eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Scleroderma: Treatment & Medication

Author: Sergio A Jimenez, MD, Director, The Scleroderma Center; Co-Director, Jefferson Institute of Molecular Medicine; Director, Division of Connective Tissue Diseases; Professor of Medicine, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University
Coauthor(s): Patrick M Cronin, DO, FACR, Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital; Andrew Koenig, ; Marie Spevak O'Brien, DO, Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group
Contributor Information and Disclosures

Updated: Oct 14, 2008

Treatment

Medical Care

  • Skin thickening can be treated with D-penicillamine and other experimental drugs or interventions (interferon-gamma, mycophenolate mofetil, cyclophosphamide, photopheresis, allogeneic bone marrow transplantation16 ). However, the US Food and Drug Administration (FDA) has not approved any therapies for systemic sclerosis. No placebo-controlled studies have demonstrated superiority, although some large uncontrolled series suggest beneficial effect from D-penicillamine. Interferon-gamma is effective, but its use is limited because it activates inflammatory and endothelial cells.
  • Pruritus can be treated with moisturizers, histamine 1 (H1) and histamine 2 (H2) blockers, tricyclic antidepressants, and trazodone.
  • Raynaud phenomenon can be treated with calcium channel blockers (to tolerance),14 prazosin, prostaglandin derivatives such as prostaglandin E1, dipyridamole, aspirin, and topical nitrates. In the event of thrombosis and vascular flow compromise, a tissue plasminogen activator, heparin, and urokinase may be necessary. In very severe cases, patients may benefit from a pharmacologic cervical sympathectomy or from surgical digital sympathectomy. Bosentan, a dual endothelin receptor antagonist, may curtail the formation of new digital ulcers. Sildenafil has also been shown to be effective and well tolerated in patients with primary Raynaud phenomenon and is currently approved to treat pulmonary hypertension.17,18
  • GI symptoms may be treated with antacids, H2 blockers, reflux and aspiration precautions, proton pump inhibitors, prokinetic agents, octreotide, smaller meals, and laxatives.
  • Pulmonary fibrosing alveolitis may be treated with cyclophosphamide, either orally or in intravenous pulses.19,15 Some recent nonrandomized studies have also shown benefit from mycophenolate mofetil.20,21,22,23 Pulmonary hypertension may require supplemental oxygen. Bosentan is effective in treating primary (idiopathic) pulmonary hypertension, as well as pulmonary hypertension associated with systemic sclerosis, and has demonstrated substantial clinical and hemodynamic improvement in patients with systemic sclerosis–associated pulmonary hypertension.24 Numerous newer agents are available to treat pulmonary hypertension or are currently being tested in open and randomized controlled trials. These newer agents include other endothelin receptor antagonists such as sitaxsentan and ambrisentan; prostaglandin derivatives such as epoprostenol, treprostinil, beraprost, and iloprost; and phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil.
  • Renal crisis episodes are best prevented and treated with the aggressive use of ACE inhibitors at the earliest signs of hypertension.
  • Myositis may be treated cautiously with steroids (first choice), methotrexate, and azathioprine. Doses of prednisone greater than 40 mg/d are associated with a higher incidence of sclerodermal renal crisis.25
  • Arthralgias can be treated with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Proteinuria is not uncommon in patients with scleroderma who are receiving D-penicillamine.

Surgical Care

Digital sympathectomy may be used in patients with severe Raynaud phenomenon who have an unrelenting acute attack and who are threatened by digital loss. Debridement or amputation may be required in severe ischemic or infected digital lesions. Hand surgery may be performed to correct severe flexion contractures. Removal of severely painful or draining of infected calcinotic deposits is occasionally required.

Consultations

Ensure that all patients with systemic sclerosis are treated in conjunction with an experienced rheumatologist who has a full understanding of the disease, the complications of the therapies, and the frequently serious adverse effects.

Diet

Instruct the patient to avoid large does of vitamin C (>1000 mg/d) because it stimulates collagen formation and may enhance its deposition.

Activity

  • Ensure that the patient maintains a core body temperature to try to minimize the Raynaud phenomenon.
  • Assist the patient in avoiding contamination of any skin wound caused by ischemic lesions or calcinosis.
  • Digital ulcers must be kept clean and dry.
  • Instruct the patient to perform continuous physical and occupational therapy to maintain range of motion and to minimize or delay contractures.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Primary drug treatment aims at inhibiting tissue fibrosis and vascular and immune system alterations, which may be primarily responsible for the wide variety of systemic morbidity.

