Scleroderma: What Gets Better, and Why (Part 2 of 2 Parts)

By Lee Shapiro, M.D., FACP, The Center for Rheumatology, LLP, Albany, New York (originally published in "Scleroderma Voice," 2003 Issue #1)

Dr. Virginia Steen and Dr. Thomas Medsger recently published another paper which I would interpret as encouraging regarding the natural history of scleroderma.

They studied the records of almost 1,000 patients with diffuse scleroderma to determine the incidence and timing of severe involvement of the kidney, heart, lung, and gastrointestinal tract. These are the organs most at risk in diffuse scleroderma.

It was once thought that the risk of severe internal organ system involvement in patients with diffuse disease increased linearly, in parallel with disease duration. This is not the case. The periods of high risk are not endless. Renal crisis occurs most often during the first four years. Eighty percent of individuals who develop this complication do so within the first four years of their scleroderma.

When it comes to fibrosis of the lung, the period of high risk is even less prolonged: the first two years of the disease. Organ damage, if it is going to occur, most often occurs early.
How is this good news? What it tells me is that our biggest struggle is to see those of you with diffuse scleroderma through the first few years of the disease. If you find yourself free of internal organ involvement after the first four years of disease, you are likely to remain so.

The Importance of Early Intervention

In early disease, we need to be especially vigilant—not simply to watch bad things happen, but because, increasingly, we have the tools for effective intervention. Increasingly, we can change the natural history of the disease.

As recently as 25 years ago, renal crisis was the worst complication, a uniformly fatal complication of scleroderma. This is no longer the case. We have been witness to an amazing change. Now, when identified early, renal crisis can be addressed.

For the rheumatologist, the risks are not the same as those of a member of a bomb squad, but the rewards as just as great: a life and a kidney can be saved. Early use of an ACE inhibitor will almost always control blood pressure and prevent progression to kidney failure.

But late discovery won’t prevent a bad outcome, and bad outcomes still occur too often. Our challenge now is the process of identifying and educating those at risk, and educating the physicians who treat them. We need to do all we can to make sure renal crisis is rapidly diagnosed and just as rapidly, and correctly, treated.

Renal Crisis: A Model of What Can Go Right (or Wrong)

The change in the management of renal crisis is, for me, a model in many ways—both of accomplishment and failure. The accomplishment is magnificent: an effective treatment of a life-threatening problem. This resulted from years of basic research in the mechanisms of hypertension in scleroderma. The substance responsible for inducing spasm in the renal arteries was identified and after years of effort, an antagonist to this substance was developed. It worked so well that within a year or two of development, it became the standard therapy. Suddenly, kidney disease could be added to the list of aspects of scleroderma that can get better.

The failure is that 22 years after development of the drug, some individuals with scleroderma still develop kidney failure and require dialysis. Just as knowledge led to the miracle of effective drug development, those who did poorly suffered for lack of knowledge. They were treated too late because they didn’t know they had scleroderma or they did not know they were at risk of kidney disease or how to monitor for it. Or perhaps, they were treated in an emergency room or urgent care clinic and did not receive an ACE inhibitor.

In a world with information overload, we have a forbidding task in identifying those at risk and educating them, and educating the physicians likely to treat them.

Lung Disease: We Are Learning More and Daring to Hope

Treatment of lung disease in scleroderma appears to be entering a similar period of rapid improvement and promise for those with early disease. Soon we hope that lung disease can be added to the list of aspects of scleroderma that can get better.

We now know that the early phase of pulmonary fibrosis is one of inflammation. As in the skin, inflammatory cells are present in the walls of the lung. These white cells release signals that, just as in the skin, transform fibroblasts into more active and productive cells producing collagen.

Pilot studies suggest that early therapy with cytoxan can often prevent this progression from inflammation to fibrosis.

As with the kidney, those with late disease are not so lucky. There is no drug that will correct this distorted architecture of advance lung disease.

If ongoing studies confirm the efficacy of cytoxan, our job as physicians is to identify those individuals with early and often very subtle disease so they can be treated when the treatment works—and not told, “Sorry, if we had only seen you sooner.”

Pulmonary Hypertension: We Are Developing New Treatments

The latest exciting frontier is treatment of pulmonary hypertension, the only complication more common to those with limited rather than diffuse disease.

The natural history of scleroderma led to the belief that this, too, was a problem that progressed, and had no solution. In pulmonary hypertension, blood flow through the lungs diminishes due to narrowing of small pulmonary vessels. The right side of the heart struggles to generate sufficient pressure to pump blood through these narrowed channels, and oxygen delivery to red cells diminishes to the point that shortness of breath results. Without treatment, this will progress to breathlessness at rest, and signs of right heart failure such a leg swelling will develop.

This is a complication, like many others in scleroderma, reflecting the other recurring theme, not of fibrosis, but rather narrowing and obliteration of blood vessels. Over the past few years, basic researchers have identified many of the agents responsible for inducing spasm of blood vessels and proliferation of the lining cells in vessel walls. They have identified antagonists to these triggers, agents which can relax vessels and hopefully even result in remodeling of narrowed vessels.

We now have two agents approved for treatment of pulmonary hypertension: Prostacyclin and, more recently, Bosentan, and others are soon to follow.

Gastrointestinal Tract: Here We Have Less Progress to Report

In this organ system, so far, we have failed to alter the natural history of the disease.

Symptoms are usually the consequence of advanced changes—of thinning of the muscular wall or scarring in it. Our treatments try to compensate for the consequences of these changes in esophageal or bowel structure, but we have not yet learned how to prevent this loss or normal function.

When attention is sufficiently focused on the issue, I am sure we will make progress and treatments will result, but these treatments will be most effective for those not yet afflicted.

Evaluating a Patient’s Prognosis and Specific Risks

Systemic sclerosis has components of autoimmune dysfunction, blood vessel damage, and fibrosis or scarring. The rate of disease progression and the pattern of organ involvement vary greatly from individual to individual. Only in the very recent past have we defined subsets of the disease and blood markers that allow us to individualize statements about disease prognosis and risk of internal organ involvement. We will do this better in the future.

Conclusion

What gets better? First, you may once have felt alone, but you are no longer alone—just look around the room at any support group meeting. Now that you know you have company, I hope the anxiety and fear that may have paralyzed and immobilized you are going or gone. In place of fear, hopefully now you know something about your disease. For example, I hope you know whether you have limited or diffuse disease or an overlap syndrome.

I hope you have some know-ledge of the risks you face and of the complications which are unlikely to occur to you. If you don’t, ask your doctor.

Remember, almost everything written about scleroderma was written in the past 50 years, and most of it in the past 10 or 20 years. As each year passes, your doctors are in a position to know more about this disease. Treatments exist for problems thought hopeless not so long ago. Even without treatment, in many individuals certain features of the disease spontaneously improve: including skin thickening, hand swelling, joint pain, and itching. Organ problems, if they occur, almost always occur within the first few years of the disease, with the exception of pulmonary hypertension in those with limited disease.

What doesn’t get better? As with any disease, advanced changes of scarring or atrophy can’t be fixed. Treatments exist for almost every problem, but some are admittedly more cumbersome or less effective than others. Sometimes we are forced to work around a problem we can’t fix.

But stick around. Changes are coming much more rapidly now—dramatic changes in the treatment and prevention of renal crisis, pulmonary fibrosis, and pulmonary hypertension. There is more basic research in scleroderma than ever before. New knowledge will take us, I am sure, just as far as it did in the treatment of polio—from a state of fear and iron lungs to disease prevention.