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BackgroundRates of enrolment in clinical trials in inflammatory bowel disease [IBD] have decreased dramatically in recent years. This has led to delays, increased costs and failures to develop novel treatments.AimsThe aim of this work is to describe the current bottlenecks of IBD clinical trial enrolment and propose solutions.MethodsA taskforce comprising experienced IBD clinical trialists from academic centres and pharmaceutical companies involved in IBD clinical research predefined the four following levels: [1] study design, [2] investigative centre, [3] physician and [4] patient. At each level, the taskforce collectively explored the reasons for declining enrolment rates and generated an inventory of potential solutions.ResultsThe main reasons identified included the overall increased demands for trials, the high screen failure rates, particularly in Crohn’s disease, partly due to the lack of correlation between clinical and endoscopic activity, and the use of complicated endoscopic scoring systems not reflective of the totality of inflammation. In addition, complex trial protocols with restrictive eligibility criteria, increasing burden of procedures and administrative tasks enhance the need for qualified resources in study coordination. At the physician level, lack of dedicated time and training is crucial. From the patients’ perspective, long washout periods from previous medications and protocol requirements not reflecting clinical practice, such as prolonged steroid management and placebo exposures, limit their participation in clinical trials.ConclusionThis joint effort is proposed as the basis for profound clinical trial transformation triggered by investigative centres, contract research organizations, sponsors and regulatory agencies.

Objectives To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA. Methods We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365. MRIs at baseline and days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, osteitis, tenosynovitis, periarticular inflammation, bone erosions, joint space narrowing and bone proliferation were assessed using the PsAMRIS. A novel total inflammation score was tested. Results MRIs for 123 patients were included. On day 169, ABA10 and ABA30/10 significantly reduced MRI synovitis and tenosynovitis, respectively, vs placebo [differences −0.966 (P = 0.039) and −1.652 (P = 0.014), respectively]. Synovitis in the placebo group increased non-significantly from baseline to day 169, total inflammation and tenosynovitis decreased non-significantly and all measures improved significantly after a switch to ABA10 [−1.019, −0.940, −2.275 (P Conclusion Adults with PsA receiving ABA10 and ABA30/10 demonstrated significant resolution of inflammatory components of disease, confirmed by MRI, with synovitis and tenosynovitis improvements consistent with previously reported clinical responses for these doses. Results indicate that a reduction in OMERACT PsAMRIS inflammation scores may provide proof of tissue-level efficacy in PsA clinical trials. Registration ClinicalTrials.gov (https://clinicaltrials.gov), NCT00534313.

Objective Data from two double-blind, randomized, Phase III studies were analysed to investigate the ability of Routine Assessment of Patient Index Data 3, DAS28 (CRP), modified (M)-DAS28 (CRP) and Simplified or Clinical Disease Activity Indices to predict structural damage progression in RA. Methods This post hoc analysis included data from the 2-year Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) trial in biologic-naïve patients with active RA ( Results Adjusted logistic regression analyses included all randomized and treated patients in AMPLE (N = 646) and those who received abatacept plus MTX or MTX monotherapy in AVERT (N = 235). Baseline Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) scores significantly predicted structural progression at months 12 and 24 in AMPLE (P < 0.05) and months 6 and 12 in AVERT (P < 0.01), and were stronger predictors than Simplified or Clinical Disease Activity Indices. Conclusion In this post hoc analysis of two patient populations with RA, Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) were good at predicting structural damage. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov: NCT00929864 (AMPLE); NCT01142726 (AVERT).

Introduction Magnetic resonance imaging (MRI) is increasingly used in patients with rheumatoid arthritis (RA) to determine residual inflammation after treatment and as a predictor of structural damage progression. Establishing an optimal threshold of inflammatory activity that predicts lower risk of structural damage progression may inform treatment decisions. This post hoc analysis investigated whether patients with RA at low risk of structural damage progression can be identified based on MRI inflammation thresholds. Methods Hand and wrist MRI was performed at baseline, and at months 6 and 12 in a phase 3b, randomized, active-controlled, double-blind trial of abatacept in early RA (AVERT). Pathologies were scored using the OMERACT RA MRI Score. Data were stratified into two risk subgroups (less and more severe inflammation) for structural damage progression (erosion change > 0.5) based on baseline inflammation. In this post hoc analysis, log odds ratios of probability of progression {adjusted for baseline Disease Activity Score in 28 joints [C-reactive protein; DAS28 (CRP)]} were compared between subgroups to test the performance of inflammation thresholds. Results There were 351 randomized and treated patients with baseline MRIs, of whom 276 (78.6%) and 235 (67.0%) had MRIs available at months 6 and 12, respectively. The DAS28 (CRP)-adjusted probabilities of progression from baseline to month 12 based on scores at baseline, and from months 6 to 12 based on month 6 scores, were significantly lower among patients with less inflammation (P

OBJECTIVE: High magnetic resonance imaging (MRI)-detected inflammation is associated with greater progression and poorer outcomes in rheumatoid arthritis (RA). This analysis aimed to determine if baseline MRI inflammation was related to clinical response and remission in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) study.METHODS: AVERT was a phase IIIb, randomized, controlled trial with a 12-month, double-blind treatment period enrolling patients with early (≤2 years' duration), anti-citrullinated peptide-positive methotrexate (MTX)-naive RA. In this post hoc analysis, patients in the abatacept plus MTX (n = 114) and MTX (n = 111) arms with available MRI results were stratified into low and high baseline MRI inflammation groups based on previously developed cutoffs of synovitis and osteitis on unilateral hand-wrist contrast-enhanced MRI. Simplified Disease Activity Index (SDAI) remission (≤3.3), Clinical Disease Activity Index (CDAI) remission (≤2.8), Boolean remission, and Disease Activity Score in 28 joints using the C-reactive protein level (RESULTS: Overall, 100 of 225 patients (44.4%) had high baseline MRI inflammation. In patients with high baseline MRI inflammation, a significantly greater proportion achieved remission at 12 months with abatacept plus MTX versus MTX across SDAI (45.1% versus 16.3%; P = 0.0022), CDAI (47.1% versus 20.4%; P = 0.0065), and Boolean indices (39.2% versus 16.3%; P = 0.0156). In patients with low baseline MRI inflammation, remission rates were not significantly different with abatacept plus MTX versus MTX (SDAI: 39.7% versus 32.3%; P = 0.4961).CONCLUSION: In seropositive, MTX-naive patients with early RA and presence of objectively measured high inflammation by MRI, indicating poor prognosis, remission rates were higher with abatacept plus MTX treatment versus MTX.

To date, the impact of background glucocorticoids (GC) on the efficacy and safety of abatacept or adalimumab in patients with active rheumatoid arthritis (RA) is not clearly established. This post hoc analysis of (AMPLE) trial (NCT00929864) compared efficacy and safety outcomes over 2 years in patients treated with abatacept or adalimumab plus background methotrexate (MTX), who continued GC (&le, 10 mg/day) versus those who were not receiving GC (no-GC). Of 646 randomized patients, 317 received abatacept + MTX (161 GC, 156 no-GC) and 326 received adalimumab + MTX (162 GC, 164 no-GC). At Year 2, the adjusted mean changes from baseline in Disease Activity Score (DAS28 C-reactive protein (CRP)) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were not significantly different in the GC versus no-GC subgroups receiving abatacept or adalimumab. A similar proportion of patients achieved remission, HAQ-DI score improvement &ge, 0.3 and radiographic progression rates. No clinically meaningful safety differences were observed between GC versus no-GC subgroups either with abatacept or adalimumab. In patients with active RA of similar baseline disease activity treated with abatacept or adalimumab plus background MTX, there was no additional value of background GC on clinical, functional or radiographic outcomes over two years.

Introduction To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA). Methods Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR–BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2–immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1–3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] Results A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [−], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2− group. DXR–BMD was lower in the anti-CCP2+ vs. the anti-CCP2− groups (Gp1–3 vs. anti-CCP2−: P P P = 0.0181). Conclusion Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity. Funding Bristol-Myers Squibb. Trial Registration Clinicaltrials.gov identifier, NCT01793103.

