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ObjectivesTo investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the initial Omicron wave.MethodsWe conducted a retrospective cohort study investigating COVID-19 outcomes among patientswith SARD systematically identified to have confirmed COVID-19 from 1 March 2020 to 31 January 2022 at Mass General Brigham. We tabulated COVID-19 counts of total and severe cases (hospitalisations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared with the early COVID-19 period (reference group).ResultsWe identified 1449 patients with SARD with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (28%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend ConclusionsThe proportion of patients with SARD with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the initial Omicron wave. Advances in prevention, diagnosis and treatment of COVID-19 may have improved outcomes among patients with SARD.

Background:Busy rheumatologists may assess disease activity and risk for radiographic progression (RP) in RA with informal, qualitative versions of evaluator and/or patient global assessments (EGA and PGA). RA patient care may be improved by having a convenient, objective disease activity measure that predicts risk for RP more accurately than EGA or PGA.Objectives:To compare the abilities of MBDA score, patient global assessment and evaluator global assessment to assess risk for radiographic progression (RP), and to assess the ability of MBDA score to predict RP among patients with concordant or discordant PGA and EGA.Methods:Patients were pooled from two RCTs of patients with recent onset RA treated with conventional and biologic DMARDs (OPERA and SWEFOT, N=386) and from a registry of patients with predominantly established RA and diverse treatments (BRASS, N=380). Pearson correlations were determined between MBDA scores (adjusted for the effects of age, sex and adiposity) (scale 1-100), PGA and EGA (each on a scale of 1-10) at baseline. PGA and EGA were considered discordant when they differed by >2.5. Univariable logistic regression assessed ability to predict RP (change in TSS >5 over 1 year) for MBDA score, PGA and EGA as continuous variables; and for discordance of PGA and EGA as 2-level (concordant vs. discordant) or 3-level (PGA>EGA, concordant, EGA>PGA) categorical variables. Multivariable regression considered the main effect and interaction terms of the MBDA score, as a continuous variable, paired with each other variable, to test the ability of each pair to assess risk of RP. All models included a random effect on cohort. Odds ratios were reported for every 10-unit increase in MBDA score. Frequency of RP was determined in subgroups with MBDA score low (44) for patient groups based on PGA/EGA concordance or discordance.Results:The 766 patients studied were 76% female, 76% positive for RF and/or anti-CCP Ab, with mean age 55 years, DAS28-CRP 4.7, CRP 22 mg/L, CDAI 26, SJC 9.1, PGA 4.4, EGA 3.4, MBDA score 53. No interaction was seen between MBDA score and type of cohort (early vs established RA). PGA and EGA were discordant in 294 of 766 (38%) patients and were weakly to moderately correlated (r=0.38). Among discordant patients, PGA was >EGA in 227 cases and EGA was >PGA in 67 cases. Correlations between MBDA score and PGA or EGA were r=0.41 and r=0.34, respectively. In univariable analyses, MBDA score was a statistically significant predictor of radiographic progression (OR=1.53, p=6.3x10-8) whereas PGA, EGA, 2-level discordance and 3-level discordance were not (p=0.38, 0.47, 0.74, 0.83, respectively). In multivariable analyses, significant interactions were observed between MBDA score and discordance (2-level, p=0.0029; 3-level, p=0.0087). The interaction analysis demonstrated, in PGA/EGA-concordant patients, low risk of radiographic progression when MBDA score was low and elevated risk when it was high (OR=1.33 [1.1, 1.59]). A relationship between MBDA score and RP risk was also demonstrated, with heightened trend, among discordant patients with PGA >EGA (OR=2.04 [1.53, 2.81]) and EGA >PGA (OR=3.43 [1.37, 13.8]) (Figure 1).Conclusion:MBDA score was a significant predictor of radiographic progression, whereas PGA and EGA were not. MBDA score predicted progression whether PGA and EGA were concordant or discordant. These results suggest that MBDA score detects joint-damaging disease activity more accurately than PGA and EGA and it does so whether or not PGA and EGA are in agreement.Disclosure of Interests:Leonard Calabrese Grant/research support from: AbbVie, Bristol-Myers Squibb, Cresecendo, Genentech, Gilead, GlaxoSmithKline, Horizon, Janssen, Novartis, and Sanofi., Michael E. Weinblatt Shareholder of: Canfite, Inmedix, Scipher, and Vorso, Consultant of: AbbVie, Aclaris, Amgen, Bayer, Bristol-Myers Squibb, Crescendo Bioscience, Corrona, EqRX, GSK,Genosco, Gilead, Lilly, Novartis, Pfizer, Roche, Set Point, Grant/research support from: Bristol-Myers Squibb, Myriad Genetics, Inc.,Eli Lilly and Sanofi, Nancy Shadick Consultant of: BMS, Grant/research support from: Lilly, mallinckrodt, BMS, Amgen and Sanofi, Cecilie Heegaard Brahe: None declared, Mikkel Østergaard Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Novartis, Orion, Pfizer, Regeneron, Roche, Takeda, and UCB, Grant/research support from: AbbVie, BMS, Celgene, Myriad Genetics, Inc., Janssen, and Merck, Merete L. Hetland Speakers bureau: Orion, Grant/research support from: AbbVie, Biogen, BMS, CelltrionRoche, Myriad Genetics, Inc., Eli Lily, MSD, Pfizer, and UCB, Megan Horton Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Autoimmune

BackgroundTo assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).MethodsIn this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX. PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient’s Global Assessment of Disease Activity (PtGA), patient’s assessment of pain and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain. The primary study endpoint was at week 12. Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables.ResultsCompared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12. Improvements were maintained for measures assessed to week 52. Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05).ConclusionsBaricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52).Trial registrationNCT01710358.

ObjectivesDespite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte–macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA.MethodsIn a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)−C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28−CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24).Results326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012–June 2013). Mavrilimumab treatment significantly reduced DAS28−CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: −1.90 (0.14), 100 mg: −1.64 (0.13), 30 mg: −1.37 (0.14), placebo: −0.68 (0.14); pSignificantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (pConclusionsMavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential.Trial registration numberNCT01706926; results.

Background:The multi-biomarker disease activity (MBDA) blood test measures 12 protein biomarkers (IL-6, CRP, SAA, EGF, VEGF, VCAM, MMP-1, MMP-3, leptin, resistin, TNF-RI and YKL40). It uses a validated algorithm to provide a score on a scale of 1-100 for assessing disease activity in patients with rheumatoid arthritis (RA). The MBDA score reflects several molecular aspects of inflammation, including cytokines, acute phase reactants, growth factors, molecular adhesion, metalloproteinases and hormones. Insights gained by understanding how vaccination affects these biomarkers in healthy subjects - in whom the level of inflammation prior to vaccination should be low and stable - may aid the understanding of how vaccination affects patients with RA.Objectives:The goal of this study was to understand how immunization of healthy subjects with the influenza vaccine affects the assessment of inflammation with the MBDA score and its 12 biomarkers.Methods:A 4-strain influenza virus vaccine (Fluarix Quadrivalent, GlaxoSmithKline) was administered intramuscularly to 22 healthy volunteer subjects on October 24, 2018. Serum samples were obtained immediately prior to vaccination (baseline) and 1, 2 and 3 weeks after vaccination. No restrictions were placed on subject activity. Samples were stored at -80oC until measurement of the 12 MBDA biomarkers for determination of the adjusted MBDA score, hereafter called the MBDA score. (Adjustment accounts for the effects of age, sex and adiposity1). MBDA scores (natural scale) and biomarker concentrations (log scale) were modeled using generalized estimating equations (GEE) that account for correlations between measurements from the same subject at multiple timepoints. Significance of MBDA score change or biomarker concentration change over time was determined by a likelihood ratio test of timepoints.Results:Of the 22 healthy subjects receiving the influenza virus vaccine, 14 (63.6%) were female, with mean (SD) age of 40.0 years (8.9). MBDA scores were low (44) for 15 (68%), 6 (27%) and 1 (5%) subjects at baseline, and this distribution was stable over time (Figure 1). Overall, MBDA scores did not change significantly over time (p=0.48, Figure 2). Mean changes in MBDA score (95% CI) from baseline to weeks 1, 2 and 3 were 0.32 (-3.07, 3.71), 0.82 (-3.03, 4.67) and 2.86 (-1.10, 6.82), respectively (Figure 2); the week 3 value becomes 0.95 (-1.78, 3.68) if the week 3 outlier is removed. Among the 66 post-baseline measurements of change in MBDA score (Figure 2), 3 (5%) exceeded the 95% CI for change in MBDA score in this study (i.e., 14). When assessing the entire cohort across all timepoints, EGF was the only biomarker that demonstrated statistically significant change over time (p=5.6 x 10-7). At weeks 1, 2 and 3, the mean relative concentrations of EGF, compared with baseline, were 0.62 (0.52, 0.74), 0.86 (0.70, 1.06) and 0.62 (0.50, 0.76), respectively.Figure 1Figure 2Conclusion:Immunization of 22 healthy subjects with a quadrivalent influenza vaccine did not have a statistically significant effect on MBDA scores during a 3-week observation, and it had minimal effect on the component biomarkers.References:[1]Curtis et al.Rheumatology [Oxford]2018;58:874Disclosure of Interests:Daniel Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Consultant of: AbbVie, Actelion, Amgen, BMS, Cytori Therapeutics, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Speakers bureau: CMC Connect (McCann Health Company), Lauren Lenz Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Megan Horton Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead

Background:RA is a systemic autoimmune disease with heterogeneous manifestation. Recent advances in serum proteomics, such as the SomaScan®platform (SomaLogic, Inc., Boulder, USA), allow for a deeper exploration of the protein biomarkers associated with RA and a better understanding of the molecular aetiology of the disease.Objectives:To characterise the differences in baseline serum proteome of patients with RA (enrolled in the Phase IIIb Abatacept vs adaliMumab comParison in bioLogic-naïvERA subjects with background MTX [AMPLE] study)1compared with a healthy population, and to identify serum protein biomarkers associated with disease severity and radiographic progression.Methods:Patients in the AMPLE study had an inadequate response to MTX and were naïve to biologic DMARDs. Protein abundance was assessed in baseline serum samples from 440 AMPLE study patients and 123 healthy individuals with matching demographics using the SomaScan®platform, with 5000+ slow off-rate modified aptamers and up to 8 log of dynamic range.2Differential abundance testing was performed using linear models to identify differences in protein abundance in patients with RA vs healthy individuals. A separate analysis using a linear model was conducted in only the patients with RA to identify the proteins associated with DAS28 (CRP) and TSS. Pathway analyses were performed for proteins significantly (false discovery rate-adjusted p value Results:Compared with healthy individuals, >2000 serum proteins were significantly differentially expressed in patients with RA, including many proteins that have been associated with RA (e.g. serum amyloid A [SAA], CRP) and complement. Most of the protein expression differences were of small magnitude (fold change Conclusion:Our study revealed that thousands of serum proteins are differentially expressed and several pathways are dysregulated between patients with RA and healthy individuals. Additional pathways were identified that reflect disease severity, including joint damage, distinct from those pathways associated with the disease. The SomaScan®platform provides a unique proteomic tool with a wide dynamic range for the identification of serum protein biomarkers associated with RA and disease severity. Proteomic signatures should be considered in clinical trials to better understand disease pathogenesis and predict risk in response to treatment.References:[1]Schiff M, et al.Ann Rheum Dis2014;73:86–94.[2]Gold L, et al.PLoS One2010;5:e15004.Acknowledgments:Rachel Rankin (medical writing, Caudex; funding: Bristol-Myers Squibb)Disclosure of Interests:David Galbraith Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Minal Caliskan Employee of: Bristol-Myers Squibb, Omar Jabado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sarah Hu Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Michael Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo, Lily, Sanofi/Regeneron, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Crescendo, Gilead, Horizon, Lily, Pfizer, Roche, Sean Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Michael A Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sheng Gao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Background:Upadacitinib (UPA), an oral selective JAK1 inhibitor, has demonstrated favorable efficacy and acceptable safety in five Phase 3 global studies in patients with moderately to severely active rheumatoid arthritis (RA).1–5Objectives:This analysis reports the efficacy and safety of UPA in predefined RA patient subgroups based on differences in baseline demographics and disease activity.Methods:Data were pooled from three pivotal, double-blind, PBO-controlled, multicenter, Phase 3 studies in patients with RA who had an inadequate response(IR) to conventional synthetic DMARDs (csDMARD-IR: SELECT-NEXT [N=661]), MTX(MTX-IR; SELECT-COMPARE[N=1629]), or biologic DMARDs(bDMARD-IR: SELECT-BEYOND[N=498]). Two integrated analysis sets were evaluated: one comparing UPA 15 mg QD vs PBO(SELECT-NEXT, SELECT-COMPARE, SELECT-BEYOND) and the other comparing UPA 15 mg QD and UPA 30 mg QD vs PBO(SELECT-NEXT, SELECT-BEYOND). All patients received background treatment with csDMARDs. The proportion of patients achieving ACR20 and DAS28(CRP) ≤3.2 at Week 12 was evaluated by predefined baseline demographics and disease activity measure groups, including age, sex, weight, BMI, race, geographic region, duration of RA, RF, and ACPA status, and level of high sensitivity CRP. Non-responder imputation was used for missing data. Subgroup analyses for safety were performed for age, race, sex, weight, BMI, and Asian region.Results:Across the three Phase 3 studies, 1036, 384, and 1041 patients received UPA 15 mg QD, UPA 30 mg QD or PBO, respectively. The demographic and baseline disease characteristics in the two integrated analysis sets were balanced across treatment groups. ACR20 and DAS28 ≤3.2 response rates at Week 12 were consistently higher with UPA 15 mg and UPA 30 mg vs PBO across the evaluated demographic and baseline disease characteristics(Figure 1a,Figure 1b). The efficacy of UPA 15 mg QD was generally similar to that observed with UPA 30 mg QD. At 12 weeks, the proportion of patients with treatment-emergent AEs, serious AEs, severe AEs, and AEs leading to discontinuation were generally comparable across different age, sex, race, weight, and BMI groups. Compared with the global population, patients receiving UPA in the Asian region had a higher rate of CPK elevations(UPA 30 mg only) and herpes zoster; herpes zoster also has been observed to be higher in the Asian region with other JAK inhibitors.6,7Conclusion:In this analysis of pooled integrated efficacy data in csDMARD-IR or bDMARD-IR patients with RA, UPA 15 mg or 30 mg QD in combination with csDMARDs improved efficacy outcomes at Week 12 when compared with PBO across all predefined subgroups evaluated.References:[1]Burmester GR, et al. Lancet 2018 23;391:2503–2512;[2]Genovese MC, et al. Lancet 2018; 391:2513–24;[3]Smolen JS, et al. Lancet 2019 May 23[Epub ahead of print];[4]van Vollenhoven R, et al. Arthritis Rheumatol 2018;70(Suppl. 10): Abstract 891;[5]Fleischmann R, et al. Arthritis Rheumatol 2018;70(Suppl. 10): Abstract 890;[6]Winthrop KL, et al. Arthritis Rheum 2014;66:2675-84;[7] Winthrop KL, et al. ACR 2016 [Abstract 3027]Disclosure of Interests:Michael Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo, Lily, Sanofi/Regeneron, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Crescendo, Gilead, Horizon, Lily, Pfizer, Roche, Eduardo Mysler Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer., Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer, Andrew Ostor Consultant of: MSD, Pfizer, Lilly, Abbvie, Novartis, Roche, Gilead and BMS, Speakers bureau: MSD, Pfizer, Lilly, Abbvie, Novartis, Roche, Gilead and BMS, Aaron Broadwell Grant/research support from: Janssen Research & Development, LLC, Janssen, Eli Lilly, Consultant of: AbbVie, Amgen, AstraZeneca, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Sandoz, Speakers bureau: AbbVie, Amgen, Celgene, GSK, Horizon, Janssen, Mallinckrodt, Novartis, Pfizer, Radius, Sanofi-Regeneron, UCB, Sławomir Jeka Grant/research support from: AbbVie, Pfizer, Roche, Novartis, MSD, Sandoz, Eli Lilly, Egis, UCB, Celgene, Speakers bureau: AbbVie, Pfizer, Roche, Novartis, MSD, Sandoz, Eli Lilly, Egis, UCB, Celgene, Kendall Dunlap Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jeffrey Enejosa Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Barbara Hendrickson Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Sheng Zhong Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Katya Cherny Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Grace Wright Consultant of: AbbVie, Amgen, BMS, Exagen, Janssen, Lilly, Medac, Myriad Autoimmune, Novartis, Pfizer, Sanofi Genzyme Regeneron, and UCB, Speakers bureau: AbbVie, Amgen, BMS, Exagen, Lilly, Medical Education Resource, Myriad Autoimmune, Novartis, Sanofi Genzyme Regeneron, UCB, and Vindico

Background:Gout development follows persistent serum uric acid (sUA) elevation. Patients who are refractory to or cannot tolerate oral urate lowering therapies (ULTs) have limited treatment options. Pegloticase is effective in treating refractory gout, but many patients develop anti-drug antibodies (ADAs), which are associated with loss of urate-lowering efficacy1-3 and infusion reactions (IRs).1,2 In phase 3 trials, the pooled pegloticase responder rate during Months 3 and 6 combined was 42% (8 mg infusion every 2 weeks), with high-titer ADA positive patients losing efficacy prior to 6 months.1 The 6-month results from the MIRROR open-label trial (79% response rate [11/14], 95%CI 49-95%)4 suggest that methotrexate (MTX) administered in conjunction with pegloticase increases treatment responder rate.Objectives:To examine longer-term (12-month) exploratory endpoints from the MIRROR open-label trial, including joint, overall health, and gout global assessments. Serial dual-energy computed tomography (DECT) images were also examined when available.Methods:Adult patients with uncontrolled gout (sUA ≥6 mg/dL with ≥1 of the following: sUA ≥6 mg/dL despite ULT use, intolerance to ULT, or functionally limiting tophaceous deposits) were included. Patients with immunocompromised status, G6PD deficiency, severe renal impairment, or MTX contraindication were excluded. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase therapy (8 mg biweekly infusion for up to 52 weeks). Exploratory outcomes included mean change from baseline (CFB) in number of affected joints (tophi, swollen, tender), Health Assessment Questionnaire (HAQ) scores (Disability Index [DI; score 0−3], Pain [score 0−100], Health [score 0−100]), and Gout Global Assessments (Patient, Physician; score 0−10). A decrease in these measures reflects clinical/patient-reported health improvement. Change in urate deposition volume, as measured on DECT imaging, was also examined as available. Analyses were performed on the modified intent-to-treat (mITT) population (≥1 pegloticase infusion received).Results:14 patients (all male, mean±SD age: 49.3±8.7 years) made up the mITT population. Mean±SD sUA prior to pegloticase treatment was 9.2±2.5 mg/dL and 13 patients had visible tophi. 3 patients discontinued due to 2 consecutive sUA levels >6 mg/dL and 1 patient completed the study at week 24 (pre-protocol amendment extending treatment from 24 to 52 weeks). 10 patients completed the 52-week study. Of these, 8 patients received 26 infusions and 2 patients received 12 infusions, discontinued pegloticase after meeting their treatment goal at 24 weeks, and started allopurinol while remaining in study under observation. At week 52 (n=10, sUA=1.1±2.5 mg/dL), the number of affected joints improved, along with HAQ measures (Figure 1). Global Assessments of Gout also improved (Physician: CFB=-5.7±2.6, Patient CFB=-4.6±2.1) and majority of subjects had a score of 0 or 1 (0=“excellent health”) at week 52 (Physician: 0.3±0.5, Patient: 1.1±1.3). Two patients had available DECT imaging. One received pegloticase/methotrexate co-therapy thru week 52 and had a marked reduction in total urate volume (baseline: 128.76 cm3, week 52: 1.33 cm3). The other received only 5 pegloticase infusions, but also showed total urate volume reduction (baseline: 59.20 cm3, week 10: 25.07 cm3). Both patients displayed improvement in bone erosion healing.Conclusion:These 12-month exploratory endpoints of the MIRROR open-label trial suggest that MTX/pegloticase co-therapy results in meaningful changes in clinical evaluations (tophaceous, tender, and swollen joint counts), and patient-reported outcomes (pain, disability) in patients with uncontrolled gout.References:[1]Sundy JS et al. JAMA 2011;306:711-20[2]Baraf HS et al. J Clin Rheumatol 2014;20:427-32[3]Lipsky PE et al. Arthritis Res Ther 2014, 16:R60[4]Botson JK et al. J Rheum 2020 [Epub ahead of print]Disclosure of Interests:John Botson Speakers bureau: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Consultant of: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Grant/research support from: Horizon Therapeutics and Radius Health, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Lycera, Can-Fite BioPharma, Scipher Medicine, Inmedix, and Vorso, Consultant of: Bristol Myers Squibb, Corona, Lilly, AbbVie, Amgen, Arena, GlaxoSmithKline, Gilead Sciences, Horizon Therapeutics, Lycera, Novartis, Pfizer, Roche, Samsung, Scipher Medicine, and Set Point, Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, Lilly and Sanofi, Jeff Peterson Speakers bureau: Horizon Therapeutics plc, Grant/research support from: Horizon Therapeutics plc.

Background:In an open-label, single-arm trial in adult patients with uncontrolled gout (MIRROR open-label [OL] trial) evaluating pegloticase co-treatment with methotrexate (MTX); 78.6% patients were responders, defined as maintenance of serum uric acid 1. MTX co-treatment is shown to improve the pharmacokinetics (PK) of biologics by attenuating the formation of anti-drug antibodies2.Objectives:To determine the systemic exposures of pegloticase and methotrexate polyglutamate(s) (MTX-PGs) in uncontrolled gout patients receiving pegloticase and MTX; to evaluate the effect of MTX on the PK of pegloticase in comparison to historical pegloticase monotherapy trials (C0405 and C0406)3, 4; and to evaluate the immunogenicity of pegloticase in co-treatment with MTX.Methods:In the MIRROR OL trial, MTX (15 mg/week) was given orally 4 weeks prior to the first pegloticase dose and continued weekly, in combination with pegloticase 8 mg given intravenously every 2 weeks, for a treatment duration of up to 52 weeks. Pre-infusion samples were collected to measure MTX-PGs in red blood cells. Pre- and post-infusion blood samples were obtained to measure the peak (Cmax) and trough (Cmin) concentrations of pegloticase at multiple visits. Anti-drug antibody blood samples were collected at multiple visits. The impact of MTX on pegloticase PK was evaluated by comparing pegloticase exposures with MTX from this trial to historical monotherapy data (C0405 and C0406)3, 4. The observed pegloticase concentrations with MTX were also overlaid with the 90% prediction interval based on the population PK model5 from C0405 and C0406.Results:Pegloticase and MTX-PG levels were determined in 14 patients. The 11 responders were generally associated with higher pegloticase exposures than the non-responders, especially Cmin (Figure 1). Concomitant treatment of MTX resulted in fewer patients with Cmin below quantitation limit (BQL) (5/14 [36%] with MTX vs 63/82 [77%] without MTX), and higher overall Cmin (median: 1.03 µg/ml with MTX vs BQL without MTX); Cmax was slightly higher (median [Q1, Q3]: 2.11 [1.65, 2.59] µg/mL with MTX vs 1.51 [BQL, 2.48] µg/mL without MTX). Pegloticase co-treatment with MTX resulted in more concentrations above the predicted median value of pegloticase, compared to monotherapy. ADA data is consistent with pegloticase PK and efficacy. Significant increase in ADA titers were only observed in 2 subjects (both were non-responders) at time corresponding to the loss of pegloticase exposure and increases in sUA levels. Concentrations of MTX-PGs were maintained during the treatment course, suggesting compliance of MTX administration. There was no apparent difference in concentrations of MTX-PGs between responders and non-responders.Conclusion:Pegloticase 8 mg IV every 2 weeks co-treatment with MTX 15 mg weekly resulted in fewer patients with pegloticase Cmin below the quantification limit (BQL) and gave higher overall trough concentrations (Cmin) compared to pegloticase monotherapy in the phase 3 studies.Pegloticase 8 mg IV every 2 weeks co-treatment with MTX 15 mg weekly was associated with an improved response rate for pegloticase in association with improved drug levels in these patients with uncontrolled gout compared to pegloticase monotherapy in the phase 3 studies.References:[1]Botson J., et al. J Rheumatol. 2020; doi: 10.3899/jrheum.200460[2]Goss S. L., et al. Clin Ther;2018, 40 (2).[3]Lipsky P. E., et al. Arthritis Res Ther;2014, 16 (2).[4]Sundy J. S., et al. JAMA;2011, 306 (7).[5]Yue C. S., et al. ASCPT, Atlanta, 2010.Disclosure of Interests:Yang Song Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Yan Xin Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Canfite, Inmedix, Lycera, Vorso, Scipher, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Eli Lilly, Amgen, Jason Chamberlain Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Colleen Canavan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Srini Ramanathan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

