Gender and Rheumatoid Arthritis

Summary of a presentation at the Living with RA Workshop at HSS


Michael D. Lockshin, MD

Attending Rheumatologist, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College
Director, Barbara Volcker Center for Women and Rheumatic Disease

The traditional answer to the question "Why are autoimmune diseases women's diseases?" has been "It has to do with estrogen." But that's not a satisfactory answer because a lot of facts that don't fit this theory. So the question has been researched with greater interest in recent years.

What is autoimmunity? Some define it by tests done in a laboratory that find antibodies (such as rheumatoid factor) to normal tissue (parts of the body). Others say it's the kind of disease that cause arthritis and sometimes fevers, kidney disease and other problems. Others say any disease that causes arthritis is an autoimmune disease. Animal models are another way to define it because the autoimmune diseases that we recognize can be produced in animals by manipulating their immune systems. Because autoimmune diseases tend to run in families, we tend to use a positive family history as part of the definition. By and large, all the definitions require that an autoimmune disease not be an infectious disease, such as Lyme disease and some types of hepatitis, which would look like autoimmune disease if they were not clearly caused by an infection. (This suggests that diseases such as RA may also be infectious diseases but we just haven't identified the cause of the infection.)

Which diseases are autoimmune? Again, the answer is not totally clear. Most physicians would agree to this list: Hashimoto's thyroiditis, primary biliary disease, chronic active hepatitis, Grave's disease, lupus, scleroderma, rheumatoid arthritis, Sjogren's syndrome, and most rheumatic diseases, including ankylosing spondylitis. But there are many other diseases that some doctors consider autoimmune and others do not. The American Autoimmune Association would include such diseases as multiple sclerosis, hemolytic anemia, pemphigus, pernicious anemia, type 1 diabetes, myasthenia gravis, Goodpasture disease, and many others - but there is no clear consensus. And there is considerable controversy about some neurologic, skin, and intestinal diseases that are accepted as autoimmune by some doctors and not others.

Are all autoimmune diseases women's diseases? Not necessarily. While many are much more common in women, others are more common in men. For RA, women are affected about two and a half times more common in women compared to men.

This again raises the question of why so many autoimmune diseases are much more common in women. Two important efforts to explore the question were: a conference at Hospital for Special Surgery in 1999 exploring Gender, Biology and Human Disease; and a commission of the Institute of Medicine of the National Academy of Sciences, which last year published a book Exploring the Biological Contributions to Human Health - Does Sex Matter? - available for purchase or for free online. The NIH study looked at male/female differences in the following factors.

Environmental differences - Women may develop autoimmune diseases because they are more susceptible - or more exposed - to something in the environment. For example, scleroderma occurs spontaneously, primarily in women, but also in men who are gold and coal miners and in workers that manufacture plastics. Scleroderma-like diseases also are seen in those exposed to some toxins. Further, some drugs can cause lupus, which primarily occurs in men taking those drugs. However, no environmental culprit has been identified.

Genes - Due to genetics, women and women have some chemical reactions that are different. No genes have yet been proven to explain female predominance, but the field is just beginning to be explored.

Behavior - Some diseases are different in men and women due to behavioral differences. For example, you can develop osteoporosis based solely on personal habits because the amount of exercise you do and your body fat levels affect bone strength. Women who are intense athletes, such as marathoners, lose huge amounts of body fat, stop menstruating, and get severely osteoporotic. Girls who are anorectic and don't eat also lose their body fat and get very thin bones. Other examples are venereal diseases, which are more common in men because of their relative level of promiscuity. And Reiter's syndrome is a form of arthritis that is often triggered by venereal disease. So the theory is that women can predominate in a disease if men and women differ in basic personalities, but we don't know what personality factors could lead to diseases like RA.

Whole Organism - Issues related to being a living person at given time, for example, might include age, and most autoimmune diseases start between the ages of 15 and 45. So there is something interesting about that age range. Many issues related to age might explain female predominance, such as a long period between encountering what causes these diseases and their eventual appearance. So it might be theorized that little girls do different things from little boys but it doesn't show up as disease until 10 or 20 years later. The Army keeps blood samples of its recruits for many years; researchers have now looked at samples of this blood and found that blood tests are positive more than 10 years before the appearance of lupus and RA. So the disease has existed for more than 10 years before someone gets joint pains.

Hormones - Estrogen increases the immune response in humans and many animals. However, in some animal models we don't see more frequent disease but more severe disease in females. That's the opposite of what we see in humans; for example, the severity of RA and lupus are the same in men and women but the frequency is different. And the influence of hormones is inconsistent: during pregnancy, RA gets better but lupus may get worse or be unchanged. So there may be big differences in the way different autoimmune diseases appear when you get pregnant or take birth control pills or estrogen replacement. However, in two recent studies, it looks as if birth control pills and estrogen replacement have no effect on women with lupus. It's possible that reaching a certain threshold of hormones or the cycling of hormones in menstruation could influence disease. But we still don't know whether hormones cause disease.
Other possible differences in men and women that might relate to autoimmune disease include anatomy, pregnancy, differing physiologic responses to drugs and toxic substances, differing genitourinary tracts, influences on the baby before birth, and other factors.

Dr. Lockshin's guess is that hormones are not the explanation for female predominance of autoimmune disease. Rather, he thinks the predominance relates to different exposures to something in the environment or differences in the way men and women's bodies handle something, or some mixture of the various causes discussed above.

The differences in the male to female ratio of autoimmune diseases is the single most bizarre clinical fact about these diseases. It has not received a great deal of research attention so far, but finding the answer will teach us a great deal about these diseases.

About the Living with RA Workshop at Hospital for Special Surgery


Summary prepared by Diana Benzaia.

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