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ObjectiveIBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.DesignTranscriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.ResultsbMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.ConclusionTranscriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

Background 14–3-3η is an emerging soluble Rheumatoid Arthritis (RA) biomarker that activates intracellular pathways that lead to the upregulation of inflammatory and joint damage factors. It is reported to be highly specific and sensitive for RA as a diagnostic marker, higher levels are associated with greater joint damage progression risk and 14–3-3η9s modulation with treatment suggests a role in disease monitoring. Objectives In this study, we examine the specificity of 14–3-3η in an independent, clinically well-characterized cohort of moderate to severe RA and disease control subjects. Methods Serum 14–3-3η levels were measured in a total of 147 patients using the Augurex 14–3-3η ELISA. The patient set comprised 36 with RA and 111 controls consisting of 20 with asthma (A), 20 with Crohn9s Disease (CD), 12 presumed healthy (H), 16 with psoriasis (PsO), 20 with sarcoid arthritis (S), and 23 with spondylarthropathies (SpA). Sample testing was done independently of Augurex. Mann-Whitney testing together with Kruskal-Wallis analysis with the post-hoc Dunn9s multiple comparison test was performed to assess group differences. Receiver operator characteristic curve (ROC) analysis was performed to assess the specificity of 14–3-3η for RA. Results Median (IQR) serum 14–3-3η levels were significantly higher in RA [2.35ng/ml (0.28–19.41)] than all controls [0 (0–0)], p Conclusions Serum 14–3-3η is a highly specific RA biomarker. As a novel mechanistic disease factor, 14–3-3η is expected to provide new insights and approaches to RA management and clinical studies. References Arthritis Res Ther 2014; 16(2):R99; J Rheumatol 2014; 41(11):2104. Disclosure of Interest B. Dasgupta Employee of: Janssen R & D, LLC, Y. Cherkas Employee of: Janssen R & D, LLC, S. Lamberth Employee of: Janssen R & D, LLC, K. Hayden Employee of: Janssen R & D, LLC, C. Brodmerkel Employee of: Janssen R & D, LLC, A. Marotta Grant/research support from: Janssen R & D, LLC, M. Curran Employee of: Janssen R & D, LLC

Background Interleukin-6 (IL-6) is among the known neuroactive cytokines involved in stress coping and neuronal plasticity. Clinical and preclinical studies suggest a role for IL-6 in the pathophysiology of depression; it is unclear whether peripheral anti-IL-6 treatment can directly alleviate depressive symptoms. Depressive symptoms and fatigue commonly affect RA patients, particularly those with high disease activity. Objectives To assess the effects of sirukumab, a human IL6 antibody, on measures of depressed mood and anhedonia, and fatigue from a Ph2 trial in patients with active RA. Methods This was a post-hoc analysis of the SF-36 Mental Health and Vitality domain items from a Ph2, multicenter, randomized, double-blind, placebo-controlled study evaluating efficacy and safety of 4 dose regimens of sirukumab (25mg q4wks up to 100mg q2wks) administered SC in patients with active RA despite MTX. Serum CRP ≥10mg/L was required for enrollment, and history of an uncontrolled psychiatric or emotional disorder that was of sufficient severity to interfere with study participation was excluded. Patients using anti-depressants were excluded from analysis. Patients were grouped by presence or absence of prevalent depressed mood and anhedonia (PDMA) at entry, defined as self-reported depressed mood and anhedonia on the SF-36 with >1 item designated “most of the time” and the other at least “some of the time” for 4wks. Sirukumab treatment was defined as receiving any sirukumab regimen. Change from baseline in PDMA and fatigue at wk12 were analyzed unadjusted and adjusted for baseline and wk12 DAS28-CRP score; to investigate the relationship between depressive symptoms improvement and RA clinical response, change in PDMA symptoms was also investigated separately in ACR50 responders and non-responders Results At entry, about 26% of patients were classified as having PDMA. This group also experienced