Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study

Abstract

BackgroundAccording to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform.MethodsRA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled “signature scores” for these gene sets, and the prediction performances were assessed.ResultsGSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that “signature scores” of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively.ConclusionsWe have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1052-8) contains supplementary material, which is available to authorized users.

Identification of molecules associated with response to abatacept in patients with rheumatoid arthritis

“…The primary objective of this study was to identify novel molecules associated with therapeutic responses to ABA for patients with RA, and the secondary objective was validation of the results of the previous study [9]. Fisher's exact test and Student's t test were used to compare the categorical and continuous variables between two groups, respectively.…”

“…The GO analysis of the 392 genes downregulated in the responders did not identify a specific group of genes. The previously reported genes associated with therapeutic response to ABA, which were elongation arrest and recovery-related genes and CD56-specifically expressed genes [9], were not included in the over-or under-expressed genes.…”

“…Whole blood transcriptomic profiling using microarrays has been widely used to investigate the action mechanisms and identifying appropriate biomarkers predicting the efficacy or safety of various drugs or treatment. Microarrays have been applied to some bDMARDs including ABA [5][6][7][8][9] to realize precision medicine for RA. Although some promising data have been reported, endeavor to develop novel biomarkers is still required.…”

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

“…As a result, we also do not know which of the available antiinflammatory strategies, alone or in combination, will have the best therapeutic potential. Activity of select inflammatory pathways among different patients may affect therapeutic responsiveness to specific interventions (116). Additionally, the more recently introduced biological agents are narrowly focused on very specific targets, whereas older antiinflammatory agents such as salicylate or methotrexate may have broader effects (see below).…”

Association of Dendritic Cell Signatures With Autoimmune Inflammation Revealed by Single‐Cell Profiling

“…Transcriptional profiles that can be used to monitor disease development or predict response to treatment would be valuable for developing personalized therapies for autoimmune diseases. Multiple studies have attempted to identify signatures that can clinically stratify patients for this purpose . A recent study, for example, showed that the IFN‐stimulated genes associated with SLE were markedly different between populations of European ancestry and those of East Asian ancestry .…”