Sean E. Connolly

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.

Abatacept inhibition of T cell priming in mice by induction of a unique transcriptional profile that reduces their ability to activate antigen-presenting cells

To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA‐4Ig molecule that binds with high affinity to CD80/86 on antigen‐presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.

Abatacept inhibits T cell priming by inducing of a unique transcriptional profile that reduces their ability to activate antigen presenting cells

To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA‐4Ig molecule that binds with high affinity to CD80/86 on antigen‐presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.

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.

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

FRI0205 Relationship between Anti-Citrullinated Protein Antibody Status and Response To Abatacept or Anti-Tumour Necrosis Factor Therapy in Patients with Rheumatoid Arthritis: A US National Observational Study

Background Anti-citrullinated protein antibodies (ACPA) are associated with more severe, erosive rheumatoid arthritis (RA), but the extent to which ACPA status predicts response to therapy is not known.1,2 Objectives To evaluate in a real-world, observational RA cohort whether baseline ACPA status is associated with response to biologics among patients with RA. Methods Using the Corrona RA registry, we identified patients with RA who initiated abatacept (ABA) or a tumour necrosis factor-alpha inhibitor (TNFi) between June 2002 and January 2015, had a follow-up visit 6 months (±3 months) after initiation and anti-cyclic citrullinated peptide (anti-CCP [a surrogate of ACPA]) measured at or prior to initiation. Anti-CCP positivity was defined as anti-CCP ≥20 U/mL. The primary outcome was mean change from baseline in Clinical Disease Activity Index (CDAI) at 6 months. Secondary outcomes at 6 months included: 1) achievement of low disease activity (LDA; CDAI ≤10) among those with moderate or high disease activity who initiated treatment; 2) achievement of remission (CDAI ≤2.8) in those with low, moderate or high disease activity who initiated treatment; 3) Minimally Important Clinical Difference (MCID) in CDAI; and 4) modified ACR20/50/70. Unadjusted and adjusted linear and logistic analyses were performed based on anti-CCP status (positive [+] vs negative [–]). Results 566 patients initiated ABA: 204 (36.0%) were anti-CCP– and 362 (64.0%) anti-CCP+. There were no differences by CCP status for age (mean 57–58 years), disease duration (median 7 years) or prior biologic use (0, 1 or ≥2 prior); however, median baseline CDAI was greater in anti-CCP– vs anti-CCP+ patients (21 vs 19, p=0.035). 1715 patients initiated a TNFi: 602 (35.1%) were anti-CCP– and 1113 (64.9%) anti-CCP+. There were no differences by CCP status for age (mean 55–56 years), prior biologic use or median baseline CDAI; however, median disease duration was greater in anti-CCP+ vs anti-CCP– patients (4 vs 3 years, p=0.021). In adjusted analyses, anti-CCP+ ABA initiators had a mean (SE) change in CDAI of –8.5 (0.6) vs –4.1 (0.8) for anti-CCP– (p<0.001); in TNFi initiators, this was –7.4 (0.3) vs –6.4 (0.4) (p=0.071). In the multivariate model for secondary outcomes, the magnitude of response was greater in anti-CCP+ vs anti-CCP– ABA initiators. Outcomes did not differ by anti-CCP status in TNFi initiators (Figure). Conclusions In a clinical practice setting, anti-CCP positivity was associated with a differential treatment response to abatacept, but not TNFis. These real-world data suggest that anti-CCP+ patients with RA show incremental improvements in response while receiving abatacept therapy compared with anti-CCP– patients. References Lv Q, et al. PLoS One 2014;9:e89442. Sokolove J, et al. Ann Rheum Dis 2015; doi:10.1136/annrheumdis-2015-207942. Disclosure of Interest L. R. Harrold Grant/research support from: Pfizer, H. J. Litman Employee of: Corrona, S. E. Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Kelly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, W. Hua Employee of: Corrona, E. Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, L. Rosenblatt Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Rebello Employee of: Corrona, J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Bristol-Myers Squibb, Genentech, Lilly, Novartis, Pfizer, Employee of: Corrona, Speakers bureau: Genentech (non-branded talks only)