Anti-cyclic citrullinated peptide (CCP) antibody positivity is an established diagnostic factor for severe disease activity and joint damage and a prognostic factor for aggressive disease in rheumatoid arthritis (RA).To compare RA-related treatment, healthcare utilization, and joint erosion between anti-CCP-positive and anti-CCP-negative RA patients.Newly-diagnosed RA patients were identified from the Henry Ford Health System database between January 1, 2009 and December 31, 2014; the date of the first RA diagnosis within the study period was the index date. Baseline anti-CCP test was used to categorize patients as anti-CCP-positive or anti-CCP-negative, and outcomes were evaluated in the 6 months post-index.There were 217 anti-CCP-positive and 191 anti-CCP-negative RA patients included in the study. A higher proportion of anti-CCP-positive patients were initiated on RA treatment than anti-CCP-negative patients (70.5% vs 23.0%; p .0001). More anti-CCP-positive patients received methotrexate (73.2% vs 56.8%; p = .0374), while more anti-CCP-negative patients received hydroxychloroquine (31.8% vs 13.1%; p = .0037) in first-line therapy. A higher proportion of anti-CCP-negative patients were tested for rheumatoid factor (RF) and erythrocyte sedimentation rate (ESR). Of those tested, there were more positive test results in the anti-CCP-positive cohort compared to the anti-CCP-negative cohort (RF: 84.4% vs 18.2%, p .0001; C-reactive protein [CRP]: 69.7% vs 48.3%, p = .0008; and ESR: 89.5% vs 53.9%, p .0001). Outpatient utilization predominated, with more anti-CCP-positive patients having any outpatient physician office visit (96.3% vs 77.5%, p .0001) and a higher mean number of visits (5.3 vs 2.5, p .0001) than anti-CCP-negative patients. Among anti-CCP-positive (n = 113) and anti-CCP-negative (n = 58) patients with imaging results, more anti-CCP-positive patients had joint erosion compared to anti-CCP-negative patients (18.6% vs 8.6%; p = .0858); however, statistical significance was not reached.RA patients with positive anti-CCP antibodies had higher degrees of inflammation and disease activity as indicated by laboratory results, which likely contributed to their higher rates of healthcare utilization, joint erosion, and proportions of RA treatment.

Background Early RA patients (pts) often present with different areas of joint involvement, but limited data exist to identify which specific joint locations may be indicative of greater disease severity1. Objectives This analysis investigated the baseline (BL) prevalence of swelling and erosions in individual joint locations and their possible association with disease characteristics and prognostic factors in a unique cohort of early erosive RA patients using the AGREE study population. Methods In this post-hoc analysis of the Phase III AGREE study where methotrexate (MTX) naive RF and/or ACPA seropositive pts with early (≤2 years [yrs]) erosive RA were treated with abatacept (ABA) plus MTX (n=256) or MTX (n=253)2, prevalence of BL swollen joint status (present, absent) was analysed for 6 large and 14 small joint locations: respectively wrists, elbows, shoulders, jaw, knees, ankles and MCP1-5, PIP2-5 and MTP1-5. Similarly, prevalence of BL erosive joint status was analysed for wrist, MCP1-5, PIP2-5 and MTP1-5. The association between BL disease characteristics and BL swelling or erosions was investigated for the individual joints. Results In this cohort of early, seropositive erosive RA (n=509), BL swelling was most frequently observed in the wrist (91.90%) and MCP2 joint (90.1%), whereas BL erosion was most frequently observed in the MTP5 joint (43.5%) (Table 1). BL swelling in the knee, jaw, wrist and elbow was highly associated (p Conclusion In this cohort of early, seropositive erosive RA, swelling in the knee, jaw, wrist and elbow seems to be associated with the poorest prognosis, whereas BL MCP2 swelling seems to be associated with joint damage. While the data require further validation, a difference in joint location presentation may identify patients for an intensive treatment or a personalized treatment approach. References [1] Bergstra SA, et al. RMD Open2017;3:e000568. [2] Westhovens, et al. Ann Rheum Dis2009;68:1870–7. Disclosure of Interests Patrick Durez Speakers bureau: Bristol-Myers Squibb, Eli Lilly, Sanofi, Celltrion, Rene Westhovens Grant/research support from: Bristol-Myers Squibb, Consultant for: Celltrion, Galapagos-Gilead, Yedid Elbez Employee of: Employee of Excelya which received funding from Bristol-Myers Squibb as contract research organization., Sofie Robert Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Harris A Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Background In the placebo (PBO)-controlled Phase III aSTRAEA study (ClinicalTrials.gov, NCT01860976) in psoriatic arthritis (PsA), abatacept (ABA) 125 mg SC weekly significantly increased the aCR20 response rate at Week 24 versus PBO (39.4% vs 22.3%, respectively; p Objectives To assess aBA safety up to 2 years in patients (pts) enrolled in aSTRAEA. Methods Pts with active PsA were randomised 1:1 to aBA or PBO for 24 weeks followed by 28 weeks’ open-label (OL) aBA (total time on study: 52 weeks); pts without ≥20% improvement in joint counts at Week 16 (early escape) were switched to OL aBA (total time on study: 44 weeks).1 Pts could subsequently receive OL aBA in a 52-week long-term extension (LTE; Year 2) for the collection of safety data. The proportions of pts in the cumulative aBA population (all pts who received ≥1 dose of aBA at any time in the study) with aEs (all aEs, serious aEs [SAEs], deaths, aEs leading to discontinuation), laboratory marked abnormalities and anti-ABA antibodies over the cumulative aBA period (date of first treatment dose to end of LTE) were recorded in 1-year and 6-month intervals. Results Overall, 398 pts were included in the analysis of the cumulative aBA period (213 received aBA from study Day 1; 185 completed initial randomisation to PBO and received aBA thereafter). Of these, 322 pts entered the LTE (initial randomisation: aBA, n=162; PBO, n=160) and continued to receive OL aBA beyond the 28-week OL period. Of 162 and 160 pts initially randomised to aBA and PBO, respectively, 19 (11.7%) and 21 (13.1%) pts discontinued aBA in the LTE. Median (range) number of aBA injections in the cumulative aBA period to end of LTE was 80 (1–133). Safety during the cumulative aBA period over 2 years is shown (Table 1); 6-month interval safety data will be available at time of presentation. In the LTE, there were 3 SAEs of infection (osteomyelitis, intervertebral discitis and cellulitis) and 3 pts discontinued due to infection (hepatitis a, Epstein-Barr virus, intervertebral discitis). No malignancies or deaths were reported, and no autoimmune events were reported as serious or led to aBA discontinuation during the LTE. AEs, SAEs and aEs of special interest occurred with a similar frequency regardless of concomitant MTX or prior TNF inhibitor (TNFi) use. The proportion of pts with anti-ABA antibodies during the cumulative aBA period was higher during the post-treatment period (≥22 days after last dose; 37.1% [91/245]) than in the on-treatment period (first treatment dose date to ≤21 days after last dose; 7.1% [28/392]). No apparent relationship between anti-ABA antibodies and efficacy in the on-treatment period or aEs suggestive of systemic immune reactions was seen. Conclusion Abatacept was well tolerated up to 2 years with no new safety signals during the LTE in this Phase III study in PsA. There was no impact of concomitant MTX use or prior TNFi exposure on the safety profile of abatacept. The occurrence of anti-abatacept antibodies had no impact on abatacept efficacy or safety. References [1] Mease PJ, et al. Ann Rheum Dis2017;76:1550–8. Acknowledgement Professional medical writing: andrea Plant, PhD, Caudex; funding: Bristol-Myers Squibb. Disclosure of interests Philip J Mease Grant/research support from: abbVie, amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, SUN and UCB, Consultant for: abbVie, amgen, BMS, Galapagos, Gilead Sciences, inc., Janssen, Lilly, Novartis, Pfizer, SUN and UCB, Speakers bureau: abbVie, amgen, BMS, Celgene, Genentech, Janssen, Lilly, Novartis, Pfizer and UCB, alice B Gottlieb Grant/research support from: PI: incyte Corporation, Janssen-Ortho inc., Lilly ICOS LLC, Novartis, UCB, XBiotech, Consultant for: abbVie, Dermira, incyte Corporation, Lilly ICOS LLC, Novartis, Sun Pharmaceutical industries Ltd., avotres (unpaid), XBiotech (unpaid), Speakers bureau: abbVie, Eli Lilly and Company, Janssen Biotech; advisory board: Bristol-Myers Squibb, Celgene Corporation, Janssen Biotech, Janssen-Ortho inc., LEO Pharma, Novartis, UCB, Desiree van der Heijde Consultant for: abbVie, amgen, astellas, astraZeneca, Bristol-Myers Squibb, Boehringer ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Union Chimique Belge, Oliver FitzGerald: None declared, alyssa Johnsen Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Marleen Nys Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Subhashis Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Harris a ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Dafna D Gladman Grant/research support from: abbVie, amgen, Celgene, Lilly, Novartis, Pfizer, and UCB, Consultant for: abbVie, amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB

Objective This post hoc analysis of the phase III Active PSoriaTic Arthritis RAndomizEd TriAl (ASTRAEA) evaluated the effect of baseline body mass index (BMI) on subsequent response to subcutaneous (SC) abatacept in patients with psoriatic arthritis (PsA). Methods In ASTRAEA, patients with active PsA were randomised (1:1) to receive blinded weekly SC abatacept 125 mg or placebo for 24 weeks. Treatment response at week 24 was assessed by the proportions of patients achieving American College of Rheumatology 20% improvement response, Disease Activity Score in 28 joints (DAS28 (C reactive protein (CRP))) ≤3.6 and 30 kg/m2) and compared in univariate and multivariate models. Results Of 212/213 and 210/211 patients with baseline BMI data in the abatacept and placebo groups, respectively, 15% and 19% were underweight/normal, 36% and 27% were overweight, and 49% and 54% were obese. After adjusting for baseline characteristics, there were no significant differences for any outcome measure at week 24 with abatacept in the overweight or obese versus underweight/normal subgroup. In the placebo group, patients in the obese versus underweight/normal subgroup were significantly less likely to achieve DAS28 (CRP)

Background:The semi-quantitative Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) was developed for the evaluation of inflammatory and destructive changes in PsA,1 but has limited trial usage.Objectives:To retrospectively utilise the PsAMRIS in a multi-dose, randomised Phase IIb study of abatacept in patients with PsA who have inadequate response to DMARDs (NCT00534313).2Methods:Patients were randomised to abatacept (3, 10 or 30/10 mg/kg [the 30-mg/kg group switched to 10 mg/kg after the first two doses]) or placebo and treated for 169 days, after which all patients received abatacept 10 mg/kg through to Day 365. MRI scans of one hand or foot from 123 patients with PsA collected at baseline and on Days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, bone oedema, tenosynovitis, periarticular inflammation, bone erosion, bone proliferation and joint space narrowing were assessed as per OMERACT PsAMRIS; a novel total inflammation score was calculated from the sum of synovitis, bone oedema, tenosynovitis and periarticular inflammation. Variables were analysed using all cases (hand or foot) and by hand and foot cases separately.Results:At Day 169, the abatacept 30/10 mg/kg or 10 mg/kg group showed the most decrease (improvement) in each inflammatory assessment (Figure 1). The Day 169 change from baseline severity in synovitis and tenosynovitis in the abatacept 30/10 mg/kg and 10 mg/kg groups, respectively, were significantly reduced (improved) compared with placebo (estimated differences of –0.966 [p=0.039] and –1.652 [p=0.014], respectively) (Table 1). Patients originally randomised to placebo and then switched to abatacept 10 mg/kg at Day 169 showed significant improvements in synovitis, tenosynovitis and total inflammation from Day 169 to Day 365 (Table 1, Figure 1). The structural outcomes joint space narrowing and bone erosion remained stable within each treatment group, showing little change from baseline to Days 85, 169 and 365. After separating hand and foot analyses (72 hand and 51 foot cases), only hand tenosynovitis in the 10-mg/kg group and foot synovitis in the 3-mg/kg group were significantly reduced (improved) at Day 169 compared with placebo (differences of –2.331 [p=0.017] and –1.689 [p=0.010], respectively). In general, more comparisons in the hand analysis were statistically significant versus in the foot analysis.Conclusion:This analysis confirmed the efficacy of abatacept 10 and 30/10 mg/kg when assessed with the OMERACT PsAMRIS. The inflammatory pathologies, synovitis and tenosynovitis, appeared to be the most responsive MRI outcomes. Analysing hand and foot cases together yielded results consistent with the primary clinical efficacy endpoint (ACR20 response rate), as the abatacept 10- and 30/10-mg/kg groups showed significant differences versus placebo at Day 169;2 reduced sample size in separate hand and foot assessments may have prevented finding significant results corresponding to the combined analysis. These results also demonstrate the responsiveness of the PsAMRIS in PsA randomised clinical trials.References:[1]Glinatsi D, et al. J Rheumatol 2015;42:2473–2479.[2]Mease P, et al. Arthritis Rheum 2011;63:939–948.Table 1.MRI variables showing significant treatment effectsaBetween groups at Day 169MRI scoreComparatorComparatorDifferenceSEp valueSynovitisPlaceboAbatacept 30/10 mg/kg–0.9660.4610.039TenosynovitisPlaceboAbatacept 10 mg/kg–1.6520.6620.014Placebo group before/after switchbMRI scoreTreatment, Day 169Treatment, Day 365DifferenceSEp valueSynovitisPlaceboAbatacept 10 mg/kg–1.0180.4580.029TenosynovitisPlaceboAbatacept 10 mg/kg–0.9400.3900.018Total inflammationPlaceboAbatacept 10 mg/kg–2.2751.0670.036aBased on change from baseline at the stated time points (unadjusted p values).bPatients were switched to abatacept 10 mg/kg after Day 169.Acknowledgements:Professional medical writing and editorial assistance was provided by Rob Coover, MPH, at Caudex and was funded by Bristol Myers Squibb.Disclosure of Interests:Mikkel Østergaard Speakers bureau: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Sanofi, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, Merck, Novartis, Paul Bird Speakers bureau: AbbVie, Bristol Myers Squibb, Eli Lilly, Novartis, Pfizer, UCB, Grant/research support from: Gilead, Chahin Pachai Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shuyan Du Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Chun Wu Employee of: Bristol Myers Squibb, Jessica Landis Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Thomas Fuerst Employee of: Bioclinica, Inc., a contract research service providing radiology central reading services to pharmaceutical, biotech and medical device companies, Harris A Ahmad Employee of: Bristol Myers Squibb, Sean Connolly Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Philip G Conaghan Speakers bureau: AbbVie, Novartis, Consultant of: AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, Gilead, Novartis, Pfizer.

Central reading, that is, independent, off-site, blinded review or reading of imaging endpoints, has been identified as a crucial component in the conduct and analysis of inflammatory bowel disease clinical trials. Central reading is the final step in a workflow that has many parts, all of which can be improved. Furthermore, the best reading algorithm and the most intensive central reader training cannot make up for deficiencies in the acquisition stage (clinical trial endoscopy) or improve on the limitations of the underlying score (outcome instrument). In this review, academic and industry experts review scoring systems, and propose a theoretical framework for central reading that predicts when improvements in statistical power, affecting trial size and chances of success, can be expected: Multireader models can be conceptualised as statistical or non-statistical (social). Important organisational and operational factors, such as training and retraining of readers, optimal bowel preparation for colonoscopy, video quality, optimal or at least acceptable read duration times and other quality control matters, are addressed as well. The theory and practice of central reading and the conduct of endoscopy in clinical trials are interdisciplinary topics that should be of interest to many, regulators, clinical trial experts, gastroenterology societies and those in the academic community who endeavour to develop new scoring systems using traditional and machine learning approaches.

Introduction Patients with rheumatoid arthritis (RA) with poor prognostic factors, such as seropositivity for anti-citrullinated protein antibodies and early erosions, may benefit from early intensive treatment. However, information to guide physicians on the best choice of therapy in these patients is limited. The objective of this study was to describe the efficacy of subcutaneous abatacept versus adalimumab over 2 years in patients with seropositive, erosive early RA in the AMPLE study. Methods This exploratory post hoc analysis compared clinical, functional and radiographic outcomes in two subsets of patients: patients with early RA (≤ 6 months’ disease duration) who were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies and had > 1 radiographic erosion (Cohort 1); and patients with RA and absence of ≥ 1 of these inclusion criteria (Cohort 2). Results Of the 646 randomized patients, Cohort 1 included 38 patients receiving abatacept and 45 receiving adalimumab, and Cohort 2 included 280 patients receiving abatacept and 283 receiving adalimumab. Baseline demographics and disease characteristics were generally similar between treatment groups in both cohorts. Over 2 years, in Cohort 1, the adjusted mean change from baseline in the Disease Activity Score in 28 joints (using C-reactive protein) was numerically greater for abatacept than for adalimumab (mean difference at day 365 was 0.9, 95% confidence interval − 1.47 to − 0.33). Similar patterns of improvement were observed for other disease activity measures and physical function, but not for radiographic outcomes. No treatment-related differences were observed in Cohort 2. Conclusion This analysis indicates a trend towards improved disease activity and physical function with abatacept versus adalimumab in patients with seropositive, erosive early RA. Trial Registration ClinicalTrials.gov NCT00929864. Funding Bristol-Myers Squibb. Electronic Supplementary Material The online version of this article (10.1007/s40744-019-00174-7) contains supplementary material, which is available to authorized users.

