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Treatment of Scleroderma
Allen N. Sapadin, MD;
Raul Fleischmajer, MD
Arch Dermatol. 2002;138:99-105.
ABSTRACT
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The treatment of systemic sclerosis (scleroderma) is difficult and remains
a great challenge to the clinician. Because the cause is unknown, therapies
are directed to improve peripheral blood circulation with vasodilators and
antiplatelet aggregation drugs, to prevent the synthesis and release of harmful
cytokines with immunosuppressant drugs, and to inhibit or reduce fibrosis
with agents that reduce collagen synthesis or enhance collagenase production.
The purpose of this review is to critically analyze conventional and new treatments
of systemic sclerosis and localized scleroderma. The therapeutic options discussed
for the treatment of systemic sclerosis include the use of (1) vasodilators
(calcium channel blockers [nifedipine], angiotensin-converting enzyme inhibitors
[captopril, losartan potassium], and prostaglandins [iloprost, epoprostenol]),
(2) immunosuppressant drugs (methotrexate, cyclosporine, cyclophosphamide,
and extracorporeal photopheresis), and (3) antifibrotic agents (D-penicillamine,
colchicine, interferon gamma, and relaxin). The treatment options reviewed
for localized scleroderma include the use of corticosteroids, vitamin D analogues
(calcitriol, calcipotriene), UV-A, and methotrexate. Preliminary reports on
new therapies for systemic sclerosis are also considered. These include the
use of minocycline, psoralen–UV-A, lung transplantation, autologous
stem cell transplantation, etanercept, and thalidomide.
INTRODUCTION
Scleroderma or systemic sclerosis (SSc) is a connective tissue disease
that affects various organ systems, including skin, gastrointestinal tract,
lungs, kidney, and heart. The severity of skin and internal organ involvement
may correlate with the clinical course of the disease. Based on the degree
of skin involvement, SSc can be divided into limited cutaneous SSc or diffuse
cutaneous SSc. Limited cutaneous SSc is characterized by sclerodactyly or
acrosclerosis, with distal involvement of the extremities (distal to the elbows
and knees) with or without face involvement. This clinical picture comprises
Raynaud phenomenon, dysphagia, calcinosis cutis, and telangiectasis; it is
slowly progressive and is frequently associated with anticentromere antibodies.
The most severe complications are pulmonary hypertension and biliary cirrhosis.
Diffuse cutaneous SSc is more severe and shows proximal involvement of the
extremities (proximal to the elbows and knees), trunk, or both.1
Diffuse cutaneous SSc is often associated with pulmonary interstitial fibrosis,
renal crises, and gastrointestinal involvement (dysphagia, hypomotility, and
other disorders). Diffuse cutaneous SSc is frequently associated with Scl-70
(antitopoisomerase) and nucleolar autoantibodies (polymerase I and III, fibrillarin).
The cause of SSc is unknown and is regarded as an autoimmune disease
involving cellular and humoral immunity. Cellular infiltrates, perivascular
or diffuse, have been demonstrated in skin, lungs (alveolitis), smooth muscle
cells, esophagus, ileum and jejunum, synovium, and liver.2
These cells consist of T lymphocytes (CD4+, CD8+), B
lymphocytes, and other nonspecific inflammatory cells, such as macrophages,
mast cells, and eosinophils. Adhesion molecules are involved in homing and
retention of lymphocytes and other inflammatory cells in the tissues and may
play a role in the formation of cellular infiltrates in SSc.1-6
Vascular involvement in SSc affects mainly capillaries, arterioles. and small
arteries. The vascular pathology consists of absence or reduction in capillaries
and ectasia of capillaries (telangiectases), often accompanied by an increase
in endothelial cell proliferation.7 Soluble
mediators, adhesion molecules, and cytotoxic factors have been incriminated
in the mechanism of endothelial cell damage, including plasma factor VIII
(von Willebrand factor), transforming growth factor  , platelet-derived
growth factor, granzyme A, vascular cell adhesion molecule-1, intercellular
adhesion molecule-1, and endothelin-1.8
The mechanism of fibrosis in SSc is not fully understood, although it
is known that soluble mediators (transforming growth factor , platelet-derived
growth factor, interleukin [IL] 4, IL-6, tumor necrosis factor [TNF]  )
can affect the behavior of fibroblast growth, proliferation, collagen synthesis,
and chemotaxis.9-11
The role of humoral immunity in SSc is unknown, although about 90% of patients
with SSc show circulating antinuclear antibodies.12
The treatment of SSc is difficult and remains a challenge to the clinician.
