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Additional research is needed to establish the safety of biologic agents in pregnancy and lactation. The practitioner should convey information regarding the natural history of rheumatoid arthritis during pregnancy and safety issues related to pharmacotherapies to every woman of childbearing age with RA, well before conception and pregnancy, to ensure optimal outcomes.

Endpoints and outcome measurements to detect changes in joint structure for the assessment of single joints are needed to enable rheumatology clinical trials of therapies targeting preservation of joint structure, especially via locally applied therapies. While the assessment of certain aspects of single joint inflammation and function is accepted in the evaluation of osteoarthritis (OA) using the WOMAC, it tends to be limited to the knee and hip. The advent of therapies that are directed toward a single joint in inflammatory arthritis, including intraarticular cytokine antagonists and gene therapeutics, requires reliable measures to assess change over time in single joints and the clinical meaningfulness of such change. Traditionally, clinical trials for inflammatory arthritis have used composite response indices such as American College of Rheumatology response or improvement in Disease Activity Score as outcomes based on multiple joint clinical measures, acute phase reactants, and functional status. However, it is not known whether these will appropriately detect changes referable to single joint intervention. This Special Interest Group was developed to bring together interested individuals to identify and evaluate outcome measurements for single joints. The knee was the initial focus, as clinical, radiographic, and functional assessments have been well developed for knee OA. A PubMed English language review was conducted before OMERACT 8, evaluating existing clinical instruments in the context of the OMERACT filter. At OMERACT 8, the group developed a research agenda to perform additional validation studies of clinical and functional indices, imaging, synovial histopathology, and soluble biomarkers.

Data from population- and clinic-based epidemiologic studies of rheumatoid arthritis patients suggest that individuals with rheumatoid arthritis are at risk for developing clinically evident congestive heart failure. Many established risk factors for congestive heart failure are over-represented in rheumatoid arthritis and likely account for some of the increased risk observed. In particular, data from animal models of cytokine-induced congestive heart failure have implicated the same inflammatory cytokines produced in abundance by rheumatoid synovium as the driving force behind maladaptive processes in the myocardium leading to congestive heart failure. At present, however, the direct effects of inflammatory cytokines (and rheumatoid arthritis therapies) on the myocardia of rheumatoid arthritis patients are incompletely understood.

Background Perforin- and complement-induced cell lysis has recently been implicated in the generation of citrullinated autoantigens in rheumatoid arthritis (RA). By activating PADs in target cells, immune-mediated pore-forming pathways induce abnormal protein citrullination in the RA joint. Here, we demonstrate a novel approach to identify unique autoantibody reactivities to citrullinated proteins generated by the perforin pathway. Objectives To identify novel perforin-induced autoantigens in RA, and to characterize the antibody response to citrullinated hnRNP A1 (cit-hnRNP A1) in patients with RA. Methods 293T cells transiently transfected to express human PAD2 or PAD4 were incubated with perforin from cytotoxic granule contents (GC) to induce PAD activation. Cellular citrullination was confirmed by anti-modified citrulline (AMC) immunoblotting. Inducible autoantigens generated during perforin-mediated cytolysis were identified by immunoblotting using RA patient sera. Antigen identity was determined by 2D gel electrophoresis/mass spectrometry (MS). Recombinant hnRNP A1 was expressed in E. coli. Patients with RA (n=196) from a longitudinal cohort study (ESCAPE RA) and healthy controls (n=56) were assayed for IgG antibodies to unmodified and in vitro citrullinated hnRNP A1 by ELISA. Positivity was defined as an arbitrary unit (AU) above the 98th percentile of controls. Anti-cit-hnRNP A1 antibody specificity was determined by subtracting reactivities measured against unmodified hnRNP A1 from reactivities against cit-hnRNP A1. Results 293T cells expressing PAD2 or PAD4 were used to study PAD-isotype specific autoantigen citrullination. A 34-kDa autoantigen inducible in both PAD2- and PAD4-transfected cells was distinctly targeted by RA patient sera (Fig. 1A; GC: perforin-treated cells, NT: untreated controls). MS identified the modified protein as cit-hnRNP A1, and citrullination by both rPAD2 and rPAD4 was confirmed using purified hnRNP A1. Antibody reactivity against cit-hnRNP A1 was detected in 70 (36%) of RA patients vs. only 1 (2%) of controls (p Conclusions These studies identify hnRNP A1 as a citrullinated autoantigen in RA generated during perforin-mediated cytotoxicity. Anti-cit-hnRNP A1 antibodies may serve as a novel biomarker associated with mechanisms of joint damage in a subset of RA. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3035