Background To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA). Methods Patients with PsA were randomised (1:1) to subcutaneous abatacept 125 mg weekly/placebo for 24 weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs ≤ upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and ≥ normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed. Results In total population, numerically higher improvements in most PROs were reported with abatacept (n = 213) versus placebo (n = 211) at both time points (P > 0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements ≥ MCID and ≥ NV at week 16. At week 16, all PRO improvements were numerically greater (P > 0.05) in patients with baseline CRP > ULN versus CRP ≤ ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naïve versus TNFi-exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers. Conclusions Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations. Trial registration ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013. Electronic supplementary material The online version of this article (10.1186/s13075-018-1769-7) contains supplementary material, which is available to authorized users.

Clinical outcomes in patients with early rheumatoid arthritis (RA) were assessed by baseline symptom duration in the Assessing Very Early Rheumatoid arthritis Treatment trial (ClinicalTrials.gov; NCT01142726). Patients with early, active RA were randomized to subcutaneous (SC) abatacept 125 mg/week plus methotrexate (MTX), SC abatacept alone, or MTX monotherapy for 12 months. All RA treatments were withdrawn after 12 months in patients with Disease Activity Score in 28 joints (C-reactive protein; DAS28-CRP) 3 to ≤ 6 months, or > 6 months) and treatment group. No clinically significant differences were seen in baseline demographics or characteristics across symptom duration groups. Irrespective of baseline symptom duration, a numerically higher proportion of abatacept plus MTX-treated patients achieved DAS-defined remission at month 12 and sustained remission at month 18 compared with MTX monotherapy. A numerically higher proportion of abatacept plus MTX-treated patients with symptom duration ≤ 3 months maintained DAS-defined remission after complete treatment withdrawal from 12 to 18 months compared with longer symptom duration groups. This subgroup also had the fastest onset of clinical response (DAS28-CRP

Background Response prediction of certain biologic agents for the treatment of rheumatoid arthritis (RA) remains an unmet need in real-world clinical practice. The contribution of patient-reported components to the 28-joint Disease Activity Score (DAS28) was termed DAS28-P and investigated as a predictor of response to biologic agents, mostly tumor necrosis factor inhibitors. We aimed to evaluate DAS28-P as a predictor of the European League Against Rheumatism (EULAR) response to abatacept in patients with RA. Methods The study population was a prospective, observational, multicenter cohort of Korean patients with RA, who were followed up for a nationwide post-marketing surveillance study of abatacept. Correlation of DAS28-P with DAS28, change of DAS28, and EULAR response groups were evaluated. Logistic regression analysis was used to predict good-to-moderate EULAR response to abatacept in the study population. Results A total of 341 patients were involved in the analysis stratified on the EULAR response criteria. Presence of comorbidities, previous exposure to biologic agents, baseline DAS28, three of its components (tender joint counts, global health visual analog scale, erythrocyte sedimentation rate), and baseline DAS28-P were significantly associated with EULAR response to abatacept at 6 months. Stratified upon EULAR response, a group with good-to-moderate response had a higher baseline value and lower interval change for DAS28-P. Logistic regression analysis showed that a DAS28-P cut-off of > 0.44 was more positively associated with good-to-moderate EULAR response with abatacept treatment than naivety to biologic agents. Conclusions The DAS28-P could be predictive of response to abatacept. A higher baseline DAS28-P is associated with a favorable therapeutic response to abatacept. Trial registration Trial name, Korean Post-marketing Surveillance for Orencia®. Trial registration number, NCT01583244. Registered on April 20, 2012. Electronic supplementary material The online version of this article (10.1007/s40271-018-0347-z) contains supplementary material, which is available to authorized users.

Background To assist in clinical decision making it is important to understand the factors, and their thresholds, that might predict relapse following treatment withdrawal in patients with RA in remission. In a previous post hoc analysis of the AVERT trial (NCT01142726), in which several potential factors were assessed, erosions, synovitis and bone oedema scores on MRI and HAQ-DI scores in patients with DAS28 (CRP) Objectives To evaluate post hoc the association between different thresholds of MRI and HAQ-DI scores at Month 12 and the risk of relapse at Months 18 and 24 in AVERT. Methods This analysis compared relapse event rates at Months 18 and 24 in patients with DAS28 (CRP) 3 for synovitis,>2 for bone oedema,>7 for (weighted) combined synovitis and bone oedema,>5 for erosion and >0.5 for HAQ-DI. Univariate logistic models were conducted for comparisons and odds ratios (OR) with 95% CI and associated p values. Results All randomised and treated patients with DAS28 (CRP) 3), 28 (18.1%) had a higher bone oedema score (>2), 39 (25.2%) had a higher combined score (>7), 73 (47.1%) had a higher erosion score (>5) and 42 (27.1%) had a higher HAQ-DI score (>0.5). Relapse events at Months 18 and 24 were significantly associated with supra-threshold MRI bone oedema, erosion and combined scores and with supra-threshold HAQ-DI score at Month 12 (figure 1). There was a trend toward association of relapse at Months 18 and 24 with high synovitis score (figure 1). Conclusions It was possible to define MRI and HAQ-DI scores in patients with DAS28 (CRP) remission that were predictive of relapse 6 and 12 months after complete drug withdrawal in AVERT. Assessment of imaging and physical function, using predefined thresholds, in patients achieving remission may aid clinical decisions on when to withdraw therapy in MTX-naive patients with RA. References [1] Emery P, et al. Ann Rheum Dis2015;74:19–26. [2] Ahmad H, et al. Ann Rheum Dis2017;76(suppl 2):240. Disclosure of Interest H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. Baker: None declared, M. Ostergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Janssen, Merck, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth, P. Emery Consultant for: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, Novartis, Samsung Bioepis, T. Huizinga Grant/research support from: EU and Dutch Arthritis Foundation, Consultant for: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Novartis, Pfizer, Roche, sanofi-aventis, Schering-Plough, UCB, Eli Lilly, Speakers bureau: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, Y. Elbez Consultant for: Bristol-Myers Squibb, S. Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, P. Conaghan Grant/research support from: Bristol-Myers Squibb, Consultant for: AbbVie, GSK, Lilly, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Novartis