Effect of Anticitrullinated Protein Antibody Status on Response to Abatacept or Antitumor Necrosis Factor-alpha Therapy in Patients with Rheumatoid Arthritis: A US National Observational Study

Objective. Assess whether baseline anticyclic citrullinated peptide antibodies (anti-CCP) status is associated with treatment response in patients with rheumatoid arthritis (RA) initiating abatacept (ABA) or a tumor necrosis factor-α inhibitor (TNFi). Methods. Using the Corrona RA registry, patients were identified who initiated ABA or a TNFi (June 2004–January 2015), had a followup visit 6 months (± 3 mos) after initiation, and anti-CCP measured at or prior to initiation. Primary outcome was mean change in Clinical Disease Activity Index (CDAI) from initiation to 6 months. Treatment response was evaluated based on a typical patient profile (female, aged 57 yrs, body mass index of 30 kg/m2, baseline CDAI of 20, 1 prior biologic, and no comorbidities other than RA). Secondary outcomes included remission and low disease activity. Results. There were 566 ABA initiators [anti-CCP+ (≥ 20 units/ml): n = 362; anti-CCP− (< 20 units/ml): n = 204] and 1715 TNFi initiators (anti-CCP+: n = 1113; anti-CCP−: n = 602). Differences between treatment groups included baseline disease duration, CDAI, and prior biologic use. At 6 months, anti-CCP+ ABA initiators were associated with significantly greater CDAI response versus anti-CCP− ABA initiators; no significant difference was observed for TNFi initiators. When considering a typical RA patient profile, CDAI response was greater in anti-CCP+ versus anti-CCP− ABA initiators; anti-CCP+ versus anti-CCP− TNFi initiators were similar. Secondary outcome responses were also greater in anti-CCP+ versus anti-CCP− ABA initiators; TNFi initiators did not differ by anti-CCP status. Conclusion. In a US-based clinical practice setting, anti-CCP status was associated with a differential treatment response to ABA, but not TNFi.

Revised Reply to Letter to the Editor with regards to manuscript AR-15-1750.R1.

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Do Poor Prognostic Factors in Rheumatoid Arthritis Affect Treatment Choices and Outcomes? Analysis of a US Rheumatoid Arthritis Registry

Objective. To characterize patients with rheumatoid arthritis (RA) by number of poor prognostic factors (PPF: functional limitation, extraarticular disease, seropositivity, erosions) and evaluate treatment acceleration, clinical outcomes, and work status over 12 months by number of PPF. Methods. Using the Corrona RA registry (January 2005–December 2015), biologic-naive patients with diagnosed RA having 12-month (± 3 mos) followup were identified and categorized by PPF (0–1, 2, ≥ 3). Changes in medication, Clinical Disease Activity Index (CDAI), and work status (baseline–12 mos) were evaluated using linear and logistic regression models. Results. There were 3458 patients who met the selection criteria: 1489 (43.1%), 1214 (35.1%), and 755 (21.8%) had 0–1, 2, or ≥ 3 PPF, respectively. At baseline, patients with ≥ 3 PPF were older, and had longer RA duration and higher CDAI versus those with 0–1 PPF. In 0–1, 2, and ≥ 3 PPF groups, respectively, 20.9%, 23.2%, and 26.5% of patients received ≥ 1 biologic (p = 0.011). Biologic/targeted synthetic disease-modifying antirheumatic drug (tsDMARD) use was similar in patients with/without PPF (p = 0.57). After adjusting for baseline CDAI, mean (standard error) change in CDAI was −4.95 (0.24), −4.53 (0.27), and −2.52 (0.34) for 0–1, 2, and ≥ 3 PPF groups, respectively. More patients were working at baseline but not at 12-month followup in 2 (13.9%) and ≥ 3 (12.5%) versus 0–1 (7.3%) PPF group. Conclusion. Despite high disease activity and worse clinical outcomes, number of PPF did not significantly predict biologic/tsDMARD use. This may warrant reconsideration of the importance of PPF in treat-to-target approaches.