Background Serum 14-3-3 eta has been described to have diagnostic utility and in established RA an association has been established between the levels of this marker and the degree of joint damage. The η isoform of 14-3-3 is expressed extracellularly in much higher concentration than the Υ isoform or MMP 1 and 3 levels in the synovial fluid and serum of patients with rheumatoid arthritis compared to the normal population. Rheumatoid factor (RF) is known to be sensitive and anti CCP highly specific for RA, but a high number of patients remain seronegative. There is a need for a biomarker to prevent underdiagnosis in this subset. Objectives The purpose of the study was to investigate if serum 14-3-3 η enhanced the detection of RA over RF or anti CCP in RA patients. We also studied the utility of 14-3-3 eta as a diagnostic test by comparing presence of this protein in RA v/s non-RA patients. Methods A retrospective chart review study was conducted in RA patients at an outpatient rheumatology clinic in an inner city population at a community teaching hospital serving a large immigrant population. 91 RA patients were identified who satisfied the 2010 ACR diagnostic criteria and 37 non RA patients seen in the clinic for other rheumatologic conditions were chosen as the control group. Serum 14-3-3η protein was measured by ELISA. The positive threshold range using Quest Diagnostic for RF was 15 International Unit/ml, Anti CCP was 20 Units and for 14-3-3 eta was 0.2 ng/mL. The chi-square goodness-of-fit test was used to analyze the frequency of eta positivity in the RA population while kappa was calculated to compare the RA and non RA patients. Results Of the 91 RA patients, 75.8% were females and mean age was 58 (range 28- 90) years. The population was predominantly Hispanic (75%). In the non-RA group, 9% had psoriatic arthritis and 14% lupus, 73% were females,76% Hispanic and the mean age was 54 (range 19-93) years. In the RA population, none of group without RF or anti-CCP was positive for eta. For those with either RF or anti-CCP, the prevalence of eta positivity was 11.1% (95%CI 2.8-35.2%). For those with both RF and anti-CCP, the prevalence of eta positivity was 81.0% (95% CI 68.9-89.2%). All comparisons between groups were significant at p Conclusions Measurement of 14-3-3η complements RF and anti-CCP antibody tests in RA and may improve diagnostic sensitivity. Used in combination with other serological markers, 14-3-3 eta can increase identification of patients with RA. *Equal Contribution Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5776

Background The increased incidence of MACE in RA cannot be explained by traditional CV risk factors alone. 1 Objectives To examine associations of lipids, inflammation and RA disease activity with risk for MACE in TCZ-treated RA pts. Methods Pooled data of TCZ-exposed pts from phase 3 trials and long-term extensions were included in post hoc analyses. 50 pts with MACE (non-fatal myocardial infarction, non-fatal stroke or CV death) and 3,936 pts without MACE were identified via blinded, independent adjudicator. Cox proportional hazards models were used to evaluate the associations of various demographic, laboratory and disease measures (at baseline, wk 24 and change from baseline to wk 24) with time to future MACE. Simple univariate and multivariate models were estimated, and resulting hazard ratios with 95% CIs were used to assess predictors. Results For MACE during TCZ exposure, univariate analysis showed baseline age, history of cardiac disorders, statin use, TJC, SJC, DAS28, total cholesterol (TC)/HDL ratio, ApoB and ApoB/ApoA1 ratio as predictive (all p Conclusions Among traditional CV risk factors and disease activity measures, age, DAS28, TC/HDL and history of cardiac disorders were independently associated with MACE in RA pts subsequently treated with TCZ. Risk for MACE was broadly linked to elevated baseline disease activity and less robust therapeutic response at wk 24, whereas no statistically significant association between lipid change and MACE risk was observed. These findings suggest that mitigating CV risk in RA pts may require a multifaceted approach, including effective disease activity control. References Gonzalez A et al. Ann Rheum Dis 2008;67:64-9. Disclosure of Interest V. Rao Employee of: Roche/Genentech, A. Pavlov Consultant for: Everest Clinical Research Services, Inc., M. Klearman Employee of: Roche/Genentech, D. Musselman Employee of: Roche/Genentech, J. Giles Consultant for: Roche, UCB, Regeneron, J. Bathon: None Declared, N. Sattar Grant/Research support from: Roche, Consultant for: Roche, Pfizer, Speakers Bureau: Roche, J. Lee Employee of: Roche

