Gustavo Citera

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.

Symptomatic Efficacy of Etanercept and Its Effects on Objective Signs of Inflammation in Early Nonradiographic Axial Spondyloarthritis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial

To assess the efficacy of etanercept in the treatment of early active nonsteroidal antiinflammatory drug (NSAID)–refractory nonradiographic axial spondyloarthritis (SpA).

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study

Objective To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). Methods Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. Results 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by −1.1 for ETN/ETN and by −3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. Conclusions Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. Trial registration number NCT01258738.

Rheumatoid arthritis in Latin Americans enriched for Amerindian ancestry is associated with loci in chromosomes 1, 12, and 13, and the HLA class II region.

OBJECTIVE To identify susceptibility loci for rheumatoid arthritis (RA) in Latin American individuals with admixed European and Amerindian genetic ancestry. METHODS Genotyping was performed in 1,475 patients with RA and 1,213 control subjects, using a customized BeadArray containing 196,524 markers covering loci previously associated with various autoimmune diseases. Principal components analysis (EigenSoft package) and Structure software were used to identify outliers and define the population substructure. REAP software was used to define cryptic relatedness and duplicates, and genetic association analyses were conducted using Plink statistical software. RESULTS A strong genetic association between RA and the major histocompatibility complex region was observed, localized within BTNL2/DRA-DQB1- DQA2 (P = 7.6 × 10(-10) ), with 3 independent effects. We identified an association in the PLCH2-HES5-TNFRSF14-MMEL1 region of chromosome 1 (P = 9.77 × 10(-6) ), which was previously reported in Europeans, Asians, and Native Canadians. We identified one novel putative association in ENOX1 on chromosome 13 (P = 3.24 × 10(-7) ). Previously reported associations were observed in the current study, including PTPN22, SPRED2, STAT4, IRF5, CCL21, and IL2RA, although the significance was relatively moderate. Adjustment for Amerindian ancestry improved the association of a novel locus in chromosome 12 at C12orf30 (NAA25) (P = 3.9 × 10(-6) ). Associations with the HLA region, SPRED2, and PTPN22 improved in individuals positive for anti-cyclic citrullinated peptide antibodies. CONCLUSION Our data define, for the first time, the contribution of Amerindian ancestry to the genetic architecture of RA in an admixed Latin American population by confirming the role of the HLA region and supporting the association with a locus in chromosome 1. In addition, we provide data for novel putative loci in chromosomes 12 and 13.

Effects of Long‐Term Etanercept Treatment on Clinical Outcomes and Objective Signs of Inflammation in Early Nonradiographic Axial Spondyloarthritis: 104‐Week Results From a Randomized, Placebo‐Controlled Study

To evaluate the long‐term clinical and imaging efficacy of etanercept in patients with early, active nonradiographic axial spondyloarthritis (SpA).

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.

Efficacy and safety of etanercept in patients from Latin America, Central Europe and Asia with early non‐radiographic axial spondyloarthritis

To evaluate etanercept in patients from Latin America, Central/Eastern Europe, and Asia with non‐radiographic axial spondyloarthritis (nr‐axSpA).

Effects of Long-term Etanercept Treatment on Clinical Outcomes and Objective Signs of Inflammation in Early Non-Radiographic Axial Spondyloarthritis: 104-Week Results From the EMBARK Study

To evaluate the long‐term clinical and imaging efficacy of etanercept in patients with early, active nonradiographic axial spondyloarthritis (SpA).

SAT0372 Clinical and Imaging Efficacy of Etanercept in Early Non-Radiographic Axial Spondyloarthritis: 48-Week Treatment Data

