially developed the recommendations and one patient association representative attended a one-day meeting in September 2014. As a starting point the original recommendations were used [1]. A standardised approach to rephrase the recommendations was presented [2]. After intensive discussions the wording of each recommendation was adjusted, while maintaining the meaning. From October to December 2014, further refining of the wording was conducted by email exchange within the working group and each person was asked to indicate their level of agreement with the content of the recommendations (0-10 with 10 indicating full agreement). In January 2015, a survey was sent out to assess agreement and applicability of the recommendations in a wider group of patients and patient associations. Results The 3 overarching principles and the 15 recommendations were successfully translated into a patient-understandable version. The original text was changed in most cases. Among the patient partners, there was very high agreement with the proposed wordings (mean, 9.8±0.3). Assessment of agreement in a wider group is ongoing; preliminary results indicate high agreement; with the lowest agreement being with the recommendation stating “biologics should be given preferably with methotrexate as comedication”. Conclusions The French recommendations were successfully converted into a patient-understandable language version by a group of patients in collaboration with rheumatologists. This should improve the shared decision process in the management of RA. This project will also allow further dissemination and evaluation of the recommendations in France. References Gaujoux-Viala C, Gossec L et al. Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis. Joint Bone Spine. 2014;81(4):287-97. de Wit MP,et al. Treating rheumatoid arthritis to target: the patient version of the international recommendations. Ann Rheum Dis. 2011;70(6):891-5. Disclosure of Interest L. Gossec Consultant for: Abbvie, Celgene, Centocor, Chugai, Janssen, MSD, Novartis, Pfizer, Roche, UCB, C. Gaujoux-Viala: None declared, R. Guastalli: None declared, K. Ouladchrif: None declared, J. Janicki: None declared, B. Combe Consultant for: Abbvie, BMS, Celgene, Chugai, Janssen, MSD, Novartis, Pfizer, Roche, UCB, S. Tropé: None declared

THU0451 The Formulation of the Patient Global Assessment Question Influences the Classification of Patients with Rheumatoid Arthritis (RA) into Acr/Eular Remission: an Analysis of Patients Enrolled in ESPOIR and Comedra

Background The recently developed ACR/EULAR Boolean remission criteria for rheumatoid arthritis (RA) include not only remission for joint accounts and CRP, but also for patient global assessment (assessed by a patient visual analog scale, VAS) with a threshold value of 1/10 (ref). However, patient global assessment often seems to be a limiting factor for achieving ACR/EULAR remission. Objectives To explore the role of the patient global assessment VAS in ACR/EULAR remission: according to the disease duration, and according to the formulation used for the patient global VAS. Methods Patients: those in the ESPOIR and COMEDRA studies. ESPOIR is a national observational cohort of patients with early arthritis (at least 2 swollen joints for less than 6 months). COMEDRA is a national multicentric clinical trial involving patients with stable RA. Definitions of remission: comparison of ACR/EULAR Boolean remission (joint accounts <=1, CRP ≤10 mg/l, patient global VAS ≤1/10) and “near-remission” (identical definition, but with a patient global VAS>1/10). Frequency of remission according to disease duration: remissions evaluated in early arthritis (at 6 months in ESPOIR) and established RA (at baseline in COMEDRA). Formulation of the patient global VAS: comparison of two usual formulations of the patient global VAS: the overall global assessment VAS (how do you feel?) and a disease activity VAS (What is the activity of your RA?) (comparison available in ESPOIR only). Statistics: Non- parametric comparisons, without imputation of missing data. Results Description of the cohorts: Early arthritis (ESPOIR): N=732 patients, mean duration of symptoms 7.0±8.3 months; established RA (COMEDRA): N=948 patients, mean duration of disease 13.5±9.8 years. Frequency of remission according to the disease duration: in early arthritis, ACR/EULAR Boolean remission was more frequent than in established RA: respectively, 13.4% (N=98) versus 8.3% (N=79). However, near-remission was also more frequent in recent arthritis: respectively, 16.7% (N=122) versus 7.2% (N=68), p<0.0001. Formulation of patient global VAS: in early arthritis, using the disease activity VAS, patients were more often in complete ACR/EULAR remission (13.4%, N=98) and less often in near-remission (16.7%, N=122) than when using the overall global health VAS (respectively 9.1% and 20.9%). Conclusions In this study, as expected ACR/EULAR remission but also near-remission was more frequent in EA than in established RA. This may indicate the unclarity of the concept of patient global assessment in early disease. Furthermore, the disease activity VAS seemed to have a better agreement with objective data (eg, joint counts) in EA, indicating this formulation may take less into account patient subjectivity and reference shifts in terms of overall health. Treatment decisions based on a state of remission or not, should take these results into account. Studies to explore the patients vision on the concept of remission are also needed. References Felson DT et al. Ann Rheum Dis 2011; 70(3): 404-13. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2221