How a Healthy Lifestyle May Reduce Risk of RA

Dr Costenbader discusses her study of how following key lifestyle behaviors from not smoking to exercise and dietary changes may reduce the risk of developing rheumatoid arthritis.

Karen Costenbader, MD, MPH, is the director of the Lupus Program at Brigham and Women’s Hospital in Boston and a professor of medicine at Harvard Medical School.

Transcript:

Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your moderator, RALN. I'm very pleased to welcome Dr. Karen Costenbader, a professor of medicine at Harvard University Medical School and director of the lupus program at Brigham and Women's Hospital in Boston, Massachusetts. We're going to be discussing recent research she and her colleagues conducted into a very interesting topic, whether a healthy lifestyle might actually help to reduce the risk of developing rheumatoid arthritis among women. Thanks for taking the time to talk with us about your study, Dr. Costenbader.

Dr. Karen Costenbader:

Sure. Thank you very much for inviting me. This is fun to be here.

RALN:

Great. To begin with, what sparked your interest in this particular topic?

Dr. Karen Costenbader:

So I've been interested, I guess, in factors that are associated with increasing risk and with decreasing risk of rheumatoid arthritis and systemic lupus erythematosus related autoimmune disease for many years, probably, yeah, for all of my rheumatology career. And we've identified a lot of factors. I think when I went to medical school that the... Well, the impression I got, if not the prevailing thought was that these are diseases that come out of nowhere because you have a family history, and you inherited genes from your parents, and they're mainly genetic diseases. And I think a lot of progress has been made over the past 20, 25 years in understanding and identifying the genetic risk factors for these diseases. But, we over the years have also understood that there are many, many environmental, lifestyle, behavioral risk factors that contribute to risk as well. And I think even I did not realize the extent to which that if you add these risk factors are important for the risk of RA and lupus.

RALN:

So would you give us an overview of your study, please?

Dr. Karen Costenbader:

So this study was in the Nurses' Health Study, in the Nurses' Health Study two, which are two very large cohorts of women that have been followed for all kinds of diseases and all kinds of risk factors. The Nurses' Health Study started in 1976 and the Nurses' Health Study II in 1989. And women were all registered nurses from across the country, and they have been very, very good at filling out questionnaires over many, many years about their exposures and about their diseases.

And they're all nurses, and they've really been fantastic about staying in touch. So that's been just a treasure trove of data. And over the years, we've looked at many different risk factors for developing rheumatoid arthritis and lupus, as I mentioned.  In here, we have... So I should also say that over the years we have identified new cases, so incident cases. So the women back in 1976 were younger, obviously. We followed for many, many years up to about over 30 years now.

And we've identified new cases. So the nurses self-report that they have developed rheumatoid arthritis, then we ask them for about their symptoms, and we ask them for a release of their medical records, which we have gone through painstakingly every subreport since the beginning of time it seems like and identify whether they really did have new onset rheumatoid arthritis, when they had it, their symptoms and their treatments. And so since the beginning of the cohorts, we've identified there were 1219 cases of incident rheumatoid arthritis that were studied in this study, and that's among the 240,000 women in the Nurses' Health Study 1 and 2, which we were followed over those years. So then we looked at in time varying updated analyses. We looked at five different healthy lifestyle factors that have been associated with risks of other diseases and separately had been associated with risk of RA.

So we know that smoking is one of the strongest environmental risk factors for RA. And in many studies, it has been associated with up to an 80% increased risk in women, even higher in men. This was all women but for risk of developing RA. And then we've also shown that obesity is associated with increased risk of RA. We've shown that an unhealthy diet has been associated with risk of RA. Something called the Alternative Healthy Eating Index, which is a healthy diet. It reduces risk. We've shown that physical exercise for years prior to RA is associated with reducing risk and drinking a little bit of alcohol in the one half drink a day, very moderate, low range risk was also associated with a decreased range of risk of developing RA. So these have been looked at separately, and they've also been put together in what was called the healthy lifestyle index.

And that was associated with risk of cancer and cardiovascular disease. So in general, these are all healthy lifestyle factors that we should be promoting to everyone. But when we put them together in index, so from zero to five. If you had zero, you did nothing healthy. If you had five, you had the most healthy lifestyle. We saw a dose-response. So it didn't matter what order you did these healthy things in. If you did more healthy behaviors, your risk continued to go down. The women's future risk of developing rheumatoid arthritis years later was lower and lower for the more healthy lifestyle factors they did. And so the women who had five healthy lifestyle factors had the lowest risk, and their risk was only 0.4. So only 40% as high as... 1.1 was the reference of people who had the utmost unhealthy lifestyle.

