Stephen A. Paget, MD: I'm Dr. Stephen Paget, Chief of Rheumatology at Hospital for Special Surgery. It is a pleasure to introduce Dr. Virginia Steen, a tenured professor at Georgetown University and an international expert in scleroderma. It is a disease that seems to be improving with regard to its outcome, probably because medical care is better and patients are being referred to the right doctors. But, have we improved our concept about what causes a disease?
Virginia Steen, MD: Unfortunately, we have not come up with a cause. Lots of people are working on it. We have identified a lot of things that happen at the cellular level, but we don't know what makes them happen. We know that there are some genetic factors involved, but it is not clear whether genetics is a central factor. We know that there are autoantibodies involved, but they do not seem to have any direct relationship to the pathogenesis. And we don't know what the initiating factor is, although we would like to think that it is some sort of environmental toxin because there are several other diseases that are scleroderma-like that are caused by such things. But in several epidemiological studies, there really is very little hint of a uniform etiology.
Paget: What are the different types of scleroderma?
Virginia Steen, MD: There is a vast spectrum of patients with scleroderma, but we generally divide them into two major subsets: limited and diffuse.
Limited scleroderma used to be called the CREST syndrome. These patients have Raynaud's phenomena for years before they develop anything else. They'll get puffy fingers, and then they will have a minimal amount of joint and constitutional symptoms. Skin symptoms often don't even show up until five or 10 years after the onset of Raynaud's.
Diffuse scleroderma patients have a much more acute onset and lots of constitutional symptoms, arthralgias, and carpal tunnel syndrome. They have not just swollen fingers, but whole swollen hands and legs. Consequently, because of the swollen legs they often go to many other doctors before they get to a rheumatologist. Their Raynaud's is often delayed. When you first see them, they may not even have Raynaud's. The skin thickening starts at the fingers and works it way up through the arms and onto the trunk. And this whole thing happens within a relatively short time, usually within a couple of years, in contrast to the long duration characteristic of patients with limited scleroderma.
Tendon friction rubs that are distributed most frequently on the wrist, palm, and ankles, are a very specific finding for diffuse scleroderma. Friction rubs can be found in patients who don't have any skin thickening, just have very swollen, puffy hands or legs. These friction rubs can be very helpful early on in the disease to help the physician sort out whether the patient is going to evolve to diffuse or limited scleroderma.
Although people with both types of scleroderma can develop pulmonary fibrosis (abnormal formation of fibrous tissue in the lung), diffuse patients tend to have more severe fibrosis. With gastrointestinal involvement, both of the esophagus and the small intestines, there is really no difference between the two groups; they are identical as far as their frequency and severity.
On the other hand, pulmonary hypertension - the isolated pulmonary vasculopathy type of hypertension - occurs almost only in limited, and sclerodermal renal crisis occurs almost only in diffuse. Cardiac involvement occurs in both types of patients, with predominance in diffuse.
The natural history of these two is quite different. In limited scleroderma, we see slowly developing skin involvement of long duration and then, after many, many years, gastrointestinal malabsorption (inadequate absorption of nutrients from food) or pulmonary hypertension. In diffuse scleroderma, it is a much more acute onset -- lots of skin thickening early on and lots of internal organ involvement early on and stabilization, and then some spontaneous improvement in skin.
Paget: What are the different types of therapy used to manage scleroderma?
Virginia Steen, MD: Physical therapy consists of the typical "use it or lose it." If you don't exercise, you are going to lose your function and you can't get it back. These patients need really aggressive- both active and passive - physical and occupational therapy.
So throughout the very early stages of the illness, we work very hard with the therapist to do very aggressive flexion and extension, particularly in the upper extremities but, depending on severity, other joints as well.
We use nonsteroidal anti-inflammatory agents (NSAIDs), very low doses of corticosteroids, and we also use adequate analgesia (pain killers), because if patients have a lot of pain, they are not going to exercise.
