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Review |

Treatment of Scleroderma FREE

Allen N. Sapadin, MD; Raul Fleischmajer, MD
[+] Author Affiliations

From the Department of Dermatology, Mount Sinai School of Medicine, New York, NY.


Arch Dermatol. 2002;138(1):99-105. doi:10.1001/archderm.138.1.99.
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Published online

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.

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.16 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 β, 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 β, platelet-derived growth factor, interleukin [IL] 4, IL-6, tumor necrosis factor [TNF] α) can affect the behavior of fibroblast growth, proliferation, collagen synthesis, and chemotaxis.911 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.

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).

Table Graphic Jump LocationTable 1. Treatment of Systemic Sclerosis

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 β, 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 β 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.

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 α is a proinflammatory cytokine produced by activated T cells and macrophages. Tumor necrosis factor α 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-α 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.

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).

Table Graphic Jump LocationTable 2. Treatment of Localized Scleroderma
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 (1α,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, 1α,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.

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.

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@worldnet.att.net).

Leroy  ECBlack  CFleischmajer  R  et al.  Scleroderma (systemic sclerosis) classification, subsets and pathogenesis. J Rheumatol. 1988;15202- 205
Fleischmajer  RPerlish  JSReeves  JRT Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977;20975- 984
Link to Article
Needleman  BW Increased expression of intracellular adhesion molecule I on the fibroblasts of scleroderma patients. Arthritis Rheum. 1990;331847- 1851
Link to Article
Gruschwitz  Mvon Den Driesch  PKellner  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;27169- 177
Link to Article
Gruschwitz  MSHornstein  OPvan 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;38184- 189
Link to Article
White  B Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22695- 708
Link to Article
Fleischmajer  RPerlish  JS [3H]Thymidine labeling of dermal endothelial cells in scleroderma. J Invest Dermatol. 1977;69379- 382
Link to Article
Leroy  EC Systemic sclerosis: a vascular perspective. Rheum Dis Clin North Am. 1996;22675- 694
Link to Article
Fleischmajer  RPerlish  JSKrieg  TTimpl  R Variability in collagen and fibronectin synthesis by scleroderma fibroblasts in primary culture. J Invest Dermatol. 1981;76400- 403
Link to Article
Postlethwaitte  AE Early immune events in scleroderma. Rheum Dis Clin North Am. 1990;16125- 139
Jimenez  SAHitraya  EVargas  J Pathogenesis of scleroderma: collagen. Rheum Dis Clin North Am. 1996;22647- 674
Link to Article
Okano  Y Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am. 1996;22709- 735
Link to Article
Rodeheffer  RJRommer  JAWigley  FSmith  CRN Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon. N Engl J Med. 1983;308880- 883
Link to Article
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;1601101- 1108
Link to Article
Dziadzio  MDenton  CPSmith  RBlann  HKBowers  EBlack  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;422646- 2655
Link to Article
Rademaker  MCooke  EDAlmond  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;298561- 564
Link to Article
Belch  JJCapell  HACooke  ED  et al.  Oral iloprost as a treatment for Raynaud's syndrome: a double blind multicentre placebo controlled study. Ann Rheum Dis. 1995;54197- 200
Link to Article