Background:Rheumatoid arthritis (RA) has been shown a strong genetic association with particularHLA–DRB1alleles containing shared epitope (SE). However, whether SE is clinically useful in treatment choices is insufficiently investigated1and previous studies have presented mixed findings in the role of SE in the response of TNFi therapies2,3.Objectives:To assess the role of SE in response to TNFi treatment in real-world RA patients (pts).Methods:Pts enrolled in a large RA registry, Brigham and Women’s Hospital RA Sequential Study, with known SE and received TNFi therapies were included for the analysis. TNFi pts were identified by the first-time use of the drugs between March 2003 to June 2018. For this analysis, all pts were followed up to 1 year. Summary statistics are reported for demographics, serostatus and disease activity (DA) at baseline and follow-up, stratified by SE status. Given the strong association of SE and anti-citrullinated protein antibody (ACPA), the analysis was further stratified by ACPA status. The effect of SE on change in DA was assessed using linear regression model with age, gender, RA disease duration, baseline DA, smoking status, SE, ACPA and ACPA-SE interaction as covariates.Results:Of the 484 TNFi pts included in the study, 68.8% were SE+. SE+ pts (vs SE-) were more likely to be rheumatoid factor positive, have erosive disease and a higher disease duration, irrespective of ACPA status. No difference in the change of DA was observed by SE. In SE- pts, ACPA+ pts had a greater reduction of DA than ACPA- pts (Table 1). After accounting for baseline differences, there was no significant effect of SE status on the mean change from baseline in any of the 3 DA measures.(Figure 1) The change in DA was not associated with ACPA but was significantly affected by disease duration and baseline DA.Table 1.Disease Activity in TNFi Patients, Stratified by SE and ACPA StatusParameterSE+ (1 & 2 alleles, n=333)SE- (n=151)ACPA+ACPA–OverallACPA+ACPA-Overall(n=264)(n=69)(n=333)(n=90)(n=61)(n=151)Baseline, Mean (SD)DAS28 CRP3.94 (1.69)3.57 (1.61)3.86 (1.67)3.85 (1.49)3.45 (1.65)3.69 (1.57)CDAI23.06 (18.13)18.95 (15.96)22.25 (17.78)21.91 (15.96)17.72 (17.06)20.26 (16.48)SDAI24.08 (18.82)19.96 (16.59)23.27 (18.45)22.58 (16.34)18.55 (17.87)20.99 (17.01)Follow-up, Mean (SD)DAS28 CRP3.42 (1.55)2.69 (1.32)3.27 (1.53)3.19 (1.43)3.11 (1.53)3.16 (1.47)CDAI17.61 (15.53)12.11 (12.65)16.51 (15.14)15.15 (13.35)14.94 (14.73)15.07 (13.84)SDAI18.35 (15.73)12.45 (12.78)17.15 (15.34)15.31 (13.81)15.71 (15.45)15.46 (14.38)Change, Mean (SD)DAS28 CRP-0.48 (1.31)-0.65 (1.53)-0.52 (1.36)-0.52 (1.50)-0.24 (0.93)-0.42 (1.34)CDAI-4.29 (13.16)-4.79 (13.13)-4.39 (13.12)-6.45 (13.56)-2.63 (9.58)-4.99 (12.28)SDAI-4.74 (14.13)-5.07 (13.90)-4.80 (14.05)-6.87 (14.21)-2.97 (10.32)-5.41 (12.98)Figure 1.Linear Regression Model for Change in Disease Activity*Estimates, p-values are shown as data labels on the graphs; The above model is adjusted for age, gender, RA duration, smoking status, SE status, baseline DA, ACPA and ACPA*SE statusConclusion:This real-world study validates the finding from previous studies conducted in clinical settings that SE does not differentiate treatment response for TNFi therapies.References:[1]Saruhan-Direskeneli G, et al.Rheumatology (Oxford) 2007;46(12):1842-44[2]Skapenko A, et al.Clin Exp Rheumatol2019;37(5):783-790[3]Rigby W, et al.Annals of the Rheumatic Diseases2019;78(2):263-264Disclosure of Interests:Joe Zhuo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Joshua Bryson Shareholder of: I own shares of Bristol-Myers Squibb Company, Employee of: I am a paid employee of Bristol-Myers Squibb Company, Qian Xia Shareholder of: I own shares of Bristol-Myers Squibb Company, Employee of: I am a paid employee of Bristol-Myers Squibb Company, Niyati Sharma Consultant of: I work as a consultant for Bristol-Myers Squibb Company, Chidananda Samal Consultant of: I work as a consultant for Bristol-Myers Squibb Company, Sonie Lama Shareholder of: I own shares of Bristol-Myers Squibb Company., Employee of: I am a paid employee of Bristol-Myers Squibb Company., Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Nancy Shadick Grant/research support from: Mallinckrodt, BMS, Lilly, Amgen, Crescendo Biosciences, and Sanofi-Regeneron, Consultant of: BMS

Background:Abatacept (ABA) versus adaliMumab (ADA) comParison in bioLogic-naïvERA subjects with background MTX (AMPLE) was a Phase IIIb clinical trial to compare the safety, efficacy and radiographic outcomes of ABA vs ADA in patients with RA who exhibited an inadequate response to MTX and who were naïve to biologic DMARDs.1While both therapies demonstrated similar efficacy across multiple outcomes, their mechanisms of action (MoAs) are quite different; ABA is a T-cell co-stimulation modulator and ADA is a TNFα inhibitor. Previous transcriptomic analysis of the whole blood samples showed differential pharmacodynamic (PD) effects between the treatments.1–3Objectives:To expand our understanding of differential PD changes in the serum proteome over time in patients treated with ABA or ADA in AMPLE using a novel proteomic platform.Methods:Serum was available from 440 patients in AMPLE at four time points (Days 1, 85, 365 and 729). Serum samples from the patients in AMPLE and 123 healthy individuals with matching demographics were subjected to proteomic quantification by a highly multiplexed DNA aptamer technology with wide dynamic ranges (SomaLogic SomaScan®platform).4A linear model analysis was used to identify protein abundance changes over time and changes specific to treatment. Other covariates included in the model were country of origin, ethnicity and sex. Additionally, patient effect was adjusted for as a random factor.Results:Both treatments exhibited a significant PD effect on serum proteome over the course of the 2-year trial, with 73 proteins modulated by ABA and 125 by ADA. There were large overlaps between the two treatments, including proteins associated with RA, such as C-X-C motif chemokine ligand 13 (CXCL13), matrix metalloproteinase-3 (MMP3) and serum amyloid A1/A2 (SAA1/2). Changes in the levels of these proteins may be indicative of general improvement of the disease. The proteins modulated by the treatments were enriched in the G-protein coupled receptor (GPCR) signalling and innate immunity pathways. Among the proteins that exhibited significantly different PD effects between the treatments were CRP, CC chemokine ligand 17 (CCL17) and β-defensin 112 (Figure). While patients showed marked improvement in their symptoms after 2 years of treatment, the overall serum proteomic profiles of the patients were still different from those of a normal healthy population.Conclusion:The SomaScan®platform provides a robust method for quantifying the PD change in a broad portion of the serum proteome in clinical trials. In AMPLE, abatacept was more selective than adalimumab in modulating protein biomarkers in patients with RA, though there was large overlap in proteins modulated by both treatments. The treatment-specific changes may reflect the different MoAs leading to similar clinical outcomes. While patients in both groups benefited from treatments, their serum proteome remained notably different from that of a healthy population. Further analysis by responder status may provide additional links between the treatment responses and proteomic changes. Proteomic approaches as described in our study could contribute to clinical trials and help shape treatment strategies for patients with RA.References:[1]Schiff M, et al.Ann Rheum Dis2014;73:86–94.[2]Bandyopadhyay S, et al.Arthritis Rheum2014;66:Abstract 1520.[3]Sokolove J, et al.Ann Rheum Dis2016;75:709–14.[4]Gold L, et al.PLoS One2010;5:e15004.Disclosure of Interests:David Galbraith Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Minal Caliskan Employee of: Bristol-Myers Squibb, Omar Jabado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sarah Hu Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Michael Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo, Lily, Sanofi/Regeneron, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Crescendo, Gilead, Horizon, Lily, Pfizer, Roche, Sean Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Michael A Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sheng Gao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Background:The multi-biomarker disease activity (MBDA) score, adjusted for age, sex and adiposity (MBDAadj), has been shown to be better than several conventional disease activity measures for predicting risk for radiographic progression (RP) in patients with rheumatoid arthritis (RA).1Serologic status and other non-disease activity measures are also predictive of RP risk. Combining them with the MBDAadjshould result in a stronger prognostic test for RP than any one measure alone.Objectives:Develop a multivariate model for predicting risk for RP that includes the adjusted MBDA score and other known predictors of RP.Methods:Four RA cohorts were used, two for training (OPERA and BRASS, n=555) and two for validation (SWEFOT and Leiden, n=397). Each pair of cohorts was heterogeneous in disease duration and treatment history. BMI data were not available for one validation cohort, so a BMI surrogate was modeled using forward selection with the two training cohorts and 3 others (CERTAIN, InFoRM, RACER) (N=1411). An RP risk score was then trained using forward selection in a linear mixed-effects regression, considering disease-related and demographic variables as predictors of change in modified total Sharp score over one year (ΔmTSS), with a random effect on cohort. The RP risk score was validated as a predictor of RP with two cutoffs (ΔmTSS >3 and >5) using logistic mixed-effects regression. Odds ratios (OR) and 95% profile likelihood-based confidence intervals (CI) were calculated from the models and significance was assessed by likelihood ratio tests. Risk curves were generated to show probability of RP as a function of the RP risk score.Results:The BMI surrogate included leptin, sex, age and age2and correlated well with BMI (ρ = 0.76). In training, the most significant independent predictors of RP were MBDAadj(p = 0.00020), seropositivity (p = 9.3 x 10-5), BMI surrogate score (p = 0.013) and use of targeted therapy (p = 0.0026). The final model was: RP risk score = 0.024 x MBDAadj+ 0.093 if seropositive – 0.063 x BMI surrogate score – 0.61 if using a targeted therapy. In validation, the OR (95% CI) of the RP risk score for predicting ΔTSS >3 or >5 were 2.2 (1.6, 3.2) (p = 2.6 × 10-6) and 3.1 (2.0, 5.0) (p = 5.7 × 10-8), respectively (Figure 1). The odds of a patient having RP increases by 50% for each 21-unit or 15-unit increase in MBDAadj, for RP defined as ΔTSS >3 or >5, respectively.Figure 1.Conclusion:A multivariate model containing adjusted MBDA score, seropositivity, a BMI surrogate and use of targeted therapy has been trained and validated as a prognostic test for radiographic progression in RA.References:[1]Curtis, et al.Rheumatology [Oxford].2018;58:874Disclosure of Interests:Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Nancy Shadick Grant/research support from: Mallinckrodt, BMS, Lilly, Amgen, Crescendo Biosciences, and Sanofi-Regeneron, Consultant of: BMS, Cecilie Heegaard Brahe: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis, Saedis Saevarsdottir Employee of: Part-time at deCODE Genetics/Amgen Inc, working on genetic research unrelated to this project, Megan Horton Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Brent Mabey Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Darl Flake Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Rotem Ben-Shachar Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Eric Sasso Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Alexander Gutin Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Elena Hitraya Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Jerry Lanchbury Shareholder of: Myriad Genetics, Inc., Employee of: Myriad Genetics, Inc., Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB

Background:Gout is a painful inflammatory arthritis caused by persistently elevated serum uric acid (sUA) levels. Pegloticase, an infused recombinant PEGylated uricase, rapidly lowers sUA levels by converting uric acid to allantoin, a water-soluble molecule that is readily excreted by the kidneys. In the phase 3 clinical trials, 42% of patients1dosed with pegloticase every two weeks maintained sUA levels below 6.0 mg/dL during months 3 and 6 of pegloticase treatment. The loss of pegloticase efficacy has been attributed to the development of anti-drug antibodies (ADAs)1-3and these ADAs have been associated with infusion reactions (IRs).1,2Case reports4and prospective case series5, 6indicate that methotrexate (MTX) may allow patients to attain more complete therapeutic benefits, presumably through attenuation of pegloticase immunogenicity. The current study prospectively examines the efficacy and safety of MTX-pegloticase co-therapy in patients with uncontrolled gout.Objectives:To assess efficacy and safety of concomitant pegloticase and MTX therapy in patients with uncontrolled gout.Methods:Adult patients with uncontrolled gout who were beginning pegloticase therapy were considered for enrollment in this ongoing multicenter, open-label, efficacy and safety study of pegloticase with MTX co-treatment (NCT03635957). Patients were administered oral MTX (15 mg/week) and folate (1 mg/day) 4 weeks prior to the first pegloticase infusion (Day 1) and throughout the pegloticase treatment period. Blood was drawn prior to each infusion to measure sUA level, monitor clinical parameters, and examine for ADA development. All patients followed typical IR prophylaxis protocols (fexofenadine one day before and the morning of each infusion and acetaminophen and IV corticosteroid the morning of each infusion). Patients also received gout flare prophylaxis with either NSAIDs, colchicine or prednisone initiated at least 1 week prior to Day 1. The primary study outcome was the proportion of responders, defined as sUA Results:A total of 17 patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 months timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting stopping rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. One serious AE of bacterial sepsis occurred (resolved). AEs that occurred in >1 patient during the co-treatment period were: diarrhea and upper respiratory tract infection in 3 patients each, sinusitis, muscle strain, and hypertension in 2 patients each. Gout flares occurred in 12/14 (85.7%) patients. No new safety concerns were identified.Conclusion:An increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase (78.6%) when compared to the previously reported 42% using pegloticase alone.1These results support and reflect the improved response rates demonstrated in two prior case series.5,6A definitive randomized double-blinded trial evaluating pegloticase with MTX vs. pegloticase with placebo is ongoing.References:[1]Sundy JS et al.JAMA2011;306:711-20.[2]Baraf HS et al.J Clin Rheumatol2014;20:427-32.[3]Lipsky PE et al.Arthritis Res Ther2014;16:R60.[4]Bessen SY et al.Semin Arthritis Rheum2019;49:56-61.[5]Botson J, Peterson J.Ann Rheum Dis2019;78:A1289.[6]Albert JA et al.Arthritis & Rheumatology2019;71(S10):A1236.Disclosure of Interests: :John Botson Grant/research support from: Horizon Therapeutics (PI and study site), Radius Health (study site), Consultant of: Horizon Therapeutics, Speakers bureau: Celgene, Eli Lilly, Horizon Therapeutics, Mallinckrodt, Novartis, Pfizer, Paul M. Peloso Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Jeff Peterson Grant/research support from: Abbvie, UCB, Smith Klein, Horizon Therapeutics, Consultant of: Lilly, Norvartis, Horizon Therapeutics, Speakers bureau: Lilly, Novartis, Horizon Therapeutics, Abbvie, Genentech

