J Ye

Body mass index and clinical response to intravenous or subcutaneous abatacept in patients with rheumatoid arthritis

This post hoc analysis of ACQUIRE (NCT00559585) explored the effect of baseline body mass index (BMI) on the pharmacokinetics of and clinical response to subcutaneous (SC) or intravenous (IV) abatacept in patients with rheumatoid arthritis (RA). ACQUIRE was a phase 3b, 6-month, double-blind, double-dummy study in which patients with RA were randomized (1:1) to SC (fixed - dose; 125xa0mg/week) or IV (weight-tiered; ~xa010xa0mg/kg/month) abatacept plus methotrexate. In this analysis, minimum abatacept plasma concentration (Cmin) was measured at 3 and 6xa0months, and clinical remission over 6xa0months was assessed by Disease Activity Score 28 (C-reactive protein; DAS28 [CRP], <xa02.6), Simplified Disease Activity Index (SDAI, ≤xa03.3), and Clinical Disease Activity Index (CDAI, ≤xa02.8). Data were stratified by baseline BMI (underweight/normal, <xa025xa0kg/m2; overweight, 25 to <xa030xa0kg/m2; obese, ≥xa030xa0kg/m2) and administration route. Of the 1456/1457 patients for whom baseline BMIs were available, 526 (36%; SC 265, IV 261) patients were underweight/normal, 497 (34%; SC 249, IV 248) were overweight, and 433 (30%; SC 221, IV 212) were obese. Median Cmin abatacept concentration was ≥xa010xa0μg/mL (efficacy threshold) at 3 and 6xa0months in >xa090% of patients across BMI groups with both administration routes. DAS28 (CRP), SDAI, and CDAI remission rates at 6xa0months were similar across BMI groups and 95% confidence intervals overlapped at all time points in both separate and pooled SC/IV analyses. Therapeutic concentrations of abatacept and clinical remission rates using stringent criteria were similar across patient BMIs and administration routes.

SAT0468 Presence of poor prognostic factors may predict response to abatacept in patients with active psoriatic arthritis: results from a post hoc analysis from a phase iii study

Background Abatacept, a selective T-cell co-stimulation modulator, significantly increased ACR20 response and had an overall beneficial effect on musculoskeletal symptoms in patients (pts) with active psoriatic arthritis (PsA) in the Phase III Active pSoriaTic athritis RAndomizEd triAl (ASTRAEA, NCT01860976).1 Factors that may predict responses to abatacept were explored in this post hoc analysis. Objectives To evaluate the relationship between baseline characteristics and abatacept response in a post hoc analysis of ASTRAEA. Methods Pts were randomized (1:1) to SC abatacept 125 mg weekly or placebo for 24 weeks in this trial. Pts without >20% improvement in joint counts at Week 16 were switched to open-label abatacept (early escape). ACR20 response rate in pts stratified by baseline variables was investigated in a multivariate analysis and odds ratios (ORs) generated to identify differences in response. Using a cut-off of OR 1.2, indicating pt subgroups in whom abatacept appeared to have a meaningful treatment benefit, baseline variables were further investigated in a univariate analysis and estimated differences calculated. Results Of 424 pts enrolled, 213 received abatacept and 211 placebo. In abatacept-treated pts, the multivariate model showed a difference in ACR20 response (OR >1.2) for baseline CRP (>upper limit of normal [ULN] vs ≤ULN; OR 1.346 [95% CI 0.668, 2.712]), DAS28 (CRP) (>5.1 vs ≤5.1; 1.489 [0.782, 2.836]), dactylitis (>0 vs 0; 1.372 [0.708, 2.659]), and median baseline erosions (≥3 vs <3; 1.924 [1.032, 3.587]). In placebo-treated pts, the OR was >1.2 for dactylitis only (1.406 [0.619, 3.193]). These factors, which have been identified previously as indicating poor prognosis in PsA, were balanced between treatment arms at baseline. In the univariate model by poor prognostic factors, the differences in ACR20 response rates with abatacept treatment vs placebo in distinct subgroups were numerically greater in pts who were positive for these prognostic factors at baseline than in those who were not (Figure). Conclusions These findings identified subgroups of pts with PsA with certain baseline characteristics in whom abatacept is most likely to be effective. The predictive factors identified are aligned with poor prognostic factors in the EULAR and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines,2,3 and may indicate pts with the highest unmet medical need. References Mease P, et al. Arthritis Rheumatol 2016;68(Suppl 10):[Abstract 1041]. Gossec L, et al. Ann Rheum Dis 2016;75:499–510. Coates L, et al. Arthritis Rheumatol 2016;68:1060–71. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Biosciences, Corrona, Demira, Janssen, Lilly, Novartis, Pfizer, Sun, UCB, Zynerba, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo Biosciences, Genentech, Janssen, Novartis, Pfizer, UCB, I. McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Janssen, UCB, Consultant for: Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, AbbVie, UCB, V. Strand Consultant for: AbbVie, Amgen Corporation, AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Corrona, Crescendo Biosciences/Myriad Genetics, EMD Serono, Genentech/Roche, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, UCB, O. FitzGerald Grant/research support from: AbbVie, Pfizer, Bristol-Myers Squibb, Consultant for: AbbVie, Pfizer, Bristol-Myers Squibb, Celgene, Janssen, Novartis, UCB, Lilly, H. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, AbbVie, UCB, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Banerjee Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study

