Scleroderma:
What Gets Better, and Why (Part 2 of 2 Parts)
 |
| Lee
Shapiro, M.D., FACP |
By Lee Shapiro,
M.D., FACP, The Center for Rheumatology, LLP, Albany, New
York (originally published in Scleroderma Voice, 2003
Issue #1)
Editor's note:
You can skip directly to the subheads that interest you, by
clicking on these links:
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. |