To manage severe Raynaud's, we are all pretty comfortable with the usual calcium channel blockers (a class of drug widely used to treat hypertension by relaxing the walls of blood vessels). But when you have someone who has a severe ulceration and you are trying to optimize everything, you need to maximize the dose of calcium channel. You also need to do Doppler blood flow studies (a form of ultrasound to evaluate blockage in blood flow), particularly looking for some larger vessel disease. We do sympathetic blocks for maximum vasodilation (i.e. to widen the blood vessels) and pain, but my plastic surgeon does it through the hand rather than systemically. Another important thing is to control the pain with narcotics. Do not worry about addiction. At this point, the main goal is that patients don't have a circle of pain and more spasm. We treat the infections, including local management typical of wound care with soaks and antibiotic and occlusive dressings (a covering bandage that seals a wound completely to prevent moisture from escaping and to prevent infection from entering). Our plastic surgeons are doing digital sympathectomies (surgical procedures to remove sympathetic nerves involved in pain); these are not just blocks but carefully peeling off all of the sympathetic fibers. There really have been some dramatic improvements in individual ulcers, much faster than usual, after this procedure.
Treatment of the gastrointestinal involvement has benefited from the use of proton pump inhibitors -- drugs that reduce gastric acid secretion in esophagitis (inflammation of the esophagus). Hypomotility (low movement of food through the intestines) problems became more of a problem when cisapride (Propulsid) was withdrawn from the market. [It is available now only on limited-access protocol. - Ed.] Metoclopromide (Reglan) is not as good and has a lot of side effects.
Some of the worst problems come from pseudo-obstruction (symptoms that make it seem as if your gastrointestinal system is obstructed, but it is not) and malabsorption. I use a lot of antibiotics for bacterial overgrowth. I don't go through the craziness of trying to prove that malabsorption is bacterial overgrowth, because I don't think there is a reliable method to evaluate it. I think most people with this problem have bacterial overgrowth. We use a variety of broad spectrum antibiotics, such as metronidazole (Flagyl), ciprofloxacin (Cipro), and the old tetracycline and ampicillin in creative ways -- such as every day, every other day, two weeks on, two weeks off, three weeks on, one week off, whatever can be done to try to get control of the diarrhea.
Sometimes we use hyperalimentation (in which nutrients and vitamins are given to a person in liquid form through a vein) to improve the patient's nutritional status until the bowel can now begin to work again. That works sometimes and buys us some time, and often the patients are able to come off the hyperalimentation and at least have a time where they don't have a lot of problems.
Another problem in the limited form of scleroderma is the large bowel involvement with severe constipation and obstipation (extreme constipation), managed with multiple regimens. There is no easy remedy. We use a lot of lactulose (Cholac, Cephulac) to help with this problem; lactulose is a sugar that is neither metabolized nor absorbed by the body and that works to pull water into the colon and soften the stool. Although perforation (escape of intestinal contents through a hole in the intestine) can occur, it is rare but it's often missed. A lot of these problems with the intestines are not associated with a severe pain; so don't just assume that if you have a lot of pain it is just related to the scleroderma GI problem.
Rectal problems have become a major difficulty for a lot of limited scleroderma patients. They have rectal prolapse (protrusion of part of the rectum through the anus to the outside of the body) but also have lots of seepage of stool, which can be very embarrassing. It is important to differentiate diarrhea from just losing some stool. The old Kegel exercises and formal biofeedback that some rectal physicians do can be helpful in those circumstances.
Severe dysphagia (problems swallowing) is not nearly as much a problem as we used to have because of the use of proton pump inhibitors. The type of dysphagia must be sorted out. Some types of dysphagia may overlap with a non-inflammatory type of myopathy (muscle disorder), and proton pump inhibitor drugs can help. But it may be necessary to do a barium swallow or cine-esophagram test (an X-ray examination of the esophagus) to find out whether there is a stricture or a severe dysmotility. Often, there is a complication of candida esophagitis (inflammation of the esophagus due to candida, a yeast infection). So endoscopy is necessary to sort this out in order to provide the proper treatment. (This involves inserting a flexible tube down into the esophagus; an optical device is attached that enables the physician to examine the condition of the esophagus and, if necessary to go further down, the stomach.)
