M. Maldonado

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.

Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.

Objectives To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study. Methods In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1–Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. Results Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1–Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. Conclusions In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab. Trial registration number NCT00929864.

Estimating disease activity using multi‐biomarker disease activity scores in patients with rheumatoid arthritis treated with abatacept or adalimumab

To assess the ability of a multi‐biomarker disease activity (MBDA) test (Vectra DA) to reflect clinical measures of disease activity in patients enrolled in the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic‐Naive RA Subjects with Background Methotrexate) trial.

Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab.

To assess the ability of a multi‐biomarker disease activity (MBDA) test (Vectra DA) to reflect clinical measures of disease activity in patients enrolled in the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic‐Naive RA Subjects with Background Methotrexate) trial.

Patient-Reported Outcomes From a Two-Year Head-to-Head Comparison of Subcutaneous Abatacept and Adalimumab for Rheumatoid Arthritis.

To report 2‐year patient‐reported outcomes (PROs) from the head‐to‐head Abatacept versus Adalimumab Comparison in Biologic‐Naive RA Subjects with Background Methotrexate (MTX) (AMPLE) trial.

FRI0039 Modulation of the ACPA Fine Specificity in Patients with RA Treated with Either Abatacept or Adalimumab in the AMPLE Study

Background Anti-citrullinated protein antibodies (ACPAs) are markers of RA and emerging evidence suggests they may play a role in disease progression. Analysis of biomarkers from AMPLE provides a unique opportunity to probe the differential effects of treatment with biologic DMARDs with distinct mechanisms of action (MoA).1 Here we characterize the changes in ACPA profiles over time and evaluate the relationship between ACPA and clinical outcomes. Objectives To assess the relationship between changes in ACPA and disease activity in patients (pts) treated with either abatacept (ABA) or adalimumab (ADA). Methods Pts in AMPLE were MTX failures but naïve to biologic DMARDs.1 Anti-CCP2+ status was determined based on a commercial anti-CCP2 ELISA established cut-off. ACPA analysis included 20 specificities and was performed using a custom assay.2 The anti-CCP2 ELISA was performed at baseline (BL) while the ACPA fine specificities were measured at BL, 85, 365 and 729 days. DAS28 (CRP) and ACPA changes were compared using an ANCOVA model with treatment as a factor and BL values and DAS28 (CRP) strata as covariates. Comparisons of pts who achieved or failed to achieve a Major Clinical Response at Day 729 (MCR729) were also made. Results Of the available pt BL serum measures, 185/251 (74%) were anti-CCP2+ in the ABA arm and 203/257 (79%) were positive in the ADA arm. For both treatments, BL anti-CCP2+ pts showed greater improvements in both DAS28 (CRP) and HAQ than BL negative pts. For the BL anti-CCP2+ pts, mean change (95% CI) from BL in DAS28 (CRP) at Day 729 was −2.82 (−3.03, −2.62) and −2.72 (−2.92, −2.53) for ABA- and ADA-treated pts, respectively. For BL negative pts, mean change (95% CI) from BL in DAS28 (CRP) at Day 729 was −2.26 (−2.61, −1.90) and −2.13 (−2.52, −1.75) for ABA- and ADA-treated pts, respectively. HAQ showed a similar pattern, with a mean change (95% CI) at Day 729 in the ABA arm of −0.78 (−0.89, −0.68) for anti-CCP2+ pts and −0.59 (−0.76, −0.41) for negative pts. In the ADA arm, respective values were −0.82 (−0.91, −0.72) and −0.49 (−0.69, −0.29). Reductions in specific ACPAs were observed in both treatment arms over the 2-year study, independent of clinical response, although they followed different patterns (Figure). Certain ACPAs had a greater mean reduction from BL in ABA- than ADA-treated pts, most notably ACPAs against apolipoprotein E and histones 2A and 2B during Year 2 of treatment. In pts with MCR729, ABA treatment produced a continued decline in the median levels of most ACPAs beyond Year 1 of treatment (Figure – left). The median levels of most ACPAs rebounded after Year 1 in ADA-treated pts who reached MCR729 (Figure – right). Conclusions AMPLE provided an opportunity to evaluate the molecular differences in RA pathology altered by treatment with two biologics with distinct MoA. Both agents resulted in a greater response in anti-CCP2+ pts and impacted the overall pattern of ACPA fine specificities. Among patients with similar sustained clinical response, abatacept and adalimumab induced different impacts on ACPA over time suggesting different effects on adaptive immunity.3 References Schiff M, et al. Ann Rheum Dis 2014;73:86–94; 2. Sokolove J, et al. PLoS ONE 2012;7:e35296. 3. Cope A, et al. J Clin Inves 1994;94:749–760 Disclosure of Interest S. Connolly Shareholder of: BMS, Employee of: BMS, M. Maldonado Shareholder of: BMS, Employee of: BMS, M. Schiff Consultant for: Bristol-Myers Squibb, Abbvie, Speakers bureau: Bristol-Myers Squibb, Abbvie, M. Weinblatt Grant/research support: BMS, Crescendo Bioscience, UCB, Consultant for: BMS, Crescendo Bioscience, UCB, AbbVie, Roche, Janssen, R. Fleischmann Grant/research support: AbbVie, Amgen, Astellas, Astra Zeneca, BMS, Celgene, Dynavax, Genzyme, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi Aventis, UCB, Xoma, Consultant for: AbbVie, Amgen, Astra Zeneca, BMS, Celgene, Janssen, Eli Lilly, Pfizer, Roche, Sanofi Aventis, UCB, W. Robinson: None declared, J. Sokolove Grant/research support: Lab receives research support from BMS DOI 10.1136/annrheumdis-2014-eular.2469

Randomized Clinical Trial Design to Assess Abatacept in Resistant Nephrotic Syndrome

Introduction Treatment-resistant nephrotic syndrome is a rare form of glomerular disease that occurs in children and adults. No Food and Drug Administration−approved treatments consistently achieve remission of proteinuria and preservation of kidney function. CD80 (B7-1) can be expressed on injured podocytes, and administration of abatacept (modified CTLA4-Ig based on a natural ligand to CD80) has been associated with sustained normalization of urinary protein excretion and maintenance of glomerular filtration rate in experimental and clinical settings. Methods In this report, we describe the rationale for and design of a randomized, placebo-controlled, clinical trial of abatacept in patients with treatment-resistant nephrotic syndrome caused by focal segmental glomerulosclerosis or minimal change disease. The design is a hybrid of a parallel-group and crossover design (switchover) with the primary objectives assessed in the first period of the study and the secondary objectives assessed using data from both periods. All participants will receive the active agent in 1 of the periods. The duration of treatment will be 4 months per period. Results The primary outcome will be improvement in nephrotic-range proteinuria to subnephrotic range, that is, reduction from baseline to 4 months in urine protein:creatinine ratio ≥ 50% and to a level < 3. The projected sample size is 90 patients, which has 80% power to detect a treatment difference of 28%. Conclusion This study advances efforts to validate CD80 as a therapeutic target for treatment-resistant nephrotic syndrome, and implements a precision medicine-based approach to this serious kidney condition in which the selection of a therapeutic agent is guided by the underlying disease mechanism operating in individual patients.

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.

Weekly subcutaneous abatacept confers comparable onset of treatment response and magnitude of efficacy improvement over 6 months when administered with or without an intravenous abatacept loading dose

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.