Abstract
Anti-drug antibody (ADAb) development is associated with secondary therapeutic failure in biologic-treated rheumatoid arthritis (RA) patients. With a treat-to-target goal, we aimed to identify biomarkers for predicting ADAb development and therapeutic response in adalimumab-treated patients. Three independent cohorts were enrolled. In Cohort-1, 24 plasma samples (6 ADAb-positive and 6 ADAb-negative patients at baseline and week 24 of adalimumab therapy, respectively) were assayed with immune-related microarray containing 1,636 correctly folded functional proteins. Next, we executed statistically powered autoantibody profiling analysis of 50 samples in Cohort-2 (24 ADAb-positive and 26 ADAb-negative patients). Subsequently, immunofluorescence assay was performed on 48 samples in Cohort-3 to correlate with ADAb titers and drug levels. The biomarkers were identified for predicting ADAb development and therapeutic response using the immune-related microarray and machine learning approach. ADAb-positive patients had lower drug levels at week 24 (median = 0.024 μg/ml) compared with ADAb-negative patients (median = 6.38 μg/ml, p < 0.001). ROC analysis based on the ADAb status revealed the top 20 autoantibodies with AUC ≥ 0.7 in differentiating both groups in Cohort-1. Analysis of Cohort-2 dataset identified a panel of 8 biomarkers (TROVE2, SSB, NDE1, ZHX2, SH3GL1, CARD9, PTPN20, and KLHL12) with 80.6% specificity, 77.4% sensitivity, and 79.0% accuracy in discriminating poor from EULAR responders. Immunofluorescence assay validated that anti-TROVE2 antibody could highly predict ADAb development and poor EULAR response (AUC 0.79 and 0.89, respectively). Multivariate regression analysis proved anti-TROVE2 antibody to be an independent predictor for developing ADAb. Immune-related protein microarray and replication analysis identified anti-TROVE2 antibody as a useful biomarker for predicting ADAb development and therapeutic response in adalimumab-treated patients.
Highlights
Rheumatoid arthritis (RA), an inflammatory articular disease, is characterized by chronic synovitis and bone erosions [1], and tumor necrosis factor- (TNF-) α is a crucial inflammatory mediator in this disease [2]
The important role of TNF-α in RA pathogenesis is supported by the effectiveness of biologics targeting this cytokine [2,3,4], the efficacy diminishes in some patients over time [5]
Hagiwara et al recently demonstrated that anti-Ro/SSA antibodypositive patients treated with infliximab had a higher proportion (50%, 3/6) of anti-drug antibodies (ADAb) compared with anti-Ro/SSA antibody-negative patients (0%, 0/12), with all three anti-drug antibody- (ADAb-)positive patients being poor responders to infliximab [16]
Summary
Rheumatoid arthritis (RA), an inflammatory articular disease, is characterized by chronic synovitis and bone erosions [1], and tumor necrosis factor- (TNF-) α is a crucial inflammatory mediator in this disease [2]. The important role of TNF-α in RA pathogenesis is supported by the effectiveness of biologics targeting this cytokine [2,3,4], the efficacy diminishes in some patients over time (secondary failure) [5]. Accumulating evidence indicates that the presence of anti-drug antibodies (ADAb), the so-called immunogenicity, may be associated with low or undetectable drug levels and ensuing reduction of therapeutic responsiveness to TNF-α inhibitors [6,7,8,9,10,11]. Given a treat-to-target goal [12] and the uncertainty of therapeutic responsiveness to TNF-α inhibitors, physicians are eager to find biomarkers which can predict the emergence of ADAb and the effectiveness of biologics. There is scant research into circulating potential biomarkers to predict the developing ADAb in RA patients receiving anti-TNF therapy
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