Reactive arthritis

Several years ago, brilliant young cardiologist Dr. Paul Ridker became intrigued with the fact that half of all heart attacks occurred in people with normal cholesterol levels. For decades, experts considered cholesterol the principal agent behind the gumming up of our arteries and the chief culprit in the development of cardiovascular disease. The young researcher sifted through the medical literature, searching for scientific clues to a possible coconspirator. The trail led to research suggesting that low-grade arterial inflammation is as dangerous as high cholesterol levels in raising the risk of heart attack and stroke.

"Inflammation is the process whereby our body responds to injury," Dr. Ridker told the Post. "The critical issue is that we now recognize that hardening of the arteries, or atherosclerosis, is very much an inflammatory disease in the same way that we think of arthritis as an inflammatory disease."

To gauge the level of arterial inflammation, Dr. Ridker identified a simple, reliable, and inexpensive blood test that detects and measures levels of C-reactive protein (CRP), a substance produced in the liver when arteries become inflamed. In the past few years, study after study has demonstrated the value of administering the high-sensitivity C-reactive protein (hs-CRP) test to help identify individuals at high risk for coronary heart disease long before it becomes life-threatening. And Ridker's investigation is breaking new ground, changing the way that physicians think about heart attack and stroke.

"The high-sensitivity CRP test provides us with a way to measure very low levels of inflammation which turn out to be highly predictive of future heart attacks and stroke," Dr. Ridker explains. "When we combine the new hs-CRP test with standard cholesterol screening, we appear to be able to do a far better job in terms of predicting who will ultimately go on to have a heart attack or stroke than if we had relied on cholesterol levels alone."

Today, the medical establishment is embracing the important role of inflammation in heart disease and screening patients for the risk factor. Last August during a physical, President George W. Bush underwent the C-reactive protein test, and given the Chief Executive's exemplary exercise regimen, it comes as no surprise that he passed with flying colors.

The findings of a recent landmark study by Ridker and his colleagues published in the New England Journal of Medicine may soon affect federal guidelines for cardiovascular disease detection.

"In our study we found that individuals with high C-reactive protein but low cholesterol levels were actually at higher risk than those with high cholesterol levels but low CRP," Dr. Ridker, lead author of the study, explained. "Yet such individuals are routinely missed by current screening procedures."

To update readers on the latest research into C-reactive protein and useful steps you can take to lower your risk for heart disease and stroke, the Post interviewed Paul Ridker, M.D., director of the Center for Cardiovascular Disease Prevention at the Brigham and Women's Hospital in Boston.

Post: We spoke with you two years ago (Sept./Oct. 2000 Post) about emerging evidence on the role of C-reactive protein in cardiovascular disease. With all the supportive studies and research, should physicians now routinely incorporate CRP levels in combination with cholesterol levels in monitoring the overall risk profile of their patients?

Ridker: The CDC and the American Heart Association are putting out guidelines for screening in a few months. My best guess is that they are going to suggest that screening should mostly be used for primary prevention in healthy middle-aged men and women where knowing their CRP level could change risk.

Post: Two years ago, there was one FDA-approved assay for measuring high-sensitivity CRP. Is the test more widely available today?

Ridker: The so-called high-sensitivity CRP test is very widely available now. There are many out there, and they have all been standardized. It is very easy to get. Basically, any outpatient laboratory in the country could provide the test. It's a very cheap test. The reality is that the reimbursement is somewhere between $12 and $16.

Post: What percentage of people in the United States have normal cholesterol levels but high CRP levels--and are thus at high risk for a cardiac event?

Ridker: We think it is around 25 to 30 million Americans.

Post: With screening and follow-up, could we potentially find a person at high risk for a coronary event and save lives?

Ridker: Fifty percent of all patients who get heart attacks and strokes have normal cholesterol levels. Identifying these people very early allows us to motivate them to diet, exercise, and stop smoking. It motivates them to stay within the treatment program. Compared to not knowing their high risk, it is extremely valuable information. And that's before we even start talking about whether individuals with high levels of CRP should be treated with any particular therapy.

Post: Do age and gender play a role in high levels of CRP?

Ridker: Gender only plays a role in the sense that women who take hormone replacement therapy have elevated levels of CRP, but otherwise the levels between men and women are basically the same.

