"Scleroderma:
a treatable disease"
By Joseph Korn,
M.D. (1947–2005),
Cleve Clin J Med 2003;70:954-968. Copyright © 2003 The
Cleveland Clinic Foundation. All rights reserved.
Editor's note:
This is a long article. You can skip directly to the sections
that interest you, by clicking on these links:
ABSTRACT
Many effective treatments for scleroderma
have emerged in recent years, including bosentan, an endothelin
receptor antagonist, and epoprostenol, a prostacyclin, both
of which target vasoconstriction. Cyclophosphamide may soon
be proven effective against interstitial lung disease.
SCLERODERMA
has always been difficult to treat, and survival rates have
traditionally been low. But it can be effectively treated
in many cases now, thanks to a better understanding of its
pathogenesis and the development of new therapies.
This article reviews
our current understanding of scleroderma, strategies for preventing
and treating major complications, and avenues for future research.
MORE THAN SKIN DEEP
 |
| The author has
indicated that he has received grant or research
support from the Actelion, Biogen, and Genzyme corporations
and from the National Institutes of Health; serves
as a consultant for the Actelion and Genzyme corporations;
and is on the speaker’s bureau of the Actelion
corporation. This paper discusses therapies that
are experimental or are not approved by the US Food
and Drug Administration for the use under discussion.
Medical Grand Rounds articles are based on edited
transcripts from Division of Medicine Grand Rounds
presentations at The Cleveland Clinic. They are
approved by the author but are not peer-reviewed. |
|
Scleroderma means
“hard skin,” named for the disease’s prominent
feature: thickened, shiny skin. However, it is more properly
termed “systemic sclerosis,” because involvement
extends throughout the body. It is a complex disturbance of
connective tissue, the vasculature, and the immune system.1
Multiple genes probably
play a role in scleroderma’s development. Some genes
may redispose patients to the vascular problems, some to the
immune dysfunction, and some to the fibrotic aspects of the
disease. The mixture of genes determines a patient’s
overall susceptibility to scleroderma as well as the course
of the disease.
SURVIVAL RATES IMPROVED
Not long ago, patients
with scleroderma had a very poor prognosis: 30 years ago the
5-year survival rate was about 50% for the healthiest category
of patients (those without lung, heart, or kidney manifestations).
For patients who had either pulmonary or cardiac involvement,
only about one third survived 5 years, and almost everyone
who developed acute renal disease died within 6 months.
This bleak outlook
has changed markedly. We can now expect patients to have a
better quality of life than in the past, and for 80% to 90%
to survive 5 years and 70% to 80% to survive 10 years. Renal,
cardiac, and pulmonary involvement, however, remain the major
complications that limit survival.
In the past, kidney
disease was the leading cause of death, but early detection
and treatment have brought this largely under control. Pulmonary
disease is today’s major challenge: only 30% of patients
with a diffusing capacity of lung for carbon monoxide (DLCO)
of less than 60% survive 5 years.
| TABLE
1 |
 |
|
Subtypes of systemic sclerosis
Diffuse cutaneous systemic
sclerosis
Skin involvement in trunk, upper arms, and legs
Raynaud phenomenon
Gastrointestinal involvement
Renal involvement (about 30%)
Interstitial lung disease (30%–40%)
Pulmonary hypertension—may be primary arterial
hypertension (small percentage) or
secondary to interstitial lung disease
Myositis
Cardiac involvement
Scl 70 antibodies (30%–40%)—increased
risk of interstitial lung disease
RNA polymerases I, III—increased risk of
renal disease, probably cardiac disease
Limited cutaneous systemic
sclerosis
(Formerly termed CREST syndrome: calcinosis, Raynaud
phenomenon, esophageal dysmotility, sclerodactyly [eg,
the scleroderma is limited to the fingers and face],
telangiectasia)
Skin involvement of fingers, later hands, face,
and feet
Raynaud phenomenon
Gastrointestinal involvement
Primary pulmonary hypertension (25%–50%)
Interstitial lung disease (10%)
Anticentromere antibodies (50%–60%)—indicates
increased risk for pulmonary hypertension |
 |
TWO DISTINCT SUBTYPES
There are two distinct
subtypes of scleroderma based on the amount and distribution
of skin
involvement:
- Diffuse cutaneous systemic sclerosis, in which skin disease
covers the trunk and proximal
extremities, and
- Limited cutaneous systemic sclerosis, in which skin involvement
is primarily in the fingers in the early stages, then arises
in the face and feet.