Black  CMHazkier-Sorensen  LBelch  JJ  et al.  Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled dose-comparison study. Br J Rheumatol. 1998;37952- 960
Link to Article
Wigley  FMKorn  JNCsuka  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;41670- 677
Link to Article
Steigerwald  JC Chlorambucil in the treatment of progressive systemic sclerosis. Block  CMMyers  AReds.Systemic Sclerosis (Scleroderma) New York, NY Gower Medical Publishing Ltd1985;423- 427
Furst  DEClements  PJHill  S  et al.  Immunosuppression with chlorambucil versus placebo for scleroderma: results of a three-year parallel, randomized, double-blind study. Arthritis Rheum. 1989;32584- 593
Link to Article
van den Hoogen  FHBoerbooms  AMSwaak  AJRasker  JJvan Lier  HJvan 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;35364- 372
Link to Article
Degiannis  DSeibold  JRCzarnecki  MRaskova  JRaska  K Soluble interleukin-2 receptors in patients with systemic sclerosis: clinical and laboratory correlation. Arthritis Rheum. 1990;33375- 380
Link to Article
Needelman  BWWigley  FMStair  RW Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor–α and interferon-γ levels in sera from patients with scleroderma. Arthritis Rheum. 1992;3567- 72
Link to Article
Clements  PJLachenbruch  PASterz  M  et al.  Cyclosporine in systemic sclerosis. Arthritis Rheum. 1993;3675- 83
Link to Article
Rock  AHFreundlich  BJegasothy  BV  et al.  Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol. 1992;128337- 346
Link to Article
Enomoto  DNMekkes  JRBossyt  PM  et al.  Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy (photopheresis). J Am Acad Dermatol. 1999;41915- 922
Link to Article
Sinclair  HDWilliams  JDRahman  MA Clinical efficacy of antithymocyte globulin in systemic sclerosis: results of a placebo-controlled trial [abstract]. Arthritis Rheum. 1994;36 (suppl) s217
Steen  VDMedsger  TA  JrRodnan  GP D-penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med. 1982;97652- 659
Link to Article
Clements  PJFurst  DEWong  WK  et al.  High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis. Arthritis Rheum. 1999;421194- 1203
Link to Article
Chetrit-Ben  ELevy  M Colchicine: 1998 update. Semin Arthritis Rheum. 1998;2848- 59
Link to Article
Alarcon-Segovia  DRamos-Niembro  FIbanez de Kasep  GAlocer  JPerez-Tamayo  R Long-term evaluation of colchicine in the treatment of scleroderma. J Rheumatol. 1979;6705- 712
Hunzelmann  NAnders  SFierlberg  G  et al.  Systemic scleroderma: multicenter trial of 1 year of treatment with recombinant interferon gamma. Arch Dermatol. 1997;133609- 613
Link to Article
Polisson  RPGilkeson  GSPyun  EHPisetsky  DSSmith  EASimon  LS A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels. J Rheumatol. 1996;23654- 658
Grassegger  ASchuler  GHessenberger  G  et al.  Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial. Br J Dermatol. 1998;139639- 648
Link to Article
Black  CMSilman  AJHerrick  AI  et al.  Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results from a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42299- 305
Link to Article
Unemori  ENPickford  LBSalles  AL  et al.  Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest. 1996;982739- 2745
Link to Article
Seibold  JRKorn  JHClements  PJ  et al.  Recombinant human relaxin in the treatment of scleroderma: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2000;132871- 879
Link to Article
Whitman III  HHCase  DBLaragh  JH  et al.  Variable response to oral angiotensin-converting enzyme blockade in hypertensive scleroderma patients. Arthritis Rheum. 1982;25241- 248
Link to Article
Alpert  MAPressly  TAMukerji  VLambert  CRMukerji  B Short- and long-term hemodynamic effects of captopril in patients with pulmonary hypertension and selected connective tissue disease. Chest. 1992;1021407- 1412
Link to Article
Chang  YJSpiera  H Renal transplantation in scleroderma. Medicine (Baltimore). 1999;78382- 385
Link to Article
Badesch  DBTapson  VFMcGoon  MD  et al.  Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med. 2000;132425- 434
Link to Article
