The impact of genetic variations on the treatment of early rheumatoid arthritis

Characterized by inflammation in the connective tissues of the joints, rheumatoid arthritis (RA) can be a painful, crippling autoimmune disease. Traditionally, patients have been treated with disease-modifying antirheumatic drugs, or DMARDs, such as methotrexate (MTX). Several new therapies, however, focus on blocking tumor necrosis factor, or TNF, one of the body's chemical messengers with a role in regulating the inflammation. Although MTX and TNF blockers work well in the treatment of RA, they vary widely with regard to effectiveness and side effects, and there are currently no markers to predict response to particular drugs.

In a recent study, published in the September 2004 issue of Arthritis & Rheumatism, researchers set out to examine whether specific genetic variations could predict the response to treatment of early RA. Led by S. Louis Bridges, Jr., M.D., Ph.D. of the University of Alabama at Birmingham and Lindsey A. Criswell, M.D., M.P.H. of the University of California, San Francisco, the group analyzed genetic and clinical data on 457 patients in the early stages of RA who participated in a clinical trial comparing weekly methotrexate, 10 milligrams twice weekly of the anti-TNF drug etanercept, and 25 milligrams of etanercept twice weekly (the currently approved dose for RA). The results of this clinical trial have been previously published (Bathon et al. New Engl J Med 343:1586-1593, 2000).

Researchers examined patients for a particular genetic marker in the HLA region associated with susceptibility to RA (the so-called shared epitope), as well as genetic variants in the TNF gene region. Results of genetic testing were then correlated with treatment responses. Among patients treated with standard-dose etanercept, those with two copies of the shared epitope were four times more likely to achieve 50 percent improvement in disease activity (according to the criteria of the American College of Rheumatology) at 12 months than were patients with one copy or no copies of the shared epitope. Furthermore, patients with particular HLA genes in addition to particular genetic variations in the TNF gene region were found to have better responses to treatment, regardless of which drug was used.

"Results of the current study suggest that, at least for RA patients with early active disease, genetic variations in the HLA and TNF gene regions are associated with response to treatment," Dr. Criswell concludes. "Additional work is required to confirm these results," Dr. Bridges adds, acknowledging the complexity of genetic involvement in RA, "as well as to extend these observations to patients of other ethnicities, and more precisely define the individual genes and haplotypes responsible for these associations."

Article: "The Influence of Genetic Variation in the HLA-DRB1 and LTA-TNF Regions on the Response to Treatment of Early Rheumatoid Arthritis With Methotrexate or Etanercept," Lindsey A. Criswell, Raymond F. Lum, Kevin N. Turner, Blanche Woehl, Yuanqing Zhu, Jinyi Wang, Hemant K. Tiwari, Jeffrey C. Edberg, Robert P. Kimberly, Larry W. Moreland, Michael F. Seldin, and S. Louis Bridges, Jr., Arthritis & Rheumatism, September 2004, 50:9; pp. 2750-2756.

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