The general skin pattern largely predicts visceral complications
(TABLE 1)
RAYNAUD PHENOMENON IS MOST COMMON
COMPLAINT
The Raynaud phenomenon
is the most common presenting problem of scleroderma, occurring
in about 90% of patients. However, it is not pathognomonic
of scleroderma, as it also occurs in 5% to 10% of the general
population. Because scleroderma is so uncommon (occurring
in only 200 to 300 people per million), most patients with
the Raynaud phenomenon do not have scleroderma.
The phenomenon involves
a triphasic response to cold or emotion. The fingers successively
turn white (pallor, as described by Maurice Raynaud), blue
(cyanosis), then red (hyperemia).
Hallmark blood
vessel changes
The Raynaud phenomenon starts as a functional abnormality,
but eventually structural changes in the blood vessels occur.
These changes are visible by angiography: the transition from
normal vessel to disrupted areas to vessel blockage can be
seen in a single artery. Such abnormalities occur in vessels
ranging in size from digital arteries to precapillary arterioles.
Blood vessel changes
are caused by the proliferation of intimal cells, endothelial
cells, and smooth muscle cells, which lay down a matrix of
connective tissue. There is also a characteristic perivascular
band of fibrosis. This results in obliteration of the vascular
lumen and decreased blood flow.
Vascular injury
to blame
Exactly why these structural changes occur is unclear, but
vascular injury is known to be involved. Scleroderma patients
have signs of endothelial cell injury in their circulation,
including elevated von Willebrand factor. Cold appears to
be a trigger both clinically and in vitro: refrigerating endothelial
cells causes release of factor VIII antigen and other molecules
characteristic of cell injury.
When endothelial
cells are injured, they release vasoconstrictors such as thromboxane
and endothelin, which counteract normal vasodilation. Endothelin
is also a profibrotic stimulus, as is transforming growth
factor beta (TGF beta). Not only do they cause vasoconstriction,
but they also damage blood vessels. Then a mixture of thrombotic
and inflammatory events, including action of TGF beta, oxidation
products, and platelet aggregation, leads to vascular occlusion.
The loss of normal
endothelial cells also results in reduced levels of the beneficial
trophic factors that they produce, including prostacyclin
and nitric oxide, which contribute to vasodilation and intimal
integrity.
Treat with warmth
and medications
The best treatment for Raynaud phenomenon when it is still
a functional problem is by having the patient stay warm to
avoid vasoconstriction. Not only the hands, but the entire
body should stay warm, because core temperature determines
peripheral vasoconstriction.
A variety of medications
are also effective, including calcium channel blockers, alpha-adrenergic
inhibitors, nitroglycerin, and angiotensin-converting enzyme
(ACE) inhibitors. If one medication doesn’t work, physicians
should try another: for unknown reasons, some patients respond
only to a single category of drugs or even only to an individual
medication within a category. The severity of the Raynaud
phenomenon, its impact on patient function, and the presence
of tissue injury such as infarct or ulcer determine when pharmacologic
approaches are used.
Digital ulcers
are not trivial
It is important to treat Raynaud phenomenon, both for patient
comfort and to prevent the resultant dryness and cracking
of the skin. Dry, cracked skin, combined with the inadequate
vascular supply characteristic of scleroderma, provides an
environment highly conducive to developing digital ulcers.
