Differential Changes in ACPA Fine Specificity and Gene Expression in a Randomized Trial of Abatacept and Adalimumab in Rheumatoid Arthritis
Authors: Omar Jabado, Michael A. Maldonado, Michael Schiff, Michael E. Weinblatt, Roy Fleischmann, William H. Robinson, Aiqing He, Vishal Patel, Alex Greenfield, Jasmine Saini, David Galbraith & Sean E. Connolly
The biologics abatacept and adalimumab have different mechanisms of action (MoAs). We analyzed data from patients with rheumatoid arthritis treated in AMPLE (NCT00929864) to explore the pharmacodynamic effects of abatacept or adalimumab on anti-citrullinated protein antibodies (ACPAs) and gene expression.
AMPLE was a phase IIIb, 2-year, randomized, head-to-head trial of abatacept versus adalimumab. Post hoc analyses of baseline anti-cyclic citrullinated peptide-2 (anti-CCP2, an ACPA surrogate) positive (+) status and ACPA fine-specificity profiles over time, as well as transcriptional profiling (peripheral whole blood), were performed.
Of 646 patients treated (abatacept, n = 318; adalimumab, n = 328), ACPA and gene expression data were available from 508 and 566 patients, respectively. In anti-CCP2+ patients (n = 388), baseline fine specificities for most ACPAs were highly correlated; over 2 years, levels decreased with abatacept but not adalimumab. By year 2, expression of genes associated with T cell co-stimulation and antibody production was lower for abatacept versus adalimumab; expression of genes associated with proinflammatory signaling was lower for adalimumab versus abatacept. Treatment modulated the expression of T- and B-cell gene signatures, with differences in CD8+ T cells, activated T cells, plasma cells, B cells, natural killer cells (all lower with abatacept versus adalimumab), and polymorphonuclear leukocytes (higher with abatacept versus adalimumab).
In AMPLE, despite similar clinical outcomes, data showed that pharmacodynamic/genetic changes after 2 years of abatacept or adalimumab were consistent with drug MoAs. Further assessment of the relationship between such changes and clinical outcomes, including prediction of response, is warranted.
ClinicalTrials.gov identifier, NCT00929864.
Key Summary Points
Why carry out this study?
Improved knowledge of the relevant pathological processes in rheumatoid arthritis (RA) has led to the development of targeted therapies with differing mechanisms of action (MoAs), such as adalimumab and abatacept.
We aimed to provide new insights into the pharmacodynamic (PD) effects of treatment with abatacept versus adalimumab by profiling ACPAs and gene expression in patients from the AMPLE phase 3 clinical study.
What was learned from this study?
PD changes, as reflected by differing ACPA and gene expression profiles and immune cell signatures, observed after 2 years of abatacept or adalimumab treatment were consistent with the hypothesized MoAs of these agents; expression of genes related to activation of the immune system was lower with abatacept.
These findings illustrate how gene expression studies can provide potentially valuable information in addition to that gained from conventional clinical assessments, as they investigate underlying processes that are beyond the clinical manifestations of disease.
Further analysis of this data set from the AMPLE study is warranted and may provide valuable information regarding predictive biomarkers of response and disease progression.