Scleroderma: A Therapeutic Challenge
By the late Joseph Korn, M.D. (1947-2005), Alan S.
Cohen Professor of Medicine, Boston University Medical
Center, (originally published
in "Scleroderma Voice," 2004 #2)
Any disease without known cause presents a therapeutic
challenge, certainly for cure and even for management.
In scleroderma, there appear to be multiple underlying
causes, including genetic factors, which are obviously
not amenable to change.
There are also obstacles to new drug development: the
course of disease varies widely among patients and there
is often spontaneous improvement in some organs, particularly
the skin. The disease is uncommon, making large clinical
trials difficult.
Nonetheless we have gained a better understanding about
the mechanisms of disease, of how change and damage
to organs occur, and how that has resulted in marked
improvement in both management, in quality of life and
of life expectancy.
Scleroderma Symptoms
The signs and symptoms of scleroderma are due to injury
to blood vessels and to fibrosis, or scarring.
The blood vessel injury, and resulting abnormal blood
flow, leads to Raynaud, kidney disease, pulmonary hypertension,
and other manifestations.
The fibrosis, due to increased amounts of collagen
and other proteins, is most evident in the skin but
occurs also in the lungs, gastrointestinal tract, heart,
and within the blood vessels.
Progress in Treating Renal Crisis
Until 25 years ago, the major cause of death was kidney
disease; patients who developed scleroderma “renal
crisis,” the term for sudden onset of high blood
pressure and kidney failure, had greater than 99% mortality
within a year. The development of a class of drugs called
angiotensin converting enzyme inhibitors (ACE inhibitors),
as well as the availability of dialysis, has entirely
changed that picture.
Improvement in Survival Rate
Overall survival from scleroderma has improved from
50% at 7 years to 80% or more at 10 years. Despite this
improved survival, scleroderma still has a major impact
on function and on life expectancy.
The improved survival from kidney disease resulted
from identifying the substances in the body that led
to high blood pressure and kidney damage as well as
early recognition and aggressive treatment of kidney
disease.
By analogy, it is likely that understanding the molecular
mechanisms, the precise pathways, of vascular disease
and fibrosis, along with better diagnostic techniques
and aggressive approaches, will prevent organ damage
in other systems.
Because scleroderma is a platform disease, a model,
for fibrosis and vascular injury, it has attracted the
attention of investigators and biotechnology companies
interested in lung fibrosis and pulmonary hypertension
that occurs outside the setting of scleroderma as well
as related disease like cirrhosis (liver fibrosis).
This balances the problem of scleroderma being a rare
disease with a small potential market size for newly
developed drugs.
What Causes Scleroderma and What Can We Do About
It?
Let’s get back to the questions of what causes
scleroderma. Genetic factors play a role: we see families
with multiple autoimmune diseases, including scleroderma,
lupus erythematosus, and rheumatoid arthritis in different
members.
The inherited genes predispose to autoimmunity, increased
activity of the immune system with the body reacting
to and attacking itself.
There is also evidence that blood vessels are injured
but the cause and mechanism of injury are unclear.
Finally, fibroblasts, cells that are major constituents
of the skin, lungs and other organs, are turned on and
make increased amounts of collagen.
There are several key questions. How are these events,
fibroblast, immune system, and blood vessels interrelated?
What initiates the process? What key points in the pathways
are amenable to intervention? Will interventions alter
the long term course of disease, i.e., will new therapies
have long term positive effects?
How Are New Treatments Developed?
How are new therapies developed? One approach is to
identify rational or reasonable targets. Some of the
processes involved in fibrosis and blood vessel constriction
and injury are already known. Agents that block these
pathways can be tested in laboratory cell culture and
in animal models of disease.
An alternative approach is to search for novel pathways,
ones that may be unique to scleroderma and might not
be intuitively obvious.
One recent approach that has been used in cancer studies
among others is gene profiling. What this means is that
one looks at cells or tissues from scleroderma patients
to see which genes are abnormally switched on or off
compared to healthy controls. The products of those
genes then become targets for therapy.
For example, substance X might be overproduced in scleroderma
cells; X could be a cellular receptor that signals the
cell to turn up its metabolism.
One might first investigate whether turning up X in
normal cells leads to other scleroderma abnormalities,
increased collagen for example. If so, an antibody to
X, or a decoy molecule that binds to X without turning
it on might be used for treatment in an animal model.
The two approaches noted above, rational targets and
hunting for new gene targets, are both being used in
trying to find new ways to treat scleroderma.
Two molecules that are thought to play a role in fibrosis
and in blood vessel injury are TGFß (transforming
growth factor beta) and endothelin 1. A safety trial
with an antibody to TGFß was just completed. An
inhibitor of the receptor to which endothelin binds,
bosentan, is currently used to treat pulmonary hypertension
in scleroderma and is in trials for scleroderma lung
disease and digital ulcers.
Trials are planned or underway for phosphodiesterase
inhibitors (a class of agents which includes Viagra)
to treat blood vessel disease, antibody to CTGF (connective
tissue growth factor) which stimulates collagen production,
and drugs that suppress the immune system and might
block the process at an early stage.
Summary
While progress has been slow, never has the picture
been more promising for finding better treatments for
scleroderma.
Progress in basic research means we are learning more
about the processes involved and have better molecular
tools at our disposal to identify and test new therapies.
We have partners in biotechnology and the pharmaceutical
industry who are interested in developing treatments.
The result has been more active clinical trials in
scleroderma than ever before, and drugs that have actually
been approved by the FDA for treating the disease.
Scleroderma is a treatable disease and treatment will
get better. |