Digital ulcers form
around the nail and at the fingertips. Although they may seem
to be a relatively minor problem, digital ulcers are a major
source of disability: they cause severe pain, preventing many
activities of daily living. If a digital ulcer hasn’t
healed in 3 or 4 days, the patient should be treated with
antibiotics such as cephalexin, dicloxacillin, or ciprofloxacin.
Established ulcers may take months to heal, and patients may
require several-week courses of rotating antibiotics.
Treat severe ulcers
aggressively
Superinfections can develop and spread to the bone, sometimes
requiring amputation of the digit. For advanced infections,
intra-arterial vasodilators are indicated. Prostenoids are
most effective, such as the intravenous prostacyclin, epoprostenol
(Flolan). Some patients do well on sildenafil (Viagra), 75
mg every 6 hours, over 3 to 14 days, depending on response.
The new medication
bosentan (Tracleer) is an endothelin receptor antagonist that
targets the potent vasoconstricting effects of endothelin.
Although it is not the best treatment for existing ulcers,
in one preliminary study it appeared to prevent multiple ones
from occurring.
For patients who
get recurrent ulcers or infections despite treatment, a sympathetic
nerve block or digital or cervical sympathectomy may be indicated.
VASCULAR CHANGES OCCUR SYSTEMICALLY
Raynaud phenomenon
is the most obvious vascular manifestation of scleroderma,
but blood vessel disruption is also the underlying basis for
the myriad other problems of the disorder. The vascular pathology
seen by angiography in the digits is, in fact, widespread
throughout the body. Even organs that are not clinically involved,
like the pancreas, have evident vascular disease.
RENAL INVOLVEMENT COMES ON ABRUPTLY
Renal disease was
once the chief killer of scleroderma patients: it can come
on suddenly and lead to permanent kidney failure within days
after symptom onset. Its vascular origin is apparent by the
large infarcts visible by renal angiography. There is loss
of cortical vessels, reduced blood flow, and pruning of the
normal arterial tree.
Acute severe hypertension
is the presenting sign in 9 out of 10 patients during a scleroderma
renal crisis. The remaining 10% develop an identical renal
pathology, with functional loss but without clinical hypertension.
All patients develop proteinuria, and most have microangiopathic
hemolytic anemia due to trauma in the blood vessels.1,2
Home blood pressure
and urine checks save lives
Early detection and prevention of a renal crisis is key. All
patients with diffuse scleroderma should screen themselves
two or three times a week with a home blood pressure device.
They should also check their urine for protein using a dipstick
once a week; this ensures that the 10% of patients with renal
failure who never develop hypertension are also caught in
time.
Treat crises aggressively
with ACE inhibitors
Increasing blood pressure or proteinuria, even in the absence
of rising creatinine, should be a signal to start ACE inhibitor
therapy. Even mild but persistent increases in blood pressure,
eg, from 120/60 to 140/85 mm Hg, should be treated. Patients
who develop renal crises, severe blood pressure elevations
with or without rising creatinine, or proteinuria should be
aggressively treated in the hospital with increasing doses
of ACE inhibitors to rapidly bring the diastolic blood pressure
to under 80 mm Hg. Angiotensin II receptor antagonists are
also useful but may be less effective.
Sometimes the creatinine
level rises after patients are started on ACE inhibitors,
and the temptation is to change medications. However, very
rarely is the ACE inhibitor at fault in such cases. The creatinine
level may continue to rise for several days but should return
to normal.
Despite treatment,
some patients progress to needing dialysis, particularly if
treatment is delayed. Of those requiring dialysis, 30% to
40% eventually recover renal function if blood pressure is
controlled.
ACE inhibitors do
more than control blood pressure; they also affect endothelin
and many growth factors. Because of this, some researchers
have treated patients prophylactically with normal doses of
ACE inhibitors to try to avert a renal crisis. This approach
has not proven successful, however, and is not recommended.
