Rheumatoid arthritis and sex differences

September 28, 2006

To thoroughly investigate sex differences in RA, a team of researchers turned to families with a history of the disease among both their female and male members. The results indicate that male sex exerts a significant influence on underlying RA mechanisms, particularly the production of anti-CCP an

Rheumatoid arthritis (RA), a chronic autoimmune disease marked by tissue inflammation and joint destruction, has a well established predisposition for women.

Among the adults it strikes--currently about two million in the United States--the female to male ratio is three to one. RA incidence also varies by age within each sex. Among women, disease occurrence increases from the age of menarche and peaks around menopause; RA is rare in men under age 45. These trends have prompted numerous studies into the role of hormones in the development of RA. However, sex differences in specific risk factors, disease expression, and response to treatment have remained largely unexplored.

To thoroughly investigate sex differences in RA, a team of researchers affiliated with the University of California turned to families with a history of the disease among both their female and male members. The results, presented in the October 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), indicate that male sex exerts a significant influence on underlying RA mechanisms, particularly the production of anti-CCP antibodies.

The study focused on 1,004 affected members of 467 Caucasian families within which two or more siblings met the American College of Rheumatology (ACR) criteria for RA. All families were recruited from the North American Rheumatoid Arthritis Consortium, a resource for gene mapping studies. Each RA patient was interviewed to collect relevant personal details, including age at onset of RA symptoms, age at RA diagnosis, medication history, and smoking history. Each patient was examined for joint tenderness, completed a Health Assessment Questionnaire (HAQ), and underwent radiographs of the hands and wrists to evaluate bone erosions. Each patient was also genotyped for markers in the HLA region and tested for two hallmarks of the disease: rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (CCP).

Comparisons of demographic and clinical features between men and women with RA revealed several differences. Although male patients had significantly later onset of RA, they showed more signs of erosive disease, were more likely to test positive for RF factor and anti-CCP antibodies, and had higher titers or concentrations of these autoantibodies than female patients. Men were also significantly more likely to have a history of smoking. Female patients had significantly higher HAQ scores, which translates into poorer function, and were more likely to have other autoimmune diseases, particularly autoimmune thyroid disease, than male patients.

The most notable finding involved women who shared RA with a brother. Among them, the presence and production of anti-CCP antibodies was significantly higher than among female patients without an affected male sibling. In fact, the findings suggest that the sisters of men with RA are approximately twice as likely to be anti-CCP autoantibody positive and to have higher anti-CCP titers as the general population of women with RA. What's more, the researchers concluded that increased production of anti-CCP antibodies appears to be a feature of families with affected males rather than an inherent characteristic of male RA patients.

"The significantly increased autoantibody titers among male patients and among families with affected male siblings is particularly striking and represents a novel observation," stresses the study's leading author, Lindsey A. Criswell, M.D., M.PH. "Anti-CCP antibody production is a very strong predictor of RA, particularly erosive RA."

This comprehensive study of sex differences offers important implications for the early detection and effective treatment of RA--for both sexes. Additional studies of families with affected males may identify additional genetic or other risk factors for this complex autoimmune disease.
Article: "Influence of Male Sex on Disease Phenotype in Familial Rheumatoid Arthritis," Damini Jawaheer, Raymond F. Lum, Peter K. Gregersen, and Lindsey A. Criswell, Arthritis & Rheumatism, October 2006; (DOI: 10.1002/art.22120).


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