Abstract
An important goal for personalized treatment is predicting response to a particular therapeutic. A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome. Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α. By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA− patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/β-expressing memory B cells in ADA+ vs. ADA− RA patients. We also assessed the predictive value of SIRPα/β expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRPα/β-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRPα/β-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease that manifests as pain, swelling and stiffness of the joints [1], with a 0.5–1% prevalence in the adult population [2]
To identify biomarker/s associated with anti-drug antibodies (ADA) response to adalimumab we examined the surface immune-signature of PMBCs isolated from 10 ADA− to 10 ADA+ RA patients treated with adalimumab for a minimum of 12 months (Table 1)
PBMCs were stained with fluorescently-conjugated antibodies identifying CD4+T cells, CD19+B cells, immature, mature, and memory B cell subsets in addition to the 332 cell surface markers included in the LEGENDScreenTM panel (Figure S1)
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease that manifests as pain, swelling and stiffness of the joints [1], with a 0.5–1% prevalence in the adult population [2]. A significant percentage of patients with RA receiving biologics will mount an immune response against the drug (immunogenicity), leading to the production of anti-drug antibodies (ADA), often within the first 6 months of therapy [5]. This is associated with lower blood drug levels, unresponsiveness to the drug, and a worse clinical outcome [6]. Lower drug levels combined with the presence of ADA at 3 months after treatment initiation, predicted lack of response to adalimumab at 12 months [17]. Since not all patients treated with biological therapies develop ADA, the ability to identify a biomarker/s to predict immunogenicity would considerably improve the clinical management of RA
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