Background Patients (pts) with early RA often present with multiple areas of involvement. Limited data exist to identify which specific joints or joint locations may be indicative of poorer prognosis and require more intensive initial therapy. 1 Objectives This analysis investigated which joint locations have the poorest prognosis and compared clinical response rates between abatacept (ABA)+MTX and MTX monotherapy by baseline (BL) swollen joint status for specific joint locations. Methods Data from AGREE (NCT00122382), a double-blind Phase III study of ABA+MTX (n=256) vs MTX (n=253) in biologic-naive pts with early (≤2 years [yrs]) erosive RA, were analysed by BL swollen joint status (present, absent) for 8 different joint locations: hands, wrists, elbows, shoulders, jaw, knees, ankles and feet. Overall characteristics and study results were reported previously. 2 Swelling was evaluated at BL and after 6 months (mths) of treatment. Differences between treatment groups in clinical response endpoints (i.e. DAS28 [CRP] Results In an early RA cohort of pts at risk of active, rapidly progressing disease, the proportions of pts (n=509) with a swollen joint at BL were 99% hand, 92% wrist, 79% ankle, 69% knee, 66% foot, 48% elbow, 34% shoulder and 9% jaw. Pts with a swollen jaw (n=45) had more tender joints (mean [SD] 40.0 [15.1] vs 30.1 [14.1]), more swollen joints (35.9 [13.3] vs 21.1 [9.5]), higher total Sharp score (9.4 [10.1] vs 6.9 [9.1]) and longer disease duration (11.7 [9.2] yrs vs 6.0 [6.9] yrs) than those without jaw swelling (n=464). Higher HAQ-DI was seen in pts with a swollen knee or shoulder (1.8 [0.6] vs 1.5 [0.7] and 1.9 [0.6] vs 1.6 [0.7], respectively). Presence of BL synovitis was not associated with greater BL anti-citrullinated protein antibodies or RF positivity, probably due to the inclusion of mainly seropositive pts. In general, absence of BL swelling was associated with higher clinical response at 6 mths, both for ABA+MTX and MTX. Independent of BL swollen joint status, ABA+MTX had higher clinical response rates (DAS28, SDAI, CDAI, Boolean and HAQ remission) than MTX, except for the non-swollen wrist. Overall mean Boolean remission rates were 13.7% for ABA+MTX vs 5.5% for MTX with difference in proportions (95% CI) of 8.1% (2.6, 13.7) (p=0.003). The largest difference in Boolean remission rate (95% CI) favouring ABA+MTX was 9.6% (4.2, 15.1) (p Conclusions BL swelling in the shoulder, knee and jaw is associated with a more severe RA profile. Remission rates were higher with ABA+MTX than MTX when BL swelling was present, especially in the wrist. Also, swollen joint resolution was more pronounced with ABA+MTX, especially in the hands. References [1] Bergstra SA, et al. RMD Open2017;3:e000568. [2] Westhovens R, et al. Ann Rheum Dis2009;68:1870–7. Disclosure of Interest P. Durez Speakers bureau: Bristol-Myers Squibb, Eli Lilly, Sanofi, S. Robert Employee of: Bristol-Myers Squibb, A. Thiry Employee of: Bristol-Myers Squibb, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Background Binary cut-offs for disease activity are frequently used in clinical decision-making for patients with RA because they are accurate reflections of disease activity, discriminate well between disease acvitiy states and are feasible to perform in routine clinical practice.1 Results from a previous post hoc analysis of the randomized, controlled, head-to-head AMPLE trial (NCT00929864) indicated a trend for increased efficacy, as assessed using DAS28 (CRP), for abatacept (ABA) compared with the TNF inhibitor adalimumab (ADA) in patients with seropositive, erosive early RA.2,3 Objectives To evaluate post hoc the impact of treatment with either SC ABA or ADA on sustained validated definitions of remission and DAS28 (CRP) Methods This post hoc analysis of the AMPLE trial builds on previous work3 to compare clinical outcomes between treatment groups in two subsets: patients with disease duration ≤6 months, RF or anti-citrullinated protein antibody seropositivity and >1 radiographic erosion (Cohort 1), and patients in whom ≥1 of these inclusion criteria were absent (Cohort 2). Disease activity and patient-reported outcomes were evaluated at Weeks 26, 52 and 104. Endpoints were defined as percentages of patients with DAS28 (CRP) Results Of 646 randomized patients, 83 were included in Cohort 1 (ABA, n=38; ADA, n=45) and 563 in Cohort 2 (ABA, n=280; ADA, n=283). At Week 52, significantly more ABA- than ADA-treated patients achieved DAS28 (CRP) Conclusions This post hoc analysis indicates a trend towards increased efficacy for abatacept compared with adalimumab on measures of sustained remission and DAS28 (CRP) References: [1] Anderson J, et al. Arthritis Care Res (Hoboken) 2012;64:640-7. [2] Schiff M, et al. Ann Rheum Dis 2014;73:86-94. [3] Fleischmann R, et al. EULAR 2017; poster SAT0041. [4] Harrold LR, et al. J Rheumatol 2018;45:32-9. [5] Emery P, et al. Ann Rheum Dis 2015;74:19-26. Disclosure of Interest: R. FleischmannGrant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, EMD-Serono, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, Consultant for: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, GSK, Eli Lilly, Novartis, Pfizer, Sanofi-Genzyme, UCB, M. Weinblatt Grant/research support from: Bristol-Myers Squibb, Amgen, Crescendo Bioscience, Sanofi, Consultant for: Bristol-Myers Squibb, Amgen, Crescendo Bioscience, AbbVie, Eli Lilly, Pfizer, Roche, Merck, Samsung, Novartis, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Y. Elbez Consultant for: Bristol-Myers Squibb, M. Schiff Consultant for: Abbvie, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb

Background Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk. Methods We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate–vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT01009463 and HZC102970/NCT01017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period. Results Baseline characteristics distinguishing the pneumonia and non-pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m2, P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV1 (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV1 in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095). Conclusion Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD., Video abstract

The Integrated Zone Comparison Technique (IZCT) was utilized with computerized polygraph instrumentation and the Academy for Scientific Investigative Training’s Horizontal Scoring System ASIT PolySuite algorithm, as part of a blind study in the detection of deception. This paper represents a synergy analysis of combining fMRI only deception data with each of the three individual physiological parameters that are used in polygraph. They include the electro-dermal response (EDR), pneumo, and cardio measurements. In addition, we compared the detection accuracy analysis using each single parameter by itself. The fMRI score and each individual polygraph parameter score on individual subjects were averaged to establish an overall score.

Background Factors predictive of relapse need to be identified to aid therapy withdrawal decisions for patients with RA achieving remission with treatment. AVERT (NCT01142726) was a Phase IIIb, randomized, active-controlled trial in patients with early RA. 1 After a 12-month, double-blind treatment period with abatacept + MTX, or abatacept or MTX monotherapy, patients with DAS28 [CRP] Objectives To evaluate post hoc whether MRI scores, patient characteristics and disease activity at Month 12 were predictors of clinical relapse at Month 18 and Month 24 after treatment withdrawal in AVERT. Methods Synovitis, erosion and bone oedema in the dominant hand and wrist MRI were scored at Month 12 using the RA MRI scoring system (RAMRIS). Patient characteristics (pain, age, weight, HAQ-DI) and disease measures (CRP, SJC28, TJC28, DAS28 [CRP], CDAI, SDAI) were recorded at Month 12. The influence of these factors on the proportion of patients who relapsed (doubling of TJC28 and SJC28, and DAS28 [CRP] ≥1.2 increase relative to Month 12) by Month 18 and Month 24 was assessed. Results A total of 172 patients achieving DAS28 remission (DAS28 [CRP] Conclusions MRI and HAQ-DI scores in patients in DAS28 remission predicted clinical relapses 6 and 12 months after complete drug withdrawal in the AVERT trial. The clinical decision on whether to withdraw therapy in MTX-naive patients with RA in remission may benefit from an assessment of imaging and physical function prior to drug withdrawal. References Emery P, et al. Ann Rheum Dis 2015;74:19–26. Disclosure of Interest H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. Baker: None declared, M. Ostergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Janssen, Merck, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth, P. Emery Grant/research support from: AbbVie, Merck, Pfizer, Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, Novartis, Samsung Bioepis, T. Huizinga Grant/research support from: EU & Dutch Arthritis Foundation, Consultant for: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Biosciences, Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, UCB, Inc., Eli Lilly, Speakers bureau: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, P. Conaghan Grant/research support from: Bristol-Myers Squibb, Consultant for: AbbVie, Lilly, Novartis, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Roche

Background Clinicians rely on time-efficient, validated disease activity assessments to help predict disease progression accurately in patients (pts) with RA. The utility in predicting structural damage progression for the Routine Assessment of Patient Index Data 3 (RAPID3) 1 is largely unknown, while that of DAS28 (CRP) 2 and modified (M-)DAS28 have been previously reported. 3 Objectives This post hoc analysis examined the relationship between baseline disease activity measures and their ability to predict structural damage progression in the Phase III AMPLE (NCT00929864) trial. 4 Methods AMPLE was a randomized, investigator-blinded study in which MTX-experienced pts with active RA ≤5 years received SC abatacept 125 mg weekly or adalimumab 40 mg every 2 weeks in combination with stable-dose MTX. Logistic regression analysis was used to correlate the effect of disease activity at baseline on radiographic (X-ray) progression at Months (M) 12 and 24. Disease activity was assessed using M-DAS28, 3 DAS28 (CRP), RAPID3, CDAI and SDAI. Radiographs were scored using the modified Sharp/van der Heijde scoring system; progression was defined as change from baseline in total score greater than the smallest detectable change, which was calculated as SD/square root (2) x 1.96 (where SD is standard deviation of paired differences of change from baseline in total score between two readers). Results Logistic regression analysis was carried out for all randomized and treated pts (abatacept, n=318; adalimumab, n=328). For these patients, M-DAS28, DAS28 (CRP) and RAPID3 at baseline were significant predictors of radiographic progression at M12 and M24, baseline SDAI was a significant predictor at M12 but not M24 and baseline CDAI was not a significant predictor at either time point (Table). Receiver operating characteristic curves showed that M-DAS28, DAS28 (CRP) and RAPID3 had higher predictive value (area under the curve) than CDAI or SDAI for radiographic progression at M12 and M24 (Table). There was no impact of treatment arm on predictors of radiographic outcomes. Conclusions In this post hoc analysis, disease activity scores at baseline according to M-DAS28, DAS28 (CRP) and RAPID3 were good predictors of radiographic progression at M12 and M24 and were more predictive than other measures of disease activity tested, with M-DAS28 demonstrating the greatest degree of prediction. References Yazici Y, et al. J Rheumatol 2008;35:603–9. Salaffi F, et al. BMC Musculoskelet Disord 2011;12:120. Baker JF, et al. Arthritis Rheumatol 2014;66:794–802. Schiff M, et al. Ann Rheum Dis 2014;73:86–94. Disclosure of Interest E. Keystone Grant/research support from: Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, Janssen, Lilly, Novartis, Pfizer, sanofi-aventis, UCB, Consultant for: Abbott, AstraZeneca, Biotest, Bristol-Myers Squibb, Crescendo, F. Hoffmann-La Roche, Genentech, Janssen, Lilly, Merck, Pfizer, UCB, Speakers bureau: Amgen, Abbott, AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, Janssen, Pfizer, Sanofi, Genzyme, UCB, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Y. Yazici Grant/research support from: Genentech, Celgene, Bristol-Myers Squibb, Consultant for: Genentech, Celgene, Bristol-Myers Squibb, E. Muratti Employee of: Bristol-Myers Squibb, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Bergman Shareholder of: Pfizer, Johnson & Johnson, Consultant for: AbbVie, Bristol-Myers Squibb, Amgen, Celgene, Genentech, Pfizer, Janssen, Speakers bureau: Norvatis, Abbvie, Celegene