The purpose of this review is to critically analyze conventional and new treatments
of SSc and localized scleroderma and briefly review new therapeutic approaches
under current investigation.
TREATMENT OF SYSTEMIC SCLEROSIS
Skin Involvement
Vasodilators
Vasodilators are used in SSc to reduce vasospasm (Raynaud phenomenon)
and to improve peripheral circulation (ischemia, gangrene) secondary to arterial
blood vessel damage (Table 1).
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Table 1. Treatment of Systemic Sclerosis
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Calcium channel blockers inhibit smooth muscle cell contraction by reducing
the uptake of calcium, which is needed for muscle contraction. There are 2
groups of calcium channel blockers: (1) the pyridine dicarboxylic acids (nifedipine,
nicardipine hydrochloride) and (2) the dimethoxyphenyls (verapamil hydrochloride,
diltiazem). Nifedipine, in dosages ranging from 30 to 60 mg daily, reduces
the severity of Raynaud phenomenon.13 More
recently, it was shown that nifedipine was superior to biofeedback techniques
in reducing the frequency of Raynaud phenomenon episodes.14
Nifedipine is well tolerated, and the most common adverse effects are headaches,
flushing, and edema of the feet and ankles. Nifedipine therapy can also be
combined with antiplatelet aggregation drugs (low-dose aspirin) and dipyridamole
(up to 400 mg daily, in slow increments).8
Pentoxifylline (400 mg, 3 times daily), alone or in combination with nifedipine,
reduces blood viscosity by increasing red blood cell deformability and can
be used to improve capillary function.
More recently, losartan potassium, an antagonist of angiotensin II receptor
type I, was found effective in the treatment of Raynaud phenomenon.15 In this study, a regimen of losartan potassium, 50
mg daily, was compared with nifedipine, 40 mg daily. After 2 weeks, both drugs
reduced the severity of Raynaud phenomenon, but only losartan reduced the
frequency of episodes. Losartan was well tolerated, and the most common adverse
effects were dry cough, muscle cramps, back pain, dizziness, and insomnia.
Prostaglandins are potent vasodilators. Iloprost is a chemically stable
prostacyclin antagonist that was found effective in the treatment of Raynaud
phenomenon secondary to SSc. Iloprost induces prolonged vasodilation, reduces
platelet aggregation, and promotes endothelial cell lining. The drug was administered
by continuous intravenous infusion (2 ng/kg per minute) for 8 hours daily
for 3 days.16 More recently, an oral preparation
of iloprost was used for the treatment of Raynaud phenomenon.17
A study comparing iloprost, 50 to 150 µg daily, vs placebo noted a decrease
in duration and severity of Raynaud phenomenon episodes, although the difference
was not statistically significant. Another study18
involving 103 patients showed significant improvement in duration and severity
of attacks but not in frequency, compared with the placebo. However, a third
multicenter study19 involving 308 patients
showed that oral iloprost, 50 µg twice daily, was no better than the
placebo.
Immunosuppressant Drugs
Because there is evidence for activation of cellular and humoral immunity
in SSc, several immunosuppressant drugs have been previously used, with questionable
benefits, including purine antimetabolites (6-thioguanine, azathioprine) and
alkylating agents (chlorambucil, cyclophosphamide).20
More recently, investigations have been carried out with methotrexate, cyclosporine,
cyclophosphamide, and extracorporeal photopheresis.
A controlled, parallel randomized, double-blind trial with chlorambucil
vs placebo was carried out involving 64 patients with SSc. After a 3-year
follow-up, chlorambucil had obtained no better results than the placebo.21
Methotrexate was used in a randomized, double-blind trial involving
29 patients with SSc. Patients received weekly injections of 15 mg of methotrexate
or placebo, and the dosage was increased to 25 mg per week for poor responders.
After a 24-week follow-up, significant improvement was noted in skin induration
and handgrip strength.22 Additional trials
involving larger numbers of patients are necessary to confirm these results.
Before initiating methotrexate therapy, a thorough evaluation of the patient
should be completed. Baseline laboratory tests should include complete blood
cell count, platelet count, liver function tests, serum urea nitrogen, creatinine,
and creatinine clearance.
