In rheumatic and autoimmune diseases, men and women differ markedly in the frequency and clinical presentation of various diseases. While the gender differences are well established, the origin of these differences and their effects on treatment remain open to debate.
“When we talk about gender differences, we are currently talking about disease frequency rather than severity,” says Michael Lockshin, MD, director of the Barbara Volcker Center for Women and Rheumatic Disease at the Hospital for Special Surgery in New York City. “Lupus is seen in a 9:1 ratio in women, rheumatoid arthritis [RA] in 1.5 to two women for every man. Others, such as ankylosing spondylitis [AS], are being seen in greater numbers in males.”
As research continues, there are some areas of inquiry that may someday change opinions. One of these is an increasing understanding that men and women have different genetics, mostly related to the proteins that come from the various permutations of X and Y chromosomes.
“What has happened in the last decade is the recognition that the gender-related differences are probably not driven by hormones, as many doctors would have thought earlier,” says Dr. Lockshin. “People are now looking at the differences in the X and Y chromosomes and things like double-dosing of genes based on the way women’s and men’s cells are constituted.”
One aspect is that there are many more genes in the active phase in female cells than in the male. In the female, each and every cell has to inactivate the X chromosomes, and that is done in a random fashion. This makes women genetic mosaics compared to men.
Some cell lines contain X chromosomes from both parents, and thus different copies of the same gene. Men can only have the X chromosome gene that their mothers had. Since about 10% of genes on the “inactivated” X chromosome remain active, women have double-dosing and a double effect for those genes.
Dr. Lockshin points to the work of M. Eric Gershwin, MD, chief of the division of rheumatology, allergy, and clinical immunology at the University of California, Davis School of Medicine, in primary biliary cirrhosis, where there is a 10:1 woman-to-man difference. Dr. Gershwin argues that the cause of the female predominance is due to 2-nonynoic acid, a chemical that, for genetic reasons, is badly handled by the body. Intriguingly, this chemical is almost only found in cosmetics. Although the genetic abnormality is shared equally in the genders, the use of cosmetics obviously differs substantially.