LUNG INVOLVEMENT IS THE BIGGEST CHALLENGE
Pulmonary complications
are responsible for the greatest number of deaths from scleroderma
today. The two main problems are interstitial fibrosis and
pulmonary hypertension. Other problems sometimes develop secondary
to these conditions:
- Bronchiectasis—a result of pulling on the bronchi
by fibrosis
- Aspiration pneumonia
- Pleural disease with pleural effusion (associated with
a poor prognosis).
A
small percentage of patients also develop chest wall restriction
and decreased function, probably from fibrosis of the chest
wall.
Interstitial
fibrosis associated with diffuse-type scleroderma
Interstitial fibrosis is the leading cause of scleroderma-related
deaths. It develops in 30% to 40% of patients with the diffuse
type of scleroderma and tends to occur in the first 2 to 4
years after onset of scleroderma symptoms.
The extent of pulmonary
fibrosis determines a patient’s prognosis, and thus
detecting it early is important to prevent the disease from
progressing. Timely detection is not easy, however, because
early signs are often subtle. A typical patient with interstitial
fibrosis might be extremely short of breath, but have only
a few crackles at the bases detectable by lung examination
and a completely normal chest radiograph.
High-resolution computed
tomography (CT) is a better diagnostic tool; it shows “ground-glass”
changes, indicative of extensive alveolitis. Scans should
be performed with the patient prone; otherwise, it is difficult
to distinguish fibrosis from blood pooling. We also use bronchoalveolar
lavage to confirm inflammatory disease.
Interstitial fibrosis
starts as inflammatory alveolitis, with mononuclear cells
infiltrating the alveoli and destroying their structure. Lung
biopsy reveals both inflammation and areas of fibrosis.
Pulmonary function
tests are useful for screening asymptomatic patients.
Cyclophosphamide
may be future treatment
Studies are now underway with the National Institutes of Health
to determine the effectiveness of cyclophosphamide (Cytoxan,
Neosar) for interstitial lung disease. Early results are encouraging.
Not only does alveolitis largely clear up, but pulmonary function
improves, as does mental function. Cyclophosphamide probably
does not restore normal alveolar architecture, but by reducing
fibrosis, it allows better lung expansion in healthy tissue.
Skin manifestations of scleroderma also improve.
An earlier retrospective
study3 found that patients with interstitial fibrosis
who had received cyclophosphamide had a small increase in
their functional vital capacity and essentially no change
in their DLCO. Patients who had not received the drug had
an 8% to 10% decrease in both these measures.
We use cyclophosphamide
as a monthly intravenous infusion, 600 to 800 mg/m2. We also
give prednisone 30 mg/day, tapering over a few months.
Pulmonary hypertension
associated with limited scleroderma
Pulmonary hypertension is a serious complication that occurs
in 25% to 50% of people with the limited type of scleroderma.
Only 40% of those patients subsequently survive 2 years if
untreated. It usually occurs late in the disease, often 10
to 15 years after symptom onset. A rapidly fatal form occurs
in a small percentage of patients and tends to appear earlier.
Early detection and
treatment may improve survival rates, so it is worthwhile
to regularly screen asymptomatic patients with limited scleroderma
by echocardiography.
Pulmonary hypertension
typically comes on insidiously. It should be suspected in
patients with late scleroderma, such as those who have prominent
telangiectasia and the CREST syndrome (calcinosis, Raynaud
phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).
Patients with pulmonary hypertension may be short of breath
but have a normal lung examination. Other signs are:
- Increased second pulmonic heart sound (P2)
- A right ventricular heave
- Normal pulmonary function tests
- Markedly decreased DLCO, or DLCO that is disproportionately
decreased compared with vital capacity.
Characteristic
vascular origins
Pulmonary hypertension seems to have the same vascular origins
as sclerodermal kidney disease and finger ulcers. Angiography
reveals the same kind of intimal occlusion and proliferation
that are seen in peripheral vessels. The interior elastic
lamina stays preserved, so the problem is not vasculitis.
Some hypertrophy of smooth muscle occurs, and a perivascular
cup of connective tissue develops.