Cyclosporine is an immunosuppressive drug that selectively inhibits
the release of IL-2 from activated T lymphocytes. There is evidence that serum
levels of IL-2, its soluble receptors, or both are frequently elevated in
early SSc.23-24 An open clinical
trial with cyclosporine was conducted in 10 patients with SSc.25
The starting dosage was 1 mg/kg per day, which was increased progressively
until toxicity appeared or when 5 mg/kg per day was reached. After 48 weeks'
follow-up, there was a decrease in skin induration but no improvement in pulmonary
or cardiac involvement. Nephrotoxicity was frequent but usually transient
and appeared mainly in patients receiving more than 3 to 4 mg/kg per day.25
Because renal involvement in SSc is not uncommon, cyclosporine in the
treatment of SSc should be used with great caution. Patients must be carefully
monitored for the development of nephrotoxicity, hypertension, and malignant
neoplasm, particularly lymphoma. Many drug interactions occur, and the patient
should be questioned about concomitant medications.
Extracorporeal photopheresis has been used to treat SSc. The principle
of this technique is to administer oral 6-methoxypsoralen, followed by extracorporeal
activation of lymphocytes by UV-A. The blood carrying covalently cross-linked
DNA-psoralen lymphocytes is then transferred into the patient to elicit a
specific immune response that may block proliferation of certain T-lymphocyte
clones. An initial multicenter trial was encouraging and showed significant
improvement in skin induration but no effect on pulmonary function.26 However, additional trials questioned the efficacy
of extracorporeal photopheresis.27 Furthermore,
extracorporeal photopheresis for SSc is not approved by the Food and Drug
Administration.
Another approach for immunosuppression in SSc was the use of antithymocyte
globulin (3-5 mg/kg for 5 days). After 6 months' follow-up, no improvement
in skin score or pulmonary function was noted compared with a placebo group.28
Corticosteroids are not useful in improving or preventing the progression
of skin involvement in SSc. However, they may be helpful in controlling pain
caused by arthralgia or myalgia. Similar benefits can be achieved with nonsteroidal
antiinflammatory agents.
Antifibrotic Agents
Fibrosis consists of massive deposition of newly synthesized connective
tissue, mostly collagens, which is frequently responsible for the development
of organ insufficiency. Fibrosis is a prominent feature in SSc and can develop
in other disorders, such as atherosclerosis, cirrhosis of the liver, and idiopathic
or secondary pulmonary fibrosis. Pharmacodynamics of antifibrotic agents are
geared (1) to reduce synthesis, excretion, or polymerization of collagen fibrils,
(2) to enhance collagenase activity, and (3) to neutralize cytokines capable
of stimulating collagen synthesis, such as transforming growth factor ,
IL-4, and IL-6.
D-Penicillamine is a copper chelating agent that also blocks aldehyde
groups involved in intermolecular and intramolecular cross-linkages of collagen.
Early clinical trials showed that D-penicillamine was beneficial in the treatment
of SSc, resulting in skin softening, slower progression of internal involvement,
fewer renal crises, and increased survival time.29
The usual dosage was 250 mg, 3 times daily. Several adverse effects may occur,
including bone marrow depression, nephrotic syndrome, gastrointestinal distress,
and skin reactions, such as pemphigus vulgaris. A recent multicenter, double-blind,
randomized clinical trial was conducted in 134 patients with diffuse SSc of
early (<18 months) duration. One group of patients received 750 to 1000
mg of D-penicillamine daily, while the other group was treated with 125 mg
every other day. After 24 months' follow-up, there were no statistical differences
between the groups in skin score (induration), incidence of renal crises,
or survival time.30 Furthermore, 80% of adverse
effects occurred in the high-dosage group. This study raises serious questions
about the therapeutic efficacy of D-penicillamine in SSc. However, if patients
are treated with D-penicillamine, there is no advantage in using more than
125 mg every other day.