significantly more fatigue and nervousness than those without PDMA. The severity of PDMA symptoms in this group was not significantly correlated with RA chronicity or severity, or with baseline serum levels of inflammatory biomarkers. Clinical efficacy of sirukumab on RA disease symptoms as measured with the DAS28-CRP occurred in patients with and without PDMA at entry. Patients in the PDMA group receiving sirukumab but not PBO achieved significant improvements at wk12 in PDMA symptoms (p=0.0006), and fatigue (p=0.0157). In patients with PDMA, significant improvements on PDMA symptoms upon sirukumab treatment, but not PBO, were observed in both ACR50 responders (p=0.0024) and non-responders (p=0.0014). In patients with PDMA treated with sirukumab, baseline soluble IL-6 receptor (sIL-6R) level significantly correlated with improvement at wk12 in PDMA symptoms (Spearman r=0.44, p=0.015). Conclusions These novel findings link IL-6 signaling pathway dysregulation to depressive symptoms and fatigue, and suggest that peripheral anti-IL-6 treatment can improve depressive symptoms in RA patients independently of clinical response. References Hodes GE et al,PNAS 2014;111(45):16136-16141. Smolen JS et al,ARD 2014;73:1616-1625. Disclosure of Interest B. Hsu Employee of: Janssen, D. Wang Employee of: Janssen, Y. Sun Employee of: Janssen, G. Salvadore Employee of: Janssen, J. Singh Employee of: Janssen, M. Curran Employee of: Janssen, I. Caers Employee of: Janssen, W. Drevets Employee of: Janssen, G. Wittenberg Employee of: Janssen, G. Chen Employee of: Janssen

Background Genome wide association studies (GWAS) have yielded over 100 genetic loci associated with rheumatoid arthritis (RA). However, the utility of GWAS studies for drug discovery is limited because most GWAS hits do not reside in coding regions and have no known function. Elucidating potential transcriptional regulatory roles of GWAS hits will allow functional annotation of disease-related GWAS loci and lead to better understanding of RA etiology. Objectives To identify potential molecular drivers of RA by mapping expression quantitative trait loci (eQTLs) from gene expression and genotype data from a cohort of RA patients. Methods eQTLs were mapped using whole blood transcriptome data (Affymetrix microarray) from 377 RA patients with inadequate response to methotrexate enrolled in a clinical trial at baseline. Genotypes were generated from whole genome sequencing of DNA from the same subjects. eQTL mapping was performed by linear regression on adjusted data and FDR was estimated with a permutation method separately for local and distant associations. Results We report over 6,000 unique genes with significant eQTLs that represent potential molecular drivers. These eQTLs are enriched for genetic variants associated with RA. Additionally, the genes associated with these RA GWAS loci represent several disease-relevant biological pathways, including antigen presentation and B cell signaling. While there are multiple published eQTL datasets from non-RA cohorts, our analysis suggests that there is utility in detecting eQTLs from disease-relevant cohorts. Indeed, we identified several eQTLs overlapping with RA GWAS loci that have not been reported previously. We also demonstrate that integration with publicly available epigenomics datasets enables elucidation of cell-type-specific relationships. In particular, genes with expression driven by active enhancers in specific immune cell types (e.g., B cells and T helper cells) were identified, generating hypotheses that can be validated experimentally. Conclusions As one of the first studies to detect eQTLs from RA patients, this work provides a valuable resource to better understand the genetic basis for RA and aid in translating genetics research into therapeutic interventions. Overall, this analysis highlights the value of studying peripheral blood given the challenge of obtaining large numbers of synovial tissue biopsies from RA patients. Disclosure of Interest A. Walsh Employee of: Johnson & Johnson, J. Whitaker Employee of: Johnson & Johnson, C. Huang Employee of: Johnson & Johnson, Y. Cherkas Employee of: Johnson & Johnson, S. Lamberth Employee of: Johnson & Johnson, C. Brodmerkel Employee of: Johnson & Johnson, M. Curran Employee of: Johnson & Johnson, R. Dobrin Shareholder of: Johnson & Johnson, Employee of: Johnson & Johnson