Background Our previous data show that Etanercept (ETN) has superior clinical and anti-inflammatory efficacy to placebo (PBO) in patients with non-radiographic axial spondyloarthritis (nr-axSpA) and inadequate response to NSAIDs in a 12 week double-blind PBO controlled trial. Objectives To examine clinical and anti-inflammatory efficacy of ETN at wk 48 (12 wk double blind followed by 36 wk open-label treatment phase). Methods Patients with symptom duration >3 mths–<5 yrs, fulfilling ASAS axSpA criteria without meeting radiographic criteria for ankylosing spondylitis, having BASDAI ≥4, and failure with ≥2 NSAIDs were enrolled and randomized to ETN 50 mg QW or PBO. Both groups continued stable NSAID therapy. After 12 wks all patients received ETN 50 mg open-label. Clinical assessments (ASAS, ASDAS, BASDAI, BASFI) and MRI of sacroiliac (SI) joint and spine were performed (SPARCC and ASspiMRI scoring methods). Analyses used an ANCOVA model with baseline scores, treatment, MRI sacroiliitis +/-, as variables. Results Of 215 initially randomized patients (mITT population), 205 entered the open label phase (ETN=100; PBO=105). The proportion of patients achieving ASAS40 by 12 wks (primary endpoint) was 33.3% of those treated with ETN and 14.7% of PBO treated patients, improving to 52.7% of patients in the combined groups by wk 48. MRI-SI joint inflammation was reduced from baseline to wk12 in ETN and PBO treatment groups by 56.7% and 16.4%, respectively, and 65.2% (combined treatment groups) by wk 48. SAE caused 1 discontinuation (pyrexia) between wks 12–48 and infections (the most frequent AE) occurred in 43/208 patients. Table 1. Effects of ETN vs PBO in patients with nr-axSpA at wk 48 Endpoint Double-blind phase Open label phase Wk 12 Wk 48 ETN50 PBO Combined groups, all received ETN50 n=105** n=109** n=205** % patients achieving ASAS40-all patients 33.3 14.7 52.7 ASAS40-patients with elevated CRP 47.9 18.2 66.3 ASAS 5/6 34.3 11.9 47.3 BASDAI50 43.8 23.9 62.4 Baseline [N=215]* % Improvement from baseline Mean (SE) ASDAS-CRP (clinical improvement 1.1; major improvement 2.0) 3.0 (0.1) 42.2 21.3 54.5 BASDAI 6.0 (0.1) 39.3 27.9 55.8 BASFI 4.0 (0.2) 37.8 23.0 53.2 SPARCC 6 DVU score (0–108; MCID 5.0) 7.2 (0.7) 40.1 11.1 60.8 SPARCC SI joint score (0–72; MCID 2.5) 7.4 (0.8) 56.7 16.4 65.2 ASspiMRI 1.5 (0.2) 40.1 7.7 40.9 MCID, minimum clinically important difference. *Modified intention to treat population, includes PBO and ETN50 treatment groups. **May vary for the different outcomes. Conclusions In patients with early, active nr-axSpA and an inadequate response to ≥2 NSAIDs, clinical and imaging outcomes improved from baseline to a greater extent with etanercept therapy than with PBO, during the first 12 weeks. In the ensuing 36 week open label period, these outcomes continued to improve. There were no new safety signals. Acknowledgements The study NCT01258738 was funded by Pfizer Inc. Medical writing support was provided by Rachael Profit of Engage Scientific, Envision Pharma Group, and was funded by Pfizer Inc. Disclosure of Interest W. Maksymowych Grant/research support: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Synarc, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Synarc, and UCB, Employee of: CaRE Arthritis Ltd, D. van der Heijde Grant/research support: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, Chugai, Daiichi, Eli Lilly, GlaxoSmithKline, Janssen Biologics, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, Chugai, Daiichi, Eli Lilly, GlaxoSmithKline, Janssen Biologics, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, and Vertex, Employee of: Imaging Rheumatology bv, M. Dougados Grant/research support: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer, Roche, and Sanofi-Aventis, J. Sieper Consultant for: Abbott, Eli-Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Speakers bureau: Abbott, Eli-Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, J. Braun Grant/research support: Abbott, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, and UCB, G. Citera Grant/research support: Pfizer, Consultant for: Bristol-Myers Squibb, Pfizer, and Abbott., C. Miceli-Richard Grant/research support: AbbVie, Bristol-Myers Squibb, Janssen, and Pfizer, Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, and Pfizer, J. Wei Grant/research support: Abbott, AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eli Lilly, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB, Consultant for: Abbott, AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eli Lilly, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB, R. Pedersen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Bonin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Logeart Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Wajdula Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Rahman Employee of: Pfizer Inc at the time of the study, B. Vlahos Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bukowski Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.1138