Colchicine has been suggested for the treatment of SSc, based on the
rationale that it interferes with collagen synthesis by depolymerizing microtubules,
reduces fibroblast proliferation, enhances collagenase activity, and has some
antiinflammatory properties.31 An early uncontrolled
study32 involved 19 patients with a follow-up
of 19 to 57 months. This study noted improvement in skin elasticity, mouth
opening, and finger motility, and a reduction in dysphagia. The mean dosage
is 0.6 mg twice daily. The drug is well tolerated, and the main adverse effect
is diarrhea. Blood cell counts and liver function tests should be performed
periodically for patients receiving long-term therapy. It is unfortunate that
double-blind placebo-controlled clinical trials are not available.
Interferon gamma has been shown in vitro to reduce collagen production
and interfere with fibroblast proliferation. Interferon alfa also inhibits
collagen production but to a lesser degree than interferon gamma.11 Early investigations in the treatment of SSc with
interferon gamma or interferon alfa showed a modest improvement in skin score.11 Recent multicenter clinical trials were carried out
with recombinant interferon gamma (50 µg subcutaneously, 3 times weekly
for 1 year)33 or with recombinant interferon
gamma (0.01 mg/m2 per day for 18 weeks).34
Both studies showed a modest improvement in skin score. Adverse effects were
common, mostly consisting of a flulike syndrome. Another multicenter, randomized
controlled clinical trial with interferon gamma concluded that this drug has
mild beneficial effects in skin sclerosis and disease-associated symptoms.35 A 1-year double-blind placebo-controlled trial with
interferon alfa showed no benefit in the treatment of scleroderma, and in
some patients it was deleterious.36
Relaxin is a pregnancy polypeptide, cytokine growth factor that in vitro
decreases the synthesis and secretion of interstitial collagens, blocks transforming
growth factor overexpression of type I and II procollagens, increases
overexpression of matrix metalloproteinases, and reduces the production of
tissue inhibitor of metalloproteinases.37 Early
investigations using porcine-derived relaxin in the treatment of SSc were
inconclusive. However, recently, a multicenter, randomized, double-blind clinical
trial was carried out with human recombinant relaxin. Sixty-eight patients
with moderate to severe diffuse SSc of less than 5 years' duration received
25 or 100 µg/kg per day or a placebo, both administered by continuous
subcutaneous infusion for 24 weeks. Patients receiving relaxin showed improvement
in skin induration, oral aperture, hand extension motion, and pulmonary forced
vital capacity. Adverse effects consisted of menometrorrhagia, reversible
anemia, and irritation and focal infections at the site of the subcutaneous
drug delivery.38 However, additional follow-up
observation did not corroborate the efficacy of relaxin, and the study was
discontinued.
Kidney Involvement
Angiotensin-converting enzyme (ACE) inhibitors, including captopril
and enalapril maleate, have been shown to be effective in controlling high
blood pressure in SSc secondary to renal crisis. Furthermore, early treatment
may prevent the onset of renal failure.39 In
addition, oral captopril in dosages of 12.5 to 50 mg daily may reduce pulmonary
vascular resistance during pulmonary hypertension.40
A retrospective study41 on renal transplantation
in SSc gave encouraging results. The data were obtained from the United Network
for Organ Sharing Scientific Renal Transplant Registry. Eighty-six patients
with SSc from 1987 to 1997 received renal transplants. After a 5-year follow-up,
47% of the patients were alive, and the 5-year graft survival was similar
to that seen with renal transplantation in patients with systemic lupus erythematosus.
This study suggests that patients with severe renal insufficiency who do not
improve after receiving angiotensin-converting enzyme inhibitors or kidney
dialysis should be considered as candidates for renal transplantation.
Lung Involvement
Epoprostenol is an arachidonic acid, naturally occurring prostaglandin
with vasodilator activity and inhibitory effect on platelet aggregation. Epoprostenol
was used by continuous intravenous infusion in 111 patients with moderate
to severe pulmonary hypertension secondary to SSc. After 2 weeks of treatment,
there was improved exercise capacity and cardiopulmonary hemodynamics. There
was also improvement in the severity of Raynaud phenomenon and healing of
digital ulcers. Adverse effects included jaw pain, nausea, and anorexia. Local
complications consisted of sepsis, cellulitis, hemorrhages, and pneumothorax
(4% incidence for each condition).42 Intravenous
iloprost was also effective in the treatment of pulmonary hypertension.43
Cyclophosphamide alone or in combination with low-dose prednisone was
found effective in the treatment of severe interstitial lung disease in SSc.44-45 More recently, cyclophosphamide was
used in a retrospective cohort study46 involving
103 patients with SSc associated with lung inflammation (alveolitis) proved
by bronchoalveolar lavage or by lung biopsy. The dosage consisted of 1 to
1.5 mg/kg per day orally to up to 2 mg/kg per day. In addition, they received
intravenous cyclophosphamide, 800 to 1400 mg monthly, for 6 to 9 months. The
patients treated with cyclophosphamide showed stabilization of forced vital
capacity and carbon monoxide diffusing capacity. Improvement in survival was
also demonstrated. Myelosuppression, bladder toxicity (hemorrhagic cystitis,
bladder carcinoma), and carcinogenicity are complications of cyclophosphamide
therapy. Baseline monitoring includes complete blood cell count with differential
and platelets, serum chemistry profile, and urinalysis.
NEW THERAPIES—PRELIMINARY REPORTS
Minocyline
Eleven patients with early SSc were treated with minocycline (100 mg
daily for 4 weeks; 200 mg daily for 11 months). Complete resolution of skin
involvement was noted in 4 patients following 9 and 12 months of therapy.
The mechanism of action of minocycline in SSc remains unknown.47
This is an unexpected result and should be pursued further with controlled
trials.
Psoralen–UV-A
A small uncontrolled study48 treated
4 patients with SSc with psoralen–UV-A (total dosage, 3.5-9.6 J/cm2). All patients showed significant improvement in skin induration,
hand closure, and flexion range of fingers and knee joints. Because UV-A was
also shown to improve localized scleroderma (see the "Psoralen–UV-A
and UV-A" subsection of the "Treatment of Localized Scleroderma" section),
further controlled clinical trials are warranted.
Lung Transplantation
In a recent study,49 6 patients with
limited cutaneous SSc and 1 with diffuse SSc underwent lung transplantation.
Five patients were alive after a follow-up of 2 to 15 months. These results
compare favorably with the overall survival reported for lung transplantation.
Furthermore, 3 patients maintained satisfactory forced vital capacity (53%-71%).
This study suggests that lung transplantation is a feasible procedure and
may prolong survival of patients with both SSc and severe lung involvement.
Oral Etretinate
Thirty-two patients with chronic graft-vs-host disease who did not respond
to previous therapies were treated with oral etretinate in an open clinical
trial. Among 27 patients who completed 3 months of therapy, 24 showed improvement
in skin induration, flattening of cutaneous lesions, increased range of motion,
and improvement in performance status.50 Because
sclerodermalike lesions in chronic graft-versus-host disease closely resemble
SSc, a controlled clinical trial investigating the use of etretinate in the
treatment of SSc may be desirable.
Autologous Stem Cell Transplantation
Autologous stem cell transplantation has been suggested for the treatment
of autoimmune disease. Such a procedure was carried out in a 10-year-old patient
with SSc of 6 years' duration who did not respond to various forms of therapy.
This patient was conditioned with CD34+ selection, cyclophosphamide,
and infusion of a CAMPATH-1G monoclonal antibody. After 2 years' follow-up,
there was a 50% improvement in skin score, disappearance of exertional dyspnea
and alveolitis, and improvement in growth rate.51
Another study52 included 8 patients with severe
SSc treated with high-dose immunosuppressive therapy and radiation, followed
by autologous stem cell transplantation. After a 1-year follow-up, 5 patients
were alive and showed improvement in skin score and in results on a modified
Health Assessment Questionnaire, while pulmonary function remained stable.
Two patients died from interstitial pneumonitis, probably related to radiation
toxicity.
Etanercept
Tumor necrosis factor is a proinflammatory cytokine produced
by activated T cells and macrophages. Tumor necrosis factor stimulates
the synthesis of other proinflammatory cytokines (IL-1, IL-8, IL-6, and granulocyte-macrophage
colony-stimulating factor), promotes fibroblast proliferation, and enhances
matrix metalloproteinase activity. Specific blocking agents against TNF-
have been developed, including monoclonal antibodies (infliximab)53 and a fusion protein of soluble TNF receptor linked
to human immunoglobulin (etanercept).54 Etanercept
has been shown to be effective in various forms of arthritis. In a preliminary
pilot study,55 10 patients with diffuse SSc
were treated with etanercept, 25 mg subcutaneously, twice weekly. After 6
months of therapy, there was improvement in skin score (4 patients) and healing
in digital ulcers, while pulmonary function remained stable. The patients'
sense of well-being improved, and tolerance was good.