Background Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease resulting in joint inflammation and damage. Despite the current therapies available, only a small percentage of RA pts achieve remission. To improve care and treatment for RA pts, a deeper understanding of the mechanisms that drive disease and response to therapy are desirable. The molecular understanding of disease and treatment mechanisms of RA continues to evolve. Objectives To explore the utility of peripheral blood expression profiling for informing disease and treatment mechanisms, samples derived from the GO-FURTHER golimumab study in RA were evaluated. This study examines if whole blood (WB) gene expression profiles can be utilized to: identify a baseline disease profile (DP) for pts with moderate-to-severe RA elucidate the pharmacodynamic (PD) and response profile of golimumab IV treatment, and delineate the peripheral biological processes dysregulated in RA and modulated by golimumab IV. Methods mRNA from 487 WB samples collected in a Phase III study of golimumab IV (GO-FURTHER) in pts with active RA despite methotrexate (MTX) therapy was isolated and profiled using the Affymetrix HT HG-U133+ PM Array (Santa Clara, CA). Samples were collected at Wks 0 and 14 from pts treated with IV placebo + MTX (PBO; n=161) or IV golimumab 2mg/kg + MTX (GLM; n=326) administered at Wks 0, 4, and every 8 wks thereafter. Non-RA WB samples (healthy controls; n=22) were obtained from Bioreclamation (Hicksville, NY). Results A disease profile comparing baseline gene expression profiles of RA to healthy controls yielded about 2000 differentially expressed genes (DEGs), while comparison of post-treatment to pre-treatment samples generated a PD profile of about 3000 DEGs. Over 70% of genes in the DP are downregulated as well as humoral immune response and B and T cell receptor signaling pathways. Pathways upregulated in the DP include innate immune response, Toll-like receptor (TLR), and cell activation. Treatment with golimumab modulates more than 30% of the disease profile, while just over 25% of PD effect is shared with the DP. The above mentioned pathways are common between the DP and PD profiles and are reversed, in part, through changes in peripheral cell populations post-golimumab treatment. A significant decrease in neutrophils and increase in lymphocytes was observed in the periphery at Wk 12 and in gene expression profiles representative of these cells at Wk 14 post-treatment. In addition, response to golimumab at Wk 14 was associated with more gene changes in B and T cell receptor signaling pathways in comparison to nonresponders. Conclusions Gene expression from the periphery of RA pts can be used for identification of a DP as well as the PD effect and response profile to golimumab IV. The most significant biological pathways and functions associated with the DP or PD effect are related to immune response and function. At baseline, RA pts had an increased innate and decreased adaptive immune profile in the periphery and majority of these processes were reversed by treatment with golimumab IV. Defining the pathways dysregulated in RA and modified by effective treatment as well as those that remain dysregulated aids in defining novel areas for potential therapeutic intervention. Disclosure of Interest Y. Cherkas Employee of: Janssen Research & Development, LLC., C. Brodmerkel Employee of: Janssen Research & Development, LLC., M. Curran Employee of: Janssen Research & Development, LLC., S. Lamberth Employee of: Janssen Research & Development, LLC. DOI 10.1136/annrheumdis-2014-eular.2032