The role of genetic
factors is becoming clearer. A form of primary pulmonary hypertension
is due to a mutation in the bone morphogenic protein receptor
type 2. A recent finding also links other forms of pulmonary
hypertension with defects in the signaling pathway involving
angiopoietin-1, bone morphogenic protein receptor type 2,
and other factors.4
Treating pulmonary
hypertension
Calcium channel blockers are the first line of treatment for
patients without scleroderma who develop idiopathic pulmonary
hypertension. For patients with scleroderma, calcium channel
blockers may be helpful in early pulmonary hypertension but
do not seem to prevent disease progression.
Anticoagulation also
improves survival for patients without scleroderma. It is
also used for patients with scleroderma, although its effectiveness
for this group has not been confirmed.
Aerosolized prostacyclin
analogs, subcutaneous prostacyclin analogs, and treprostinil
(Remodulin) have become available this year to treat pulmonary
hypertension. Inhaled nitric oxide, another endothelium-derived
vasodilator, is used in some centers, although it has some
inconveniences.
Epoprostenol improves
survival and quality of life
Epoprostenol offers the most effective therapy for pulmonary
hypertension in scleroderma patients. The drawbacks are that
it is difficult to obtain, and with a half-life of only minutes,
it must be given continuously by central infusion.
My colleagues and
I treated 14 patients with epoprostenol, four of whom had
New York Heart Association class IV disease (symptomatic at
rest). Three of those four improved to a higher class, one
to the level of class II (symptomatic with ordinary activity).
The mean decrease in pulmonary vascular resistance was about
40%, and about two thirds of patients had a more than 25%
improvement. Cardiac output increased by about 40%; in some
patients it doubled. One patient would have died within months
without epoprostenol, and she is still alive 3 years later,
albeit in poor health.
A larger randomized
controlled study5 of 111 patients found that 38%
of patients treated with epoprostenol improved functionally
as measured by the New York Heart Association classification,
while almost all the control patients got worse. As an added
benefit, treated patients also had a reduction in Raynaud
syndrome, with fewer digital ulcers.
Other prostacyclins
show promise
A European trial6 studied inhaled iloprost (Ilomedin),
a synthetic prostacyclin. Patients improved functionally,
although not as dramatically as with epoprostenol. Pulmonary
vascular resistance improved 20% over baseline, which was
actually a 30% improvement over placebo because the patients
without medication worsened. Cardiac output improved by 15%.
Treprostinil, a subcutaneously
active prostacyclin, recently became available. It causes
functional and hemodynamic improvements comparable to epoprostenol,
but severe injection-associated local reactions limit its
use.
Endothelin: An
important vasoconstrictor
Endothelin is a 21-amino acid peptide and the most potent
vasoconstrictor known. It binds to receptors on endothelial
and smooth muscle cells, causing smooth muscle contraction.
Scleroderma patients have increased blood levels of endothelin,
as well as increased endothelin in pulmonary macrophages.
Endothelin also
apparently plays a role in fibrosis, stimulating fibroblast
proliferation in collagen synthesis. In addition, animals
that are transgenic for endothelin I and produce excess endothelin
develop pulmonary fibrosis.
Counteracting
vasoconstriction with bosentan
Endothelin receptor antagonists block lung antigen-induced
inflammation and have proven effective against pulmonary hypertension
in animal models. An important new medication in this class
is bosentan.
An early placebo-controlled
study7 looked at patients with pulmonary hypertension
treated with bosentan. Those on placebo had increased pulmonary
artery pressure, while patients on bosentan had unchanged
pulmonary artery pressure, as well as improved pulmonary vascular
resistance and an improved cardiac index. Patients treated
with bosentan improved dramatically in their performance on
the 6-minute walk test, while the placebo group deteriorated.
