Getting to the Root of Raynaud’s PDF Print E-mail
Friday, 30 April 2010 17:18
Dr. Fredrick Wigley is a professor of medicine at Johns Hopkins School of Medicine and director of the Johns Hopkins Scleroderma  Center. A rheumatologist, he has been studying Raynaud’s since 1978. The New York Times recently interviewed Dr. Wigley, and today, we have included some of the more pertinent questions asked of him.

Q. How widespread a problem is Raynaud’s disease?

A. In most surveys around the world, 3 to 5 percent of the general population has Raynaud’s phenomenon. If you look at certain populations like young women between the ages of 15 and 40, it’s as high as 15 percent.

The majority of people with Raynaud’s have primary Raynaud’s, which means there’s no underlying disease. The remaining 5 to 10 percent have secondary Raynaud’s, which means they have an underlying cause, such as an autoimmune disease like scleroderma, lupus or another connective tissue disease. To me, something that affects 3 to 5 percent of the population is huge. Rheumatoid arthritis affects 1 to 2 percent of the population, and Raynaud’s is twice that.

Q. If Raynaud’s is such a big problem, why don’t we hear more about it?

A. We’ve done surveys here in Baltimore and found that many people don’t put Raynaud’s on their list of concerns. It’s often not severe enough to bother them, or they perceive it as a normal reaction to the cold weather. This suggests that the prevalence of Raynaud’s in the community is actually greater than it is in a doctor’s office. In my office, where most patients have scleroderma, you’d find that almost every patient has Raynaud’s.

Q. Why do more women than men suffer from Raynaud’s?

A. We think it has to do with women having more estrogen, which may influence vascular reactivity to cold temperatures. In one study from Boston, which followed thousands of nurses, the prevalence of Raynaud’s was higher in women who had used estrogen treatments than women who had not. We know from the Women’s Health Initiative that estrogen increases the risk for vascular disease.

Of course, it’s not only estrogen that influences Raynaud’s. We know there are genetic influences, too. If you go into a family of a person who has primary Raynaud’s, you will find 30 percent of the time that there will be another family member who has Raynaud’s. Also, autoimmune diseases are more common in women.

Q. How close are we to understanding the cause of Raynaud’s?

A. We’ve actually come a long way since Maurice Raynaud first described the condition in 1862. In the 1930s, they thought women were more likely to have Raynaud’s because they were more anxious than men. Some thought women had more active sympathetic nervous systems (which govern our stress response) and released more signals that triggered the vasospasm of Raynaud’s. Some people thought women were more anxious because they worried that they weren’t going to get married. Although we still don’t fully know the biological defect that causes Raynaud’s, we do know that that theory was incorrect and influenced by the bias of that time. Studies show no defect in the amount of sympathetic output in Raynaud’s patients, nor differences between men and women.

What we do know is that our skin has little nerve fibers that sense temperature, and that the nature of these fibers may differ among people. Once the message from the skin goes to the brain that you are cold, the brain sends signals via the sympathetic nervous system to thermoregulatory blood vessels in the skin, telling the vessels to constrict and shift the blood flow from the skin to our inner circulatory system to keep us warm. Most thermoregulatory blood vessels are in the skin of the fingers and toes but they’re also in the nose, ears, cheeks, chest and knees.

Years ago, experts thought there were differences in the brain signals or the number of messengers sent out by the brain that caused Raynaud’s. But the idea now is that the problem is a local fault in the thermoregulatory blood vessels in the skin. Research by Nicholas Flavahan at Johns Hopkins has found that a particular receptor on the muscles of the blood vessels is cold sensitive and may be responsible for Raynaud’s.

Q. Tell us more about that research.

A. In the skin, there are molecules on the surface of the smooth muscle of the thermoregulatory blood vessels that cause blood vessels to contract. One of these, the alpha-2 receptors, come in three classes — a, b and c. Dr. Flavahan’s team has shown that the alpha-2c receptors on smooth muscles change expression based on the temperature.

If it cools down, these receptors flip up from inside the muscle cell, and more are exposed on the muscle surface. When there are more receptors, signals from the sympathetic nervous system have a bigger effect; there are more receptors to trigger a more intense constriction of the blood vessels. The theory is that if more alpha-2c receptors flip up, then you would be more sensitive to the cold.

