Gene Expression May Influence Lack of Response to RA Treatment
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Genes might explain why some patients with rheumatoid arthritis respond better to anti-TNF therapy than others, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in San Francisco, Calif.
Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Drugs known as tumor necrosis factor, or TNF, inhibitors are often prescribed to individuals with rheumatoid arthritis. They work by targeting and blocking the inflammation, and can help reduce pain, morning stiffness, tender and swollen joints, limit damage to the joints and improve function.
Treatment strategies used in blocking tumor necrosis factor have been very successful in treating patients with RA. For reasons that are unknown, significant numbers of these patients do not respond to this type of treatment, and there are currently no means by which to identify these patients in advance of treatment.
While all cells in an individual contain the same genetic material, different cells may produce, or express, differing amounts of individual genes.
Researchers analyzed the gene expression in the white blood cells of 42 Dutch patients with RA prior to starting TNF inhibitor therapy. They identified patterns in gene expression levels in a group of 34 genes that were associated with responsiveness to anti-TNF therapy. These genes included the inflammatory genes PTGS2, EGR1, IL8 and IL28A. Researchers also identified a gene that showed a decrease in expression of two particular gene components, called exons, in patients who did not respond to anti-TNF medications, in comparison to those who did.
This gene expression analysis was also studied in 30 U.S. patients with RA, confirming that lack of response to anti-TNF treatment is associated with a low expression of these two exons. This suggests that the particular gene expression patterns in RA patients may serve as new biomarkers for predicting response to therapy with anti-TNF drugs.
“Patients with rheumatoid arthritis are often treated with medication directed to tumor necorsis factor alpha, anti-TNF therapy,” explains Marieke Coenen, PhD; Nijmegen Centre for Molecular Life Sciences and Institute of Genetic and Metabolic Disease, research lab for multifactorial diseases, division of DNA-diagnostics, department of human genetics, Radboud University Nijmegen Medical Centre, Nijmengen, The Netherlands, and lead investigator in the study. “Given the extremely high costs of anti-TNF therapy and the risk of adverse effects, it would be beneficial to predict whether an individual patient will benefit from this treatment, beforehand. In this study we identified a gene that might be used to determine which patients will respond to anti-TNF treatment.”
Patients should talk to their rheumatologists to determine their best course of treatment.
The ACR is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with or at risk for arthritis and rheumatic and musculoskeletal diseases. For more information on the ACR’s annual meeting, see http://www.rheumatology.org/annual.
Editor’s Notes: Dr. Coenen will present this research during the ACR Annual Scientific Meeting at the Moscone Center from 3:00 – 3:15 PM on Monday, October 27, in Room 102. Dr. Coenen will be available for media questions and briefing at 8:30 AM on Monday, October 27 in the on-site press conference room, 114.
Presentation Number: 1204
Gene Expression Profiling of Rheumatoid Arthritis Patients Treated with Anti-Tumour Necrosis Factor
Marieke J.H. Coenen1, Erik J.M. Toonen1, Franak Batliwalla2, Piet L.C.M. van Riel1, Wietske Kievit1, Joris A. Veltman1, Agnes M.M. Eijsbouts3, Christian F.H.A. Gilissen1, Aarti Damle2, Hans Scheffer1, Timothy R.D.J. Radstake1, Peter K. Gregersen2, Pilar Barrera1, Barbara Franke1. 1Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; 2The Feinstein Institute for Medical Research, Manhasset, NY; 3Sint Maartenskliniek, Nijmegen, Netherlands
Purpose: Treatment strategies blocking TNFα have proven very successful showing beneficial effects in at least 60% of the patients with rheumatoid arthritis(RA). However, a significant subset of patients do not respond for reasons that are unknown 1,2, and there is currently no means of identifying these patients. In this study we test the hypothesis that gene expression profiles can be used to predict anti-TNF response and we examine the effect of therapy on these profiles.
Methods: Expression profiles of white blood cells of 42 patients before therapy were analyzed using the Affymetrix GeneChip® Human Exon 1.0 ST Array. The search was focused on the differences in gene expression between treatment responders and non-responders at baseline. Treatment responses were assessed using European League Against Rheumatism (EULAR) response criteria.
Results: We identified expression profiles of a subset of 34 genes that are able to distinguish between anti-TNF responders and non-responders. Genes in this subset included the inflammatory genes PTGS2, EGR1, IL8 and IL28A. We also identified a gene which showed a decrease in expression of two exons in anti-TNF non-responders compared to responders. The results were verified using quantitative PCR. Analysing the expression of the two exons in 32 patients of our cohort (DREAM) and in 30 patients from a U.S. cohort (ABCoN) showed that non-response was significantly associated with a low expression of the two exons.
Conclusions: The identified gene expression patterns and splice variants may serve as new biomarkers for predicting anti-TNF response.
1. Coenen, M. J., Toonen, E. J., Scheffer, H., Radstake, T. R., Barrera, P., and Franke, B. Pharmacogenetics of anti-TNF treatment in patients with rheumatoid arthritis. Pharmacogenomics, 8: 761-773, 2007.
2. Toonen, E. J., Barrera, P., Radstake, T. R., van Riel, P. L., Scheffer, H., Franke, B., and Coenen, M. J. Gene Expression Profiling in Rheumatoid Arthritis; current concepts and future direction. Ann Rheum Dis, Epub February 2008.
Disclosure Block: M.J. Coenen, None; E.J. Toonen, None; F. Batliwalla, None; P.L. van Riel, None; W. Kievit, None; J.A. Veltman, None; A.M. Eijsbouts, None; C.F. Gilissen, None; A. Damle, None; H. Scheffer, None; T.R. Radstake, None; P.K. Gregersen, consultant for Roche, 9; P. Barrera, None; B. Franke, None.
Source: American College of Rheumatology (ACR)
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