Background A rigorously ascertained psoriatic arthritis (PsA) cohort demonstrated considerable genetic heterogeneity and provided preliminary evidence that MHC genes determine quantitative traits within the PsA phenotype with different patterns of MHC effect. (Arth & Rheum 2012. 64: 1134). Objectives To investigate any potential association of clinical phenotypes with already well characterised and quantified genotypes of PsA patients belonging to a genetically relatively homogeneous population Methods A consecutive cohort of 283 PsA patients underwent detailed skin and rheumatologic assessments. We chose four traits to analyze - sacroiliitis, enthesitis, joint deformity and dactylitis. To examine their genotypic interaction, we assigned a score to each patient’s allele and haplotype. +1 if an allele or haplotype was associated with a high risk for the trait, and -1 if it conferred a low risk in univariate analysis. Alleles or haplotypes not significantly associated with a trait were assigned “0”, and the score summed assuming an additive risk model. Results A total of 283 PsA patients [mean age 55±12 years; 47% male; mean PsA duration=19±9 years; 25% with sacroiliitis; 44.5% with radiographic erosions; 34% with enthesitis; 53% with dactylitis, 60% of this PsA cohort requiring TNFi therapy] were studied. The figure shows the frequency of each trait as a function of the risk score for the alleles and haplotypes associated with high or low risk and the average change in the odds of having each trait per 1 unit increase in the genotype risk score, e.g. the OR of developing enthesitis with an alleles/haplotypes genotype score of +2 to +4 was 13.9, p Image/graph Conclusions HLA genotype importantly influences the clinical phenotype of psoriatic arthritis; and these phenotypes are likely the result of cis and trans interactions of multiple individual alleles. Disclosure of Interest None Declared

IntroductionIn cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.MethodsIncidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.ResultsThe incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59 ± 7 vs. 55 ± 6 years old, p=0.03), had higher triglyceride levels (137 ± 86 vs. 97 ± 60 mg/dL, p=0.03), and higher systolic blood pressure (129 ± 17 vs. 117 ± 15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p

Background Tissue-infiltrating multinucleated giant cells (MNGs) within geographic necrosis are pathologic hallmarks of granulomatosis with polyangiitis (GPA). However, the origin, phenotype, and function of these cells in GPA remain undefined. Methodology/Principal Findings MNG phenotype in GPA lung tissue was examined by immunohistochemistry using antibody directed against cathepsin K and calcitonin-receptor. Tartrate-resistant-acid-phosphatase (TRAP) expression was assessed using enzymatic color reaction. Peripheral blood mononuclear cells (PBMCs) from 13 GPA patients (5 with localized and 8 with systemic disease) and 11 healthy controls were cultured in the presence of RANKL and M-CSF for 9 days, and TRAP+ MNGs containing 3 or more nuclei were identified. GPA lung granulomata contained numerous MNGs that expressed osteoclastic TRAP and cathepsin K but not calcitonin receptors. In the presence of RANKL and M-CSF, PBMCs of GPA patients formed significantly more MNGs than healthy controls (114±29 MNG/well vs. 22±9 MNG/well, P = 0.02). In a subgroup analysis, patients with systemic disease generated significantly more MNGs than patients with localized disease (161±35 MNG/well vs. 39±27 MNG/well, P

Background: Inflammation plays a key role in modulating cardiovascular (CV) risk. Rheumatoid arthritis (RA) patients treated with the interleukin-6 receptor inhibitor tocilizumab have marked reductions in C-reactive protein but modest increases in lipid parameters. The relative contributions of inflammation and lipids to CV risk in this population have not been fully defined. Methods: Data were compared from RA patients with (n = 50) and without (n = 3936) major adverse cardiovascular events (MACE) in tocilizumab phase 3 trials. Univariate Cox proportional hazards modeling was used to evaluate MACE risk factors at baseline, after 24 weeks of tocilizumab treatment and changes from baseline to 24 weeks with time to MACE as the time variable; multivariate Cox proportional hazards models were fit to obtain best prediction of time to MACE. Results: Univariate modeling showed baseline age, prior cardiac disorders, statin use, RA disease activity score (DAS28), total cholesterol/highdensity lipoprotein ratio, apolipoprotein-B and apolipoprotein-B/apolipoprotein-A1 ratio as predictive of MACE on tocilizumab. Baseline age, history of prior cardiac disorders, DAS28, and total cholesterol/high-density lipoprotein ratio were robust predictors of MACE in multivariate modeling. Posttreatment decreases in inflammation markers and lipid increases up to week 24 did not predict future MACE. However, higher levels of RA disease activity measures: swollen joints (hazard ratio [HR] [95% CI]=1.092 [1.051-1.136], p