Objective To evaluate the effects of the T-cell costimulation blocker abatacept on anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) in early rheumatoid arthritis (RA), and associations between changes in serological status and clinical response. Methods Post hoc analysis of the phase III AGREE study in methotrexate (MTX)-naïve patients with early RA and poor prognostic factors. Patients were randomised to abatacept (~10u2009mg/kg intravenously according to weight range) or placebo, plus MTX over 12 months followed by open-label abatacept plus MTX for 12 months. Autoantibody titres were determined by ELISA at baseline and months 6 and 12 (double-blind phase). Conversion to seronegative status and its association with clinical response were assessed at months 6 and 12. Results Abatacept plus MTX was associated with a greater decrease in ACPA (but not RF) titres and higher rates of both ACPA and RF conversion to seronegative status versus MTX alone. More patients converting to ACPA seronegative status receiving abatacept plus MTX achieved remission according to Disease Activity Score in 28 joints (C-reactive protein) or Clinical Disease Activity Index than patients who remained ACPA seropositive. Patients who converted to ACPA seronegative status treated with abatacept plus MTX had a greater probability of achieving sustained remission and less radiographic progression than MTX alone or patients who remained ACPA seropositive (either treatment). Conclusions Treatment with abatacept plus MTX was more likely to induce conversion to ACPA/RF seronegative status in patients with early, erosive RA. Conversion to ACPA seronegative status was associated with better clinical and radiographic outcomes. Trial registration number NCT00122382

Identification of biomarkers of response to abatacept in patients with SLE using deconvolution of whole blood transcriptomic data from a phase IIb clinical trial

Objective To characterise patients with active SLE based on pretreatment gene expression-defined peripheral immune cell patterns and identify clusters enriched for potential responders to abatacept treatment. Methods This post hoc analysis used baseline peripheral whole blood transcriptomic data from patients in a phase IIb trial of intravenous abatacept (~10u2009mg/kg/month). Cell-specific genes were used with a published deconvolution algorithm to identify immune cell proportions in patient samples, and unsupervised consensus clustering was generated. Efficacy data were re-analysed. Results Patient data (n=144: abatacept: n=98; placebo: n=46) were grouped into four main clusters (C) by predominant characteristic cells: C1—neutrophils; C2—cytotoxic T cells, B-cell receptor-ligated B cells, monocytes, IgG memory B cells, activated T helper cells; C3—plasma cells, activated dendritic cells, activated natural killer cells, neutrophils; C4—activated dendritic cells, cytotoxic T cells. C3 had the highest baseline total British Isles Lupus Assessment Group (BILAG) scores, highest antidouble-stranded DNA autoantibody levels and shortest time to flare (TTF), plus trends in favour of response to abatacept over placebo: adjusted mean difference in BILAG score over 1u2009year, −4.78 (95% CI −12.49 to 2.92); median TTF, 56 vs 6 days; greater normalisation of complement component 3 and 4 levels. Differential improvements with abatacept were not seen in other clusters, except for median TTF in C1 (201 vs 109 days). Conclusions Immune cell clustering segmented disease severity and responsiveness to abatacept. Definition of immune response cell types may inform design and interpretation of SLE trials and treatment decisions. Trial registration number NCT00119678; results.