Background In the Phase III ASTRAEA study (NCT01860976), abatacept (ABA) significantly increased ACR20 responses, with benefits on other musculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA). 1 As PsA impacts HRQoL, assessing treatment (tmt) effect using patient-reported outcomes (PROs) is important. Objectives To explore the effect of ABA tmt using PROs in intent-to-treat and post hoc analyses of ASTRAEA. Methods Pts were randomized (1:1) to SC ABA 125 mg weekly or placebo (PBO) for 24 weeks (W). At W16, pts without ≥20% improvement in joint counts started open-label ABA. Adjusted mean changes from baseline (BL) to W16 (all pts) and W24 (responder analysis) in Short Form-36 (SF-36; physical and mental component summary [PCS, MCS] and individual domains using spydergrams), pain VAS and HAQ-DI scores, Dermatology QoL Index (DLQI) and FACIT-Fatigue scale (FACIT-F) were evaluated in the total population and subgroups stratified by BL CRP level and prior TNFi use. Proportions of pts reporting improvements ≥minimal clinically important difference (MCID) in SF-36 summary (≥2.5) and domain (≥5.0), FACIT-F (≥40) and HAQ-DI ( Results In the total population, improvements in all PROs were numerically greater for ABA (n=213) vs PBO (n=211) at W16 and W24 and significant for SF-36 PCS at W16 and HAQ-DI at W24 (Table). At W16, improvements in all SF-36 domains were numerically greater with ABA, and significant for physical function, bodily pain and vitality. A higher proportion of pts receiving ABA vs PBO reported improvements ≥MCID in SF-36 PCS, MCS, SF-36 domains, FACIT-F, HAQ-DI (Fig) and DLQI (not shown) at W16. The proportion of pts whose scores were ≥normative values at W16 was higher with ABA vs PBO in SF-36 PCS, MCS, FACIT-F and HAQ-DI scores. At W24, improvements in SF-36 domain scores accrued in both groups, with numerical differences in favour of ABA except in social function. Improvements in PROs were greater with ABA tmt in BL CRP>upper limit of normal (ULN) vs CRP≤ULN and in TNFi-naive vs -exposed subpopulations. Conclusions Abatacept treatment improved many PROs in pts with active PsA, with larger benefits in the CRP>ULN and TNF-naive subpopulations. References Mease P, et al. Arthritis Rheumatol 2016;68(suppl 10): [Abstract 1041]. Disclosure of Interest V. Strand Consultant for: AbbVie, Amgen Corporation, AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Corrona, Crescendo/Myriad Genetics, EMD Serono, Genentech/Roche, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, UCB, E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, T. Lehman Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, S. Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, Genentech, Janssen, Novartis, Pfizer, UCB

Background Abatacept, a selective T-cell co-stimulation modulator, significantly increased ACR20 response and had an overall beneficial effect on musculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA) in the Phase III Active pSoriaTic athritis RAndomizEd triAl (ASTRAEA, NCT01860976). 1 Factors that may predict responses to abatacept were explored in this post hoc analysis. Objectives To evaluate the relationship between baseline characteristics and abatacept response in a post hoc analysis of ASTRAEA. Methods Pts were randomized (1:1) to SC abatacept 125 mg weekly or placebo for 24 weeks in this trial. Pts without >20% improvement in joint counts at Week 16 were switched to open-label abatacept (early escape). ACR20 response rate in pts stratified by baseline variables was investigated in a multivariate analysis and odds ratios (ORs) generated to identify differences in response. Using a cut-off of OR 1.2, indicating pt subgroups in whom abatacept appeared to have a meaningful treatment benefit, baseline variables were further investigated in a univariate analysis and estimated differences calculated. Results Of 424 pts enrolled, 213 received abatacept and 211 placebo. In abatacept-treated pts, the multivariate model showed a difference in ACR20 response (OR >1.2) for baseline CRP (>upper limit of normal [ULN] vs ≤ULN; OR 1.346 [95% CI 0.668, 2.712]), DAS28 (CRP) (>5.1 vs ≤5.1; 1.489 [0.782, 2.836]), dactylitis (>0 vs 0; 1.372 [0.708, 2.659]), and median baseline erosions (≥3 vs 1.2 for dactylitis only (1.406 [0.619, 3.193]). These factors, which have been identified previously as indicating poor prognosis in PsA, were balanced between treatment arms at baseline. In the univariate model by poor prognostic factors, the differences in ACR20 response rates with abatacept treatment vs placebo in distinct subgroups were numerically greater in pts who were positive for these prognostic factors at baseline than in those who were not (Figure). Conclusions These findings identified subgroups of pts with PsA with certain baseline characteristics in whom abatacept is most likely to be effective. The predictive factors identified are aligned with poor prognostic factors in the EULAR and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines, 2,3 and may indicate pts with the highest unmet medical need. References Mease P, et al. Arthritis Rheumatol 2016;68(Suppl 10):[Abstract 1041]. Gossec L, et al. Ann Rheum Dis 2016;75:499–510. Coates L, et al. Arthritis Rheumatol 2016;68:1060–71. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Biosciences, Corrona, Demira, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Zynerba, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Biosciences, Genentech, Janssen, Novartis, Pfizer, UCB, I. McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Janssen, UCB, Consultant for: Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, AbbVie, UCB, V. Strand Consultant for: AbbVie, Amgen Corporation, AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Corrona, Crescendo Biosciences/Myriad Genetics, EMD Serono, Genentech/Roche, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, UCB, O. FitzGerald Grant/research support from: AbbVie, Pfizer, Bristol-Myers Squibb, Consultant for: AbbVie, Pfizer, Bristol-Myers Squibb, Celgene, Janssen, Novartis, UCB, Lilly, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, AbbVie, UCB, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Background Patients (pts) who are anti-citrullinated protein antibody (ACPA) positive tend to develop more severe erosive disease than ACPA-negative pts.1 The presence of seropositivity and erosions have been noted in EULAR treatment guidelines as poor prognostic factors to identify pts with RA who require early and aggressive clinical intervention.2 Since the disease in pts with seropositive, erosive early RA is mostly driven by immunological features, response to RA therapy may vary based on therapeutic mechanism of action (MOA). Objectives To investigate the efficacy of abatacept (ABA) vs adalimumab (ADA) in pts with seropositive, erosive early RA. Methods AMPLE (NCT00929864)3 was a 2-year, Phase IIIb study in which biologic-naive pts with RA were randomized 1:1 to either SC ABA 125 mg weekly or SC ADA 40 mg biweekly, both with background MTX. This post hoc analysis of AMPLE compared clinical outcomes between treatment groups in a subpopulation of pts with specified baseline criteria: disease duration ≤6 months, RF or ACPA seropositivity and >1 radiographic erosion. Disease activity and patient-reported outcomes were evaluated at Weeks 26, 52 and 104. Endpoints were compared between ABA and ADA groups using chi-square test for categorical variables, analysis of covariance model (ANCOVA) controlling for baseline covariates and DAS28 (CRP) stratification for continuous variables. Results Of 318 and 328 pts in the ABA and ADA groups, respectively, 38 and 45 pts had all specified baseline characteristics (Cohort 1) and 280 and 283 pts had an absence of at least 1 of the specified characteristics (Cohort 2). Overall, the baseline characteristics, including anti-cyclic citrullinated peptide titres, were well balanced between the groups, with the exception of weight. For Cohort 1, adjusted mean change (95% CI) from baseline DAS28 (CRP) with ABA vs ADA was –2.18 (–2.61, –1.75) vs –1.56 (–2.01, –1.11) at Week 26, –2.58 (–2.99, –2.17) vs –1.68 (–2.10, –1.25) at Week 52 and –2.50 (–2.97, –2.03) vs –2.0 (–2.49, –1.50) at Week 104. Similar trends of increased efficacy with ABA vs ADA were observed for changes from baseline CDAI, SDAI, HAQ-DI, pain and fatigue; no differences in radiographic progression were observed. For Cohort 2, no differences in clinical outcomes between ABA and ADA groups were observed. Given the differences in baseline weight between ABA and ADA groups in Cohort 1, sensitivity analyses that excluded pts >100 kg and adjusted for baseline weight were performed and demonstrated minimal effect of weight on treatment efficacy. Conclusions This post hoc analysis seems to indicate a trend of increased efficacy for abatacept in pts with seropositive, erosive early RA compared with the TNF inhibitor adalimumab. Given the small sample size, additional pre-specified randomized studies are needed to compare the benefit of biologic DMARDs with different MOAs in pts with early, rapidly progressing RA. References Combe B, et al. Ann Rheum Dis 2016 Dec 15. doi: 10.1136/annrheumdis-2016–210602. Aletaha D, et al. Arthritis Rheum 2010;62:2569–81. Weinblatt M, et al. Arthritis Rheum 2013;65:28–38. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, sanofi-aventis, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, Roche, sanofi-aventis, UCB, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, UCB, DxTerity, Consultant for: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, UCB, AbbVie, Lilly, Pfizer, Roche, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Schiff Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, JNJ, UCB, Speakers bureau: AbbVie

Background Patients with RA who are at a higher risk for progressive and destructive arthritis could be identified using anti-cyclic citrullinated peptide (anti-CCP) levels. 1 Treatment guidelines recommend the use of non-biologic DMARDs as initial treatment in RA; but, if warranted, biologic (b)DMARDs could be considered in early treatment of RA. 2 Real-world data describing treatment patterns based on anti-CCP designations are limited. Objectives This study evaluated treatment patterns of patients with RA who are anti-CCP positive (+) or negative (–). Methods This retrospective study was based on electronic medical record (EMR) data with a supplemental chart review from a large integrated delivery system. Patients newly diagnosed with RA (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 714.0x) were identified between 1 January 2009 and 31 December 2014. The first RA diagnosis date was designated as the index date. Patients were required to have 12 months of continuous activity in the EMR (6 months pre- and 6 months post-index). Based on the baseline anti-CCP test results, patients were categorized as anti-CCP+ (≥7.0 U) or anti-CCP– ( Results Overall, 217 anti-CCP+ and 191 anti-CCP– patients with RA were included in this study. A higher proportion of anti-CCP+ (153, 70.5%) than anti-CCP– patients (44, 23.0%; p Conclusions After diagnosis of RA, patients who are anti-CCP+ were more likely to start therapy, indicating that physicians were more aggressive in treating this cohort. Patients were treated according to guidelines with non-biologic DMARDs, predominantly MTX. Patterns of treatment change differed between the cohorts; however, treatment response was similar with a complete response rate of 20%. References Singh JA, et al. Arthritis Rheumatol 2016;68:1–26. Niewold TB, et al. QJM 2007;100:193–201. Disclosure of Interest K. Price Employee of: Bristol-Myers Squibb, Y. Doleh Employee of: Bristol-Myers Squibb, M. Eaddy Consultant for: Xcenda, A. Ogbonnaya Employee of: Xcenda, H.-C. Shih Employee of: Xcenda, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, L. Lamerato Grant/research support from: Centers for Disease Control, National Cancer Institute, Policy Analysis, Inc, Outcomes Research Solutions, Xcenda, eMAXHealth, Merck Pharmaceuticals, Pfizer Pharmaceuticals, Reagan Udall Foundation, AstraZeneca, Employee of: Henry Ford Health System, University of Michigan-Dearborn, A. Szymialis Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Purpose To achieve minimal inter-observer variability in assessment of spleen and liver volume changes using a novel MRI reading method in the context of a phase III clinical trial of a new therapy for Gaucher disease. Materials and methods Abdominal MRI examinations at screening and after 6 and 9 months' exposure to a novel plant-cell-derived recombinant enzyme, taliglucerase alfa, were taken in 31 patients with Gaucher disease and at least 8-fold greater than expected splenomegaly. Transverse T2, T1, and in/out-of-phase, and coronal T1 sequences were performed using standardized settings across 11 sites globally. Spleen and liver volumes were semi-automatically delineated using an automatic segmentation algorithm followed by manual correction by experienced technologists using advanced editing tools. Data of all randomized patients were then submitted for efficacy evaluation to two independent experts blinded to time-point and treatment. Results Mean (± SD) percent variability over all time-points was 0.30% ± 0.46% for spleen and 0.53% ± 0.69% for liver using 178 spleen and liver volumes measured twice. Adjudication due to ≥ 5% variability between observers was not required. Conclusion The measurement method was found to be precise in monitoring spleen and liver volume changes over time, with a much lower variability than traditional manual methods, supporting the accuracy of the results. Given the observed minimal variability rates among multiple readers, a single read of each volume would be sufficient.

Despite its importance and potential impact in clinical trials, central reading continues to be an under-represented topic in the literature about inflammatory bowel disease (IBD) clinical trials. Although several IBD studies have incorporated central reading to date, none have fully detailed the specific methodology with which the reads were conducted. Here we outline key principles for designing an efficient central reading paradigm for an ulcerative colitis (UC) study that addresses regulatory, operational and clinical expectations. As a step towards standardization of read methodology for the growing number of multicenter phase 3 clinical trials in IBD, we have applied these principles to the design of an optimal read methodology that we call the ‘2 þ 1 paradigm.’ The 2 þ 1 paradigm involves the use of both site and central readers, validated scoring criteria and multiple measures for blinding readers, all of which contribute to reducing bias and generating a reliable endoscopic subscore that reflects endoscopic disease severity. The paradigm can be utilized while maintaining a practical workflow compatible with an operationally feasible clinical trial. The 2 þ 1 paradigm represents a logical approach to endoscopic assessment in IBD clinical trials, one that should be considered attractive to prospective sponsors, contract research organizations, key opinion leaders and regulatory authorities and be ready for implementation and further evaluation.

Clinical trials in inflammatory bowel disease (IBD) are evolving at a rapid pace by employing central reading for endoscopic mucosal assessment in a field that was, historically, largely based on assessments by local physicians. This transition from local to central reading carries with it numerous technical, operational, and scientific challenges, many of which can be resolved by imaging core laboratories (ICLs), a concept that has a longer history in clinical trials in a number of diseases outside the realm of gastroenterology. For IBD trials, ICLs have the dual goals of providing objective, consistent assessments of endoscopic findings using central-reading paradigms whilst providing important expertise with regard to operational issues and regulatory expectations. This review focuses on current approaches to using ICLs for central endoscopic reading in IBD trials.

Objectives To evaluate if the mean smallest detectable change (SDC) of multiple time intervals using the Bland & Altman (B&A) levels of agreement (LoA) method is an appropriate surrogate for the generalisability analysis method for estimating the overall SDC of radiological progression in rheumatoid arthritis (RA) trials. Secondly, to compare the SDC based on 95% LoA with the SDC based on 80% LoA, and to investigate the association between SDC and baseline damage and progression. Methods Fifteen datasets from randomised controlled trials in RA were scored by 13 experienced readers as pairs according to the modified Sharp/van der Heijde method. The SDC using the 95% and 80% LoA and the generalisability methods was calculated. Results 21 295 radiographic time points from 7643 patients were included. The mean (range) SDC for the LoA and the generalisability methods was 3.1 (2.3–4.3) and 3.2 (2.3–4.6) units, respectively. The mean±SD difference between the two methods was −0.13±0.28. The mean SDC including all intervals (n=31) was 3.0±0.7 for 95% LoA and 2.0±0.4 for 80% LoA. No relationship was observed between baseline damage and the SDC, whereas the SDC increased with increasing radiological progression. Conclusions The mean of the interval SDCs obtained by the simple LoA method is a valid surrogate for the SDC obtained by complex generalisability methods. The SDC depends on the level of radiographic progression rather than on the level of absolute damage. In addition, the use of an SDC based on 80% rather than on 95% LoA is proposed.