Introduction Lung involvement is a common extra-articular manifestation of rheumatoid arthritis (RA) that confers significant morbidity and mortality. The objective of the present study is to assess which respiratory symptoms and patient and disease characteristics are most highly associated with pulmonary function test (PFT) abnormalities in an RA patient cohort without clinical cardiovascular disease. Methods A total of 159 individuals with RA and without clinically evident cardiovascular disease were evaluated. Respiratory symptoms were assessed with the Lung Tissue Research Consortium questionnaire and all patients underwent evaluation with PFTs. Demographic, lifestyle, RA disease and treatment characteristics were collected. Subclinical coronary artery disease was assessed by cardiac computed tomography. Multivariable regression analysis was used to identify pulmonary symptoms and nonpulmonary parameters associated with PFT abnormalities. Areas under the receiver operating characteristic curves (AUC) were calculated to evaluate the discrimination of these variables for identifying patients with PFT abnormalities. Results Respiratory symptoms were reported by 42% of the patient population. Although only 6% carried a prior diagnosis of lung disease, PFT abnormalities were identified in 28% of the subjects. Symptoms combined with other patient and RA characteristics (body mass index, current smoking, anti-cyclic citrullinated peptide antibodies, and current prednisone use) performed satisfactorily in predicting the PFT abnormalities of obstruction (AUC = 0.91, 95% confidence interval = 0.78 to 0.98), restriction (AUC = 0.79, 95% confidence interval = 0.75 to 0.93) and impaired diffusion (AUC = 0.85, 95% confidence interval = 0.59 to 0.92). Co-morbid subclinical coronary artery disease did not modify these relationships. Conclusions Assessment of respiratory symptoms along with a limited number of clinical parameters may serve as a useful and inexpensive clinical tool for identifying RA patients in need of further pulmonary investigation.

Data from population- and clinic-based epidemiologic studies of rheumatoid arthritis patients suggest that individuals with rheumatoid arthritis are at risk for developing clinically evident congestive heart failure. Many established risk factors for congestive heart failure are over-represented in rheumatoid arthritis and likely account for some of the increased risk observed. In particular, data from animal models of cytokine-induced congestive heart failure have implicated the same inflammatory cytokines produced in abundance by rheumatoid synovium as the driving force behind maladaptive processes in the myocardium leading to congestive heart failure. At present, however, the direct effects of inflammatory cytokines (and rheumatoid arthritis therapies) on the myocardia of rheumatoid arthritis patients are incompletely understood.

Introduction Rheumatoid arthritis (RA) is a multi-organ inflammatory disorder associated with high cardiovascular morbidity and mortality. We sought to assess cardiac involvement using a comprehensive cardiac magnetic resonance imaging (cMRI) approach and to determine its association with disease characteristics in RA patients without symptomatic cardiac disease. Methods RA patients with no history and/or clinical findings of systemic or pulmonary hypertension, coronary artery disease, severe valvular heart disease, atrial fibrillation, diabetes mellitus, or echocardiographic abnormalities underwent contrast-enhanced cMRI on a 1.5T scanner. Adenosine triphosphate was used to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced imaging was obtained for the assessment of myocardial inflammation/fibrosis. We explored the associations of cMRI abnormalities with RA disease activity and severity measures. Results Eighteen patients (78% female) with a mean age of 57 ± 10 years were studied. Eight patients (45%) demonstrated a myocardial abnormality. Perfusion defects under pharmacologic stress were seen in two patients (11%), one of whom had a circumferential subendocardial perfusion defect and one had a non-segmental subendocardial perfusion defect. Seven patients (39%) were found to have delayed enhancement, only one of whom also demonstrated a perfusion defect. Mean disease activity score (DAS)28 was significantly higher in the group with delayed enhancement compared to the group without by an average of 1.32 DAS28 units (4.77 vs. 3.44 units, respectively; P = 0.011). Corresponding trends to statistical significance were noted in systemic inflammatory markers, with both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) quantitatively higher in the group with delayed enhancement. Other RA characteristics, such as disease duration, autoantibody status, and current treatments were not significantly associated with cardiac involvement. Conclusions Myocardial abnormalities, as detected by cMRI, were frequent in RA patients without known cardiac disease. Abnormal cMRI findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA.