In a recent study, researchers found an association between cigarette smoking and a specific gene deletion that leads to more severe rheumatoid arthritis (RA).

According to the results of this study, which is published in the March issue of Arthritis & Rheumatism, women with RA who have smoked tobacco and lack the gene for a detoxifying enzyme called the glutathione S-transferase M1 (GSTM1) are more likely to have severe RA disease. Rheumatoid arthritis is a chronic, inflammatory and systemic disease that causes debilitating symptoms, including morning stiffness, disfiguring painful joints, and skin nodules. An estimated 85% of RA patients have positive serum Rheumatoid Factor (RF), which is often associated with more severe disease. While both genetic and environmental factors are suspected to be contributory causes of RA, the cause of RA is still unknown. Recent studies demonstrated that smoking is linked to more severe RA disease and higher concentrations of RF. In the A&R article, Dr. D.L. Mattey of the North Staffordshire Hospital, Stoke-on-Trent, UK, and colleagues demonstrated that deletion of GSTM1 (a gene that codes for an enzyme that detoxifies carcinogens found in tobacco smoke) that render it nonfunctional are associated with more severe RA. Deleted GSTM1 is found in approximately 50% of Caucasians, and some studies have suggested that a deletion GSTM1 gene is associated with smoking-related cancers and coronary artery disease. Postulating that smoking in patients lacking the GSTM1 gene might play a role in development of severe RA, Mattey and colleagues analyzed the association between GSTM1 genotype, smoking history and disease severity in a cross-sectional retrospective study. 164 female RA patients who had the disease for at least 5 years were enrolled. Disease severity was assessed using the Health Assessment Questionnaire (HAQ), radiographic analysis using Larsen scores (a measure of x-ray damage), and serum RF levels. Current and past smoking history was quantified and categorized according to "never smoked," "past smoker" and "current smoker." The GSTM1 genotype was identified by extracting leukocyte DNA and using a polymerase chain reaction assay to classify patients to GSTM1-1, the functional gene, and GSTM1-null, the deleted gene. Of the 164 women with RA, 51.3% were never smokers, 29.9% were current smokers and 58.5% had the GSTM1-null genotype. Past and current smokers had significantly higher Larsen and Health Assessment Questionnaire (HAQ) scores than non-smokers, indicating more severe disease in RA patients with a smoking history. While the Larsen and HAQ scores did not significantly differ between GSTM1-1 and GSTM1-null patients after adjustment for age and disease duration, GSTM1-null patients with a history of smoking had significantly higher Larsen and HAQ scores than GSTM1-null patients who never smoked. Radiographic outcome was worse in GSTM1-null patients with a smoking history than GSTM1-1 patients with a smoking history. GSTM1 status and smoking history were also strongly associated with RF status and concentration. Among GSTM1-null patients, those with a smoking history were 3.1 times more likely to be RF positive than GSTM1-null patients who never smoked. GSTM1-null current smokers were 5.1 times more likely to be RF positive and more likely to have higher RF concentrations than GSTM1-null patients who never smoked. No significant difference in RF status was found between GSTM1-1 patients with and without a smoking history. The authors conclude that the data suggest, "that the risk of developing severe disease in female RA patients is increased in those who have the GSTM1-null polymorphism and who have also smoked." They add, "our data also suggest that if smoking is involved in the initiation process, it leads to more severe disease than it does in patients in whom smoking is not involved (particularly if the patients are GSTM1-null)." (Reference: "Smoking and Disease Severity in Rheumatoid Arthritis: Association with Polymorphism at the Glutathione S-Transferase M1 Locus," Derek L. Mattey, David Hutchinson, Peter T. Dawes, Nicola B. Nixon, Sheila Clarke, June Fisher, Ann Brownfield, Julie Alldersea, Anthony A. Fryer, and Richard C. Strange, Arthritis & Rheumatism 2002, 46:3; pp. 640-646.) Arthritis & Rheumatism is an official journal of the American College of Rheumatology and covers all aspects of inflammatory disease. The journal is published by John Wiley & Sons, and is available online via Wiley InterScience.

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