Over the last 20 years, we have had a significant decrease in death from renal crisis in patients, but we have had an increase in the frequency of pulmonary fibrosis. We also see some disease and scarring of the pleura - the membrane that surrounds the lungs. We can get bronchiectasis (dilation of the tiny tubes in the lungs) and spontaneous pneumothoraces (air collecting in the pleura) in patients who have severe fibrosis. The alveoli (the air cells in the lungs) may get inflamed, called alveolitis. Lung capacity does not necessarily determine whether breathing symptoms occur, although pulmonary function tests are important and CT scans may be needed to evaluate the lungs. Cyclophosphamide (Cytoxan) has become the favorite treatment for alveolitis to help improve the vital capacity of the lung but controlled studies are being done to determine its effectiveness.
Limited scleroderma patients are the most likely to get isolated pulmonary hypertension without scarring or fibrosis in the lung. A helpful predictor of pulmonary hypertension is a low diffusing capacity on the pulmonary function tests. The treatment of this in the past few years has been helped by the use of continuous infusion of prostacyclin analogues, including epoprostenol (Flolan) and treprostinil (Remodulin). [An endothelin receptor antagonist, bosentan (Tracleer), has also become available - subsequent to this interview. -- Ed.] These drugs may interfere with the progression from cell injury to blood vessel thickening, improve function and thus are very exciting.
Lung cancer is an important issue in patients with severe fibrosis. Often, patients will come in with more symptoms, with pleural effusions, with changes on their chest x-ray, and it is just attributed that to more fibrosis. But, epidemiologically, we know lung cancer is increased in scleroderma patients. It is most often in long-standing patients with severe fibrosis in both limited and diffuse. Cancer usually presents as an acute deterioration, although we have found patients who have cancer by doing a high resolution CT scan. Most of it is unrelated to smoking.
With regard to heart disease, cardiomyopathy is most frequent in diffuse scleroderma. Arrhythmia is common in both groups, but those with diffuse scleroderma tend to have more of the severe ventricular problems, and the limited scleroderma patients tend to have more conduction defects and atrial problems. We don't know what causes these other than that there are fibrotic changes and there is evidence of some ischemic changes, seen on exercise and cold-induced tests. Treatment of all of these really is just treatment of the individual manifestations, and we depend on the cardiologist to assist.
Our success story is with renal (kidney) crisis, in which severe hypertension occurs and the creatinine rises. (Creatinine is the end-product of the body's metabolism of creatine, a normal body substance. A rise in creatinine usually signals a kidney problem.) Often, even after the blood pressure is controlled, the creatinine continues to go up. Almost half the patients will have a microangiopathic hemolytic anemia (a type of anemia in which the patient's red blood cells are destroyed) and thrombocytopenia (an abnormal decrease in blood platelets). Congestive heart failure (in which the heart fails to pump blood adequately) and pericardial effusions (fluid accumulation around the heart) are common both before the onset, as well as at the time of renal crisis. Those most likely to develop renal crisis have early diffuse scleroderma with rapidly progressive skin disease. We should not use high dose steroids in patients with scleroderma because it may be associated with the development of renal crisis.
But the success is that angiotensin converter enzyme (ACE) inhibitors have made a major difference in our treatment of renal crisis. It has really dramatically changed the outcome. More than half of our patients have a good outcome. Some of them don't ever have dialysis. Some of them have temporary dialysis and still are able to come off dialysis. We still have a significant amount of early deaths. Most of these are because the patients aren't started on ACE inhibitors early. They are not identified as having renal crisis. They are started on the wrong medication. So we have to continue to work to identify patients at risk and get them started earlier.
Paget: Thank you, Dr. Steen.
From an interview with Dr. Virginia Steen by Dr. Stephen A. Paget