To develop a comprehensive listing of the greatest unmet scientific and clinical needs in rheumatology. The 20th annual international Targeted Therapies meeting brought more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of five disease-specific groups with 20–30 experts assigned to each group based on expertise. Specific groups included rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus, connective tissue diseases and a basic science immunology group spanning all of these clinical domains. In each group, experts were asked to consider recent accomplishments within their clinical domain in the last year and update the unmet needs in three categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. While progress was noted among some of previously identified needs, both new needs were identified and themes from prior meetings were re-iterated: the need for better understanding the heterogeneity within each disease, and for identifying preclinical states of disease allowing treatment and prevention of disease in those at risk, and the elusive ability to cure disease. Within the clinical care realm, improved comorbidity management and patient-centred care continue to be unmet needs, and the need for new and affordable therapeutics was highlighted. Unmet needs for new and accessible targeted therapies, disease prevention and ultimately cure remain a priority in rheumatology.

Methotrexate (MTX) is known to improve blood levels and clinical outcome to anti-tumour necrosis factor (anti-TNF) therapy by reducing the formation of antidrug antibodies.1 Recent findings indicate that MTX prevents immunisation against TNF inhibitors through de novo purine biosynthesis inhibition and generation of immunosuppressive adenosine.2 This effect is mediated by activation of MTX prodrug to MTX polyglutamates (MTXPG), and we previously reported that MTXPG levels were associated with improved steady state levels of infliximab.3 In this study, we extended these observations and evaluated the impact of MTXPG on adalimumab and etanercept levels. The study was cross-sectional by design, multicentred (three sites) and enrolled 169 consecutive consented adult rheumatoid arthritis subjects under MTX in combination with adalimumab (83 subjects) or etanercept (86 subjects). All patients enrolled were inadequate responders to MTX prior to starting anti-TNF therapy and had received MTX with anti-TNF therapy for least 3 months. At the time of a single visit, anticoagulated blood was collected randomly …

Objectives Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR). Methods 1041 patients with moderate–severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks. Results There were no significant differences in ACR20 responses at week 24 or mTSS change from baseline at week 52 among treatment groups. Declines were seen in CD20+ B cells and immunoglobulin levels in tabalumab groups, but not placebo: B cells (−15.0%, −18.8%, 5.3%, in the 120/Q4W, 90/Q2W, and placebo groups, respectively); IgM (−16.3%, −19.4%, −0.1%), IgA (−11.4%, −4.7%, 1.2%) and IgG (−8.6%, −7.8%, 0.1%). Discontinuations due to adverse events were similar between groups. Numerically more serious infections were reported in tabalumab groups (1.7%, 0.6%, 0.3%); numerically more injection-site reactions were reported in the 90/Q2W group (2.3%, 4.3%, 2.3%). Conclusions Neither clinical efficacy nor significant safety signals were observed with tabalumab despite evidence of biological activity. This study was terminated early due to insufficient efficacy. Trial registration number NCT01198002.

As difficult as it may now be to believe, there was a time when it was unclear whether methotrexate (MTX) would be tolerated in the long-term treatment of patients with rheumatoid arthritis (RA). Data from Scandinavian patients with psoriasis indicated that there was an incidence of hepatic cirrhosis of 26%.1 There was thus a need to establish the actual risk of clinically significant liver disease (CSLD) in patients with RA treated for many years with the drug. Because of the obvious clinical effectiveness of MTX, and the absence of effective alternatives in the first few decades of its widespread use, there was a need to demonstrate the ability to sustain treatment without creating a population of subjects with chronic liver disease. Thus, studies of hepatic safety were performed that included both baseline and annual liver biopsies.2 3 This experience along with other publications on hepatic safety of MTX4 lead to the publication of suggested guidelines for the hepatic monitoring of MTX.5 The guidelines were derived from the experience from baseline and annual liver biopsies prospectively performed over a period of many years along with regular monitoring of hepatic transaminase enzymes and serum albumin with a mean interval of 37.7 days between the sequential laboratory measures.6 It was thus possible to seek correlations of any elevation in transaminase enzymes with the evolution of hepatic histological changes by different grading systems, with particular attention paid to early fibrosis.2 In doing so, we …

Investigator-initiated trials, some of which have been referred to as comparative effectiveness trials, pragmatic trials, or strategy trials, are sometimes considered to be of greater clinical importance than industry-driven trials, because they address important but unresolved clinical questions that differ from the questions asked in industry-driven trials. Regulatory authorities have provided methodological guidance for industry-driven trials for the approval of new treatments, but such guidance is less clear for investigator-initiated trials. The European League Against Rheumatism (EULAR) task force for the update of the recommendations for the management of rheumatoid arthritis has critically looked at the methodological quality and conduct of many investigator-initiated trials, and has identified a number of concerns. In this Viewpoint paper, we highlight commonly encountered issues that are discussed using examples of well-known investigator-initiated trials. These issues cover three themes: (1) design choice (superiority vs non-inferiority designs); (2) statistical power and (3) convenience reporting. Since we acknowledge the importance of investigator-initiated research, we also propose a shortlist of points-to-consider when designing, performing and reporting investigator-initiated trials.

Objective Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). Methods Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15–25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape

Objectives Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA).\ud \ud Methods Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12.\ud \ud Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP

There is little disagreement that screening for latent tuberculosis (TB) infection (LTBI) prior to biologic therapy is necessary. Unfortunately, there is much less agreement with regard to how best to accomplish this task. A decade ago, we had just one screening tool, the tuberculin skin test (TST), and screening algorithms for such patients were presumably straightforward. With the recent introduction and fairly widespread adoption of interferon γ release assays (IGRAs), clinicians have a new tool that theoretically improves their ability to screen. However, since the introduction of IGRAs, the studies conducted within the biologic therapy setting that compare IGRAs and TST have been fraught with a lack of statistical power and heterogeneity (eg, differing underlying inflammatory disease states, variable immunosuppressive therapies or underlying BCG status),1 ,2 and firm conclusions regarding the relative sensitivity of these two screening tests (Quantiferon-Gold TB In-tube (QFT-IT) or the T-SPOT. TB assay) is only now becoming more clear. Kleinert et al and Mariette et al have published two studies to overcome some of these limitations,3 ,4 and along with other data, we believe the time has arrived to offer a screening algorithm that is practical in its approach. While we believe IGRAs have become the preferred screening tool in this setting, unfortunately these recent data argue that an IGRA alone is insufficient to identify all patients at risk. TB is rumoured to infect nearly a third of the world's population. The risk of LTBI progression to active TB is clearly heightened by antitumour necrosis factor α (anti-TNF) therapy, and the absolute risk of this complication is driven by the background prevalence of LTBI in a particular region and the probability of infection in an individual. Within low prevalence countries, rates of anti-TNF-associated TB are typically 5–10-fold higher than background general populations, …

Objectives Evaluate the effi cacy of intravenous golimumab 2 mg/kg+methotrexate (MTX) in patients with active rheumatoid arthritis (RA) receiving MTX. Methods Patients (n=592) with active disease (≥6/66 swollen, ≥6/68 tender joints, C-reactive protein ≥1.0 mg/dl, rheumatoid factor positive and/or anticyclic citrullinated protein antibody positive at screening) despite MTX (15‐25 mg/week) participated in this double-blind, placebo-controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg, or placebo infusions at weeks 0 and 4 and every (q) 8 weeks; patients continued MTX. Placebo patients with

Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect.Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time.The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p0.001). Associations were found between SE and serum levels of rheumatoid factor (p0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p0.001, with correlation of 0.25) but not with serum C-reactive protein.The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

ObjectivesTo examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study.MethodsIn this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1–Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates.ResultsBaseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1–Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group.ConclusionsIn AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab.Trial registration numberNCT00929864.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as ‘opportunistic infections’ (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as ‘indicator’ infections, defined as specific pathogens or presentations of pathogens that ‘indicate’ the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

Investigator-initiated trials, some of which have been referred to as comparative effectiveness trials, pragmatic trials, or strategy trials, are sometimes considered to be of greater clinical importance than industry-driven trials, because they address important but unresolved clinical questions that differ from the questions asked in industry-driven trials. Regulatory authorities have provided methodological guidance for industry-driven trials for the approval of new treatments, but such guidance is less clear for investigator-initiated trials. The European League Against Rheumatism (EULAR) task force for the update of the recommendations for the management of rheumatoid arthritis has critically looked at the methodological quality and conduct of many investigator-initiated trials, and has identified a number of concerns. In this Viewpoint paper, we highlight commonly encountered issues that are discussed using examples of well-known investigator-initiated trials. These issues cover three themes: (1) design choice (superiority vs non-inferiority designs); (2) statistical power and (3) convenience reporting. Since we acknowledge the importance of investigator-initiated research, we also propose a shortlist of points-to-consider when designing, performing and reporting investigator-initiated trials.

ObjectivesOSKIRA-4 evaluated the efficacy of fostamatinib monotherapy versus placebo on the signs and symptoms of rheumatoid arthritis over 6 weeks by Disease Activity Score C reactive protein (DAS-28(CRP)) and assessed non-inferiority to adalimumab monotherapy at Week 24 by DAS-28(CRP).MethodsOverall, 279 patients not currently taking disease-modifying antirheumatic drugs were randomised to: (A) fostamatinib 100 mg twice daily for 24 weeks plus placebo injection every 2 weeks (PBOI); (B) fostamatinib 100 mg twice daily for 4 weeks, then 150 mg once daily up to Week 24, plus PBOI; (C) fostamatinib 100 mg twice daily for 4 weeks, then 100 mg once daily up to Week 24, plus PBOI; (D) adalimumab 40 mg every 2 weeks for 24 weeks, plus oral placebo twice daily; or (E) oral placebo twice daily for 6 weeks, plus PBOI, then a switch to arm A or B.ResultsFostamatinib demonstrated a significant improvement in DAS-28(CRP) score from baseline versus placebo at Week 6 for arms A and B, but not C. Fostamatinib was significantly less effective than adalimumab at Week 24 based on DAS-28(CRP). Adverse events observed with fostamatinib treatment were consistent with those reported in previous studies, including hypertension and diarrhoea.ConclusionsFostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24.Trial registration numberClinicaltrials.gov: NCT01264770.