Medical imaging is now utilized extensively in clinical trials for eligibility, efficacy, and safety evaluations. The uses of imaging span from a qualitative assessment of disease findings to quantitative assessments, each resting on diagnosis of the condition or change in the severity of the condition. This introductory chapter is designed for the novice with a limited or no background in radiological techniques and aims to briefly review the different imaging techniques, technology, terminology, and optimal imaging uses.

Objective The aim of this study is to provide data on the adjudication rate for a predetermined threshold of difference in change score between two readers in randomized controlled trials (RCTs). Methods Fifteen datasets from RCTs in RA were scored by 13 experienced readers as pairs according to the modified Sharp-van der Heijde method. The theoretical adjudication rates for thresholds of between 3 and 20 units were calculated. We investigated the influence of the number of time points within the same session, the length of the interval and disease duration on the adjudication rates. Results A total of 21,295 time points from 7643 patients from 15 databases were included in the analysis. The adjudication rate was inversely related to the threshold. Higher adjudication rates were observed with a higher number of time points, longer time intervals and in early versus established RA. The adjudication rates ranged from 0% to 22% depending on the scenario. Conclusion With trained and experienced readers, the adjudication rate in RA RCTs is low even with very conservative adjudication thresholds.

Background In rheumatoid arthritis (RA), the concept that subclinical inflammation causes damage progression is now well established, but there is little work on how much inflammation is safe. 1 A previous study established RA MRI Scoring (RAMRIS) synovitis and osteitis thresholds (≤3 each and ≤9 [≤3 plus 2*≤3] as a total inflammation score) that correlated with a low risk of structural damage progression. 2 Further validation of these thresholds may guide physicians in clinical practice more reliably to identify individuals with a low likelihood of structural damage progression. Objectives To validate the performance of RAMRIS synovitis, osteitis and combined total inflammation thresholds in the prediction of structural damage progression. 1 Methods AVERT (Assessing Very Early Rheumatoid arthritis Treatment) was a Phase IIIb, randomized, active-controlled, 24-month trial, with a 12-month, double-blind treatment period. Patients with early RA received abatacept + MTX, abatacept monotherapy or MTX. Contrast-enhanced MRIs of the dominant hand and wrist were performed. MRI data were pooled from all three treatment arms (intent-to-treat population) for this post hoc analysis. Inflammation (synovitis, osteitis and combined) and erosion were scored by two central readers at baseline, Month 6 and Month 12. Structural damage progression was defined as erosion change >0.5. Patients were stratified into “low” and “not low” risk groups for MRI structural progression based on their inflammation scores at the start of the observation period: low: ≤3 for synovitis, ≤3 for osteitis and ≤9 when combined (with osteitis double-weighted due to its strong correlation with progression), as suggested by Baker et al. 2 Log odds ratio of probability of progression were compared between subgroups. Results 351 patients were randomized and treated, with MRIs at baseline; 276 (78.6%) and 235 (67.0%) also had MRI data available at Month 6 and Month 12, respectively. The percentage of patients with structural damage progression at follow-up was significantly higher in the “not low” versus “low” risk subgroup for all comparisons (Table). The probability of progression from Month 6 to Month 12 was significantly lower among patients with synovitis score ≤3, osteitis score ≤3, and total inflammation score ≤9 at Month 6. Conclusions The applied inflammation thresholds distinguished between patients with RA at lower or higher risk of structural damage progression, validating the previously proposed thresholds. This provides further support for the clinical value of measuring inflammation via MRI, as well as its role in predicting structural damage progression. References Gandjbakhch F, et al. J Rheumatol 2014;41:398–406. Baker J, et al. Arthritis Rheumatol 2015; 67(Suppl 10):S832. Disclosure of Interest H. A. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. F. Baker: None declared, M. Ostergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Janssen, Merck, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, P. Emery Grant/research support from: AbbVie, Merck, Pfizer, Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, Novartis, Samsung Bioepis, P. G. Conaghan Consultant for: AbbVie, Lilly, Novartis, Pfizer, Speakers bureau: AbbVie, Janssen, Roche

Background SDC is an important statistic in evaluating radiographic progression in clinical trials in Rheumatoid Arthritis (RA). Two methods to estimate the SDC are available: one is based on the standard deviation (SD) of the difference between change-scores obtained by two readers (according to Bland&Altman (B&A)) and the other is based on generalisability analysis (using ANOVA). ANOVA is required in the case of multiple time points and multiple readers, but is more complicated and time consuming. Objectives To evaluate if the average SDC of all available time intervals using the B&A method is a valid surrogate for the ANOVA method to estimate the SDC of radiological progression in RA studies including multiple time points. Methods Fifteen datasets from radiographic trials in RA comprised of 20,098 radiographic time points from 7,643 patients were scored by 13 readers as pairs. Scoring was performed by each reader independently according to the modified Sharp van der Heijde method (SHS)1 with the reader blinded to chronological sequence. The number of time points per study was 2 in 2 trials, 3 in 10 trials, and 4 in 3 trials. According to the B&A method, the datasets were evaluated to calculate the 95% limits of agreement SDC [(± 1.96*SDΔ (changescore))/($√ $2*$√ $K)], where K represents the number of readers, for all intervals between different time points per study and its average. Using the ANOVA method, calculations of the SDC per study were performed considering all time points. Statistical analysis was performed using SPSS software version 18.0. Results Median (range) baseline- and progression score was 32 (18-48) and 0.9 (0.5-1.8) units, respectively. Table 1 shows the results for all SDCs using both methods. The average SDC of all intervals calculated with the B&A method was very similar to SDC obtained by ANOVA. The mean difference between both methods was -0.13 (SD 0.28, range -0.48-0.25) units. Conclusions We propose to report the mean interval SDC as a good surrogate for the true SDC in trials with multiple time points. References van der Heijde DM. Lancet. 1989 May 13;1(8646):1036-8. Disclosure of Interest None Declared

Background For the evaluation of radiographic progression in RCTs, at least 2 readers should read all films in order to constrain measurement error. If differences in change scores between readers exceed a certain threshold, a third reader (adjudicator) can be used to obtain a more precise result. While the selection of a threshold that triggers this 3rd read is somewhat arbitrary (historically between 7 and 15 points), regulatory authorities suggest a cause for concern if 20% or more of the cases in a given clinical trial results in adjudication. Objectives To provide data on which percent of sets of radiographs need adjudication for a predetermined cut-off of difference in change score from baseline between two readers in RCTs in patients with early and established RA. Methods Fifteen datasets from radiographic trials in RA were scored by 13 readers as pairs according to the modified Sharp van der Heijde method (SHS). The reader was blinded to chronological sequence. The number of time points per study was 2 in 2 trials, 3 in 10 trials, and 4 in 3 trials. We calculated the theoretical adjudication rates if adjudication thresholds from 3 to 20 units were selected per study plus the weighted mean for all studies. We investigated the influence of the number of time points within the same session, the length of the interval, and mean disease duration (early (≤3 years) versus established RA) on the adjudication rates. Statistical analysis was performed using SPSS software version 18.0. Results 20.098 time points from 7.643 patients were included in the analysis. Median (range) sample size of the studies was 517 (103-901) patients, and the number of time points within one reading session was 2 for 1172 patients, 3 for 5296 patients and 4 for 1175 patients. Median (IQR) baseline radiological damage- and progression scores were 32 (18-48) and 1.05 (0.5-2.0) respectively. The percentage of adjudicated cases was inversely related to the threshold. The higher the number of time points within the same reading session, and the longer the time interval, the higher the adjudication rate. The adjudication rate was also higher in RCTs with early vs established RA, especially at lower thresholds. In all cases, the adjudication rate remained below 19%, even with a very conservative threshold selection of 3 units. Conclusions With trained and experienced readers, the adjudication rate in RCTs with patients with RA is low even with very conservative adjudication thresholds, which adds to the validity of the SHS scoring method as a precise and reliable outcome measure in RA. The adjudication rate is higher in RCTs with early- vs established RA. Disclosure of Interest None Declared