Therapy/Treatment of Systemic Sclerosis
By Daniel Furst,
M.D. (originally published in "Scleroderma Voice,"
Winter 2000–2001)
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| Daniel
Furst, M.D. |
Evidence supporting
a genetic basis for systemic sclerosis (SSc) is found in family
data, where several cases of SSc are associated with a number
of other connective-tissue diseases. Examination of the genetics
of the TSK mouse reveals a mutation of chromosome 1, possibly
in the col 3 alpha-1 gene.
The
environment can also be a factor
A number of external
stimuli have been associated with systemic sclerosis. These
include such disparate environmental factors as
- organic solvent;
- L-tryptophan; and
- graft-versus-host disease.
Genes and environment
both contribute
Genetic and environmental factors
combine to stimulate the immune system. Evidence supporting
the activity of the immune system is relatively abundant.
Approximately 95% of SSc patients have positive ANA in their
sera, and soluble interleukin 2 receptor is increased in patients
with fatal SSc.
The
impact of immune-system stimulation
The immune mediators
released by the immune system stimulate scleroderma fibroblasts.
Not only does an
activated immune system stimulate fibroblast proliferation,
but it can damage the endothelium.
In fact, SSc serum
is cytotoxic to the endothelium. Anti-Endothelial Cytotoxic
antibodies in SSc correlate with digital ulcerations, interstitial
lung disease, and decreased renal (kidney) function.
When damaged, the
endothelium activates the immune system by releasing intracellular
adhesion molecules and endothelium lymphocyte adhesion molecules,
thus amplifying immune activation.
In turn, this results
in lymphocyte adherence, diapedesis, and increased immune
damage.
Interrupting
the pathogenetic cycle
All that remains
to close the pathogenetic circle is to show that collagen
can cause immunological activation.
It is reasonable
to approach the treatment of systemic sclerosis by trying
to interrupt the pathogenetic cycle. For example, treatment
might be aimed at
- addressing the vascular damage;
- preventing fibrosis; or
- suppressing the immune response.
Results
of recent clinical drug trials
Trial
of a prostacyclin-derivative
A 12-week randomized
trial of a prostacyclin derivative, infused into patients
with systemic sclerosis and pulmonary hypertension, showed
only small changes in pulmonary artery pressure and pulmonary
vascular resistance.
There was a decrease
in fatigue and dyspnea (shortness of breath, difficult or
labored breathing), and an increase in the distance patients
were able to walk in six minutes.
Two
iloprost trials
A double-blind trial
of intravenous iloprost infusions was positive, but a double-blind
trial using iloprost orally was negative.
To date, interrupting
this step in the pathogenetic cycle of systemic sclerosis
has been only minimally effective.
Interferon
gamma
A trial using interferon
gamma to treat interstitial pulmonary fibrosis in idiopathic
pulmonary fibrosis significantly improved pulmonary function
tests in the interferon gamma-treated patients compared to
the controls used in the study.
Relaxin
[We have omitted
Dr. Furst's discussion of the preliminary investigations of
Relaxin, in view of the fact that Connetics Corporation discontinued
its Phase III Relaxin Trials on Oct. 8, 2000 due to disappointing
results. —Editor]
D-penicillamine
A study of low-dose
D-penicillamine (62.5 mg daily) to high-dose D-penicillamine
(750 mg daily) examined patients with early diffuse systemic
sclerosis.
No changes were found
in skin score, mortality, or the incidence of renal crisis
in the trial.
It is highly unlikely
that D-penicillamine is effective in systemic sclerosis, either
to decrease fibrosis or as an immunosuppressive agent.
There is slowly accumulating
evidence that fibrosis can be reversed, or at least stabilized
in systemic sclerosis, though more data and evidence still
need to be accrued.
Chlorambucil
A trial examining
chlorambucil versus placebo in systemic sclerosis patients
was one of the first well-controlled trials to test the importance
of the immune system in SSc.
This negative trial
was flawed by the use of patients with both diffuse and limited
disease and the entry of patients with relatively late systemic
sclerosis (7.9 years).
Cyclosporin
A
Cyclosporin A is
a medication which is relatively selective for T-cell suppression.
A small open trial
showed improvement in skin score, but was associated with
nearly universal decreased renal (kidney) function.
While a double-blind
trial of Cyclosporin A is still awaited its toxicity is unlikely
to make Cyclosporin a very useful treatment.
Methotrexate
A double-blind, randomized
placebo-controlled crossover trial of methotrexate in systemic
sclerosis used a logical, but complex definition of improvement.
This trial showed
improvement in 63% of methotrexate-treated patients versus
17% of placebo-treated patients.
Cyclophosphamide
Cyclophosphamide
is an effective, alkylating immunosuppressive which has been
used to decrease both B-cell and T-cell function.
A trial showed that
in patients with alveolitis by bronchoalveolar lavage, cyclophosphamide
seemed to improve or stabilize pulmonary function.
Among patients with
BAL-proven alveolitis, cyclophosphamide resulted in improvement
or stabilization of disease in 15 of 17 patients.
In contrast, out
of 11 patients without alveolitis, seven patients stabilized
and four worsened (none improved).
Summary
of results of recent clinical drug trials
These trials, in
general, seem to encourage the use of immunosuppressive agents
to treat systemic sclerosis, but none of them is definitive.
In most cases, some improvement was noted in some patients
but cure never occurred.
Stem
cell transplantation: risks and rewards
A more definitive
test of the usefulness of immunosuppression for systemic sclerosis
would be a trial of stem cell transplantation (SCT).
If stem cell transplantation,
which nearly totally abbrogates the immune system, did not
successfully treat selected patients with systemic sclerosis,
it would be hard to recommend immunosuppressive therapy for
the disease.
SCT is a very dangerous
procedure. Only patients with the most progressive systemic
sclerosis (whose prognosis is predictably poor) would be appropriate
for such a procedure.
Selection
criteria for SCT
Criteria include
the presence of pre-defined amounts of skin involvement, disease
duration (3 years), pre-defined internal organ involvement,
and the lack of a number of well-defined exclusion criteria
which would make SCT so dangerous that patients might not
survive.
Forty-one procedures
have been done in SSc patients worldwide. A limited number
of mobilization regimens, conditioning regimens, and purging
regimens were used.
Results
of SCT to date
Results have been
encouraging, but there has been near a 25% mortality rate.
Deaths among SCT-treated patients included three who died
during mobilization, two who died secondary to disease progression,
and two who died secondary to regimen-related toxicity.
Of eight patients
in a Seattle cohort with at least one-year follow-up, six
showed marked improvement, with 30% improvement in the skin
score and four out of five who returned, or were preparing
to return, to work. Two patients died from what was believed
to be regimen-related toxicity, but the treatment regimen
has since been altered and the next 10 patients have not,
thus far, developed the previous regimen-related toxicity.
Conclusions
The treatment of
SSc remains difficult, although there is an increasing number
of potentially effective regimens.
There is limited
evidence supporting the use of prostacyclin derivatives to
treat systemic sclerosis, some evidence that antifibrotic
regimens may be effective, and moderate evidence that immunosuppression
may be effective, at least in certain stages of this disease.
While we can be hopeful,
only well-controlled, multi-center studies can eventually
result in effective therapy for SSc. We strongly encourage
this approach.
Daniel Furst,
M.D., is the editor, with Philip Clements, M.D., of the authoritative
medical text. Systemic Sclerosis (published by Williams &
Wilkins).
We thank Dr. Furst
and the Scleroderma Association of British Columbia, a sister
organization of the Scleroderma Foundation, for allowing us
to print this version of a speech given by Dr. Furst.
Note: In one or
two instances. Dr. Furst's discussion differs slightly from
Dr. Feghali's article in this issue. The explanation is that
Dr. Furst's speech was given five months before the American
College of Rheumatology meeting in November, on which Dr.
Feghali 's article is based.
For example, Dr.
Furst cites a nearly 25% mortality rate for the stem cell
transplantation procedure, but notes, "The treatment
regimen has since been altered and the next 10 patients have
not, thus far, developed the previous regimen-related toxicity.
" Indeed, in Dr. Feghali's report composed after the
November ACR meeting, she notes an overall 20% mortality rate
for the stem cell transplantation procedure, which represents
a significant improvement. —Editor. |