Here at Johns Hopkins, we did a study that involved biopsies of the skin. We found that alpha-2 receptor activity was greater in patients with sclerodema than in normal people. Dr. Flavahan’s research has also found that estrogen increases the smooth muscle expression of alpha-2c receptors and may increase the number of receptors. It’s possible that this complex system of receptors is over-expressed in some individuals, thanks to hormones or diseases that disturb the blood vessels, like scleroderma.

Q. How good are we at predicting whether a case of Raynaud’s will go from a minor nuisance to heralding an autoimmune disease like scleroderma?

There’s a lot being done to help patients determine whether they have primary or secondary Raynaud’s. In the past, we had to wait and follow the patient for a year or two to find out. Now we know that using nailfold capillary tests, blood tests for antinuclear antibodies and the age of onset, we can reliably predict who has secondary Raynaud’s.

Researchers from Canada published a study in Arthritis & Rheumatism involving about 600 patients, whom they followed for about 15 years. In patients suspected of having connective tissue disease and scleroderma, they saw nailfold abnormalities, including giant capillaries, microhemorrhages and a reduction or loss of capillaries. Many of these patients also tested positive for antinuclear antibodies (ANAs) in their blood. Most people with these abnormalities went on to develop the disease they were suspected of having. At the same time, people who had normal nailfolds and who tested negative for ANAs generally did not develop secondary Raynaud’s but remained the primary type.

In general, if someone has Raynaud’s attacks that are symmetrical and never caused sores, but who is healthy by history and examination, then you can be pretty sure this person has primary Raynaud’s. It’s also more likely to be primary if the age of onset is 30s or younger. Being male and developing Raynaud’s after the age of 40 makes it more likely to be secondary to an underlying disease process.

Q. How do you measure the severity of Raynaud’s?

Measuring the severity of Raynaud’s is important both to help decide if it is primary — which is less severe — or secondary, and to help determine if therapy is working. The traditional way involves asking the patient. Patients keep a diary of the number and duration of attacks and then score the severity of the attacks, taking into account the impact on their lives and the degree of pain and disability. But how do you measure the impact of Raynaud’s? Is it the frequency? The ability to do things? The number of attacks?

We’ve devised a computer the size of a ring that measures skin temperature as a surrogate for blood flow. The patient wears it for several days, and we get a plot of what her temperature has been in real life situations. Skin temperature is not a perfect measure of blood flow. But this objective measurement is important if you’re going to give someone a treatment. If you’re going to give somebody a medication, you want to make sure it works. There has not been a lot of work in Raynaud’s done to show whether a medication works. Until now, it’s all been subjective measurements.

Q. Are there any new drug treatments that show promise for relieving Raynaud’s?

Only a small percentage of people with primary Raynaud’s need drug therapy, but those with secondary Raynaud’s are almost always treated with medications. So while the potential market for Raynaud’s is huge, the numbers of people taking a drug for it is small.

All the medications now being used for Raynaud’s are off-label, meaning they’re approved by the F.D.A. for other problems but not for Raynaud’s. Calcium channel blockers like nifedipine (Procardia) and amlodipine (Norvasc), for example, are primarily used for blood pressure control and are the most popular vasodilators used for Raynaud’s. They are generally effective at reducing the number, duration and severity of Raynaud’s attacks and well tolerated. To date they are the most practical medications available.

Phosphodiesterase inhibitors like sildenafil (Viagra) and tadalafil (Cialis), which are used for erectile dysfunction, may have some merit in patients with secondary Raynaud’s, but they are expensive. Some patients have also been treated with common anti-depression medications (namely the S.S.R.I.’s) like fluoxetine (Prozac). Recent studies have found some benefits from Botox injections. But the results on Botox are not yet proven, and it’s very expensive.

A national study is getting underway to look at an oral form of a prostaglandin known as prostacycline. These drugs are potent vasodilators that inhibit platelet aggregation and are given as an intermittent I.V. infusion to people with pulmonary hypertension, or high blood pressure in the arteries of the lungs. Prostaglandins work by stimulating nitric oxide in blood vessels and causing them to open up. But they are not yet available in an oral form.

Q. So what is the best way to treat Raynaud’s?

None of the drugs is as potent as staying warm, and that does work for the majority of people with Raynaud’s. Wear hats, scarves and layered clothes to keep the whole body warm. Avoid the frozen food aisles at the supermarket. Use car starters to warm up the car. Avoid cold breezes. Use space heaters and chemical warmers. But if there is a secondary cause with associated severe Raynaud’s, and especially if there are digital wounds like ulcers, then one would want to move on to medications.

Source: Yu, W. (2010), "Getting to the root of Raynaud’s", The New York Times
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