So they reduced their risk by 60%, which is enormous, by following a very healthy lifestyle. And we did say that very strong trend or dose-response. And then when we looked at the entire cohort about... We figured out a metric called the Population Attributable Risk. So how much of the risk of rheumatoid arthritis among all these women in both cohorts could be attributed to these risk factors or to adhering to a healthy lifestyle. We found that 34% of the risk of rheumatoid arthritis overall could be attributed to adhering to greater than equal to four lifestyle factors. So if you were in the most healthy, you had at 4 or 5 of these healthy lifestyle factors, 34% of the risk of RA was reduced. So I think they were really very strong results. It makes sense because we've seen individually these things are associated with RA, but I was really impressed myself with the dose-response and how low the risk can be if you follow a very healthy lifestyle.

RALN:

You not only looked at RA among women in general but also you looked at seropositive and seronegative subtypes. What kind of differences did you find among those populations with respect to their risk of RA and how healthy lifestyle contributed to reducing the risk?

Dr. Karen Costenbader:

You're right. So there are 2 different flavors or types of rheumatoid arthritis, and we call them seropositive or seronegative and that has to do with rheumatoid factor and anti-CCP antibodies and whether they're detectable in women in this case or people who are being newly diagnosed with rheumatoid arthritis. And this is generally the rule in rheumatoid arthritis in the world rolled over that about two-thirds of the cases are seropositive, and there's another third of cases that are seronegative when we can't detect those antibodies.

There may be other antibodies that we, to this day, just don't know how to detect because the diseases are pretty similar otherwise. So here, of the 1219 women with incident RA, 776 had seropositivity at time of diagnosis and 443 was seronegative. So another striking result I thought was that the results were very similar for both seropositive and seronegative women. So the seropositive RA risk was reduced by about the same extent as a seronegative result. So for each healthy lifestyle index increase, that has the ratio fell by about the same amount for both seropositive and seronegative. There was a little bit stronger... A little bit stronger for seropositivity because we know that smoking in particular is more strongly associated with seropositivity.

So we get a little bit more bang for not smoking there. But overall they were both very, very strong. So it's a very strong take-home message for the public health impact of following a healthy lifestyle. There are many, many reasons to follow a healthy lifestyle, not just rheumatoid arthritis prevention. But if you have a family history of rheumatoid arthritis, it's really important, and rheumatoid arthritis can be a very severe disease.

RALN:

So of course to help reduce the risk of RA, it's necessary to identify patients who may be at the greatest risk of developing RA. So how do we do that? Is it mostly about genetics, about seropositivity? Are there biomarkers that practicing rheumatologists should check or even the primary care physician if they're treating patients who have family history of this disease?

Dr. Karen Costenbader:

Well, that's a great question. That's one of my favorite questions. And I think that's where I have been looking for my research in the past and in the future. So now that we know things to do to prevent RA, of course everybody should be following a healthy lifestyle. It does make the message a little bit stronger if we know exactly how to target which people. And there are other things we know are related to risk of rheumatoid arthritis, and there might even be medications in the future that we could start earlier to prevent rheumatoid arthritis. So how do we identify the people at highest risk? You're right that family history is very important and genetics are very important, but there are other risk factors as well. So we have put them. And there are biomarkers, as you say. So seropositivity.

So people who have family members who have rheumatoid arthritis or other related autoimmune diseases are also at risk. So rheumatoid arthritis tends to hang with other autoimmune diseases like autoimmune thyroid disease, multiple sclerosis, systemic lupus, vitiligo. There are all kinds of autoimmune diseases that may increase your risk for autoimmunity in general and rheumatoid arthritis.

And then we have looked at... In the Nurses' Health Study, we've done some prediction modeling, putting all the known risk factors. We knew at that point. Actually, we've identified some more since then. But we put in genetics and biomarkers of seropositivity, ACPA, anti-CCP or ACPA and rheumatoid factor, as well as lifestyle factors, where people live. We've seen some geographic variation probably because of environmental exposures and air pollution, other things. And we can get the predictive value or the predictive ability of our models, the area under the curve for correctly classifying people who will develop RA in the future up to about 0.76 or 0.8 even, 0.79.