In terms of age, there is a little bit of a drift up the older you get, but that's also because the older we get, the higher the risk of having events. That's normal for cholesterol at the same time.

Post: If you have an infection or an autoimmune disease--rheumatoid arthritis, for example--would you have high levels of C-reactive protein?

Ridker: This is not about infection; this is about inflammation. Among Americans who consider themselves healthy, 99.9 percent have a CRP level. It's about 50 percent inherited from our parents and about 50 percent due to the environment that you live in--how much we exercise, diet, and whether we smoke or not. This has nothing to do with autoimmunity in that sense of the word. This is a test for the average, healthy person. For that one tenth of one percent of the population that has lupus or juvenile rhematoid arthritis or some severe autoinflammatory disease, yes, they have high levels of CRP, but that's not the point.

Post: Does obesity play a role in CRP levels?

Ridker: Obesity plays a very big role. We know that obesity is a major risk factor for heart disease, stroke, and diabetes. Fat cells produce chemicals called cytokines that lead to the production of CRP. We showed about a year and one half ago that CRP levels not only predict heart attack and stroke, but also who is going to get diabetes. The concept here is that this inflammatory response is picking up the risk of diabetes as well as heart disease, which of course go together. Obesity does not explain the phenomenon; it's just one part of it. But the reason that obese patients have this cluster of diabetes and heart disease, we think, is largely related to the inflammation.

Post: With the dramatic increase in obesity among our youth, is CRP going to play a role there, too?

Ridker: We know that CRP levels in our children reflect those in their parents, but that is the genetic component. We also know that people who eat a poor diet put on weight. To me, exercise is even more important than the obesity.

Post: Can lifestyle changes help reduce CRP levels?

Ridker: The most important ways to lower CRP levels in my mind are to stop smoking, to go to the gym and work out, and to lose weight. Those are the three things that we know overwhelmingly lower your risk of heart disease and seem to lower your risk of diabetes as well.

Post: Could you tell us about your ongoing studies evaluating the role of aspirin and lipid-lowering drugs, such as the statins, in decreasing CRP levels?

Ridker: The aspirin story is fairly simple. We have shown that the benefit of aspirin is greatest among patients with high CRP levels. That's pretty straightforward. The statin data are much more complicated and interesting. We have been able to show that these LDL-lowering drugs--the statins--are sort of a two-for-one kind of drug. They not only lower cholesterol, which is very important, but they also lower CRP levels. We've just launched a very large nationwide trial, called JUPITER, of about 15,000 patients. We will start enrolling this spring. It's a very unique study because we are taking patients who have very low cholesterol levels--the LDL level must be less than 130, which is way below guidelines--but have high CRP levels. We are going to see whether putting those patients on a statin can actually reduce the risk of an event.

Post: If readers are interested in participating in the study, how would they enroll?

Ridker: They should talk to their doctors.

Post: Does alcohol in anyway moderate CRP levels?

Ridker: We have been able to show that low-dose alcohol, the definition of which is one drink per day, does seem to be associated with lower cardiovascular risk and, interestingly enough, seems to be associated with lower CRP levels, One glass of wine a day or a beer a day does seem to be associated with lower cardiovascular risk. But this does not mean, however, seven drinks on Saturday or bingeing.

Post: Is CRP implicated in diseases other than heart disease and diabetes?

Ridker: The fact that CRP levels are elevated in patients with, let's say, cancer or Alzheimer's is not relevant. That does not mean that CRP levels were elevated before you developed cancer or Alzheimer's. As far as we can tell, CRP levels in healthy individuals predict future myocardial infarctions, strokes, and sudden cardiac death. Interesting enough, it does not predict future cancer. But it does predict diabetes. The Alzheimer's data that I have seen have to do with people already with Alzheimer's. Cause and effect are turned upside down.

Post: Will you be conducting studies?

Ridker: The JUPITER study is probably the biggest thing that we just launched. It's critically important because we really don't know how to treat these patients. And we are looking at a variety of different kinds of drugs. The Holy Grail here is the development of therapies that are actually truly anti-inflammatory.

Post: What is the main message that you want the public to know?

Ridker: The bottom line is that half of all heart attacks and strokes in the United States occur in people with normal cholesterol levels, and we can do a much better job of predicting risk. If that can motivate people to diet and exercise and stop smoking, we will have a tremendous public health benefit.

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