de la Mata  JGomez-Sanchez  MAAranzana  MGomez-Reino  JJ Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases. Arthritis Rheum. 1994;371528- 1533
Link to Article
Silver  EMWarrick  JHKinsella  MBStaudt  LSBaumann  HMStrange  C Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol. 1993;20838- 844
Akesson  AScheja  ALundin  AWollheim  FA Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum. 1994;37729- 735
Link to Article
White  BMoore  WCWigley  FMXiai  HQWise  RA Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med. 2000;132947- 954
Link to Article
Le  CHMorales  ATrentham  DE Minocycline in early diffuse scleroderma. Lancet. 1998;3521755- 1756
Link to Article
Kanekurat  TFukumaru  SMatsushita  STerask  KMizoguchis  SKanzaki  T Successful treatment of scleroderma with PUVA therapy. J Dermatol. 1996;23455- 459
Schachna  LWigley  FMWhite  BGelber  ACRosas  IOrens  JB Lung transplantation in scleroderma: the Johns Hopkins experience [abstract]. Arthritis Rheum. 2000;43 (suppl) s392
Marcellus  DCAltomonte  VLFarmer  ER  et al.  Etretinate therapy for refractory sclerodermatous chronic graft-versus-host disease. Blood. 1999;9366- 70
Martini  AMaccario  RRavelli  A  et al.  Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis. Arthritis Rheum. 1999;42807- 811
Link to Article
Furst  DEMcSweeney  PNash  R  et al.  High-dose immunosuppressive therapy (HDIT) with autologous stem cell transplantation (SCT) for systemic sclerosis (SSc): results in the first 8 patients [abstract]. Arthritis Rheum. 2000;43 (suppl) s392
Elliott  MJMaini  RNFeldmann  M  et al.  Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor–α (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;3441105- 1110
Link to Article
Spencer-Green  G Etanercept (Enbrel): update on therapeutic use. Ann Rheum Dis. 2000;59 (suppl 1) i46- i49
Link to Article
Ellman  MHMcDonald  PAHayes  FA Etanercept as treatment for diffuse scleroderma: a pilot study [abstract]. Arthritis Rheum. 2000;43 (suppl) s392
Oliver  SJMoreira  AKaplan  G Reduced fibrosis and normalization of skin structure in scleroderma patients treated with thalidomide [abstract]. Arthritis Rheum. 1999;42 (suppl) s187
Link to Article
Fleischmajer  RNedwich  A Generalized morphea: histology of the dermis and subcutaneous tissue. Arch Dermatol. 1972;106509- 514
Link to Article
Arnett  FCTan  FKYosef  U  et al.  Autoantibodies to the extracellular matrix microfibrillar protein fibrillin-1 in patients with localized scleroderma. Arthritis Rheum. 1999;422656- 2659
Link to Article
Elst  EFVan Suijlekom-Smit  LWOranje  AP Treatment of linear scleroderma with oral 1,25-dihydroxyvitamin D3 (calcitriol) in seven children. Pediatr Dermatol. 1999;1653- 58
Link to Article
Hulshof  MMPavel  SBreedveld  FCDijkmans  ACVermeer  BJ Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol. 1994;1301290- 1293
Link to Article
Cunningham  BBLandells  IDRLangman  CSailer  DEPaller  AS Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol. 1998;39 (pt 2) 211- 215
Link to Article
Kerscher  MMeurer  MSander  C  et al.  PUVA-bath photochemotherapy for localized scleroderma. Arch Dermatol. 1996;1321280- 1282
Link to Article
Kerscher  MVolkenandt  MGruss  C  et al.  Low-dose phototherapy for treatment of localized scleroderma. J Am Acad Dermatol. 1998;3821- 26
Link to Article
Wlaschek  MBriviba  KStricklin  PSies  HScharffetter-Kochanek  K Singlet oxygen may mediate the ultraviolet-A–induced synthesis of interstitial collagenase. J Invest Dermatol. 1995;104194- 198
Link to Article
Wallace  CA The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum. 1998;41381- 391
Link to Article
Seyger  MMBvan den Hoogen  FHJde Boo  TElke  MGJde Jong  MD Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol. 1998;39220- 225
Link to Article
Uziel  YFeldman  BMKrafchik  BRYeung  RSLaxer  RM Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;13691- 95
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Treatment of Systemic Sclerosis
Table Graphic Jump LocationTable 2. Treatment of Localized Scleroderma

References

Leroy  ECBlack  CFleischmajer  R  et al.  Scleroderma (systemic sclerosis) classification, subsets and pathogenesis. J Rheumatol. 1988;15202- 205
Fleischmajer  RPerlish  JSReeves  JRT Cellular infiltrates in scleroderma skin. Arthritis Rheum. 1977;20975- 984
Link to Article
Needleman  BW Increased expression of intracellular adhesion molecule I on the fibroblasts of scleroderma patients. Arthritis Rheum. 1990;331847- 1851
Link to Article
Gruschwitz  Mvon Den Driesch  PKellner  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;27169- 177
Link to Article
Gruschwitz  MSHornstein  OPvan 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;38184- 189
Link to Article
White  B Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22695- 708
Link to Article
Fleischmajer  RPerlish  JS [3H]Thymidine labeling of dermal endothelial cells in scleroderma. J Invest Dermatol. 1977;69379- 382
Link to Article
Leroy  EC Systemic sclerosis: a vascular perspective. Rheum Dis Clin North Am. 1996;22675- 694
Link to Article
Fleischmajer  RPerlish  JSKrieg  TTimpl  R Variability in collagen and fibronectin synthesis by scleroderma fibroblasts in primary culture. J Invest Dermatol. 1981;76400- 403
Link to Article
Postlethwaitte  AE Early immune events in scleroderma. Rheum Dis Clin North Am. 1990;16125- 139
Jimenez  SAHitraya  EVargas  J Pathogenesis of scleroderma: collagen. Rheum Dis Clin North Am. 1996;22647- 674
Link to Article
Okano  Y Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am. 1996;22709- 735
Link to Article
Rodeheffer  RJRommer  JAWigley  FSmith  CRN Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon. N Engl J Med. 1983;308880- 883
Link to Article
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;1601101- 1108
Link to Article
Dziadzio  MDenton  CPSmith  RBlann  HKBowers  EBlack  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;422646- 2655
Link to Article
Rademaker  MCooke  EDAlmond  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;298561- 564
Link to Article
Belch  JJCapell  HACooke  ED  et al.  Oral iloprost as a treatment for Raynaud's syndrome: a double blind multicentre placebo controlled study. Ann Rheum Dis. 1995;54197- 200
Link to Article
Black  CMHazkier-Sorensen  LBelch  JJ  et al.  Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled dose-comparison study. Br J Rheumatol. 1998;37952- 960
Link to Article
Wigley  FMKorn  JNCsuka  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;41670- 677
Link to Article
Steigerwald  JC Chlorambucil in the treatment of progressive systemic sclerosis. Block  CMMyers  AReds.Systemic Sclerosis (Scleroderma) New York, NY Gower Medical Publishing Ltd1985;423- 427
Furst  DEClements  PJHill  S  et al.  Immunosuppression with chlorambucil versus placebo for scleroderma: results of a three-year parallel, randomized, double-blind study. Arthritis Rheum. 1989;32584- 593
Link to Article
van den Hoogen  FHBoerbooms  AMSwaak  AJRasker  JJvan Lier  HJvan 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;35364- 372
Link to Article
Degiannis  DSeibold  JRCzarnecki  MRaskova  JRaska  K Soluble interleukin-2 receptors in patients with systemic sclerosis: clinical and laboratory correlation. Arthritis Rheum. 1990;33375- 380
Link to Article
Needelman  BWWigley  FMStair  RW Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor–α and interferon-γ levels in sera from patients with scleroderma. Arthritis Rheum. 1992;3567- 72
Link to Article
Clements  PJLachenbruch  PASterz  M  et al.  Cyclosporine in systemic sclerosis. Arthritis Rheum. 1993;3675- 83
Link to Article
Rock  AHFreundlich  BJegasothy  BV  et al.  Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol. 1992;128337- 346
Link to Article
Enomoto  DNMekkes  JRBossyt  PM  et al.  Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy (photopheresis). J Am Acad Dermatol. 1999;41915- 922
Link to Article
Sinclair  HDWilliams  JDRahman  MA Clinical efficacy of antithymocyte globulin in systemic sclerosis: results of a placebo-controlled trial [abstract]. Arthritis Rheum. 1994;36 (suppl) s217
Steen  VDMedsger  TA  JrRodnan  GP D-penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med. 1982;97652- 659
Link to Article
Clements  PJFurst  DEWong  WK  et al.  High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis. Arthritis Rheum. 1999;421194- 1203
Link to Article
Chetrit-Ben  ELevy  M Colchicine: 1998 update. Semin Arthritis Rheum. 1998;2848- 59
Link to Article
Alarcon-Segovia  DRamos-Niembro  FIbanez de Kasep  GAlocer  JPerez-Tamayo  R Long-term evaluation of colchicine in the treatment of scleroderma. J Rheumatol. 1979;6705- 712
Hunzelmann  NAnders  SFierlberg  G  et al.  Systemic scleroderma: multicenter trial of 1 year of treatment with recombinant interferon gamma. Arch Dermatol. 1997;133609- 613
Link to Article
Polisson  RPGilkeson  GSPyun  EHPisetsky  DSSmith  EASimon  LS A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels. J Rheumatol. 1996;23654- 658
Grassegger  ASchuler  GHessenberger  G  et al.  Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial. Br J Dermatol. 1998;139639- 648
Link to Article
