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Research article
Nancy J Olsen
Penn State MS Hershey Medical Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6588-3364
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Methotrexate (MTX) and biologic therapies have remarkably improved outcomes in patients with rheumatoid arthritis (RA). However, choices of therapeutic regimens in an individual patient remain empiric, resulting in a risk of delayed control of inflammation consequent joint damage. In previous studies we have shown that a large number of protein-coding genes are dysregulated in RA and that the expression levels of the majority of these dysregulated genes return to normal in patients who have control of disease after initiating MTX monotherapy. Furthermore, in vitro responses to MTX are rapid, suggesting that changes in expression could precede clinical outcome, and have prognostic value. The aim of the current study was to analyze whole blood gene expression for correlates of clinical responses to MTX, with the long-term objective of developing prognostic biomarkers.
Methods: RA patients (N=32) and healthy controls (HC; N=8) were from the Investigation of Remission in Rheumatoid Arthritis (IRRA) cohort at Pennsylvania State M.S. Hershey Medical Center. The RA group included 16 patients with active disease and 16 with controlled disease; 8 patients in each group were currently being treated with MTX. Whole blood RNA profiling was carried out in the Penn State College of Medicine Genomics core laboratory. Transcript data were analyzed using clustering algorithms and pathways analysis software to determine relatedness of groups.
Results: Patients with active RA showed patterns of gene dysregulation that were farther from HC values than RA patients with controlled disease, whether or not MTX was a current medication. Comparison of the four RA groups determined by activity levels and MTX use showed over-expression of genes in alpha/beta and gamma interferon pathways, especially in active RA patients not currently taking MTX, suggesting contributions to maintenance of active disease.
Conclusion: Levels of genes that are expressed in peripheral blood of RA patients correlate with disease activity and also with MTX treatment status. Longitudinal studies to determine how early in the treatment course changes in gene expression levels are detectable will be of interest to determine the potential for development of prognostic biomarkers to guide therapeutic decisions.
Keywords
Rheumatoid arthritis, Methotrexate, RNA profiling, Interferons, Gene expression, Disease remission
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This is a preprint. It has not completed peer review.
Research article
Nancy J Olsen
Penn State MS Hershey Medical Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6588-3364
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 17 Dec, 2019
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Medical Genetics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Methotrexate (MTX) and biologic therapies have remarkably improved outcomes in patients with rheumatoid arthritis (RA). However, choices of therapeutic regimens in an individual patient remain empiric, resulting in a risk of delayed control of inflammation consequent joint damage. In previous studies we have shown that a large number of protein-coding genes are dysregulated in RA and that the expression levels of the majority of these dysregulated genes return to normal in patients who have control of disease after initiating MTX monotherapy. Furthermore, in vitro responses to MTX are rapid, suggesting that changes in expression could precede clinical outcome, and have prognostic value. The aim of the current study was to analyze whole blood gene expression for correlates of clinical responses to MTX, with the long-term objective of developing prognostic biomarkers.
Methods: RA patients (N=32) and healthy controls (HC; N=8) were from the Investigation of Remission in Rheumatoid Arthritis (IRRA) cohort at Pennsylvania State M.S. Hershey Medical Center. The RA group included 16 patients with active disease and 16 with controlled disease; 8 patients in each group were currently being treated with MTX. Whole blood RNA profiling was carried out in the Penn State College of Medicine Genomics core laboratory. Transcript data were analyzed using clustering algorithms and pathways analysis software to determine relatedness of groups.
Results: Patients with active RA showed patterns of gene dysregulation that were farther from HC values than RA patients with controlled disease, whether or not MTX was a current medication. Comparison of the four RA groups determined by activity levels and MTX use showed over-expression of genes in alpha/beta and gamma interferon pathways, especially in active RA patients not currently taking MTX, suggesting contributions to maintenance of active disease.
Conclusion: Levels of genes that are expressed in peripheral blood of RA patients correlate with disease activity and also with MTX treatment status. Longitudinal studies to determine how early in the treatment course changes in gene expression levels are detectable will be of interest to determine the potential for development of prognostic biomarkers to guide therapeutic decisions.
Figure 1
Figure 2
Figure 3
Figure 4
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