And then we validated those in a cohort from Sweden that included men as well. So we have prediction models that are not completely ready for primetime because they don't capture a hundred percent of people and there are certainly other things. But I think that in the future, we will be able to, especially... Maybe we'll have therapies that are available for people or very targeted prevention messages if people have strong family histories or tested for antibodies. Certainly if they have early symptoms, we should be able to look at genetics, which are more and more available, as well as ask some very simple questions about... Are you smoking? You're looking at their alcohol intake, their exercise, exposure to other things, air pollution, pesticides, things like that we know are also related to rheumatoid arthritis and maybe turning it off before it gets really out of control.

RALN:

One interesting point is that if somebody doesn't have RA or isn't aware that they are at risk, they're probably not going to be seeing a rheumatologist. They'll be going to their primary care physician or to an internal medicine physician. You mentioned some early symptoms. What should those clinicians look for among their patients to give them a clue that this may be a patient who has RA beginning to develop or who is really at high risk for developing it?

Dr. Karen Costenbader:

And that's a good question too, because that's a very important question for getting the message out for primary prevention. So in general, people who do or don't have family histories of rheumatoid arthritis but early presentation can be fatigue, which is often missed because there's so many things that can cause fatigue with joint pains, especially hands and feet, especially across these knuckle, the large knuckles of the hands and as well as the smaller knuckles, not the tips of the fingers, and the wrists, the hands, the feet, the ankles. Morning stiffness, waking up in the morning and feeling like you're the Tin Man. I've had a lot of patients tell me that they feel like the Tin Man, that feeling of really being stiff in the morning, sometimes for several hours.

And after inactivity, feeling like people are accelerated aging. People say they feel so old, they're stiff, they don't have the energy, maybe low-grade fevers. These are all things that should be taken very seriously. And then labs will help, X-rays help, and a rheumatologist helps. But having a low bar for thinking about rheumatoid arthritis, about among other things that can cause inflammatory arthritis as well.

RALN:

So these lifestyle modifications, as you mentioned yourself, these are just great lifestyle modifications for everybody or lifestyle behaviors, I should say. For many people, they would be modifications. This wasn't part of your study I'm sure, but do you have any suggestions for practicing clinicians who want to help their patients make lifestyle changes, quit smoking, eat a healthier diet, start exercising? Because these are notoriously difficult changes for many people to make. What do you tell a colleague who is really struggling with how to really encourage patients effectively to take these steps?

Dr. Karen Costenbader:

That is a very, very big tall order. You're right. Because in medicine in general, we struggle with how to effectively help people. Smoking cessation is so hard. And people are a little bit more interested in dietary modification, actually. I take it back. But weight loss, people struggle with weight loss and exercise, and it's just staying on that they can lose weight and then it comes back, and they can't keep it up. And the same thing with the recidivism in smoking. And there's a huge field of medicine of encouraging, doing trials, the best way to encourage people to make lifestyle modifications, incentivize them, talk about them. And many physicians do not have time in a 20-minute appointment, 10-minute appointment to talk about all these things.

I actually was involved... We actually did a trial a few years ago called PRE-RA where we took people who did have a family history of rheumatoid arthritis.

There are about 270 of them. And they were randomized to 3 groups, and one just got some information about... They all got some testing but they also... The first group just got a standard pamphlet about this is rheumatoid arthritis. And the second one got more in-depth, talking to them about their lifestyle factors. And then the third got genetics and a genetic counselor as well to talk to them about their genetic risk and these lifestyle factors. And then each group was asked to think about which lifestyle factor they'd like to change. And there were smoking and obesity and others that are related to RA. So it did turn out that just the... We looked at some what's called the stages of motivation of change, Prochaska's ladder. So the outcome was just, could we motivate patients to move up the ladder towards change? Were they more interested in changing their lifestyle and making a change for as good to reduce their risk of rheumatoid arthritis?

And it was the group that was randomized to getting... Well, both getting personalized feedback about their personal risk factors and about their genetics more than just getting, "This is RA, and it's coming to you." So I think that education is really, really important. This is hopefully one more thing we can educate our patients about, but I understand that it is very, very hard, and that is a little bit where we are. Now how do we now identify these risk factors? But how do we get the word out? How do we motivate people to take care of themselves, to follow all these healthy lifestyles and make some very difficult changes sometimes?

RALN:

Well, congratulations on a very interesting study, and I look forward to speaking with you again, I hope, about further research that you're doing along these lines. And thank you for spending this time with us today.

Dr. Karen Costenbader:

Thanks, Rebecca. It was nice to meet you. It was fun talking.