Thalidomide
Because thalidomide may be effective in treating chronic graft-versus-host
disease, it was also used in an open trial involving 10 patients with SSc.
There was improvement in skin repigmentation, healing of digital ulcers, regrowth
of hair, and a decrease in gastrointestinal reflux.56
Histopathological examination of skin suggested a reduction in fibrosis. Immunologic
studies revealed up-regulation of CD4+ ligand in T cells and increased
expression of IL-2 and IL-8.
TREATMENT OF LOCALIZED SCLERODERMA
Localized scleroderma is a connective tissue disorder that affects the
skin and subcutaneous tissue. The disease occurs in children and adults and,
clinically, can be divided into morphea, localized or diffuse, deep morphea,
and a linear form that usually affects arms and legs. Histopathological examination
reveals an early inflammatory stage consisting mostly of mononuclear cell
infiltrates and a late stage of severe fibrosis.57
Although the cause of localized scleroderma remains unknown, an autoimmune
mechanism is suspected because of its frequent association with antinuclear
antibodies, rheumatoid factor, anti–single-stranded DNA, and antihistone
antibodies.58 Although spontaneous resolution
is possible, the disease may cause severe functional (muscle atrophy) and
cosmetic (severe scarring) disability, particularly in children during the
growing stage. The treatment is difficult, although new therapeutic approaches
appear encouraging (Table 2).
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Table 2. Treatment of Localized Scleroderma
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Topical Corticosteroids
Topical corticosteroids (fluorinated, medium potency, and hydrocortisone)
may be of some help during the early inflammatory stage, although controlled
clinical trials are not available. Intralesional triamcinolone, 5 mg/mL, once
a month for 3 months, may improve or stop the progression of morphea and linear
scleroderma affecting the scalp and forehead (coup de sabre).
Calcitriol and Calcipotriene
Calcitriol (1,25-dihydroxyvitamin D3) and calcipotriene
are analogues of vitamin D and have been used for the treatment of psoriasis.
Both compounds have a similar receptor binding and affinity, although calcipotriene
is less potent and has minimal effects on calcium metabolism. Besides affecting
keratinocyte differentiation and proliferation, calcitriol also inhibits fibroblast
proliferation, collagen synthesis, and, possibly, T-lymphocyte activation.59 Oral calcitriol, in dosages of 0.50 to 0.75 µg
daily, improved joint mobility and skin extensibility in adult patients with
generalized morphea, following 3 to 7 months of therapy.60
In a more recent study,59 7 children with linear
scleroderma were treated with this agent, and 5 showed an excellent response.
Because oral calcitriol may have a dose-dependent effect on calcium metabolism,
monitoring of serum and urine calcium, inorganic phosphate, creatinine, and
urea is advised, particularly when treating children.59
Topical calcipotriene ointment (0.005%) was used in 12 patients aged
12 to 38 years with biopsy-documented active morphea or linear scleroderma.
After 3 months of therapy, all patients showed improvement, including decreases
in erythema, telangiectases, and depigmentation.61
The ointment was well tolerated, and there were no adverse effects. Furthermore,
there were no alterations in calcium metabolism as measured by serum levels
of ionized calcium, parathyroid hormone, 1,25-dihydroxyvitamin D3, and urinary calcium excretion. These results are encouraging but
will have to be confirmed by a controlled clinical trial.
Psoralen–UV-A and UV-A
Psoralen–UV-A bath phototherapy has been shown to be effective
in the treatment of widespread morphea and linear scleroderma.62
In this study, 17 patients were evaluated clinically and by ultrasound before
and after treatment. The patients were immersed for 20 minutes in a warm water
bath containing 1 mg/L of methoxsalen, followed by UV-A exposures, 0.2 to
0.5 J/cm2, increased every third day to a maximum tolerable dosage
of 1.2 to 3.5 J/cm2. After about 15 treatments, clearance or marked
improvement was noted in 13 of 17 patients. More recently, it has been reported
that marked improvement was achieved in 18 (75%) of 24 patients by using low-dose
UV-A alone in the range of 340 to 400 nm, 20 J/cm2,
to a cumulative dosage of 600 J/cm2.63 Two patients in this series with subcutaneous localized
scleroderma failed to respond to UV-A therapy. Histopathological findings
corroborated the clinical results. Although the mechanism of UV-A in localized
scleroderma is unknown, it is noteworthy the UV-A may activate interstitial
collagenases.64
Methotrexate
It is known that methotrexate is an effective drug for the treatment
of rheumatoid arthritis and juvenile rheumatoid arthritis.65
Adult widespread morphea has been treated with oral methotrexate, 15 mg/wk,
and the dosage was increased to 25 mg/wk in resistant cases. After 24 weeks
of therapy, 6 of 9 patients showed significant improvement in skin induration.