We would like to thank van der Maas and colleagues1 for their interest in, and useful feedback on, our review.2 They raise several important points. First, regarding the interpretation of the studies included in the review, we focused on studies examining discontinuation of biologic disease modifying antirheumatic drugs (DMARDs) that examined patient outcomes. Thus, we had difficulty in …

We would like to thank Dr Boers for his critical comments on our study raised in his eLetter,1 and address his concerns regarding our manuscript.2 First, we would like to emphasise that we are in support of the statements in the guidelines issued by the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) in early 2011,3 and acknowledge that the Disease Activity Score 28 erythrocyte sedimentation rate (DAS28(ESR)) based definition of clinical remission (DAS28(ESR)

Background RA leads to high burden on patient (pt) work, functioning and quality of life. Certolizumab pegol (CZP)+MTX improves physical function,1 and workplace and household productivity,2,3 in established and early active RA. Here we report impact of maintaining, reducing frequency or stopping CZP from Week (Wk) 52 to 104 in pts who achieved sustained low disease activity (sLDA) following 1 year (yr) of CZP+optimized MTX. Objectives To assess effect of 2 dosing frequencies of CZP+MTX vs stopping CZP on physical function and workplace/household productivity in Period 2 of C-EARLY, a phase 3 study in early RA pts with severe progressive disease. Methods CZP+MTX-treated pts achieving sLDA (DAS28[ESR]≤3.2 at Wks40 and 52) in C-EARLY Period 1 (NCT01519791)4 entered Period 2 (NCT01521923), a randomized, double-blind study. Pts were randomized 2:3:2 to CZP standard dose (200mg Q2W+MTX), CZP reduced-frequency dose (200mg Q4W+MTX) or CZP stopped (PBO+MTX). Physical function (HAQ-DI) and %pts achieving normative physical function (HAQ-DI≤0.5) from Wk52 to 104 are reported (ANCOVA model with factors treatment, region, time since diagnosis at BL [≤4 vs >4 months], and BL/Wk52 values as covariate and logistic regression models [treatment, region and time since diagnosis at BL as factors] respectively; CZP stopped as comparator; LOCF). Workplace/household productivity (Work Productivity Survey, WPS)5 at Wk52 and 104 are reported (LOCF); non-parametric bootstrap-t method (CZP stopped as comparator). Results In Period 2, 289 pts were included in the full analysis set: CZP Q2W+MTX (n=84), CZP Q4W+MTX (n=126) or PBO+MTX (n=79). Improvements in physical function were maintained from Wk52 to 104 in CZP Q2W+MTX (HAQ-DI mean [SD] 0.32 [0.42] to 0.37 [0.48], respectively) and CZP Q4W+MTX (0.33 [0.49] to 0.41 [0.57]), whereas deterioration was seen in PBO+MTX (0.33 [0.47] to 0.57 [0.65]). %pts with normative function was generally maintained between Wk52 to 104 in CZP Q2W+MTX (80.7% to 71.4%) and CZP Q4W+MTX (80.2% to 70.6%), but decreased in PBO+MTX pts (75.9% to 57.0%). At Wk104, employed CZP Q2W+MTX and CZP Q4W+MTX pts maintained on average the improvements in workplace productivity, whereas worsening was seen in pts stopping CZP (Table). Similar trends were observed in household productivity and need for regular assistance (Table). Conclusions Pts continuing CZP treatment (both dose frequencies) after 1yr further maintained improvements at 2yrs in physical function and workplace/household productivity, compared with pts who stopped CZP. References Strand V. Arthritis Res Ther 2009;11:R170; Kavanaugh A. Arthritis Care Res 2009;61(11);1592–1600; Emery P. Ann Rheum Dis 2015;74(S2);712; Weinblatt M. Arthritis Rheumatol. 2015;67(S10); Osterhaus J. Arthritis Res Ther 2009;11:R73 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest C. Bingham Consultant for: UCB Pharma, P. Emery Consultant for: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, X. Mariette Grant/research support from: Pfizer, GlaxoSmithKline and Roche. Consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, O. Purcaru Employee of: UCB Pharma, V. Bykerk: None declared

Background Clinical studies demonstrated that baseline disease activity including C-reactive protein (CRP) level was a predictor variable for radiographic joint damage in patients with rheumatoid arthritis (RA). Objectives To identify variables associated with radiographic joint damage in patients with RA treated with intravenously administered golimumab (GLM) + Methotrexate (MTX) or MTX + placebo (PBO). Methods GO-FURTHER was a multicenter, randomized, placebo-controlled study. Adult patients with active RA despite MTX therapy (≥6 tender and swollen joints, CRP ≥1.0 mg/dL, and RF and/or anti-CCP positive) were randomized to placebo (PBO) + MTX or GLM (2mg/kg) plus MTX at week 0, 2, and every 8 week thereafter (GLM group). Patients in PBO group with Sharp score (TSS). The correlations of TSS with hemoglobin, disease activity score (DAS28-CRP)and physical function evaluated with Health Assessment Questionnaire (HAQ) were assessed using Spearman9s correlation or multivariable liner regression model. Anemia was defined based on World Health Organization (WHO) criteria as Hgb Results Moderate to severe RA was demonstrated by a mean DAS28 score of 5.9 with TSS of 48.5 in all patients group at baseline. In linear regression models, baseline DAS28, HAQ score, and Hgb level was correlated with baseline TSS with Spearman9s correlation coefficient (r) of 0.148 (p Conclusions Hemoglobin level is an independent variable predicting radiographic progression in MTX refractory RA patients. Disclosure of Interest R. Westhovens Grant/research support from: Janssen R & D, LLC, C. Han Employee of: Johnson & Johnson Pharmaceutical Services, LLC, M. Weinblatt Grant/research support from: Janssen R & D, LLC, L. Kim Employee of: Janssen R & D, LLC, E. Hsia Employee of: Janssen R & D, LLC, D. Parenti Employee of: Janssen Scientific Affairs, LLC, S. Kafka Employee of: Janssen Scientific Affairs, LLC, C. Bingham III Grant/research support from: Janssen R & D, LLC

Background Baricitinib (bari), a JAK1 and JAK2 inhibitor, was efficacious compared to placebo (PBO) and adalimumab (ADA) in a 52-week (Wk) Ph 3 study in patients (pts) with active rheumatoid arthritis (RA) and an inadequate response (IR) to methotrexate (MTX) 1 . Objectives To evaluate changes in lipid and lipoprotein profile over 52 wks of treatment with bari or ADA compared with PBO in the aforesaid study. Methods MTX-IR pts with active RA were randomized 3:3:2 to bari 4mg once daily (QD), PBO, or ADA 40mg biweekly. Lipid profile was evaluated at baseline and at Wks 12, 24, and 52 and nuclear magnetic resonance (NMR)-measured lipoprotein particle size and number at baseline and Wk 12. Results Treatment with both bari and ADA resulted in significant mean increases from baseline to Wk 12 in total cholesterol (PBO -0.2%, bari 15%, ADA 7%), triglycerides (PBO 1%, bari 17%, ADA 12%), LDL-C (PBO -0.6%, bari 16%, ADA 9%), and HDL-C (PBO 0.8%, bari 17%, ADA 8%). These increases persisted through Wk 52. The NMR lipoprotein profile revealed similar changes for bari and ADA relative to PBO regarding an increase in large LDL, a decrease of all types of small LDL, and increases in IDL, VLDL and subfractions, and total HDL as well as large and small HDL particles (Table 1). Significant increases in total LDL particle numbers were not observed with either bari or ADA. Conclusions The increase in LDL-C and HDL-C with both bari and ADA is accompanied by an increase in large LDL, total HDL particles and a decrease in small LDL. The nature of these changes may potentially indicate a more atheroprotective profile than that of the PBO group. References Taylor et al. Arthritis Rheumatol 2015;67(suppl10). Abstract 2L. Disclosure of Interest P. Taylor Grant/research support from: UCB, GlaxoSmithKline, Celgene, Consultant for: UCB, Eli Lilly & Company, Pfizer, Galapagos, Merck, GSK, AbbVie, Takeda, BMS, E. Keystone Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, F. Hoffman-La Roche Inc, Janssen, Eli Lilly & Company, Novartis, Pfizer, Sanofi-Aventis, Consultant for: Abbott, AstraZeneca, Biotest, BMS, F. Hoffmann-La Roche, Genentech, Janssen, Eli Lilly & Company, Merck, Pfizer, UCB, Speakers bureau: Abbott, Amgen, AstraZeneca, BMS Canada, F. Hoffmann-La Roche, Janssen, Pfizer, UCB, Y. Tanaka Grant/research support from: Mistubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Celgene, Daiichi, Eli Lilly & Company, Galapagos, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, Employee of: Director Imaging Rheumatology BV, J. Zhong Employee of: Quintiles Transnational, Inc, S. Thanabalasundrum Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, G. Ruotolo Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Rooney Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Zuckerman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. de Bono Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly & Company, Crescendo Bioscience, Pfizer, AbbVie

Background Baricitinib (bari), an oral JAK1 and JAK2 inhibitor, was efficacious in a Ph 3 study (RA-BEAM) in RA patients (pts) with active disease and an inadequate response (IR) to MTX. 1 Objectives To evaluate patient-reported outcomes (PROs) from RA-BEAM. Methods Pts on stable background MTX were randomized to placebo (PBO), bari 4 mg QD, or adalimumab (ADA) 40 mg Q2W. PROs listed in the table and the Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) were collected on electronic tablets during study visits. Bari vs. PBO and bari vs. ADA were assessed with ANCOVA and logistic regression models. Results 1305 pts were randomized. Functional disability at baseline (mean HAQ-DI) was: 1.55, 1.57, 1.59 for PBO, bari, and ADA, respectively. Compared to PBO, bari was superior in physical function, Pt9s Global Assessment of Disease Activity (PtGDA), pain, fatigue and quality of life (physical component score [PCS]), at Wk 12 and 24. Compared to ADA, bari was superior in physical function, PtGDA, and pain at Wks 12, 24 and 52. Compared to PBO, a similar proportion of bari and ADA pts were employed throughout the study. Statistically significant improvements in all components of the WPAI-RA (absenteeism, presenteeism, work productivity loss and activity impairment) were seen in the bari pts compared to PBO at Wk 12; statistically significant improvements were seen for work loss and activity impairment for bari pts compared to ADA at Wk 12. Conclusions In this Ph 3 study of RA patients with an IR to MTX, treatment with bari resulted in significant improvement in most PROs compared with PBO or ADA, including functional disability, pain, and fatigue. References Taylor et al. Arthritis Rheumatol 2015;67(S10) Disclosure of Interest E. Keystone Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Eli Lilly and Company, Merck, Pfizer Pharmaceuticals, UCB, P. Taylor Consultant for: Eli Lilly & Company, UCB, Pfizer, Galapagos, AbbVie, Takeda, Bristol-Myers Squibb, Y. Tanaka Consultant for: Eli Lilly & Company, AbbVie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers Squibb, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, GlaxoSmithKline, UCB, Teijin, MSD, Santen, Taisho-Toyoma, Kyowa-Kirin, C. Gaich Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, A. DeLozier Employee of: Eli Lilly and Company, A. Dudek Consultant for: Eli Lilly and Company, J. Velasco Zamora Consultant for: Eli Lilly and Company, J. Covarrubias Cobos Consultant for: Eli Lilly and Company, S. de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, V. Arora Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, L. Yang Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, B. Linetzky Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Weinblatt Consultant for: Eli Lilly & Company, AbbVie, Pfizer, Crescendo Bioscience

Background Mavrilimumab, a fully human monoclonal antibody, which targets granulocyte-macrophage colony-stimulating factor receptor-α, has demonstrated efficacy and an acceptable safety profile in prior 12- and 24-week studies.1,2 Objectives This analysis evaluated all long-term (LT) safety and efficacy, through 74 weeks of treatment, of mavrilimumab. Methods This open-label extension (OLE) study (NCT01712399) enrolled adult rheumatoid arthritis (RA) patients (pts) who had completed the EARTH EXPLORER 12 and 2 (NCT01715896) Phase IIb studies or were rescued as inadequate responders (from Week 12). Pts received subcutaneous mavrilimumab 100 mg every other week (eow), consistent with data from the Phase IIa study1. The primary objective was to assess the LT risk:benefit ratio of mavrilimumab via evaluation of i) Treatment emergent adverse events (TEAEs), TE serious AEs (TESAEs), and independently adjudicated pulmonary function tests (PFTs) ii) Exploratory LT efficacy endpoints (DAS28–CRP/ACR responses). AEs with onset date after start of mavrilimumab are presented. Change from baseline (BL) in modified Total Sharp Score (mTSS) was used to explore radiographic progression in EARTH EXPLORER 1 pts. Results At the 74 week (includes original study) cutoff, 391 pts had been enrolled in the OLE study. Of these, 329 (84.1%) continued on treatment, 62 (15.9%) discontinued (due to withdrawal of consent, 9 [2.3%]; adverse event, 7 [1.8%]; non study-related site closure, 20 [5.1%]; other, 24 [6.1%]; lost-to-follow-up, 1 [0.3%]; death [sudden cardiac arrest, preferred term cardiopulmonary failure], 1 [0.3%]), and 239 (61.1%) were assessed for efficacy at Week 74. Between the Phase IIb and OLE studies, 440 pts received mavrilimumab, with a safety exposure of 603 pt years (yr) and median duration of 1.6 yr. Most common TEAEs (n [/100 pt yr]) were nasopharyngitis (51 [8.45]), bronchitis (36 [5.97]) and hypertension (32 [5.30]); the serious infection rate was 1.82/100 pt yr. Pulmonary events/defined PFT changes occurred in a few pts and were generally transient with no signal identified (Table). Mavrilimumab demonstrated sustained efficacy (DAS28–CRP/ACR responses) (Table). After 74 weeks of treatment, 68% of pts showed no radiographic progression ( Conclusions Mavrilimumab continues to demonstrate a sustained efficacy and safety profile in pts with active RA, over the 74 week treatment duration reported. Although mavrilimumab 100 mg eow is suboptimal compared with 150 mg eow in DMARD-IR pts,2 efficacy results are comparable with those of previous studies.1,2 References Burmester G, et al. Ann Rheum Dis 2013;72:1445–1452 Burmester G, et al. Arthritis Rheum 2014;66:S1231 Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Joint senior authors: D. Close and M. Weinblatt Disclosure of Interest G. Burmester Consultant for: MedImmune, I. McInnes Grant/research support from: Research award to University of Glasgow, Consultant for: MedImmune, AstraZeneca, J. Kremer Shareholder of: Corrona, Grant/research support from: Abbvie, Amgen, Genentech, Lilly, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer, Employee of: Corrona, P. Miranda Grant/research support from: Clinical trials Amgen, Medimmune, Janssen, Pfizer, Celltrion, Abbott, Sanofi, Actelion, Merck & Co, Boehringer, BMS, Consultant for: Pfizer for Etanecept (fee less than USD5000), J. Vencovský Consultant for: Pfizer, Servier, Samsumg, Eli lilley, BMS, Novartis, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close, Employee of: MedImmune, M. Weinblatt, Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche

Background Baricitinib (bari), a JAK1 and JAK2 inhibitor, showed significant improvements across multiple measures of disease activity as early as week (wk) 1 that were maintained through wk 52 in ph 3 studies of patients (pts) with active RA.1,2 Objectives To determine if, in bari-treated pts, early changes in disease activity predicted later achievement of low disease activity (LDA) or remission. Methods 1305 pts with inadequate response to methotrexate (MTX) were randomized in RA-BEAM (3:3:2, oral PBO/4 mg bari QD/SC injection adalimumab [ADA] Q2W, 52 wks); 584 MTX-naive pts were randomized in RA-BEGIN (4:3:4, oral MTX QW/4 mg bari QD/4 mg bari QD+MTX QW, 52 wks). Improvement from baseline (BL) to wk 4 was used to predict LDA or remission defined by Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) at wks 12/24 (bari 4 mg arm, both studies). Early responder and early nonresponder were predefined as Clinical Disease Activity Index (CDAI) improvement ≥6 and Results Compared to PBO or ADA (RA-BEAM) or MTX (RA-BEGIN), treatment with bari was associated with rapid decrease in DAS28 and CDAI from wk 1.1,2 By wk 4, 86% (RA-BEAM) and 85% (RA-BEGIN) of bari pts had a CDAI decrease ≥6. In both studies, LDA/remission rates at wks 12/24 were higher in pts with CDAI improvement ≥6 compared to pts with CDAI improvement Conclusions In RA-BEAM/RA-BEGIN, lack of early clinical response to bari 4 mg (failure to achieve CDAI improvement ≥6 at 4 wks) was associated with low rates of LDA/remission at wks 12/24. These results are consistent with similar analyses from previous ph 3 studies of bari.3 The majority of bari pts had improvement in CDAI ≥6 at wk 4; these decreases were associated with improved clinical responses at wks 12/24. Early identification of pts (4 wks) who are not likely to achieve LDA/remission may be useful in tailoring therapy to individual pts. References Taylor PC et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Fleischmann R et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Kremer J et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Disclosure of Interest M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, P. Taylor Grant/research support from: UCB, GlaxoSmithKline, Celgene, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, Takeda, USB, Y. Tanaka Grant/research support from: Mistubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Schiff Grant/research support from: Eli Lilly and Company, Consultant for: Eli Lilly and Company, R. Fleischmann Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, L. Yang Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, V. Arora Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Holzkaemper Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Takeuchi Grant/research support from: Eli Lilly and Company, Chugai Pharmaceutical Co,. Ltd, Consultant for: Eli Lilly and Company

Background C-EARLY (NCT01519791) assessed the efficacy and safety of certolizumab pegol (CZP)+optimized MTX vs placebo (PBO)+optimized MTX in inducing and maintaining a sustained clinical response, and inhibiting radiographic damage, in DMARD-naive patients (pts) with active, severe, progressive RA. 1 Here, we examine the association between an inadequate response to PBO+MTX or CZP+MTX treatments at Week (Wk) 12 (lack of improvement from baseline [BL] in DAS28[ESR], DAS28[CRP] or CDAI) and corresponding response at Wk 52. Objectives To examine the association between Wk12 response and Wk52 clinical response (remission [REM]/low disease activity [LDA]) in recently diagnosed DMARD-naive pts with active, severe, progressive RA, treated with CZP+optimized MTX vs PBO+optimized MTX. Methods This multicenter, double-blind, randomized controlled trial enrolled pts who were DMARD-naive with active, severe, progressive RA ( Results The NPV of Wk12 responses were high (Table): PBO+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥0.6 had 94% probability of not being in REM or LDA at Wk52. CZP+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥1.2 had 93% probability of not being in REM at Wk52. NPV of changes in DAS28(CRP) and CDAI at Wk12 were less informative for predicting remission at 1yr (Table). Conclusions In early RA pts treated with optimized-dose MTX, failure to achieve a ≥0.6 DAS28(ESR) reduction from BL at Wk12 was associated with a low probability (6%) of DAS28(ESR) REM/LDA at Wk52, supporting treatment step-up at 3 months. For pts with active, severe RA with poor prognostic factors where CZP has been initiated as first-line treatment, failure to achieve a rapid decrease of 1.2 points was associated with a reduced likelihood of achieving REM (7%). These findings in DMARD-naive pts are consistent with the negative predictability outcomes for CZP in established RA. 2 References Weinblatt M. Arthritis Rheumatol 2015;67(S10); van der Heijde D. J Rheumatol 2012;39:1326–33 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest X. Mariette Grant/research support from: Pfizer and GlaxoSmithKline., Consultant for: Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, UCB Pharma and Sanofi-Aventis, C. Bingham Consultant for: UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, V. Bykerk: None declared, P. Emery Consultant for: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Employee of: Director of Imaging at Rheumatology BV, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, C. Arendt Employee of: UCB Pharma, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma

Background Autoantibody production, including RF and anti-citrullinated protein antibody (ACPA), may play a role in RA disease pathogenesis. 1 ACPA positivity(+) in patients (pts) with RA is a strong predictor of joint erosions and radiographic progression. 1,2 However, data evaluating the association of seropositive, erosive disease with disease activity and resource use (RU) are limited. Objectives To evaluate the association of ACPA+/RF+ with erosions and disease activity; to compare activity, RU and work productivity (WP) in ACPA+ pts with erosions vs all other RA pts. Methods Pts enrolled in the BRASS Registry were analysed. BRASS comprises mostly pts with established RA who were evaluated annually on clinical measures and semi-annually on clinical pt-reported outcomes and resource utilization parameters. Baseline (BL) visit was the time of enrolment into BRASS. ACPA levels at BL and annual follow-up were measured using a validated ELISA (Inova Diagnostics, San Diego, CA) until its discontinuation in 2011, and the Euro-Diagnostica assay (IBL-America, Minneapolis, MN) thereafter. RF levels at BL and follow-up were measured during the annual rheumatologist visit. RU and WP were measured at 6 months (M) via pt questionnaires. Subgroups at BL were described using Wilcoxon rank-sum test (continuous variables) and Pearson9s chi-square test (categorical variables); multivariate logistic regression models (binary outcome variables) and ordinary least-square regression analysis (continuous outcome variables) were used. Covariates included in the multivariate models were age, sex, race, BMI, RA duration, number of co-morbidities and treatment. Results Among 1309 pts with ACPA data, 82% were female, mean (SD) age was 56.5 (14.1) yrs and DAS28(CRP) was 3.7 (1.6). Pts had mean (SD) TJC of 14.3 (14.0), ACPA levels of 128.3 (151.9) units/mL and RF levels of 127.7 (301.6) units/mL. After controlling for covariates, odds ratio (OR) for erosive disease was 2.72 (95% CI: 1.77, 4.18) for ACPA+ and 1.36 (0.88, 2.08) for RF+ (Fig. 1a). The OR for attaining SDAI LDA ( Conclusions ACPA+ has a stronger association with erosions and disease activity. The presence of ACPA+ and erosions (vs absence) is associated with higher disease activity, lower odds of remission and lower WP, even when treated with standard-of-care bDMARDs. References Aggarwal R, et al. Arthritis Rheum 2009;61:1472–83. Jilani AA and Mackworth-Young CG. Int J Rheumatol 2015;2015:72810. doi: 10.1155/2015/728610. Disclosure of Interest E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Z. Guo Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Iannaccone: None declared, M. Frits: None declared, N. Shadick Grant/research support from: Bristol-Myers Squibb, Crescendo Biosciences, Amgen, UCB, Questcor, M. Weinblatt Grant/research support from: Bristol-Myers Squibb, Crescendo Bioscience, UCB, Amgen, Consultant for: Bristol-Myers Squibb, Crescendo Bioscience, UCB, AbbVie, Roche, Janssen, Pfizer, Lilly, Amgen

Background Baricitinib (bari; an oral JAK 1/JAK 2 inhibitor) is in development for patients (pts) with active RA. In healthy subjects, absolute lymphocyte counts (ALC) increased after bari administration, returning to baseline (BL) by 24 hrs. 1 Objectives To examine changes in ALC and lymphocyte (LYM) subsets in pts with active RA treated with bari (4 mg QD), placebo (PBO), or adalimumab (ADA, 40 mg Q2W). Methods 1305 pts with active RA despite MTX treatment were randomized 3:3:2 to PBO, bari, or ADA. ALC, T, and B cell subsets (T: Th1, Th17, CD4, CD8, T reg, CD3+CD4+CD127-/loCD25+; B: switched/nonswitched memory, mature naive, immature transitional), and natural killer (NK) cells were quantified by flow cytometry at BL and wks 4, 12, and 24. Wk 4 phlebotomy was postdose bari or PBO; wks 12 and 24 were predose. Results ALC and T cells/subsets increased with bari and ADA at wk 4 (generally within normal ranges), returning to near BL at wks 12 and 24 in bari but remaining elevated in ADA (Table). B cells/subsets increased at wks 4 in bari and ADA and remained elevated through wk 24. NK cells were increased at wk 4 in bari and were below BL but within the normal range at wks 12 and 24; NK cells were increased at wks 12 and 24 in ADA. The percentages of pts with ≥1 low NK cell count were 20.5%, 32.6%, and 20.6% in PBO, bari, and ADA, respectively; percentage of pts with ALC CTCAE grade ≥2 were 14.1%, 9.9%, and 10.0%. Through wk 24, serious infection rates were 1.4%, 1.0%, and 0.6% for PBO, bari, and ADA; rates were 1.0%, 1.3%, and 0%, respectively, in pts with ≥1 low NK cell count and 2.9%, 4.2%, and 0% in pts with ≥1 ALC CTCAE Grade ≥2 value. Rates of herpes zoster (HZ) were 0.4%, 1.4%, and 1.2% for PBO, bari, and ADA; rates were 0%, 0.6%, and 0%, respectively, in pts with ≥1 low NK cell count and 1.4%, 2.1%, and 0% in pts with ≥1 ALC CTCAE Grade ≥2 value (no statistically significant differences between treatment groups). Conclusions Changes in ALC and subpopulations with bari in RA-BEAM were largely within normal ranges and are consistent with previous data. 2 Sustained increases in B cells were observed in bari and ADA. Sustained increases in ALC/T cells were only seen in ADA. A modest reduction in NK cells at wks 12 and 24 with bari was not associated with serious infection or HZ. References Shi JG, et al. J Clin Pharmacol. 2014;54:1354–61 Emery P, et al. Arthritis Rheumatol. 2015;67 (suppl 10) Disclosure of Interest Y. Tanaka Grant/research support from: Mistubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, R. Fleischmann Grant/research support from: Pfizer, Inc, Eli Lilly and Company, Consultant for: Eli Lilly and Company, Pfizer, M. Schiff Grant/research support from: Eli Lilly and Company, Consultant for: Eli Lilly and Company, T. Takeuchi Grant/research support from: Chugai Pharmaceutical Co., Ltd, Eli Lilly and Company, Consultant for: Eli Lilly and Company, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB., Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, S. Zuckerman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Issa Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Thanabalasundrum Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, B. Augendre-Ferrante Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: Eli Lilly and Company, UCB, Consultant for: UCB, Eli Lilly and Company, Pfizer, Galapagos, Merck, GlaxoSmithKline, AbbVie, Takeda, Bristol-Myers Squibb