Black  CMSilman  AJHerrick  AI  et al.  Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results from a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42299- 305
Link to Article
Unemori  ENPickford  LBSalles  AL  et al.  Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J Clin Invest. 1996;982739- 2745
Link to Article
Seibold  JRKorn  JHClements  PJ  et al.  Recombinant human relaxin in the treatment of scleroderma: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2000;132871- 879
Link to Article
Whitman III  HHCase  DBLaragh  JH  et al.  Variable response to oral angiotensin-converting enzyme blockade in hypertensive scleroderma patients. Arthritis Rheum. 1982;25241- 248
Link to Article
Alpert  MAPressly  TAMukerji  VLambert  CRMukerji  B Short- and long-term hemodynamic effects of captopril in patients with pulmonary hypertension and selected connective tissue disease. Chest. 1992;1021407- 1412
Link to Article
Chang  YJSpiera  H Renal transplantation in scleroderma. Medicine (Baltimore). 1999;78382- 385
Link to Article
Badesch  DBTapson  VFMcGoon  MD  et al.  Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med. 2000;132425- 434
Link to Article
de la Mata  JGomez-Sanchez  MAAranzana  MGomez-Reino  JJ Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases. Arthritis Rheum. 1994;371528- 1533
Link to Article
Silver  EMWarrick  JHKinsella  MBStaudt  LSBaumann  HMStrange  C Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol. 1993;20838- 844
Akesson  AScheja  ALundin  AWollheim  FA Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum. 1994;37729- 735
Link to Article
White  BMoore  WCWigley  FMXiai  HQWise  RA Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med. 2000;132947- 954
Link to Article
Le  CHMorales  ATrentham  DE Minocycline in early diffuse scleroderma. Lancet. 1998;3521755- 1756
Link to Article
Kanekurat  TFukumaru  SMatsushita  STerask  KMizoguchis  SKanzaki  T Successful treatment of scleroderma with PUVA therapy. J Dermatol. 1996;23455- 459
Schachna  LWigley  FMWhite  BGelber  ACRosas  IOrens  JB Lung transplantation in scleroderma: the Johns Hopkins experience [abstract]. Arthritis Rheum. 2000;43 (suppl) s392
Marcellus  DCAltomonte  VLFarmer  ER  et al.  Etretinate therapy for refractory sclerodermatous chronic graft-versus-host disease. Blood. 1999;9366- 70
Martini  AMaccario  RRavelli  A  et al.  Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis. Arthritis Rheum. 1999;42807- 811
Link to Article
Furst  DEMcSweeney  PNash  R  et al.  High-dose immunosuppressive therapy (HDIT) with autologous stem cell transplantation (SCT) for systemic sclerosis (SSc): results in the first 8 patients [abstract]. Arthritis Rheum. 2000;43 (suppl) s392
Elliott  MJMaini  RNFeldmann  M  et al.  Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor–α (cA2) versus placebo in rheumatoid arthritis. Lancet. 1994;3441105- 1110
Link to Article
Spencer-Green  G Etanercept (Enbrel): update on therapeutic use. Ann Rheum Dis. 2000;59 (suppl 1) i46- i49
Link to Article
Ellman  MHMcDonald  PAHayes  FA Etanercept as treatment for diffuse scleroderma: a pilot study [abstract]. Arthritis Rheum. 2000;43 (suppl) s392
Oliver  SJMoreira  AKaplan  G Reduced fibrosis and normalization of skin structure in scleroderma patients treated with thalidomide [abstract]. Arthritis Rheum. 1999;42 (suppl) s187
Link to Article
Fleischmajer  RNedwich  A Generalized morphea: histology of the dermis and subcutaneous tissue. Arch Dermatol. 1972;106509- 514
Link to Article
Arnett  FCTan  FKYosef  U  et al.  Autoantibodies to the extracellular matrix microfibrillar protein fibrillin-1 in patients with localized scleroderma. Arthritis Rheum. 1999;422656- 2659
Link to Article
Elst  EFVan Suijlekom-Smit  LWOranje  AP Treatment of linear scleroderma with oral 1,25-dihydroxyvitamin D3 (calcitriol) in seven children. Pediatr Dermatol. 1999;1653- 58
Link to Article
Hulshof  MMPavel  SBreedveld  FCDijkmans  ACVermeer  BJ Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol. 1994;1301290- 1293
Link to Article
Cunningham  BBLandells  IDRLangman  CSailer  DEPaller  AS Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol. 1998;39 (pt 2) 211- 215
Link to Article
Kerscher  MMeurer  MSander  C  et al.  PUVA-bath photochemotherapy for localized scleroderma. Arch Dermatol. 1996;1321280- 1282
Link to Article
Kerscher  MVolkenandt  MGruss  C  et al.  Low-dose phototherapy for treatment of localized scleroderma. J Am Acad Dermatol. 1998;3821- 26
Link to Article
Wlaschek  MBriviba  KStricklin  PSies  HScharffetter-Kochanek  K Singlet oxygen may mediate the ultraviolet-A–induced synthesis of interstitial collagenase. J Invest Dermatol. 1995;104194- 198
Link to Article
Wallace  CA The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum. 1998;41381- 391
Link to Article
Seyger  MMBvan den Hoogen  FHJde Boo  TElke  MGJde Jong  MD Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol. 1998;39220- 225
Link to Article
Uziel  YFeldman  BMKrafchik  BRYeung  RSLaxer  RM Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;13691- 95
Link to Article

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