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.”
Genetic Differences
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.
“I have often stated that the single most interesting clinical clue to lupus is the 9:1 sex ratio,” says Dr. Lockshin. “Understanding why that happens is going to be infinitely more important to finding the cause and treatment than any of the other science currently ongoing. It can’t be just a coincidence. There has to be a reason behind it, and the reason has to be critical to causation of illness.”
Other research tidbits are coming to the forefront that, while not proving a genetic link, at least give researchers a reason to continue looking for one.
“Although systemic lupus erythematosus (SLE) is much more common in women, men with lupus sometimes have unusual genetic backgrounds,” says David Felson, MD, professor of medicine at Boston University. This can give them characteristics more commonly found in women. “This unusual background may predispose them to the disease,” he says.
Same Disease, Different Presentation?
Some of the differences in incidence in at least some of the diseases may be related to differences in presentation. In AS it is well documented that men tend to present with spinal arthritis and other symptoms that march up the spine. Women, on the other hand, are more likely to see a doctor initially for complaints related to the neck or peripheral joints, but not the lower back.
There may also be differences in the environments of the two genders that affect the incidence and possibly the susceptibility of an individual. While scleroderma appears spontaneously in women, men with the disease tend to be over-represented in the gold- and coal-mining industries.
The environmental differences may also show up only after long lead times. Dr. Lockshin points to research done in Army recruits that shows positive blood tests for SLE and RA up to 10 years prior to diagnosis. Are there things that little girls are exposed to in greater amounts that manifest themselves only 10 to 20 years later?
Perceptions Another Variable
Perceived differences in severity appear to be a fertile area for behavioral differences to be important.
“It is known that pain perception is different in women than in men, females having a somewhat lower threshold at which a stimulus is perceived as pain,” says Ronald van Vollenhoven, MD, associate professor of rheumatology at the Karolinska Institute in Sweden. “This could imply that pain symptoms are experienced more severely by female patients, which could contribute to the slightly worse long-term prognosis for female patients with inflammatory disease of the joints, such as RA. Our recent studies have suggested that this, indeed, might be the case, and that treatment decisions may not sufficiently reflect these differences.”
“Some of the gender differences in severity of RA at diagnosis may be that men tend to ignore or discount their symptoms for a longer period of time than women,” says Dr. Felson. “They continue to work jobs that are more destructive to the joint and do a lot of damage until the pain gets to be excessive. Then they initially present to the doctor with more advanced disease.”
However, is this advanced disease related to the gender or the behavior?
Hormonal Influences?
“For some diseases, such as RA and lupus, hormonal differences may prove to be important, although their specific roles are not known despite a lot of investigation,” says Dr. Felson. “These effects probably will vary by disease and hormone. Studying hormones and their effects on immune responses may provide us with insights into why the manifestations of some diseases are different between genders. It may also provide clues to better treatments.”
It is also well established that there are anatomical and physiological differences between the two sexes. How these may affect severity, presentation, and treatment is still the subject of controversy.
Roles for Anatomy and Physiology
“The normal anatomical differences between men and women can make the consequences of rheumatoid diseases more significant in the female,” says Dr. van Vollenhoven. “One example is the fact that women in general have a lower bone density than men. RA may aggravate the natural decline of bone density with age and some of the treatments for RA will add to this decline. Because the female patient starts out with a lower bone density than males, the consequences may become more serious in the former.”
Differences in physiology are another area that some of the experts find especially interesting. “One of the clues in AS may be gender-related changes in the lymphatic system,” says Dr. Lockshin. “Men and women have different drainage systems in the pelvis. To the extent that AS may be induced by infections, this presents us with one possible explanation.”
In contrast to the well-established gender differences in the occurrence of rheumatic and autoimmune diseases, there is no evidence that men and women metabolize medications differently. While some cardiac drugs have been shown to be less efficacious in one gender, there are no similar examples among the classes of medications used in rheumatic or autoimmune diseases.
“There are, as of yet, no gender-specific treatments,” says Dr. van Vollenhoven. “On the other hand, there are obviously special issues for the female patients, because of the risks that drugs may have in terms of reproductive side effects and/or excretion into the breast milk with passage to the child during breastfeeding.”
He continues, “the influence that sex and gender have on the diseases themselves, the medical treatments that can be used, and the way that treatment decisions are made for female and male patients are an important area of research that may lead to better understanding of the disease mechanisms and more appropriate therapeutic approaches with better long-term prognosis for patients of both sexes.”
Overall, knowledge of the differences between men and women is rapidly increasing. The sexes differ at many levels—from molecular, as genes, to societal, as habits and exposures. No single explanation is available for the large differences in sex ratios that characterize many autoimmune and rheumatic diseases. All causes—including genes, cells, organs, hormones, whole body, and the environment—remain possible.
Kurt Ullman is a freelance writer based in Indiana.