A more recent larger
study,8 known as BREATHE-1, examined the effect
of bosentan on function and hemodynamics in patients with
pulmonary hypertension from a variety of causes. Bosentan
was found to be effective for both scleroderma and idiopathic
pulmonary hypertension: patients stabilized on medication
and got worse with placebo. Patients on bosentan were able
to walk about 40 meters farther in 6 minutes than those on
placebo.
GASTROINTESTINAL PROBLEMS CAN BE EXTENSIVE
Gastrointestinal
manifestations of scleroderma cause few deaths but do contribute
to significant
morbidity. Again, the underlying problem is vascular. The
blood supply to the myenteric plexus is compromised first,
resulting in the loss of normal, rhythmic peristalsis. This
loss of normal motility leads to bacterial overgrowth, deconjugation
of bile acids, and malabsorption. Muscular atrophy and fibrosis
eventually set in. Patients develop a wide range of symptoms
(TABLE 2), and a small number die from anorexia and weight
loss.
Manage reflux
with proton-pump inhibitors
By high-resolution CT the “scleroderma esophagus”
looks large and dilated throughout its entire length. Ulcers
and strictures may develop from the continual reflux, but
this has become less common thanks to effective medications.
Nowadays we see changes characteristic of Barrett’s
esophagus but very rarely of esophageal cancer.
Key to managing reflux
disease is lifestyle modification: elevating the head of the
bed; eliminating triggers like tobacco, alcohol, peppermint,
and high-fat foods; and waiting several hours after eating
to lie down.
I also prescribe
proton-pump inhibitors, which are more effective than H2 blockers
in relieving symptoms and promoting healing. Some patients
need very high doses, such as omeprazole 160 mg or equivalent
doses of other proton-pump inhibitors. Although the long-term
use of proton pump inhibitors is expensive and sometimes difficult
to negotiate with health insurers, it is invaluable in helping
to prevent strictures.
Promotility agents
are useful early, then erythromycin
Promotility agents, such as metoclopramide (Reglan), can also
be helpful, especially early in the disease while neural innervation
is still intact. Cisapride (Propulsid) is also effective but
no longer generally available because of the risk of arrhythmias.
For patients who
no longer have a neural supply, erythromycin 250 mg three
times a day is useful because it directly stimulates smooth
muscle. It loses effectiveness late in the disease, however,
when the smooth muscle is completely replaced by fibrosis.
Treat chronic
diarrhea with antibiotics
Tetracycline is an inexpensive and effective treatment for
patients with diarrhea, weight loss, and bloating. Once treated,
patients who have suffered from diarrhea for many months often
quickly regain weight. Because the clinical picture is straightforward,
there is no need to test for bacterial overgrowth.
Treat gastric
ectasia with laser ablation
Another serious gastrointestinal complication is gastric ectasia,
the appearance of which is similar to the telangiectasia typically
seen on the lips of scleroderma patients. It gives the stomach
a watermelon appearance as seen by endoscopy.
Gastric ectasia
causes recurrent bleeding, leading some patients to require
infusion with several units of blood each week. Fortunately,
it can now be effectively treated with argon laser ablation,
and as a result, few people die of this complication anymore.
CARDIAC DISEASE IS DIFFICULT TO MANAGE
Myocardial fibrosis
with arrhythmias, sometimes referred to as “scleroderma
heart,” is caused by vascular occlusion, local ischemia,
and microinfarcts. Coronary arteries are spared; only the
microvasculature in the heart is affected. ACE inhibitors
may be effective, but no data are available to confirm this.
Treatment of established disease remains a difficult challenge.
SKIN TREATMENTS ON HORIZON
No good treatment
for scleroderma’s skin changes has yet been found, despite
trials with more than a dozen agents. Once fibrosis occurs,
with the resultant loss of architecture, it is irreversible.
Loss of hair follicles, sweat glands, and nerves accompanies
the changes. Hair may regrow, but the skin does not return
to normal.