Background Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, has demonstrated efficacy and safety in disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) patients (pts) with rheumatoid arthritis (RA). 1 Objectives Few head-to-head studies in tumor necrosis factor antagonist (aTNF)-IR assess alternative aTNFs vs. other agents; this Phase IIb exploratory study (NCT01715896) evaluates the efficacy and safety of mavrilimumab and golimumab in aTNF-IR and DMARD-IR pts. Methods This 24-week study enrolled pts with active RA (28-joint Disease Activity Score [DAS28]–C-reactive protein [CRP]/erythrocyte sedimentation rate ≥3.2); ≥4 swollen joints; inadequate response to ≥1 DMARDs and/or 1–2 aTNFs receiving concomitant methotrexate (MTX; 7.5–25.0 mg/week). Pts received subcutaneous mavrilimumab 100 mg every other week (eow), based on data from the Phase IIa study, 2 or golimumab 50 mg alternating with placebo eow. Key endpoints were ACR20/50/70 responses, DAS28–CRP 0.22 at Week 24 and safety/tolerability. Treatment estimates for mavrilimumab and golimumab are presented with standard errors. Results Pts were randomized to mavrilimumab or golimumab (1:1) (Table). Data for pts receiving mavrilimumab 100 mg eow and golimumab 50 mg at Week 24 are shown for the aTNF-IR, DMARD-IR and overall strata (Table). The most common treatment-emergent adverse events (TEAEs) for mavrilimumab 100 mg and golimumab 50 mg were nasopharyngitis (5.7%, 1.5%), headache (4.3%, 2.9%), upper respiratory tract infection (4.3%, 2.9%), viral upper respiratory tract infection (4.3%, 2.9%), and hepatic enzyme increase (4.3%, 2.9%), respectively. Related serious TEAEs were pneumocystis pneumonia (n=1) and lung disorder (n=1) [both in golimumab-treated pts]. No deaths were reported and no significant pulmonary safety signals were identified. Conclusions In this exploratory study, mavrilimumab 100 mg eow and golimumab 50 mg demonstrated efficacy and an acceptable safety profile in DMARD-IR and aTNF-IR pts. The study was not powered to demonstrate statistical significance between mavrilimumab and golimumab. As mavrilimumab 100 mg eow has previously been shown to be suboptimal compared with 150 mg eow in DMARD-IR pts (EARTH EXPLORER 1), 1 additional studies are needed to establish the benefit of a higher dose in pts with moderate to severe RA and inadequate response to aTNF agents. References Burmester G, et al. Arthritis Rheum. 2014;66:S1231 Burmester G, et al. Ann Rheum Dis. 2013;72:1445–1452 Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Joint senior authors: D. Close and G. Burmester Disclosure of Interest M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, Astra Zeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche, I. McInnes Grant/research support from: Research award to University of Glasgow, Consultant for: MedImmune, Astra Zeneca, J. Kremer Shareholder of: Corrona, Grant/research support from: Abbvie, Amgen, Genentech, Lilly, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer, Employee of: Corrona, P. Miranda Grant/research support from: Clinical trials: Amgen, Medimmune, Janssen, Pfizer, Celltrion, Abbott, Sanofi, Actelion, Merck & Co, Boehringer, BMS, Consultant for: Pfizer for Etanecept (fee less than USD5000), J. Vencovský Consultant for: Pfizer, Servier, Samsumg, Eli lilley, BMS, Novartis, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close, Employee of: MedImmune, G. Burmester, Consultant for: MedImmune

Background Clinical studies demonstrated that patients with rheumatoid arthritis (RA) experience lower hemoglobin level and higher prevalence of anemia than general population. Objectives This study was to examine the treatment effect of intravenously administered golimumab on improving hemoglobin (Hgb) level, and relieving anemia and anemia-related outcomes among patients with RA using data from the phase III clinical trial GO-FURTHER. Methods In the GO-FURTHER trial, adult patients with active RA were randomized to placebo + MTX (PBO group) or GLM (2mg/kg) plus MTX at week 0, 2, and every 8 weeks thereafter (GLM group). Patients in placebo group with Results At baseline, mean (SD) of Hgb was 12.1 (1.39) g/dl in female and 13.8 (1.29) g/dl in male, and 40.8% female patients and 23.4% male patients had anemia. Significantly greater improvement in hemoglobin in the GLM-treated patients than patients in the placebo group was observed as early as Week 4. At Week 12, mean improvement in Hgb was 0.34g/dl in male and 0.69g/dl in female in the GLM group, compared to an improvement of 0.01g/dl in male (p Conclusions Intravenously administered golimumab therapy improves Hgb, resulting in reduced anemia, improved physical function and fatigue in patients with moderate to severe active RA despite MTX. Disclosure of Interest C. Han Employee of: Johnson & Johnson Pharmaceutical Services, M. Weinblatt Grant/research support from: Janssen R & D, LLC, R. Westhovens Grant/research support from: Janssen R & D, LLC, L. Kim Employee of: Janssen R & D, LLC, E. Hsia Employee of: Janssen R & D, LLC, D. Parenti Employee of: Janssen Scientific Affairs, LLC, S. Kafka Employee of: Janssen Scientific Affairs, LLC, C. Bingham III Grant/research support from: Janssen R & D, LLC

Background MTX plus anti-TNF therapy is an effective treatment for early RA. It is becoming increasingly important to understand whether the dose of anti-TNF can be reduced or stopped in patients (pts) receiving long-term therapy. Objectives To demonstrate that for patients (pts) who achieved sustained low disease activity (sLDA) after 1 year (yr) with CZP 200mg Q2W+optimized MTX, continuation of certolizumab pegol (CZP) as a standard (200mg Q2W) or reduced-frequency dose (200mg Q4W) is superior to stopping CZP for maintaining pts in LDA from Week (Wk) 52 through Wk104. Methods CZP+MTX-treated pts achieving sLDA (DAS28[ESR]≤3.2 at Wks40 and 52) in C-EARLY Period 1 (NCT01519791)1 entered Period 2 (NCT01521923); pts were randomized 2:3:2 to CZP standard dose (200mg Q2W+MTX), CZP reduced-frequency dose (200mg Q4W+MTX) or CZP stopped (PBO+MTX). Pts were evaluated every 8–12 wks. The Period 2 primary endpoint was the proportion of pts who maintained LDA (DAS28[ESR]≤3.2) from Wk52 through Wk104 without flare, using non-responder imputation for missing values. CZP standard dose was compared with CZP stopped; if p The assumptions were that 455 pts would achieve sLDA in C-EARLY Period 1 and enter Period 2, with a response of 95%, 90% and 75% at Wk104 for standard, reduced-frequency and stopped dose respectively. Given α=0.05, there would be 99% and 92% power to detect a difference between CZP standard and reduced-frequency dose vs stopped dose. Results In Period 2, 289 pts (who had achieved sLDA in Period 1) were included in the full analysis set: CZP Q2W+MTX (n=84), CZP Q4W+MTX (n=126) or PBO+MTX (n=79). From Wk52 through Wk104, a greater proportion of pts continuing CZP (either Q2W or Q4W)+optimized MTX maintained LDA vs PBO+MTX (48.8% and 53.2% vs 39.2%; p=0.112 and p Conclusions Early RA pts with prognostic factors for severe disease progression achieving sLDA after 1yr of standard dose CZP+optimized MTX can taper to CZP reduced-frequency dose and maintain comparable disease activity control to CZP standard dose. Pts who stopped CZP had a tendency to have more relapses; despite this, 39.2% of these pts maintained LDA through Wk104. Further work will aim to identify the characteristics of pts who can successfully stop CZP. References Weinblatt M. Arthritis Rheumatol 2015;67(S10) Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest P. Emery Grant/research support from: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, C. Bingham Consultant for: UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, V. Bykerk: None declared, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, X. Mariette Grant/research support from: Pfizer, GlaxoSmithKline and Roche. Consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Employee of: Director of Imaging at Rheumatology BV, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, C. Ecoffet Employee of: UCB Pharma, C. Cioffi Employee of: UCB Pharma, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma

Background SB5 is a biologic agent developed as a biosimilar of the adalimumab reference product (ADL). The 24-week results of Phase III study results have been reported1. Objectives To evaluate the efficacy, safety, and immunogenicity in patients with RA who transitioned from ADL to SB5 vs. patients who maintained ADL and patients who continued to receive SB5 during the transition period after Week 24 up to Week 52. Methods Patients with RA were randomised in a 1:1 ratio to receive either SB5 or ADL 40 mg every other week (EOW) via subcutaneous injection. At Week 24, patients receiving ADL were re-randomised in a 1:1 ratio to either be transitioned to SB5 or continue on ADL EOW up to Week 50. Patients receiving SB5 continued to receive SB5 but they also followed the randomisation procedure to maintain blinding. Efficacy, safety, and immunogenicity were assessed up to Week 52. Results At Week 24, 254 patients from SB5 continued to receive SB5 (SB5/SB5), 125 patients from ADL were transitioned to SB5 (ADL/SB5), and the 129 patients from ADL continued to receive ADL (ADL/ADL). The ACR responses at Week 52 in per-protocol set were comparable between SB5/SB5, ADL/SB5, and ADL/ADL (76.9% vs 81.1% vs 71.2% for ACR20, respectively). Other efficacy endpoints were also comparable across the treatment groups. The change of modified total Sharp score was comparable with mean change of 0.17 in SB5/SB5 vs 0.25 in ADL/SB5 vs 0.50 in ADL/ADL. The safety profile during the transition period was comparable. Two patients newly reported injection site reactions only in ADL/ADL. The incidence of anti-drug antibody was 15.7% in SB5/SB5, 16.8% in ADL/SB5, and 18.3% in ADL/ADL during the transition period. Conclusions During the transition period after Week 24 up to Week 52, the efficacy, safety, and immunogenicity profiles were comparable between SB5/SB5, ADL/SB5, and ADL/ADL. There were no treatment emergent issues or clinically relevant immunogenicity precipitated by switching. References Weinblatt ME et al. Arthritis Rheumatol. 2015; 67 (suppl 10), 8L Disclosure of Interest M. Weinblatt Consultant for: AbbVie, Samsung Bioepis, Amgen, A. Baranauskaite Grant/research support from: AbbVie, Samsung Bioepis, J. Niebrzydowski Grant/research support from: Samsung Bioepis, E. Dokoupilova Grant/research support from: Samsung Bioepis, A. Zielinska Grant/research support from: Samsung Bioepis, K. Sitek-Ziolkowska Grant/research support from: Samsung Bioepis, J. Jaworski Grant/research support from: Samsung Bioepis, A. Racewicz Grant/research support from: Samsung Bioepis, M. Pileckyte Grant/research support from: Samsung Bioepis, K. Jedrychowicz-Rosiak Grant/research support from: Samsung Bioepis, V. Zhdan Grant/research support from: Samsung Bioepis, S. Y. Cheong Employee of: Samsung Bioepis, J. Ghil Employee of: Samsung Bioepis

Background ABT-494 is a novel selective JAK1 inhibitor. Objectives The safety and efficacy of ABT-494 was characterized vs placebo (PBO) in patients (pts) with moderate to severe RA and an inadequate response to stable background methotrexate therapy (MTX-IR). Methods In a phase 2b, 12-week, randomized, double-blind PBO-controlled study, MTX-IR pts with active RA on stable background MTX were randomized 1:1:1:1:1:1 to ABT-494 3, 6, 12, and 18 mg twice daily (BID), 24 mg once daily (QD), or matching PBO. The primary efficacy endpoint was ACR20 response at week 12. Results Baseline demographics and characteristics of the 299 randomized, treated pts were similar across groups. ACR20 response rates were significantly higher with ABT-494 at 6 mg BID (68%), 12 mg BID (80%), and 24 mg QD (76%) vs PBO (46%; non-responder imputation; Table 1). ACR50 and ACR70 response rates and change from baseline in DAS28(CRP) were also statistically significantly better for all ABT-494 doses (except ACR70 in 12 mg BID) vs PBO. Clinical remission by DAS28(CRP) was achieved by significantly more pts on ABT-494 (except 24 mg QD) vs PBO. Onset of action was rapid for ACR20, ACR50, and ACR70 responses, with significant (P≤0.027) differences in ACR20 observed at week 2 for all dose groups vs PBO. DAS28(CRP) ≤3.2 and CDAI ≤10 were achieved by significantly more pts on ABT-494 (except 24 mg QD for CDAI) vs PBO. AE incidence was numerically higher with ABT-494, with a trend of dose dependence (Table 2). The incidence of infections was similar across groups. One serious infection (community acquired pneumonia) occurred with ABT-494 12 mg BID. One pt receiving ABT-494 3 mg BID and 2 pts receiving 24 mg QD had non-serious zoster infections (single dermatomes). A pt in the 6-mg BID dose group, aged 79 y and smoking 40 y, was diagnosed with lung cancer 8 days after study completion and died 3 months later. No deaths occurred during the study. ABT-494 treatment resulted in dose-dependent increases in LDL and HDL cholesterol. Liver function test elevations were sporadic, with no clear dose dependence. Mean hemoglobin values remained stable or increased at lower doses, most notably in pts with elevated CRP at baseline. Dose-dependent decreases in hemoglobin were seen at higher doses, without clinical impact. Conclusions This phase 2b study evaluated a broad dose range to understand the boundaries of JAK1 selectivity and demonstrated the efficacy of ABT-494 vs PBO in MTX-IR pts with active RA on stable background MTX. ABT-494 had an acceptable safety and tolerability profile. Acknowledgement The design, study conduct, analysis, and financial support of the clinical trial (NCT02066389) were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data. Mariana Ovnic, PhD, Katherine Groschwitz, PhD, and Michael J. Theisen, PhD of Complete Publication Solutions, LLC, provided medical writing support. This presentation contains information on the investigational product ABT-494. Disclosure of Interest M. Genovese Grant/research support from: AbbVie, Consultant for: AbbVie, J. Smolen Grant/research support from: AbbVie, Consultant for: AbbVie, M. Weinblatt Consultant for: AbbVie, Eli Lilly, and Pfizer, S. Meerwein Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie, N. Khan Shareholder of: AbbVie, Employee of: AbbVie, S. Jungerwirth Shareholder of: AbbVie, Employee of: AbbVie

