Corine Gaillez

Impact of intravenous abatacept on synovitis, osteitis and structural damage in patients with rheumatoid arthritis and an inadequate response to methotrexate: the ASSET randomised controlled trial

Objectives This randomised, double-blind, placebo-controlled phase IIIb study evaluated the impact of abatacept on MRI pathology as a primary outcome in methotrexate (MTX)-refractory patients with rheumatoid arthritis. Methods Patients received intravenous abatacept (∼10u2005mg/kg) or placebo, on background MTX, for 4u2005months, followed by an 8-month open-label extension (OLE; all patients received abatacept plus MTX). Patients had 1.5T MRI with intravenous contrast at baseline, Months 4 and 12; wrist synovitis (three locations assessed), and wrist and hand (15 and eight locations assessed, respectively) osteitis and erosion were scored using OMERACT-RAMRIS. Results 26/27 abatacept- and 23/23 placebo-randomised patients completed Month 4 and entered the OLE; 26 and 21 completed Month 12. The primary endpoint was not achieved; mean change (SD) from baseline in synovitis was −0.44 (1.47) for abatacept versus 0.52 (1.38) for placebo (p=0.103) at Month 4. For mean change in synovitis adjusted for baseline score (sensitivity analysis), the difference between groups was −0.69, p=0.078. Adjusted mean changes (SE) in osteitis and erosion were −1.94 (0.86) and 0.45 (0.43) for abatacept, and 1.54 (0.90) and 0.95 (0.45) for placebo. Further MRI improvements were observed up to Month 12 for abatacept and from Months 4 to 12 for placebo-treated patients switched to abatacept at Month 4. Clinical efficacy was shown with abatacept and sustained to Month 12. Conclusions Despite small patient numbers, MRI detected structural and synovial benefit, sustained to Month 12 in abatacept+MTX-treated patients, and improvements in structural and inflammatory outcomes for placebo+MTX-treated patients following addition of abatacept. Clinical trial registration Clinicaltrials.gov NCT00420199.

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10u2005mg/kg) plus MTX for 24u2005weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number NCT00767325.

Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid arthritis starting abatacept: results from the APPRAISE study

Objectives To explore whether changes in a composite (power Doppler/greyscale ultrasound (PDUS)) synovitis score, developed by the OMERACT-EULAR-Ultrasound Task Force, predict disease activity outcomes in rheumatoid arthritis (RA). Methods Patients with RA who were methotrexate inadequate responders starting abatacept were evaluated. Individual joint PDUS scores were combined in the Global OMERACT-EULAR Synovitis Score (GLOESS) for metacarpophalangeal joints (MCPs) 2–5, all joints (22 paired) and a reduced (9 paired) joint set. The predictive value of changes in GLOESS at week 1–16 evaluations for clinical status and response (Disease Activity Score (DAS)28 (C reactive protein, CRP) <2.6; DAS28(CRP) ≤3.2; DAS28(CRP) ≥1.2 improvement) up to week 24, and correlations between DAS28 and GLOESS were assessed. Results Eighty-nine patients completed the 24-week treatment period. Changes in GLOESS (MCPs 2–5) from weeks 1 to 16 were unable to predict DAS28 outcomes up to week 24. However, significant improvements in GLOESS (MCPs 2–5) were observed at week 12 in patients with DAS28 ≥1.2 improvement at week 24 versus those who did not achieve that clinical response. In patients achieving DAS28 ≥1.2 improvement or DAS28 ≤3.2 at week 24, changes in GLOESS (22 and 9 paired joint sets) were greater in patients who already achieved DAS28 ≥1.2 at week 12 than in those who did not. No significant correlations were found between changes in DAS28 and GLOESS definitions at any time point. Conclusions PDUS was not correlated with clinical status or response as measured by DAS28-derived criteria, and PDUS changes were not predictive of clinical outcome. The discrepancies require further exploration. Trial registration number NCT00767325; Results.

FRI0242 Time to achieve remission and sustained remission for mtx-naïve patients with early ra treated with abatacept plus mtx versus mtx alone in the agree trial

Background Achieving remission from disease activity, and subsequently maintaining the remission state, is the goal of biologic treatment for early aggressive RA.1 Objectives To evaluate the time to achieve first remission or low disease activity (LDA) and time to achieve first sustained remission or LDA for MTX-naïve patients (pts) with early RA (≤2 years) treated with abatacept (ABA)+MTX vs MTX alone in a post hoc, observed-case analysis. Methods In AGREE, MTX-naïve pts with early RA and poor prognostic factors were randomized to ABA+MTX or MTX alone for 12 months.2 Cumulative probability of time to achieve first remission/LDA and sustained remission/LDA (defined as maintained at all subsequent visits up to Month 12) according to DAS28 ([CRP] <2.6), SDAI (≤3.3) and CDAI (≤2.8) was evaluated based on Kaplan–Meier estimation with corresponding 95% CI. Pts who lost remission status were censored at the time of remission loss. All analyses were performed for pts with SDAI, CDAI and DAS28 data available at baseline, Month 6 and 12. Results Overall, 419/509 (82.3%) pts had data available at baseline, Month 6 and 12 and were included (ABA+MTX n=210; MTX alone n=209). Cumulative probabilities of achieving DAS28, SDAI or CDAI-defined remission and LDA within the first 6 months, and overall in the 12-month, DB period are shown in the table. Median (95% CI) days to reach first LDA defined by DAS28, SDAI and CDAI were 139 (113, 169) vs 225 (169, 279), 140 (113, 148) vs 197 (169, 252), and 140 (113, 167) vs 199 (169, 252) for ABA+MTX vs MTX alone, respectively. Conclusions In AGREE, pts with early RA treated with ABA+MTX were more likely to achieve first remission/LDA up to Months 6 and 12, and first sustained remission/LDA up to Month 12, than pts receiving MTX alone, regardless of the criteria used to define remission and disease activity. These data support the use of abatacept as a first-line biologic in combination with DMARDs in DMARD-naïve (including MTX) pts with early RA, particularly those with poor prognostic factors. References Smolen JS, et al. Ann Rheum Dis 2010;69:964-75; Westhovens R, et al. Ann Rheum Dis 2009;68:1870-7 Disclosure of Interest: J. Smolen Grant/research support from: Abbott, Bristol-Myers Squibb, Hoffmann-La Roche, Schering-Plough, UCB, Pfizer, Consultant for: Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, Eli-Lilly, Merck, Novo Nordisk, Roche, sanofi-aventis, UCB, J. Wollenhaupt Consultant for: Bristol-Myers Squibb, Chugai, Roche, Speakers bureau: Chugai, Roche, P. Durez Speakers bureau: Bristol-Myers Squibb, J. Gomez-Reino Grant/research support from: Roche, Schering-Plough, Wyeth Pharmaceuticals, UCB, Consultant for: Hoffmann-La Roche, Roche, Schering-Plough, UCB, Pfizer, Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Roche, UCB, MSD, Pfizer, Abbott, W. Grassi Grant/research support from: Abbott, Bristol-Myers Squibb, Esaote, General Electric, Menarini, Merck Sharp & Dohme, Pfizer, Roche, Schering-Plough, UCB, Consultant for: Abbott, Bristol-Myers Squibb, Esaote, General Electric, Menarini, Merck Sharp & Dohme, Pfizer, Roche, Schering-Plough, UCB, M. Le Bars Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Gaillez Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Poncet Consultant for: Bristol-Myers Squibb, R. Westhovens Grant/research support from: Roche, UCB, Consultant for: Bristol-Myers Squibb, Galapagos, Janssen, Speakers bureau: Bristol-Myers Squibb

THU0277 Gene Expression in Whole Blood Predicts the Abatacept–Methotrexate Combination Responsiveness in Rheumatoid Arthritis: Preliminary Results from the Power Doppler Ultrasonography Appraise Study

Background The overall response rate (defined as low disease activity [LDA] related to DAS28[CRP]) to abatacept associated with MTX was 57.1% at 6 months in the 6-month open-label abatacept Power Doppler Ultrasonography (PDUS; APPRAISE) study in patients with RA and inadequate response to MTX [1–4]. Objectives The objective of this exploratory analysis was to identify potential predictors of response to the abatacept–MTX combination by whole blood gene expression profiling in order to optimize treatment choice. Methods 104 patients with active RA and inadequate response to MTX were treated with abatacept + MTX at the approved doses. Whole blood in Paxgene tubes was collected for each RA patient at baseline. At 6 months, RA patients were categorized as responders if DAS28 was ≤3.2 (LDA) and non-responders if DAS28 was >3.2. Baseline RNAs from a first set of RA patients (n=44) were hybridized to a whole human genome 4 x 44K microarray Agilent slide to identify a gene combination able to separate responders and non-responders with the GeneSpring GX software. A t-test with false discovery rate correction for multiple testing (p<0.05) was used to determine mRNAs differentially regulated between responders and non-responders. This gene combination was validated with a second set of RA patients (n=32) by qRT-PCR. Results Among these 104 RA patients, 28 were excluded from the following analysis because of missing clinical data (n=13), poor integrity of whole blood mRNA (RIN<7) (n=6), low concentration rate for reverse transcription (n=7), qRT-PCR failures (n=2). Responders (n=45) and non-responders (n=31) had similar baseline characteristics [1]. In a first set of 44 enrolled RA patients (25 responders and 19 non-responders), 87 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering almost perfectly separated these responders from non-responders. The informativeness of 12 of these 87 transcripts (selected with the lowest p-value), as measured by qRT-PCR, was re-assessed in a second set of 32 RA patients (20 responders and 12 non-responders). The combined levels of these 12 transcripts properly classified 23 out of 32 patients with a sensitivity of 80%, a specificity of 66.7%, a positive predictive value of 80%, and a negative predictive value of 66.8%. This combination enriched with more genes is in progress in order to better classify the second set of RA patients. Conclusions Our gene profiling results obtained by a non-invasive procedure have generated a list of 12 candidate genes that were associated with a response to abatacept combined with MTX in this study. This combination of genes needs to be further validated in other RA studies to support their utility as a potential diagnostic assay for predicting abatacept response in an effort to personalize treatment for RA. References DAgostino MA et al. Ann Rheum Dis 2012;71(Suppl 3):86. DAgostino MA, et al. Arthritis Rheum 2012;64(Suppl):S352. DAgostino MA, et al. Arthritis Rheum 2012;64(Suppl):S353. Lequerre T, et al Arthritis Rheum 2013;65(Suppl):S811. Disclosure of Interest : T. Lequerré Grant/research support: BMS, Consultant for: BMS, C. Derambure: None declared, M. DAgostino: None declared, M. Hiron: None declared, P. Gaudin Consultant for: BMS, C. Gaillez Shareholder of: BMS, Employee of: BMS, M. Le Bars Shareholder of: BMS, Employee of: BMS, O. Vittecoq Consultant for: BMS Advisory Board DOI 10.1136/annrheumdis-2014-eular.1567

FRI0199 In patients with established RA, abatacept efficacy is independent of baseline annual radiographic progression rate

Background In the Phase III, double-blind, placebo (PBO)-controlled AIM study, abatacept (ABA)+ MTX significantly inhibited structural damage progression vs PBO+MTX in pts with established RA and inadequate response to MTX.1Sustained inhibition of radiographic progression was seen up to yr 5.2 Previous data in pts with early RA showed a benefit of ABA in pts with faster progression.3 Objectives To assess clinical outcomes at 1 yr according to annual radiographic progression rate (ARPR) by quartile at baseline (BL) in pts with established RA in AIM. Methods BL characteristics were similar between ABA 10 mg/kg+MTX (n=433) and PBO+MTX (n=219). ARPR was defined as total Genant-modified Sharpscore divided by disease duration. Pts were categorized into four quartiles according to ARPR at BL (Q1: ≤2.78; Q2: 2.78 to ≤4.64; Q3: 4.64 to ≤8.04; Q4: >8.04). For each quartile, treatment benefit was assessed post hoc by outcomes: DAS28(CRP)-derived criteria (remission <2.6; LDAS ≤3.2), Simplified Disease Activity Index Low Disease Activity (SDAI ≤11) and ACR50 response. Results Mean (SD) BL ARPR was 8.13 (18.11) for ABA+MTX and 5.87 (5.36) for PBO+MTX. For ABA+MTX vs PBO+MTX, the percentage of pts achieving an outcome at yr 1 by ARPR quartile is shown, with treatment differences (table). 95% CI of ABA vs PBO estimate of treatment difference did not cross zero for most ARPR quartiles. For LDAS (assessed by DAS28[CRP] or SDAI) and ACR50, there was a numerically higher treatment difference for pts in some of the higher quartiles (Q3/Q4). Table 1 % (95% CI) ARPR Q1 Q2 Q3 Q4 ABA+MTX (n=84) ABA+MTX (n=90) ABA+MTX (n=94) ABA+MTX (n=103) MTX (n=43) MTX (n=41) MTX (n=39) MTX (n=32) DAS28 LDAS ABA+MTX 42.9 (32.3, 53.4) 38.9 (28.8, 49.0) 45.7 (35.7, 55.8) 40.8 (31.3, 50.3) MTX 14.0 (3.6, 24.3) 19.5 (7.4, 31.6) 2.6 (0, 7.5) 6.3 (0, 14.6) Tx Δ 28.9 (9.9, 48.0) 19.4 (0.3, 38.5) 43.2 (23.8, 62.6) 34.5 (13.9, 55.2) <2.6 ABA+MTX 29.8 (20.0, 39.5) 18.9 (10.8, 27.0) 23.4 (14.8, 32.0) 26.2 (17.7, 34.7) MTX 2.3 (0, 6.8) 4.9 (0, 11.5) 0 (0, 0) 3.1 (0, 9.2) Tx Δ 27.4 (10.8, 44.0) 14.0 (-0.8, 28.8) 23.4 (7.7, 39.1) 23.1 (5.0, 41.2) SDAI LDAS ABA+MTX 52.4 (41.7, 63.1) 43.3 (33.1, 53.6) 44.7 (34.6, 54.7) 44.7 (35.1, 54.3) MTX 20.9 (8.8, 33.1) 24.4 (11.2, 37.5) 7.7 (0, 16.1) 6.3 (0, 14.6) Tx Δ 31.5 (11.6, 51.3) 18.9 (-0.7, 38.6) 37.0 (17.5, 56.5) 38.4 (17.4, 59.4) ACR50 ABA+MTX 61.4a (51.0, 71.9) 50.6b (40.2, 60.9) 54.3 (44.2, 64.3) 48.5 (38.9, 58.2) MTX 31.0c (17.0, 44.9) 22.0 (9.3, 34.6) 25.6 (11.9, 39.3) 12.5 (1.0, 24.0) Tx Δ 30.5 (10.1, 50.8) 28.6 (8.6, 48.6) 28.6 (8.2, 49.0) 36.0 (14.6, 57.5) Values are proportion of pts (%), except Tx Δ = treatment difference. an=83; bn=89; cn=42. Conclusions Over 1 yr, pts with established RA achieved better outcomes with abatacept +MTX than PBO+MTX across all quartiles. Pts with rapid radiographic progression (Q4) showed numerically greater clinical benefits in LDAS, SDAI and ACR50 compared with Q1 pts, extending previous findings in early RA.3 References Kremer J et al. Ann Intern Med 2006;144:865–76. Schiff M. Rheum 2011;50:437–49. Westhovens R et al. Ann Rheum Dis2011;70(Suppl 3):617. Disclosure of Interest P. Emery Grant/Research support from: Abbott Immunology Pharmaceuticals, Abbott Laboratories, BMS, Centocor Research and Development, Inc., Merck Pharmaceuticals, Pfizer Inc, Roche, UCB, Inc., Consultant for: Abbott Laboratories, Amgen Inc., BMS, Centocor Research and Development, Inc., Lilly USA, LLC., Merck Pharmaceuticals, Pfizer Inc, Roche, Schering-Plough, Takeda Pharmaceuticals North America, Wyeth Pharmaceuticals, UCB, Inc., Speakers Bureau: Abbott Immunology Pharmaceuticals, BMS, Centocor Research and Development, Inc., Merck Pharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, UCB, Inc., R. Westhovens Grant/Research support from: Roche, UCB, Consultant for: Bristol-Myers Squibb, Centocor, Roche, Schering-Plough, Speakers Bureau: Bristol-Myers Squibb, M. Dougados Grant/Research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers Bureau: Bristol-Myers Squibb, R. Alten Grant/Research support from: BMS, Merck Pharma GmbH, Wyeth Pharmaceuticals, Pfizer, Consultant for: Abbott Laboratories, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, Speakers Bureau: Abbott Laboratories, BMS, Horizon Pharma, Merck Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, C. Gaillez Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, C. Poncet: None Declared, M. Le Bars Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Elegbe Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, H. Genant Shareholder of: Synarc, Inc., Grant/Research support from: Bristol-Myers Squibb, GSK, Roche, Genentech, Pfizer, Consultant for: Bristol-Myers Squibb, GSK, Roche, Genentech, Amgen, Merck, Servier, Pfizer, Lilly, Employee of: Synarc, Inc.