Background The use of whole blood gene expression to predict and follow the response to TNF inhibition therapy in RA has been challenging due to the complex nature of the data. Objectives Here we employ an approach to gene expression analysis that is based on gene expression “modules” previously reported by Chaussabel, et al. (1) Methods Whole blood RNA (PAXgene) was obtained at baseline and 12 weeks on two cohorts of rheumatoid arthritis patients beginning anti-TNF therapy. The initial cohort was enrolled by the Autoimmune Biomarkers Collaborative Network (ABCoN) and contains 50 subjects stratified by EULAR Good Responders (N=14), Moderate Responders (N=21) and Non Responders (N=15) at 12 weeks after starting therapy. Results Good and Moderate Responders exhibited highly significant changes in multiple modules using a hypergeometric analysis. These included dramatic decreases in modules related to the myeloid lineage and inflammation, along with increases in B cell and plasma cell modules as well as in a number of modules related to the MHC and ribosomal proteins and other “undefined” module groups. Strikingly, Non Responders exhibited very little change in any modules. We have replicated these data in patients enrolled in a clinical trial of Simponi®, with full expression data available on 29 Good Responders, and 37 Moderate Responders. We observed nearly identical modular changes to those identified in the ABCoN Responders after 14 weeks of treatment. Only 6 Non Responders were available for study in this dataset, making convincing replication difficult for this subgroup. Several other replication datasets are currently being analyzed. Conclusions These data suggest that using gene expression modules related to inflammatory disease may provide a valuable method of characterizing the responder status of RA patients treated with TNF inhibitors. References Chaussabel D, Quinn C, Shen J, Patel P, Glaser C, Baldwin N, Stichweh D, Blankenship D, Li L, Munagala I, Bennett L, Allantaz F, Mejias A, Ardura M, Kaizer E, Monnet L, Allman W, Randall H, Johnson D, Lanier A, Punaro M, Wittkowski KM, White P, Fay J, Klintmalm G, Ramilo O, Palucka AK, Banchereau J, Pascual V. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity. 2008 Jul 18;29(1):150-64. doi: 10.1016/j.immuni.2008.05.012. Disclosure of Interest M. Curran Employee of: Janssen Research & Development, LLC., M. Oswald Grant/research support: Janssen Research & Development, LLC., A. Lee Grant/research support: Janssen Research & Development, LLC., Y. Cherkas Employee of: Janssen Research & Development, LLC., C. Brodmerkel Employee of: Janssen Research & Development, LLC., S. Lamberth Employee of: Janssen Research & Development, LLC., P. Gregersen Grant/research support: Janssen Research & Development, LLC. DOI 10.1136/annrheumdis-2014-eular.3724

Background Currently, disease activity in Rheumatoid Arthritis (RA) is measured using scoring systems that rely primarily on a collection of subjective measures from patients and clinicians. To improve care and treatment for RA patients, objective measurements of disease activity and response to treatment are desirable. Using a small cohort derived from an ongoing study of intravenously administered golimumab (GO-FURTHER), we evaluated the performance of Vectra-DA™ (Crescendo Biosciences), a multi-biomarker serum-based test designed to measure RA disease activity through correlation with DAS28-CRP and is sensitive to anti-TNF therapy 1 . Objectives This analysis examines if Vectra-DA™ correlates with disease activity and golimumab response in a clinical trial setting. Methods 137 serum samples collected in a Phase III study of intravenously administered golimumab in pts with active RA despite methotrexate (MTX) therapy were analyzed using Vectra-DA™ (Crescendo Bioscience © ; San Francisco, CA, USA). Samples were collected at wks 0, 2, 4, and 14 from patients (pts) treated with IV placebo + MTX (PBO; n= 42) or IV golimumab 2mg/kg + MTX (GLM; n=95) who received study medications at wks 0, 4, and every 8 weeks thereafter. Healthy control serum samples (n=21) were obtained from Bioreclamation (Hicksville, NY). Results A subset of pts from the GO-FURTHER study was chosen for analysis with Vectra-DA™. Among pts in the GO-FURTHER subset, the ACR50 response rates were 35.8% for GLM and 7.1% for PBO at week 14 and 48.4% for GLM and 16.7% for PBO at wk 24. Correlation of Vectra-DA™ and DAS28-CRP scores was r=0.51 (95% CI=0.45-0.57) using all four timepoints tested. Study pts had statistically higher mean Vectra-DA™ scores (64.2 at wk 0; 45.5 at wk 2; 50.2 at wk4; 44.9 at wk14) compared to healthy controls (35.2). At baseline, there were no significant differences in GLM and PBO-treated