Background Regular disease activity assessment should be a key component of rheumatoid arthritis (RA) care. In patients with moderate-to-severe RA and inadequate response to methotrexate (MTX-IR) treated with baricitinib (bari) 1, 2, 4, or 8 mg in a Phase 2b double-blind study, bari demonstrated clinically and statistically significant improvements at 12 wks including DAS28-CRP 1 (Elevated high-sensitivity C-reactive protein (hsCRP) >1.2xULN or erythrocyte sedimentation rate (ESR) >28 mm/h was required at study entry. 1 ) In the same study, only modest, statistically significant improvements in a multi-biomarker disease activity score (MBDA) 2 were observed. 3 Objectives To investigate how MBDA correlates with clinical endpoints in the previously reported study. 3 Methods Post-hoc statistical analysis was conducted on combined bari 1, 2, 4, and 8 mg (n=189) and paired low (1, 2 mg; n=91) and high (4, 8 mg; n=98) doses using partial correlation analyses, which controls for effects of association with other variables, to assess the relationship between MBDA and absolute change from baseline in 13 disease activity measures. Results Mean MBDA improved from baseline to Wk 12 for each dose versus PBO, 3 but the two highest correlations were only of moderate strength: hsCRP [a component of MBDA] (r=0.60) and DAS28-CRP (r=0.43). For all other measures, associations with MBDA were significant (p Conclusions In MTX-IR patients treated with bari for 12 wks, significant changes in clinical response measures were seen but were not strongly correlated with MBDA. The highest correlations, although statistically significant, were of moderate strength. MBDA score changes did not have a strong correlation to clinical measures with bari. If these observations are corroborated they would suggest that caution is required when assessing clinical response to bari using the MBDA. References Keystone E et al. Ann Rheum Dis 2015;74(2):333–340. Segurado OG, Sasso EH. Clin Exp Rheumatol 2014;32(85):S29-S34. Taylor P et al. Ann Rheum Dis 2015;74(Suppl 2):257–258 as presented at EULAR 2015. Disclosure of Interest R. Fleischmann Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, M. Genovese Grant/research support from: AbbVie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, Vertex, Consultant for: AbbVie, Astellas, Crescendo Bioscience, Eli Lilly and Company, Galapagos, Pfizer, Vertex, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, J. Rancourt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, E. Nantz Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Zuckerman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: Celgene, GlaxoSmithKline, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, Takeda, USB

Background SB5 is a biologic agent developed as a biosimilar of the adalimumab reference product (ADL). Pharmacokinetic equivalence was demonstrated in a phase I study in healthy subjects1. Primary efficacy and safety results from a phase III study in rheumatoid arthritis (RA) patients showed equivalent efficacy and comparable safety and were reported previously2. Objectives To compare secondary efficacy endpoints up to Week 24 in the phase III study of SB5 vs. ADL in patients with moderate-to-severe RA despite methotrexate (MTX) treatment. Methods Patients with moderate to severe RA despite MTX treatment were randomly assigned to receive 40 mg of either SB5 or ADL administered subcutaneously every other week for 24 weeks. At Week 24, patients on ADL were randomised again to receive 40 mg of either SB5 or ADL subcutaneously every other week for an additional 28 weeks. Patients on SB5 continued to receive SB5. The primary endpoint was the ACR20 response rate at Week 24. Secondary efficacy endpoints up to Week 24, including ACR20, ACR50, ACR70, disease activity score based on 28 joints (DAS28), simplified disease activity index (SDAI), clinical disease activity index (CDAI), and health assessment questionnaire-disability index (HAQ-DI), were compared for patients receiving SB5 and ADL. Results 544 patients were randomised and 542 patients were included in the full analysis set (SB5 [N=269] or ADL [N=273]) for assessment of secondary efficacy endpoints. ACR response rates (ACR20/50/70) were comparable between the two treatment groups at every visit up to Week 24. DAS28, SDAI, and CDAI were also comparable up to Week 24. The mean change in DAS28 from baseline to Week 24 was −2.74 for SB5 and −2.68 for ADL; the 95% confidence interval of the difference in the least square means between each treatment group was −0.26 to 0.17, which was within the pre-defined equivalence margin of −0.6 to 0.6. Comparable proportions of patients on SB5 and ADL achieved low disease activity and remission at Week 24, as assessed by DAS28, SDAI, and CDAI. Patient reported outcomes, assessed by HAQ-DI, were also comparable between SB5 and ADL up to Week 24. Other efficacy endpoints (ACR-N, EULAR response) were comparable up to Week 24. Conclusions Efficacy of SB5 and of ADL was comparable up to Week 24 for all secondary efficacy endpoints, as well as for the primary efficacy endpoint. References Shin D et al. Ann Rheum Dis. 2015; 74 (Suppl2: 459–460), FRI0110 Weinblatt ME et al. Arthritis Rheumatol. 2015; 67 (suppl 10), 8L Disclosure of Interest J. Kay Grant/research support from: AbbVie, Eli Lilly and Company, Pfizer, Genentech, Roche Laboratories, Consultant for: Alexion Pharmaceuticals, Amgen, AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Company, Crescendo Bioscience, Eli Lilly and Company, Epirus Biopharmaceuticals, Genentech, Hospira, Janssen Biotech, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Pfizer, Samsung Bioepis, Sandoz, Roche Laboratories, UCB, M. Weinblatt Consultant for: AbbVie, Samsung Bioepis, Amgen, E. Keystone Grant/research support from: Pfizer, Roche, Janssen, Amgen, Consultant for: Pfizer, Roche, Janssen, Amgen, BMS, Merck, Celltrion, Samsung Bioepis, M. C. Genovese Consultant for: Samsung Bioepis, A. Baranauskaite Grant/research support from: AbbVie, Samsung Bioepis, S. Y. Cheong Employee of: Samsung Bioepis, J. Ghil Employee of: Samsung Bioepis

ObjectiveThe combination of methotrexate (MTX) with infliximab can modify infliximab pharmacokinetics and lower the incidence of antibodies against infliximab (ATIs). We hypothesised that the pharmacokinetic interaction between MTX and infliximab is related to activation of MTX to immunosuppressive MTX polyglutamates (MTXPGs).MethodsAdult patients with rheumatoid arthritis receiving weekly MTX with infliximab for more than 3 months were enrolled in a cross-sectional study. Blood was collected at trough before the infusion of infliximab. Red blood cell (RBC) MTXPGs were measured using liquid chromatography, and circulating levels of infliximab were measured using a cell-based assay. ATIs were measured using enzyme immunoassays. Statistical analyses consisted of multiple regression and Wilcoxon tests.ResultsIn the 61 patients enrolled in the study, ATIs were detected in 11 (18%). Regression analyses revealed that lower infliximab levels (median 3.3 µg/ml) were associated with the presence of ATIs and lower RBC MTXPG levels (median 28 nmol/l) (pConclusionsThese hypothesis-generating data indicate that MTXPGs are associated with infliximab pharmacokinetics and ATI formation.

ObjectivesOne goal of remission in rheumatoid arthritis (RA) is to halt joint damage. The authors assessed the progression of radiographic joint damage among RA patients in remission by the new ACR/EULAR criteria (Boolean approach) compared with remission thresholds for the simplified disease activity index (SDAI), clinical disease activity index (CDAI) and disease activity score based on 28 joints and C-reactive protein (DAS28-CRP) in an observational cohort, and evaluated the relationship between time in remission and radiographic joint damage.Methods535 RA patients underwent physical examination and laboratory assessment at baseline, 1 and 2 years. Radiographs at baseline and 2 years were scored by the van der Heijde modified Sharp score (TSS). Positive likelihood ratios for a good radiographic outcome (change in TSS 2 goodness of fit statistics.Results20% of patients in ACR/EULAR remission at baseline had radiographic progression, 24% in SDAI remission, 19% in CDAI remission and 30% of patients in DAS28–CRP remission. The positive likelihood ratio for good radiographic outcome was 2.6 for ACR/EULAR criteria, 2.1 for SDAI, 2.8 for CDAI and.1.5 for DAS28–CRP. Reduced radiographic progression was observed for patients with an increasing number of visits in remission (p2 goodness of fit statistics).ConclusionsPatients with RA in remission by any established criteria can experience radiographic progression. An increased number of visits in remission was associated with reduced radiographic damage.

Background: HLA-DRB1 shared epitope ( HLA-SE ), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). Objective: We examined associations between HLA-SE, PTPN22 , CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. Methods: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. Results: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18–4.25), and RF+ (OR 2.53, 95% CI 1.83–3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24–2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27–2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01–2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. Conclusions: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22 , but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

Background Of patients with RA, ∼40% of do not achieve a minimal acceptable improvement (ACR20) despite modern biologic therapy.1,2,3 Granulocyte-macrophage colony-stimulating factor (GM–CSF) is implicated in RA pathogenesis via myeloid and granulocyte cell lineage activation. In a 12-week Phase IIa study, mavrilimumab, a first-in-class inhibitor of the GM–CSF receptor-α demonstrated a sustained effect via this novel therapeutic pathway in RA.4 Objectives To evaluate the efficacy and safety of mavrilimumab in patients with moderate to severe, adult-onset RA in a 24-week, Phase IIb study. Methods Patients (18–80 yrs; inadequate response to ≥1 DMARDs; DAS28–CRP ≥3.2; ≥4 SJC) receiving MTX were randomized to receive 1 of 3 SC mavrilimumab dosages (150, 100, 30 mg every other week [eow]) or placebo (PBO) plus MTX (7.5–25.0 mg/week). Co-primary endpoints were change in DAS28–CRP (Day 1 to Week 12) and ACR20 response rate (Week 24). Safety and tolerability were measured through assessment of AEs and pulmonary parameters. Results were analyzed using the modified ITT population. Results 326 patients from Europe, South America, and South Africa (mean [SD] age, 51.8 [11.1] yrs; female, 86.5%; mean [SD] DAS28–CRP, 5.8 [0.9]; RF+/anti-CCP+, 81.9%) received mavrilimumab 150, 100 or 30 mg eow or PBO (N=79, 85, 81 and 81, respectively). At Week 12, a statistically significant difference in DAS28–CRP change from baseline (p 90% of patients entered a long-term, open-label extension study. Conclusions This Phase IIb study demonstrated the potential benefit of inhibiting macrophage activity via the GM–CSF receptor-α pathway on RA disease activity. The study met both co-primary endpoints with a clear dosage response. Mavrilimumb was well-tolerated over the 24-week study period. References Weinblatt ME, et al. N Engl J Med 1999;340:253–9. Lipsky PE, et al. N Engl J Med 2000;343:1594–602. Weinblatt ME, et al. Arthritis Rheum 2003;48:35–45, Burmester GR, et al. Ann Rheum Dis 2013;72:1445–52. Acknowledgements Funded: MedImmune. Editorial assistance: N Panagiotaki, QXV Communications, UK †Joint senior authors. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, BMS, Novartis, MedImmune, MSD, Pfizer, UCB, Roche, Speakers bureau: AbbVie, BMS, Novartis, MSD, Pfizer, UCB, Roche, I. McInnes Grant/research support from: MedImmune (Research award to University of Glasgow), Consultant for: MedImmune, AstraZeneca, J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Amgen, Genentech, Lilly, Pfizer, Consultant for: AbbVie, Amgen, Genentech, Lilly, Pfizer, BMS, Employee of: Corrona, P. Miranda Grant/research support from: MedImmune (to support protocol), M. Korkosz: None declared, J. Vencovsky: None declared, A. Rubbert-Roth Grant/research support from: Pfizer, Chugai, Consultant for: MSD, USB, Abbott, Pfizer, Roche, BMS, Chugai, Speakers bureau: Roche, Pfizer, UCB, E. Mysler Grant/research support from: Medimmune, Roche, BMS, Pfizer, M. Sleeman Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche