Robert M. Valente

A disease-specific activity index for Wegener's granulomatosis: Modification of the Birmingham Vasculitis Activity Score

OBJECTIVE To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegeners granulomatosis (WG). METHODS Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physicians global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearmans rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.

Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study.

Objective There is a need for comparative studies to provide evidence-based treatment guidance for biologic agents in rheumatoid arthritis (RA). Therefore, this study was undertaken as the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA. Methods Patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX, in a 2-year study. The primary end point was treatment noninferiority, assessed according to the American College of Rheumatology 20% improvement response (ACR20) at 1 year. Results Of the 646 patients who were randomized and treated, 86.2% receiving SC abatacept and 82% receiving SC adalimumab completed 12 months of treatment. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval −5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC abatacept–treated patients and 88.6% for SC adalimumab–treated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P = 0.006). Conclusion The results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab.

Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial

Objectives To compare over 2 years the safety, efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab, in combination with methotrexate (MTX), in patients with rheumatoid arthritis (RA). Methods AMPLE is a phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint. Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX. Results Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2. At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results. The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab. There were similar rates of adverse events (AEs) and serious adverse events (SAEs). More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab. There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group. Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%). Conclusions Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX, subcutaneous abatacept and adalimumab were similarly efficacious based on clinical, functional and radiographic outcomes. Overall, AE frequency was similar in both groups but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept. ClinicalTrials.gov Identifier NCT00929864.

Subcutaneous abatacept versus intravenous abatacept : a phase IIIb noninferiority study in patients with an inadequate response to methotrexate.

Objective To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. Methods In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. Results Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept–treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept–treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval –4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept–treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept–treated group and 65.2% and 4.9%, respectively, in the IV abatacept–treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)–treated patients (2.6%) and 18 IV abatacept (SC placebo)–treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept–treated patients and 2.3% of IV abatacept–treated patients. Conclusion SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

Subcutaneous abatacept for the treatment of rheumatoid arthritis: longterm data from the ACQUIRE trial.

Objective. Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA). Methods. The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported. Results. Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8–44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA. Conclusion. These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

Subcutaneous abatacept: long-term data from the Acquire Trial

Background/Purpose: MicroRNAs (miRs) are a novel class of posttranscriptional regulators. A single miR can have profound effects on cell activation due to its ability to modulate multiple pathways at once. We have previously shown that miR-155 is upregulated in rheumatoid arthritis (RA) synovial macrophages and promotes the development of autoimmunity and joint inflammation. Pre-clinical arthritis may be associated with lung changes e.g. bronchial wall thickening, thus the aim of this study was to investigate the contribution of miR-155 regulated pathways to lung homeostasis. Methods: Normal human lung tissue was tested by in situ hybridisation with miR-155 and control probes. To model the fibrotic response, WT and miR-155 / mice were given bleomycin (0.06 unit/mouse) intranasally. Intervention included intraperitoneal injections of the Liver X Receptor (LXR) agonist (GW3965 daily; 40 mg/kg). End-points included bronchial lavage (BAL) cytology, lung tissue histology, evaluation of the expression of inflammatory and fibrotic genes by qPCR and concentrations of soluble mediators in serum and BAL fluid by multiplex assays. The validation of miR-155 binding to LXR, and the LXR response element in collagen gene promoters were performed with reporter assays. Results: In situ hybridisation showed an abundant expression of miR-155 in the normal human lung suggesting that this miR may contribute to normal lung homeostasis. miR-155 / mice developed more severe bleomycininduced lung fibrosis compared to WT mice, as seen by increased collagen 1a/3a mRNA expression and protein deposition in the lungs, as well as accumulation of macrophages and lymphocytes in BAL. Gene expression analysis of lung extracts revealed an increase in the M2 pro-fibrotic macrophage markers Arginase 2, IL-13R and Ym1. In addition, the levels of pro-fibrotic cytokines such as VEGF and bFGF were significantly higher in BAL and serum of miR-155 / mice. Primary lung fibroblast lines derived from miR-155 / mice showed higher proliferation rates and motility compared to WT cells in wound healing assays. Computational analysis followed by functional luciferase assays revealed that the transcription activator LXR alpha is a direct target of miR-155 in the lungs. Expression of LXR alpha was significantly upregulated in the lungs of naive miR-155 / mice and was further increased in mice given bleomycin compared to similarly treated WT controls. Injection of the LXR agonist to WT mice increased LXR expression and mirrored the same phenotypic response to bleomycin as the miR-155 deficient mice; shown by increased collagen deposition and M2 macrophage and fibroblast activation. Promoter analysis revealed that LXRs could directly induce collagen production by binding to col1a and col3a promoters. / Conclusion: miR-155 appears important for lung homeostasis, likely by fine tuning levels of LXR thereby protecting from excessive remodelling. Given this and the emerging contribution of miR-155 to development of autoimmunity, this miR may act as a master-switch determining the duration of inflammation and the initiation of remodelling, as well as the balance between the immune and auto-immune responses.Background/Purpose: High mobility group box 1 (HMGB1) is a non-histone DNA binding protein that is passively released by dying cells or actively secreted by immunocompetent cells and the receptor for advanced glycation end-products (RAGE) is one of its receptors. Higher levels of HMGB1 have been found in patients with granulomatosis with polyangiitis (GPA) with active disease whereas higher HMGB1 and lower soluble (sRAGE) levels have been found in patients with acute atherosclerotic events suggesting sRAGE acts as a decoy receptor. This study aims to evaluate HMGB1 levels in relation to subclinical carotid atherosclerosis in GPA, and the impact of therapy on HMGB1 levels. Methods: A cross-sectional study was performed on 23 GPA patients during a quiescent phase of the disease in comparison to 20 matched controls. All study participants underwent carotid ultrasound to assess atherosclerotic plaques and intima-media thickness (IMT) and were tested for traditional risk factors for atherosclerosis, serum HMGB1 levels (ELISA-Shino Test, Kanagawa, Japan), and sRAGE levels (ELISA RD P = 0.978), HDLcholesterol (1.41 ± 0.37 vs. 1.51±0.33 mmol/L; P = 0.359), LDLcholesterol (3.01±0.79 vs. 3.29±0.82 mmol/L; P = 0.267), and a similar frequency of smoking (8.7% vs. 5.0%; P = 0.635), family history of premature coronary artery disease (CAD) (39.1% vs. 40.0%; P = 0.954), and obesity (4.3% vs. 10.0%; P = 0.446). Hypertension was only found in GPA patients (39.1% vs. 0.0%; P = 0.002) while no study participants had diabetes. Overt cardiovascular disease was found only in 13.0% of GPA patients. Statins were prescribed for 21.7% of GPA patients and 5.0% of controls (P = 0.127). Among GPA patients, prednisolone was being used by 34.8% with a median daily dose of 5.0mg (2.5-15.0) and azathioprine by 34.8%. Only two GPA patients used statins and prednisolone concomitantly. Carotid plaques were found in 30.4% of GPA patients and in 15.0% of controls (P = 0.203) and the overall IMT was similar in GPA patients and in controls (0.833±0.256 vs. 0.765±0.133mm; P = 0.861). Median serum HMGB1 levels were similar between GPA patients and controls [2.13ng/mL (1.11-7.22) vs. 2.42ng/mL (0.38-6.75); P = 0.827] as well as mean sRAGE levels (1256.1±559.6 vs. 1483.3±399.8pg/mL; P = 0.155). No correlations were found between HMGB1 and sRAGE ( = 0.068; P = 0.681) and between HMGB1 and maximum IMT in carotid arteries ( = -0.067; P = 0.720). GPA patients on prednisolone (1.77±0.76 vs. 3.53±2.06ng/ mL; P = 0.017) and statins (1.39±0.28 vs. 3.34±1.94ng/mL; P = 0.001) presented significantly lower serum HMGB1 levels whereas no difference in mean HMGB1 levels was found regarding azathioprine use (2.89±2.28 vs. 2.93±1.75; P = 0.970). Conclusion: No association was found between subclinical atherosclerosis in carotid arteries and HMGB1 levels in GPA patients. Furthermore, the use of either prednisone or statins was associated with lower HMGB1 levels in GPA patients. These findings suggest that the anti-inflammatory properties of statins include effects on serum HMGB1 levels in GPA.

Reductions in disease activity in the AMPLE trial: clinical response by baseline disease duration

Objectives To evaluate clinical response by baseline disease duration using 2-year data from the AMPLE trial. Methods Patients were randomised to subcutaneous abatacept 125 mg weekly or adalimumab 40 mg bi-weekly, with background methotrexate. As part of a post hoc analysis, the achievement of validated definitions of remission (Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, Routine Assessment of Patient Index Data 3 (RAPID3) ≤3.0, Boolean score ≤1), low disease activity (CDAI <10, SDAI <11, RAPID3 ≤6.0), Health Assessment Questionnaire-Disability Index response and American College of Rheumatology responses were evaluated by baseline disease duration (≤6 vs >6 months). Disease Activity Score 28 (C-reactive protein) <2.6 or ≤3.2 and radiographic non-progression in patients achieving remission were also evaluated. Results A total of 646 patients were randomised and treated (abatacept, n=318; adalimumab, n=328). In both treatment groups, comparable responses were achieved in patients with early rheumatoid arthritis (≤6 months) and in those with later disease (>6 months) across multiple clinical measures. Conclusions Abatacept or adalimumab with background methotrexate were associated with similar onset and sustainability of response over 2 years. Patients treated early or later in the disease course achieved comparable clinical responses. Trial registration number NCT00929864, Post-results.

FRI0193 SC vs IV abatacept in RA: post-hoc efficacy analysis of long-term acquire (SC) data with aim (IV) data

Background ACQUIRE was a Ph IIIb study demonstrating comparability of SC and IV abatacept (ABA) over a 6-mth DB period. At 6 mths, all patients (pts) entered an open-label (OL) period in which they received SC ABA. AIM was a Ph III 12-mth, DB, placebo-controlled study of IV ABA, also with an OL extension. Pts in both trials had moderate-to-severe RA, inadequate response to MTX and similar BL demographics and disease activity. Objectives To provide a long-term (LT) comparison of SC and IV ABA, we performed a post-hoc efficacy analysis of LT data from the OL periods of ACQUIRE and AIM. Methods In ACQUIRE, pts received 125 mg SC ABA weekly (after 10 mg/kg IV load on Day 1) +MTX. In AIM, pts received ∼10 mg/kg IV ABA every 4 weeks (after loading doses on Days 1, 15 & 29) +MTX; only pts who received ABA in DB and OL periods were included in this analysis. LT analysis began at Day 253 for ACQUIRE; Day 225 was selected as a comparison starting point for AIM. The most recent LT data lock for ACQUIRE (Day 897) was then used as the comparison end date for AIM as well. At the time of analysis, however, not all ACQUIRE pts had reached this later time point. As-observed data were used to assess both response to treatment (ACR 20, 50 and 70) and disease status (DAS28[CRP], SDAI and CDAI). No safety analyses were performed on this subset as larger pooled safety analyses are presented elsewhere. Results In the OL period of ACQUIRE, 1372 pts received SC ABA compared with 378 pts who received IV ABA in AIM. ACR 20, 50 and 70 rates, and DAS remission rates were sustained from Days 253/225 through Day 897 for ACQUIRE/AIM, respectively (Table). SDAI and CDAI remission rates at Day 253 (13.3%; 179/1341 and 15.6%; 211/1349) were maintained up to Day 897 (20.2%; 123/608 and 22.1%; 143/646) in ACQUIRE; in AIM, corresponding rates at Day 225 (9.9%; 36/365 and 12.2%; 45/369) were similarly maintained up to Day 897 (15.0%; 45/300 and 16.7%; 52/311). Table 1 Efficacy Parameter Study Day ACQUIRE SC ABA AIM IV ABA ACR 20  Subjects, n/m (%) Start of Comparison 968/1080 (89.6) 250/269 (92.9)  (95% CI) (87.8, 91.4) (89.9, 96.0)  Subjects, n/m (%) Day 897 493/544 (90.6) 215/236 (91.1)  (95% CI) (88.2, 93.1) (87.5, 94.7) ACR 50  Subjects, n/m (%) Start of Comparison 563/719 (78.3) 134/161 (83.2)  (95% CI) (75.3, 81.3) (77.5, 89.0)  Subjects, n/m (%) Day 897 285/371 (76.8) 107/145 (73.8)  (95% CI) (72.5, 81.1) (66.6, 81.0) ACR 70  Subjects, n/m (%) Start of Comparison 284/369 (77.0) 58/81 (71.6)  (95% CI) (72.7, 81.3) (61.8, 81.4)  Subjects, n/m (%) Day 897 130/196 (66.3) 45/72 (62.5)  (95% CI) (59.7, 72.9) (51.3, 73.7) DAS Remission  Subjects, n/m (%) Start of Comparison 210/331 (63.4) 37/61 (60.7)  (95% CI) (58.3, 68.6) (48.4, 72.9)  Subjects, n/m (%) Day 897 104/166 (62.7) 37/54 (68.5)  (95% CI) (55.3, 70.0) (56.1, 80.9) Conclusions SC abatacept provided similar efficacy to IV abatacept when compared across these 2 trials; overall, efficacy achieved in the short term was maintained in the LT. Disclosure of Interest M. Genovese Consultant for: Bristol-Myers Squibb, C. Pacheco Tena: None Declared, A. Covarrubias Cobos Grant/Research support from: Bristol-Myers Squibb, G. Leon: None Declared, E. Mysler Grant/Research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers Bureau: Bristol-Myers Squibb, M. Keiserman Grant/Research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers Bureau: Bristol-Myers Squibb, R. Valente Grant/Research support from: Pfizer, UCB, BMS, Roche, Takeda, and Lilly, P. Nash Grant/Research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers Bureau: Bristol-Myers Squibb, J. Simon Campos Speakers Bureau: Bristol-Myers Squibb, J. Box Consultant for: Bristol-Myers Squibb, Speakers Bureau: Bristol-Myers Squibb, C. Legerton III: None Declared, E. Nasonov Speakers Bureau: Roche; Bristol-Myers Squibb Company; Abbott Laboratories; Merck Sharp & Dohme Corp; UCB Pharma, Inc, P. Durez Speakers Bureau: Bristol-Myers Squibb, I. Delaet Employee of: Bristol-Myers Squibb, A. Elegbe Employee of: 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

Longterm Safety and Efficacy of Subcutaneous Abatacept in Patients with Rheumatoid Arthritis: 5-year Results from a Phase IIIb Trial

Objective. To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). Methods. The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported. Results. Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96–8.58), infection 38.60 (36.24–41.12), serious infection 1.68 (1.35–2.07), malignancies 1.09 (0.84–1.42), and autoimmune disorders 1.33 (1.05–1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study. Conclusion. These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.

