How Hormones Affect Rheumatoid Arthritis Treatments Fluctuating Levels Impact Women with Rheumatoid Arthritis

What do hormones have to do with rheumatoid arthritis, a chronic inflammatory condition that affects 2-3 million Americans? A lot, says a top rheumatologist. And women bear the brunt, going through pregnancies and menopause. Learn more... Women with rheumatoid arthritis often go into remission during pregnancy, and menopause puts them at higher risk of the inflammatory autoimmune disease. The common link? Fluctuating levels of the hormone estrogen, which dramatically increases when a woman is pregnant and decline after her periods cease. Twice as many women than men suffer from rheumatoid arthritis, and one reason may be their hormones, according to a top rheumatologist. "There are about two to three women affected with rheumatoid arthritis for every one man," says Anca Askanase, M.D., assistant professor at the New York University School of Medicine and a clinical researcher at Langone Center for Advanced Therapeutics at the NYU Hospital for Joint Diseases. "That’s the first thing that makes you wonder what the connection is there," she says. In this exclusive Lifescript interview, Askanase discusses the link between rheumatoid arthritis and hormones. How do the hormonal changes in pregnancy affect women with rheumatoid arthritis? Evidence suggests that maybe estrogen is good for arthritis. Rheumatoid arthritis gets better in women during pregnancy. Do women with rheumatoid arthritis go into remission while pregnant? There’s definite improvement – to the point where women who required significant therapy before their pregnancy are OK with limited or no therapy during pregnancy. Is it a long-term improvement? Within the first couple of months after the pregnancy, probably 90% of women have a serious flare and have to go back on their medication. Why does the relapse happen so rapidly? That’s because the amount of estrogen during pregnancy is just enormous compared to what we normally have on daily. Then, during lactation, levels decrease even further because a lot of women stop ovulating for a while after pregnancy. The drop in estrogen is very fast. How does breastfeeding impact rheumatoid arthritis? Breastfeeding is associated with a decrease in rheumatoid arthritis risk. One Swedish study suggested that there’s a protective effect from nursing. However, a [Harvard] study suggests that there’s no clear evidence of [that]. The jury’s still out. Does taking contraceptive pills affect rheumatoid arthritis? As opposed to lupus, where there’s a debate on whether hormone replacement or contraceptives are [beneficial], women with rheumatoid arthritis are never discouraged from taking birth control. There’s no clinical evidence to suggest that there’s either a beneficial or detrimental effect from oral contraceptives. The only catch is to make sure that they do not have antiphospholipid antibodies, which would increase the risk of a blood clot when taking oral contraceptives. Whenever a woman with rheumatoid arthritis asks me about whether she should take birth control, I test her for antiphospholipid antibodies. What are antiphospholipid antibodies? They're antibodies that predict a risk for blood clot. Not everybody who has them develops a clot, but the evidence suggests that if you have them and take [oral] birth control, you're more likely to develop a clot. That’s a factor in general for women with autoimmune diseases who are contemplating birth control. What’s the average age women get rheumatoid arthritis? While rheumatoid arthritis affects women of all ages, it seems to be [more prevalent] in women 40-50 years old. That is yet another piece of evidence that suggests there’s a connection between hormones and rheumatoid arthritis. The hormonal milieu of a woman going through [menopause] is when rheumatoid arthritis happens. Some data suggests that women who go into early menopause have a higher risk of developing rheumatoid arthritis than women with later menopause [onset]. What do you think is the cause? Some evidence suggests that the decrease in estrogen that comes with menopause may have something to do with it. So a lower estrogen level can flip on the rheumatoid arthritis switch? Rheumatoid arthritis is a combination of genetic and environmental factors. A little piece in the genetic factors is [simply being] a woman, and probably a little piece in the environmental factors is related to the decrease in estrogen. But, those factors are definitely not all the answers to the cause of rheumatoid arthritis, because women get this [disease] before their estrogen decreases – and men get it too. What progress have researchers made in finding the cause of rheumatoid arthritis? [Researchers] are still looking at large pools of women to better understand where all these factors play in the relationship between pregnancy, nursing, menopause and development of rheumatoid arthritis. How has rheumatoid arthritis treatments improved over the years? Over the past decade we have understood better how to treat rheumatoid arthritis, so we can prevent the long-term disabilities associated with it. We’ve probably made an impact on the cardiovascular risk too. What current rheumatoid arthritis treatments are available? As of this year, the best rheumatoid arthritis treatment is a combination of methotrexate (MTX), which is the older therapeutic medication, and tumor necrosis factor inhibitors (TNF). TNF promotes the inflammatory response. Over the past 10-15 years – since the medications have been available – it's evident that the combination of methotrexate and TNS inhibitors has the greatest impact on arresting the progression of rheumatoid arthritis. If TNF inhibitors stop the inflammatory response, how does methotrexate work? Methotrexate has been used for chemotherapy [cancer treatment] for about 30 years. In the late ‘80s, it began being used for rheumatoid arthritis. Because it’s a chemotherapy agent, it goes after some inflammatory cells. But in the joint, methotrexate works on adenosine (a naturally occurring substance in the cells),, which is a big player in the inflammatory process. Methotrexate's anti-inflammatory effects may be due in part to the increase in adenosine outside the cells. What are side effects from the treatment? Because methotrexate is a chemotherapy drug, it has some chemo-like side effects. People get nauseous and throw up. They get tired and lose their hair, which for a woman is a big deal. Autoimmune diseases are a hyperactive immune system. We want to take [that] and make it normal. We achieve that most of the time, but occasionally [doctors] overdo it and put some people at risk for infections and malignancies. Do the benefits outweigh the risks? What methotrexate and the TNF inhibitors have done for women with rheumatoid arthritis is amazing. They took people who would be crippled within a couple of years of developing rheumatoid arthritis and helped them maintain their functional abilities for decades. But it comes at a cost. These people are at a slight risk for developing infections and probably at a slight risk for malignancies. How large is the risk? Large cohort studies don’t suggest a huge increase in the risk for malignancies associated with [rheumatoid arthritis] treatments. It also may be inherent in the disease itself. There’s a big [lymphoma] cancer risk in rheumatoid arthritis. How big is the risk of lymphoma? The epidemiology data [shows] the risk of lymphoma is about two times the risk of the normal controlled population. Then the question becomes: How much is due to the disease, meaning the hyperactive immune system, and how much is due to treatment? It’s very hard to tease out. If hormones have an impact, should rheumatoid arthritis treatments be heading in that direction? Estrogen is important. A decrease in estrogen isn’t a great thing. But to say that hormone replacement is protective, nobody has made that jump. Why not try hormonal therapies? We’re not sure that hormone replacement is even good for women. The Women’s Health Initiative [a recent long-term health study] suggested that there are serious health risks related to hormone replacement. So would anyone want that? It’s complex because arthritis is associated with an increased cardiovascular risk and hormone therapies have been linked to that too. Would you want to do anything to further increase that risk?