Molecular Biomarkers of Anti-TNF Response in Patients with Rheumatoid Arthritis

2020 ◽  
Author(s):  
Niyaz Yoosuf ◽  
Mateusz Maciejewski ◽  
Daniel Ziemek ◽  
Scott Jelinsky ◽  
Lasse Folkersen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Flow Cytometry ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Treatment Initiation ◽  
Cell Types ◽  
Proteomics Data ◽  
Peripheral Blood Mononuclear ◽  
Before And After

Abstract BackgroundAdvances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF-α, the downstream mechanisms of immune suppression are not completely understood, and the reason for the reduced efficacy in a significant fraction of patients remains unclear. Hence this study was designed to detect biomarkers and expression signatures of response to TNF inhibition.MethodsIn this study, we included 39 female patients diagnosed with RA who were non-responders to methotrexate treatment. The blood samples were collected before anti-TNF treatment initiation, and three months into treatment. The clinical evaluations were performed based on European League Against Rheumatism (EULAR) and classified 23 patients as responders and 16 as non-responders after three months following the initiation of anti-TNF treatment. We investigated differences in gene expression in peripheral blood mononuclear cells (PBMCs), the proportion of cell types and cell phenotypes in peripheral blood using flow cytometry, the level of proteins in serum, as well as clinical and demographic factors.ResultsWe performed analyses to identify differences between responders and non-responders at both time points (before and after treatment initiation) as well as to detect the changes induced during the treatment using transcriptomics, flow cytometry and proteomics data. The gene expression analysis before treatment revealed notably a higher expression of EPPK1 and BCL6-AS1 in future responders. We further detected suppression of genes and proteins during treatment, most notably a suppression of expression of the gene, T-cell inhibitor CHI3L1 and its protein YKL-40 measured from flow cytometry. We identified an increase in the proportion of T- and B cells, whereas the proportion of granulocytes was suppressed during treatment in responders. Finally, our machine learning models mainly based on transcriptomics data showed high predictive utility (ROC AUC ± SEM: 0.81 ± 0.17) in classifying response before anti-TNF treatment initiation.ConclusionsOur comprehensive analyses resulted in several useful insights regarding the transcriptional and translational regulations of anti-TNF treatment in RA patients. The study reports first transcriptomics analysis using RNA sequencing of isolated PBMCs from anti-TNF naïve and anti-TNF treated RA patients to study biomarkers and predict anti-TNF response.

scholarly journals Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

2012 ◽  
Vol 39 (5) ◽  
pp. 916-928 ◽  
Author(s):  
BERTALAN MESKO ◽  
SZILARD POLISKA ◽  
SZILVIA SZAMOSI ◽  
ZOLTAN SZEKANECZ ◽  
JANOS PODANI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Multiple Testing ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Response To Treatment ◽  
Peripheral Blood Mononuclear ◽  
Gene Sets

Objective.Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment.Methods.Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders.Results.Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline.Conclusion.As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

scholarly journals Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Sergio Ramirez-Perez ◽  
Edith Oregon-Romero ◽  
Itzel Viridiana Reyes-Perez ◽  
Pallavi Bhattaram
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Inflammatory Mediators ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Gene Expression Signature ◽  
Cell Types ◽  
Cell Receptor ◽  
Matrix Metalloproteases ◽  
Peripheral Blood Mononuclear

MyD88-dependent intracellular signalling cascades and subsequently NF-kappaB-mediated transcription lead to the dynamic inflammatory processes underlying the pathogenesis of rheumatoid arthritis (RA) and related autoimmune diseases. This study aimed to identify the effect of the MyD88 dimerization inhibitor, ST2825, as a modulator of pathogenic gene expression signatures and systemic inflammation in disease-modifying antirheumatic drugs (DMARDs)-naïve RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1β. The transcriptional profiles of ST2825-treated PBMC were analyzed to identify its therapeutic potential. Ingenuity Pathway Analysis was implemented to identify downregulated pathogenic processes. Our analysis revealed 631 differentially expressed genes between DMARDs-naïve RA patients before and after ST2825 treatment. ST2825-treated RA PBMC exhibited a gene expression signature similar to that of healthy controls PBMC by downregulating the expression of proinflammatory cytokines, chemokines and matrix metalloproteases. In addition, B cell receptor, IL-17 and IL-15 signalling were critically downregulated pathways by ST2825. Furthermore, we identified eight genes (MMP9, CXCL9, MZB1, FUT7, TGM2, IGLV1-51, LINC01010, and CDK1) involved in pathogenic processes that ST2825 can potentially inhibit in distinct cell types within the RA synovium. Overall, our findings indicate that targeting MyD88 effectively downregulates systemic inflammatory mediators and modulates the pathogenic processes in PBMC from DMARDs-naïve RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.

Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-α treatments

2011 ◽  
Vol 43 (7) ◽  
pp. 365-371 ◽  
Author(s):  
E. Meugnier ◽  
F. Coury ◽  
J. Tebib ◽  
C. Ferraro-Peyret ◽  
S. Rome ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Calcium Binding ◽  
Mononuclear Cells ◽  
Gene Expression Signature ◽  
Fold Change ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Apoptosis Protein

The efficacy of anti-TNF-α therapies highlights the role of TNF-α in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism of action of these agents is poorly understood at the molecular level. The aim of this study was to characterize the effects of anti-TNF-α treatment on the global gene expression profile in peripheral blood mononuclear cells (PBMCs) of responder RA patients. Changes in gene expression were determined using oligonucleotide microarrays (25,341 genes) in PBMCs obtained before and after 12 wk of treatment with either etanercept or adalimumab from responder RA patients. Two hundred fifty-one genes displayed significant changes (false discovery rate < 0.1%) in expression level (178 upregulations with mean fold change = 1.5 and 73 downregulations with mean fold change = −1.50) after 12 wk of treatment. Importantly, the expression of several genes, including those coding for the calcium binding proteins S100A12 and A8, CD14 antigen, Selectin P, or ribosomal protein L39, reported to be upregulated in RA patients, were found to be decreased after anti-TNF-α treatment. Globally, inflammation, immune response, apoptosis, protein synthesis, and mitochondrial oxido-reduction were the most affected pathways in response to anti-TNF-α treatment. The obtained gene expression signature in PBMCs provides new information to better understand the mechanisms of action of anti-TNF-α treatment in RA patients.

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