THU0246 Subcutaneous Abatacept: Long-Term Data From the Acquire Trial

Background The Abatacept (ABA) Comparison of Sub[QU]cutaneous (SC) versus Intravenous (IV) in Inadequate Responders to MethotrexatE (MTX) (ACQUIRE) study showed comparable efficacy and safety of SC vs IV ABA over 6 mths.1 Objectives To present 32-mth safety and efficacy data from the long-term extension (LTE) of ACQUIRE, during which all patients (pts) received SC ABA. Methods ACQUIRE was a Phase IIIb, 6-mth, double-blind (DB) study in which pts with active RA (³10 swollen and ³12 tender joint count [SJC and TJC], C-reactive protein (CRP) ≥0.8 mg/dL) refractory to MTX received IV or SC ABA, plus MTX, followed by an open-label LTE when pts received SC ABA 125 mg/wk. Not all pts had reached later time points at time of analysis, as a result of differential enrolment in the trial. Results Of 1372 pts entering the LTE, 1134 (82.7%) remained on therapy at time of reporting. Mean baseline RA duration was 8 yrs, TJC and SJC were 30 and 20, respectively, and HAQ-DI was 1.7. Median (range) ABA exposure was 33 (8–44) mths. The incidence rate (IR; events/100 pt-yrs) of serious adverse events for pts treated with SC ABA in the LTE (8.76 [95% CI: 7.71–9.95]) was comparable with that for SC ABA in the DB period (9.02 [6.31–12.90]) and did not increase with increasing exposure. The IR of overall and serious infections in the LTE (44.80 [41.81–48.01] and 1.72 [1.30–2.27], respectively) did not increase vs the DB period (84.62 [74.50–96.11] and 1.48 [0.62–3.56], respectively). Bacterial, viral and hospitalised infections occurred at IRs of 27.28 (25.16–29.57), 18.25 (16.61–20.06) and 1.55 (1.16–2.07) during the LTE. The IR of malignancy did not increase in the LTE (1.19 [0.86–1.66]) vs the DB period (0.59 [0.15–2.36]). Injection-site reactions occurred in 27 (2.0%) pts in the LTE (none serious) and 19 (2.6%) pts in the DB period. Overall, 139/1365 (10.2%) and 1/153 (0.7%) pts experienced immunogenicity during the LTE and DB periods, respectively. ACR responses were maintained and comparable with original SC and IV groups: at Day 169, ACR 20 response rates were 80.2% (95% CI: 77.2, 83.2) and 80.0% (77.0, 83.0) and at Day 981 were 84.8% (80.8, 88.8) and 84.7% (80.7, 88.8). DAS28 (CRP) <2.6 rates (95% CI) were 24% (21–27; n=685) and 25% (22–28; n=667) at Day 169, and 39% (33–44; n=288) and 35% (29–40; n=275) at Day 981 for the original SC and IV groups, respectively. HAQ-DI responses (change from baseline ≥0.3) were 73% (95% CI: 69–76; n=691) and 68% (65–72; n=672) at Day 169, and 74% (69–79; n=313) and 70% (65–75; n=303) at Day 981 for the original SC and IV groups, respectively. Conclusions Over 32 mths, SC abatacept showed consistent safety with high patient retention. ACR, HAQ-DI response and DAS28 remission rates were maintained through the LTE. References Genovese MC, et al. Arthritis Rheum 2011;63:2854–64 Disclosure of Interest 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. Pacheco-Tena: None Declared, A. Covarrubias Shareholder of: UNIDAD REUMATOLOGICA LAS AMERICAS SCP, Grant/research support from: BMS, Pfizer, Lilly ICOS, G. Leon: None Declared, E. Mysler Grant/research support from: BMS, Consultant for: BMS, Speakers bureau: BMS, M. Keiserman Grant/research support from: Abbott Laboratories, Biogen Idec, Bristol-Myers Squibb, Eli Lilly and Company, Human Genome Sciences, Inc., MSD, Pfizer Inc, Roche, UCB, Inc, Novartis, Consultant for: Abbott Laboratories, Bristol-Myers Squibb, MSD, Speakers bureau: Bristol-Myers Squibb, MSD, R. Valente Grant/research support from: Pfizer, UCB, BMS, Roche, Takeda, Lilly, P. Nash Grant/research support from: BMS, Consultant for: BMS, Speakers bureau: BMS, J. Simon-Campos: None Declared, J. Box Shareholder of: Box Arthritis and Rheumatology of the Carolinas PLLC, Consultant for: BMS, Speakers bureau: BMS, C. Legerton III Consultant for: BMS, E. Nasonov Speakers bureau: Roche; Bristol-Myers Squibb Company; Abbott Laboratories; Merck Sharp & Dohme Corp; UCB Pharma, Inc, P. Durez Speakers bureau: BMS, I. Delaet Shareholder of: BMS, Employee of: BMS, M. Genovese Consultant for: Bristol-Myers Squibb