pts by Vectra-DA™ or DAS28-CRP scores. As early as week 2, GLM-treated subjects had a significant drop in Vectra-DA™ score of ∆= -18.7 (p= 16 ). The decrease in Vectra-DA™ score was maintained through wk 14, whereas PBO-treated subjects did not have a significant change in Vectra-DA™ scores from baseline to weeks 2, 4 and 14. Vectra-DA™ scores were statistically different between GLM-treated pts who achieved ACR50 at wk 14 versus nonresponders at wks 0 (p=0.024), 4 (p=0.013), and 14 (p=0.009). Vectra-DA™ scores were not statistically different between GLM-treated pts who achieved an ACR50 response at wk 24 versus nonresponders at all timepoints tested, although a trend was seen at wk 14 (p= 0.054). Conclusions Vectra-DA™ offers a molecular measurement of RA disease activity that can discriminate between normal subjects and RA pts, and also PBO and GLM-treated pts as early as wk 2 post-treatment. GLM treated wk14 responders had significantly lower Vectra-DA™ scores compared with nonresponders. The Vectra-DA™ score reflects a patient’s disease activity before and after the treatment with intravenous golimumab. References Weinblatt ME, Shadick NA, Manning W, et al. Use of a Multi-Biomarker Score for Rheumatoid Arthritis Disease Activity (Vectra™ DA) to Assess Response to Therapy.(Poster Session I: May 26, 2011, 11:45 BST). EULAR Congress 2011. Disclosure of Interest S. Lamberth Employee of: Janssen R & D, LLC, Y. Cherkas Employee of: Janssen R & D, LLC, C. Brodmerkel Employee of: Janssen R & D, LLC, M. Curran Employee of: Janssen R & D, LLC

Background Anemia of chronic inflammation is found in patients with rheumatoid arthritis (RA). Studies have found that RA patients with anemia are more likely to have more severe joint damage. 1 Hepcidin is a peptide hormone that regulates iron homeostasis, is elevated in anemic conditions, and is up-regulated by interleukin-6 (IL-6). IL-6 is also elevated in RA. Sirukumab (CNTO136), a human anti-IL-6 monoclonal antibody, was investigated for efficacy in a Phase 2b dose ranging study of patients with active RA despite concurrent methotrexate treatment. Objectives This analysis examines if sirukumab treatment had positive effects in RA patients anemic at baseline (week 0) by reducing hepcidin and increasing hemoglobin through week 12 of treatment. Methods Serum samples collected in the Ph2b study at week 0, day 5, week 2, and the pre-specified week 12 primary endpoint were analyzed for hepcidin, hemoglobin, and anemia-related markers (ferritin, iron, total iron biding capacity, unsaturated iron bind capacity). Patients were treated with SC placebo (PBO; n=30) or SC sirukumab 100 mg 2QW, 100 mg 4QW, 50 mg 4QW (n=30 for each arm), or 25 mg 4QW (n=31). Results The overall ACR 50 response at week 12 to sirukumab was 24.0% (PBO 3.3%). At week 0, 5/30 (16.7%) of PBO and 37/121 (30.6%) of sirukumab-treated patients were anemic. In the anemic patients, the mean week 0 hepcidin concentrations were 25.1 ng/mL in the PBO group, and 87.4 ng/mL in the sirukumab-treated patients. At week 12, the sirukumab-treated patients mean hepcidin concentration was significantly reduced to 38.1 ng/mL (p=0.0029), while the PBO mean hepcidin concentration was unchanged (31.4 ng/mL; p=0.6250). No dose-response of sirukumab on serum hepcidin concentration was seen. Hemoglobin levels in the anemic patients increased in the sirukumab-treated patients (10.6 g/dL at week 0; 11.8 g/dL at week 12; p Conclusions Sirukumab was effective in reducing serum concentrations of hepcidin through week 12 of treatment. Serum hemoglobin levels in anemic patients increased significantly following sirukumab treatment, with half of the patients normalizing hemoglobin levels. This indicates that in addition to demonstrating efficacy, treatment of RA patients with sirukumab may be effective in reversing inflammation-related anemia. References Peeters HR, et al. Ann Rheum Dis. 1996;55:162-168 Disclosure of Interest G. Toedter Employee of: Janssen Research & Development, LLC, S. Sague Employee of: Janssen Research & Development, LLC, X. Wu Employee of: Janssen Research & Development, LLC, M. Curran Employee of: Janssen Research & Development, LLC, B. Hsu Employee of: Janssen Research & Development, LLC