There were no serious adverse reactions.66
Ten patients with active localized scleroderma (mean age, 6.8 years) of 4
years' mean duration were treated with methotrexate (0.3-0.6 mg/kg per week)
combined with pulse intravenous methylprednisolone (30 mg/kg for 3 days monthly).
Following 3 months of treatment, 9 patients showed significant benefit, and
there were no serious adverse effects.67 Although
these data appear interesting, the use of methotrexate alone or in combination
with corticosteroids will have to be restricted to children with severe active,
disabling disease.
CONCLUSIONS
Although research continues to contribute to our understanding of the
pathogenesis of SSc, its cause is still unknown. Present therapies are directed
(1) to improve peripheral blood circulation with vasodilators and antiplatelet
aggregation drugs, (2) to prevent the synthesis and release of harmful cytokines
with immunosuppressants, and (3) to inhibit or reduce fibrosis with agents
that interfere with collagen synthesis or enhance collagenase production.
Although some progress has been achieved, the treatment of scleroderma remains
a challenge to the clinician. Further elucidation of the events that precipitate
the initial activation of the immune system in this disease is crucial for
the emergence of new therapeutic approaches.
AUTHOR INFORMATION
Accepted for publication May 2, 2001.
Corresponding author: Raul Fleischmajer, MD, Department of Dermatology,
Mount Sinai School of Medicine, 1425 Madison Ave, PO Box 1047, New York, NY
10029 (e-mail: rrfleischmajer{at}worldnet.att.net).
From the Department of Dermatology, Mount Sinai School of Medicine,
New York, NY.
REFERENCES
| |
1. Leroy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis) classification, subsets and pathogenesis. J Rheumatol. 1988;15:202-205.
ISI
| PUBMED
2. Fleischmajer R, Perlish JS, Reeves JRT. Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977;20:975-984.
ISI
| PUBMED
3. Needleman BW. Increased expression of intracellular adhesion molecule I on the fibroblasts
of scleroderma patients. Arthritis Rheum. 1990;33:1847-1851.
ISI
| PUBMED
4. Gruschwitz M, von Den Driesch P, Kellner P, et al. Expression of adhesion proteins involved in cell-cell and cell-matrix
interactions in the skin of patients with progressive systemic sclerosis. J Am Acad Dermatol. 1992;27:169-177.
ISI
| PUBMED
5. Gruschwitz MS, Hornstein OP, van den Driesch P. Correlation of soluble adhesion molecules in the peripheral blood of
scleroderma patients with their in situ expression and with disease activity. Arthritis Rheum. 1995;38:184-189.
ISI
| PUBMED
6. White B. Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22:695-708.
FULL TEXT
|
ISI
| PUBMED
7. Fleischmajer R, Perlish JS. [3H]Thymidine labeling of dermal endothelial cells in scleroderma. J Invest Dermatol. 1977;69:379-382.
FULL TEXT
|
ISI
| PUBMED
8. Leroy EC. Systemic sclerosis: a vascular perspective. Rheum Dis Clin North Am. 1996;22:675-694.
FULL TEXT
|
ISI
| PUBMED
9. Fleischmajer R, Perlish JS, Krieg T, Timpl R. Variability in collagen and fibronectin synthesis by scleroderma fibroblasts
in primary culture. J Invest Dermatol. 1981;76:400-403.
FULL TEXT
|
ISI
| PUBMED
10. Postlethwaitte AE. Early immune events in scleroderma. Rheum Dis Clin North Am. 1990;16:125-139.
ISI
| PUBMED
11. Jimenez SA, Hitraya E, Vargas J. Pathogenesis of scleroderma: collagen. Rheum Dis Clin North Am. 1996;22:647-674.
FULL TEXT
|
ISI
| PUBMED
12. Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am. 1996;22:709-735.