More than a dozen
agents have been tried to treat sclerodermal skin disease:
Potaba, colchicine, D-penicillamine, methotrexate, 5-fluorouracil,
chlorambucil, interferons alpha and gamma, cyclophosphamide,
bone marrow ablation with stem cell reconstitution, antithymocyte
globulin, cyclofenil, photopheresis, and relaxin. Trials of
anti-TGF beta, oral collagen (as a toleragen), and interferon
beta are in progress. Trials of other promising biologic agents,
including those directed at adhesion molecules, immune cells,
and cytokines, are planned. New medications should be available
within a few years.
TARGETING FIBROSIS
Fibrosis is a complex
process that suggests many potential targets for therapy.
It occurs in the lungs, around joints, in the gastrointestinal
tract, and around blood vessels. It may be immune-driven,
involving immune cytokines, injury-repair mechanisms, hypoxia,
or a metabolic defect.
According to our
current understanding, scleroderma is a vascular disease early
on. At first it is functional, with vasoconstriction causing
decreased flow. Later on it becomes a structural problem,
with proliferation of endothelial cells, smooth muscle cells,
and cytokines, which turn on fibroblasts to make matrix proteins.
The fibroblasts somehow become autonomous, no longer depending
on immune cells as a trigger: fibroblasts removed from the
body continue to overproduce matrix proteins. The matrix proteins,
in turn, lead to cutaneous and visceral fibrosis.
This model offers
many targets for therapy. We can try to intervene at the level
of the immune cells or of the blood vessels. We can potentially
disrupt growth factors, intercellular signaling, gene transcription,
and collagen and matrix synthesis pathways.
Early attempts to
use interferon gamma to reduce collagen production were unsuccessful
in improving scleroderma. Although interferon gamma blocks
collagen synthesis, it unfortunately also turns on macrophage
function and promotes the immune arm of scleroderma.
Another tack was
to destroy the immune system by bone marrow ablation and stem
cell reconstitution in the hope that the patient would regenerate
a normal immune system. Some scleroderma patients improved
with this risky procedure, but the disease recurred within
a year in many patients.
OTHER RESEARCH DIRECTIONS
Some researchers
have targeted a specific cytokine—TGF beta—which
stimulates matrix genes and causes vascular damage. Mice treated
with TGF beta get kidney disease similar to that seen in scleroderma
patients. In addition, normal fibroblasts treated with TGF
beta resemble the abnormal fibroblasts seen in scleroderma.
In the future, TGF beta inhibitors may prove to be an effective
weapon against the disease.9
It may also be worthwhile
to examine gene expression profiles of patients with scleroderma
to find the genes that cause the disease for clues for future
interventions.
Other potential agents
that are either currently undergoing or about to undergo clinical
trials against scleroderma include another growth factor,
connective tissue growth factor; endothelin receptor antagonists;
signaling pathway inhibitors; PD5 inhibitors; better sildenafil-like
agents; thalidomide (Thalomid); and halofuginone, a collagen
type-1 inhibitor.
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A Textbook of Rheumatology. 14th ed. Philadelphia, Pa: Lippincott
Williams & Wilkins; 2001:1643–1654.
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Kidney. Oxford: Oxford University Press, 2001:275–292.
- White B, Morre WC, Wigley FM, Xiao HQ, Wise RA.
Cyclophosphamide is associated with pulmonary function and
survival benefit in patients with scleroderma and alveolitis.
Ann Intern Med 2000; 132:947–954.
- Du L, Sullivan MS, Chu D, et al. Signaling molecules
in nonfamilial pulmonary hypertension. N Engl J Med 2003;
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- Badesch DB, Tapson VF, McGoon MD, et al. Continuous
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- Olschewski H, Simonneau G, Galie N, et al for the Aerosolized
Iloprost Randomized Study Group. Inhaled iloprost for
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- Channick RN, Simonneau G, Sitbon O, et al. Effects
of the dual endothelin receptor antagonist bosentan in patients
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study. Lancet 2001; 358:1119–1123.
- Rubin LJ, Badesch DB, Barst RJ, et al for the Bosentan
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