FRI0219 Association between conversion to ACPA/RF seronegative status and clinical outcomes following treatment with abatacept in combination with methotrexate compared with methotrexate alone in patients with early rheumatoid arthritis and poor prognostic indicators

Background RA is characterized by the production of autoantibodies, including anti-citrullinated protein antibodies (ACPA) and RF, which are associated with poor prognosis in RA.1–3 More data on the clinical significance of ACPA/RF seroconversion in response to treatment are needed. Evidence suggests a role for T cells in ACPA production.2,3 Objectives This post hoc analysis investigated the effect of the T-cell co-stimulation modulator abatacept (ABA) in combination with MTX vs MTX alone on conversion of ACPA positive (+) and RF+ patients (pts) to seronegative status, and the relationship between conversion to seronegative status and clinical response. Methods Data from a double-blind, randomized, Phase III study (AGREE; NCT00122382) conducted in MTX-naïve pts with early RA (≤2 years) and poor prognostic factors (ACPA+ and/or RF+ with evidence of erosions) were included.4 Pts were randomized to ABA (∼10 mg/kg IV according to weight)+MTX or placebo+MTX (MTX alone) in a 12-month (M) double-blind phase followed by 12M of open-label ABA+MTX. Autoantibody titres were assessed at baseline and 6M and 12M of the double-blind phase by ELISA. Pts with titres below the threshold for positivity (ACPA 5 AU/mL; RF [IgM] 15 IU/mL) at M6 or M12 were considered to have converted to seronegative status. The relationship between conversion to ACPA seronegative status and clinical response at M6 and M12 was determined. All analyses were descriptive and based on pts with available DAS28 (CRP) and CDAI data at baseline and M6 and M12. Results A total of 435 and 461 pts, respectively, were ACPA+ or RF+ at baseline and had known serostatus at M6 and M12. At 6M, 6.6% (15/227) and 17.0% (39/230) of ABA+MTX pts were ACPA and RF negative, respectively, vs 2.9% (6/208) and 9.5% (22/231) of MTX pts. At 12M, 7.1% (15/212) and 18.5% (41/222) of ABA + MTX pts were ACPA and RF negative, respectively, vs 4.5% (9/198) and 14.6% (32/219) of MTX pts. A higher proportion of pts receiving ABA + MTX who converted to ACPA seronegative status achieved remission (DAS28 [CRP] <2.6 or CDAI ≤2.8) compared with ABA + MTX-treated pts who remained ACPA+ or with pts treated with MTX alone regardless of whether they converted to seronegative status or not (Figure). Pts receiving ABA + MTX who converted to ACPA seronegative status also had a numerically higher cumulative probability of achieving sustained remission (DAS28 [CRP] <2.6) and lower radiographic progression than pts receiving MTX who converted to seronegative status or pts in either treatment group who remained ACPA+ (data not shown). Conclusions Compared with MTX alone, treatment with abatacept + MTX was more likely to result in conversion to ACPA/RF seronegative status in pts with early erosive RA. Conversion to ACPA seronegative status was associated with better clinical and radiographic outcomes. References Scott DL, et al. Lancet 2010;376:1094–108. Hecht C, et al. Ann Rheum Dis 2015;74:2151–6. Aletaha D, et al. Arthritis Res Ther 2015;17:229. Rombouts Y, et al. Ann Rheum Dis 2016;75:578–85. Disclosure of Interest D. Jansen: None declared, P. Emery Grant/research support from: AbbVie, Merck, Pfizer, Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, Novartis, Samsung Bioepis, J. Smolen Grant/research support from: AbbVie, Janssen, Lilly, MSD, Pfizer, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, GSK, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, R. Westhovens Grant/research support from: Roche, Consultant for: Janssen, Celltrion, Galapagos, Speakers bureau: Bristol-Myers Squibb, M. Le Bars Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, S. Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, R. Toes: None declared, T. Huizinga Grant/research support from: EU & Dutch Arthritis Foundation, Consultant for: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, UCB, Inc., Eli Lilly, Speakers bureau: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough

AB0248 The impact of therapy on anti-carbamylated protein antibody isotypes and serostatus in patients with early ra treated with abatacept and methotrexate

Background Maturation of autoantibody responses has been suggested to be a proxy for disease maturation. Autoantibody responses against post-translationally modified antigens are present in autoimmune diseases and antibodies directed against carbamylated proteins (anti-CarP antibodies) are a marker of RA. Anti-CarP antibody analysis in patients with early RA offers the opportunity to estimate whether specific intervention during such early stages of autoantibody development may have an impact on the maturation of the anti-CarP antibody response. Objectives We assessed the relationship between changes in anti-CarP isotypes and rates of seroconverson to negative in patients with early RA. Methods In the Assessing Very Early Rheumatoid arthritis Treatment study (AVERT; NCT01142726), patients with early RA were treated with abatacept (ABA)+MTX, ABA monotherapy or MTX alone.1 Patients in AVERT were anti-cyclic citrullinated peptide-2 positive at baseline for study entry.1 In this post hoc analysis, concentrations of anti-CarP isotypes were measured using custom ELISAs. Anti-CarP ELISAs for immunoglobulin (Ig)G, IgM or IgA isotypes were performed in patient serum at baseline, and at Days 85 and 365 on treatment. Baseline levels of each anti-CarP antibody isotype and % seropositivity were comparable across the three treatment arms. Adjusted mean change from baseline was calculated using a longitudinal repeated measures model. Results At baseline, 51.3, 42.5 and 29.3% of all patients with serum available in AVERT were positive for IgG, IgM (indicative of an ongoing immunoresponse) and IgA anti-CarP isotypes, respectively. Overall, approximatly 65% of patients were positive for at least one anti-CarP antibody isotype. Median % change from baseline (25%, 75%) for anti-CarP isotypes levels from baseline to Days 85 and 365 are shown (Table). Analysing patients who were positive at baseline for each of the isotypes, we observed that 19/48 (40%), 16/43 (37%) and 11/48 (23%) of the patients positive for the IgG isotype became negative on ABA+MTX, ABA and MTX, respectively, at 1 year. For the IgM isotype, 26/48 (54%), 14/36 (39%) and 15/38 (39%) became negative on ABA+MTX, ABA and MTX, respectively. For the IgA isotype, 12/26 (46%), 10/23 (43%) and 13/31 (42%) became negative on ABA+MTX, ABA and MTX, respectively.Table 1. Median % change from baseline (25%, 75%) for anti-CarP isotypes Day 85 Day 365 IgG IgM IgA IgG IgM IgA ABA −17.3 (−55.7, 0.0) −26.3 (−57.9, 0.0) −6.8 (−35.1, 0.0) −31.2 (−67.4, 0.0) 26.0 (-81.2, 0.0) −26.7 (−72.9, 13.0) MTX −19.3 (−53.6, 0.0) −35.7 (−54.4, −6.9) −27.2 (−42.4, −3.9) −17.7 (−65.1, 0.0) −38.3 (−63.7, 0.0) −21.9 (−50.3, 0.0) ABA+ MTX −38.8 (−62.3, 0.0) −44.2 (−59.5, −13.8) −41.3 (−54.9, −28.3) −55.7 (−76.7, 0.0) −45.7 (−72.5, −0.2) −46.4 (−66.7, 0.0) Conclusions Concentrations of all anti-CarP isotypes (IgM, IgA, IgG) were numerically reduced by abatacept+MTX therapy compared with MTX or abatacept alone. Abatacept+MTX trended towards higher rates of seroconversion to negative for all isotypes over 1 year of treatment. These results indicate that the extent of the anti-CarP antibody response can be modulated by intervention with abatacept on background MTX in anti-citrullinated protein antibody-positive patients with early RA. References Emery P, et al. Ann Rheum Dis 2015;74:19–26. Disclosure of Interest L. Trouw: None declared, S. Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, A. Johnsen Employee of: Bristol-Myers Squibb, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, R. Toes: None declared, T. Huizinga Grant/research support from: EU & Dutch Arthritis Foundation, Consultant for: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, UCB, Inc., Eli Lilly, Speakers bureau: Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough

FRI0513 Validating Mri-Detected Inflammation Thresholds Predictive of Structural Damage Progression in Patients with Rheumatoid Arthritis in A Randomized Placebo-Controlled Trial

Background In rheumatoid arthritis (RA), the concept that subclinical inflammation causes damage progression is now well established, but there is little work on how much inflammation is safe.1 A previous study established RA MRI Scoring (RAMRIS) synovitis and osteitis thresholds (≤3 each and ≤9 [≤3 plus 2*≤3] as a total inflammation score) that correlated with a low risk of structural damage progression.2 Further validation of these thresholds may guide physicians in clinical practice more reliably to identify individuals with a low likelihood of structural damage progression. Objectives To validate the performance of RAMRIS synovitis, osteitis and combined total inflammation thresholds in the prediction of structural damage progression.1 Methods AVERT (Assessing Very Early Rheumatoid arthritis Treatment) was a Phase IIIb, randomized, active-controlled, 24-month trial, with a 12-month, double-blind treatment period. Patients with early RA received abatacept + MTX, abatacept monotherapy or MTX. Contrast-enhanced MRIs of the dominant hand and wrist were performed. MRI data were pooled from all three treatment arms (intent-to-treat population) for this post hoc analysis. Inflammation (synovitis, osteitis and combined) and erosion were scored by two central readers at baseline, Month 6 and Month 12. Structural damage progression was defined as erosion change >0.5. Patients were stratified into “low” and “not low” risk groups for MRI structural progression based on their inflammation scores at the start of the observation period: low: ≤3 for synovitis, ≤3 for osteitis and ≤9 when combined (with osteitis double-weighted due to its strong correlation with progression), as suggested by Baker et al.2 Log odds ratio of probability of progression were compared between subgroups. Results 351 patients were randomized and treated, with MRIs at baseline; 276 (78.6%) and 235 (67.0%) also had MRI data available at Month 6 and Month 12, respectively. The percentage of patients with structural damage progression at follow-up was significantly higher in the “not low” versus “low” risk subgroup for all comparisons (Table). The probability of progression from Month 6 to Month 12 was significantly lower among patients with synovitis score ≤3, osteitis score ≤3, and total inflammation score ≤9 at Month 6. Conclusions The applied inflammation thresholds distinguished between patients with RA at lower or higher risk of structural damage progression, validating the previously proposed thresholds. This provides further support for the clinical value of measuring inflammation via MRI, as well as its role in predicting structural damage progression. References Gandjbakhch F, et al. J Rheumatol 2014;41:398–406. Baker J, et al. Arthritis Rheumatol 2015; 67(Suppl 10):S832. Disclosure of Interest H. A. Ahmad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, J. F. Baker: None declared, M. Østergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Janssen, Merck, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth, J. Ye Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, P. Emery Grant/research support from: AbbVie, Merck, Pfizer, Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, Lilly, Novartis, Samsung Bioepis, P. G. Conaghan Consultant for: AbbVie, Lilly, Novartis, Pfizer, Speakers bureau: AbbVie, Janssen, Roche