FULL TEXT
|
ISI
| PUBMED
13. Rodeheffer RJ, Rommer JA, Wigley F, Smith CRN. Controlled double-blind trial of nifedipine in the treatment of Raynaud's
phenomenon. N Engl J Med. 1983;308:880-883.
ISI
| PUBMED
14. Raynaud's Treatment Study Investigators. Comparison of sustained-release nifedipine and temperature biofeedback
for treatment of primary Raynaud phenomenon: results from a randomized clinical
trial with 1-year follow-up. Arch Intern Med. 2000;160:1101-1108.
FREE FULL TEXT
15. Dziadzio M, Denton CP, Smith R, Blann HK, Bowers E, Black CM. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical
and biochemical findings in a fifteen-week, randomized, parallel-group, controlled
trial. Arthritis Rheum. 1999;42:2646-2655.
FULL TEXT
|
ISI
| PUBMED
16. Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infusions of iloprost and oral nifedipine
in treatment of Raynaud's phenomenon in patients with systemic sclerosis:
a double blind randomised study. BMJ. 1989;298:561-564.
17. Belch JJ, Capell HA, Cooke ED, et al. Oral iloprost as a treatment for Raynaud's syndrome: a double blind
multicentre placebo controlled study. Ann Rheum Dis. 1995;54:197-200.
FREE FULL TEXT
18. Black CM, Hazkier-Sorensen L, Belch JJ, et al. Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis:
a multicenter, placebo-controlled dose-comparison study. Br J Rheumatol. 1998;37:952-960.
FREE FULL TEXT
19. Wigley FM, Korn JN, Csuka ME, et al. Oral iloprost treatment in patients with Raynaud's phenomenon secondary
to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum. 1998;41:670-677.
FULL TEXT
|
ISI
| PUBMED
20. Steigerwald JC. Chlorambucil in the treatment of progressive systemic sclerosis. In: Block CM, Myers AR, eds. Systemic Sclerosis
(Scleroderma). New York, NY: Gower Medical Publishing Ltd; 1985:423-427.
21. Furst DE, Clements PJ, Hill S, et al. Immunosuppression with chlorambucil versus placebo for scleroderma:
results of a three-year parallel, randomized, double-blind study. Arthritis Rheum. 1989;32:584-593.
ISI
| PUBMED
22. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic
sclerosis: a 24 week randomized double-blind trial, followed by a 24 week
observational trial. Br J Rheumatol. 1996;35:364-372.
FREE FULL TEXT
23. Degiannis D, Seibold JR, Czarnecki M, Raskova J, Raska K. Soluble interleukin-2 receptors in patients with systemic sclerosis:
clinical and laboratory correlation. Arthritis Rheum. 1990;33:375-380.
ISI
| PUBMED
24. Needelman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis
factor– and interferon- levels in sera from patients with
scleroderma. Arthritis Rheum. 1992;35:67-72.
ISI
| PUBMED
25. Clements PJ, Lachenbruch PA, Sterz M, et al. Cyclosporine in systemic sclerosis. Arthritis Rheum. 1993;36:75-83.
ISI
| PUBMED
26. Rock AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy:
results of a multicenter trial. Arch Dermatol. 1992;128:337-346.
ABSTRACT
27. Enomoto DN, Mekkes JR, Bossyt PM, et al. Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy
(photopheresis). J Am Acad Dermatol. 1999;41:915-922.
FULL TEXT
|
ISI
| PUBMED
28. Sinclair HD, Williams JD, Rahman MA. Clinical efficacy of antithymocyte globulin in systemic sclerosis:
results of a placebo-controlled trial [abstract]. Arthritis Rheum. 1994;36(suppl):s217.
29. Steen VD, Medsger TA Jr, Rodnan GP. D-penicillamine therapy in progressive systemic sclerosis (scleroderma):
a retrospective analysis. Ann Intern Med. 1982;97:652-659.
30. Clements PJ, Furst DE, Wong WK, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic
sclerosis. Arthritis Rheum. 1999;42:1194-1203.
FULL TEXT
|
ISI
| PUBMED
31. Chetrit-Ben E, Levy M. Colchicine: 1998 update. Semin Arthritis Rheum. 1998;28:48-59.
FULL TEXT
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