Glucocorticosteroids

These agents are used to treat inflammatory complications (eg, myositis, pneumonitis).


Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone is inactive and must be metabolized to prednisolone. Metabolism may be impaired in patients with liver disease.

Adult

2.5-5 mg PO qam initially, titrate upward prn to control symptoms, gradually decrease to maintain at lowest possible dose; doses >40 mg/d can increase risk of adrenal crisis

Pediatric

Administer as in adults

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Documented hypersensitivity; viral connective-tissue, fungal, or tubercular skin infections; GI disease; hepatic dysfunction

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Immunosuppressive agents

These agents inhibit key steps in immune reactions.


Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Adult

50-150 mg/d PO qam

Pediatric

Not established

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Loss of appetite, nausea, vomiting, skin rash, bone marrow suppression, infection, malignancy, and pancreatitis; kidney and liver disease require decreasing the dose by two thirds; increased risk of neoplasms following prior immunosuppressant treatment


Methotrexate (Folex PFS, Rheumatrex)

Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. May suppress immune system. Satisfactory response observed in 3-6 wk following administration.

Adult

7.5-25 mg/wk PO/IV/IM/SC; adjust dose gradually to attain satisfactory response

Pediatric

5-15 mg/m2/wk PO/IM/SC as single dose or divided into 3 doses q12h

Charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease effect; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase methotrexate plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase methotrexate effects and toxicity; may increase plasma levels of thiopurines

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; active infection; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Cough, diarrhea, hair loss, loss of appetite, bleeding or bruising, fever, pneumonitis, infection, and stomatitis may occur; monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated levels, eg, dehydration); may cause hematologic, renal, GI, pulmonary, and neurologic toxicity; discontinue if significant drop in blood counts occurs; folate deficiency may occur (supplement with folic acid)


Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Adult

50-150 mg/d PO single am dose; fluid intake is important (2-3 L/d); empty bladder hs

Pediatric

Not established

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and quinolones effects; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high-dose phenobarbital may increase metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Documented hypersensitivity; severely depressed bone marrow function; kidney or liver disease; active infection; pregnancy

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause infertility in men and women, loss of appetite, bone marrow suppression, infection, hemorrhagic cystitis, and malignancy; regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis


Mycophenolate Mofetil (CellCept)

Used to help limit collagen formation. Potent selective, noncompetitive, and reversible inhibitor of purine synthesis. Has cytostatic effects on lymphocytes.

Adult

1-1.5 g PO bid

Pediatric

Not established

Live vaccines are contraindicated; avoid use with alefacept, azathioprine, oral contraceptives, NSAIDs (increased risk of GI bleeding, nephrotoxicity, hypertension), and natalizumab

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Constipation; nausea; vomiting; diarrhea; headache; hypertension; GI hemorrhage; myelosuppression; increases risk of infections, malignant lymphoma (0.4-1%), confusion, tremor, and frequency of cough

Chelating agents

These agents may improve certain aspects of the disease.


Penicillamine (Cuprimine, Depen)

Inhibits the formation of mature collagen crosslinks, rendering un-crosslinked molecules more susceptible to proteolytic degradation.

Adult

750 mg/d PO on empty stomach divided bid/tid

Pediatric

5 mg/kg/d PO; may increase to 10 mg/kg/d prn

Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; effects may decrease with coadministration of zinc salts, antacids, and iron

Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia; agranulocytosis

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause diarrhea, joint pain, loss of taste or appetite, fever, hives, pruritus, nausea, vomiting, lymphadenopathy, bone marrow suppression, taste abnormalities, nephrotoxicity, and weakness

Endothelin receptor antagonist

These agents bind to endothelin receptor present in endothelium and vascular smooth muscle. The effect can result in vasodilation.


Bosentan (Tracleer)

Dual endothelin A and B receptor antagonist for treatment of pulmonary arterial hypertension. Decreases both pulmonary and systemic vascular resistance and increases cardiac output without increasing heart rate.

Adult

62.5 mg PO bid for 4 wk, then increase to 125 mg PO bid

Pediatric

Not established

Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, and cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4, causing decrease in plasma concentrations of drugs metabolized by these enzymes, including glyburide and other hypoglycemics, cyclosporin A, hormonal contraceptives, warfarin, simvastatin, and possibly other statins; hepatotoxicity increases with concomitant administration of glyburide; coadministration with sildenafil increases bosentan levels by 50% and reduces sildenafil levels by 63%

Documented hypersensitivity; pregnancy; concomitant administration with cyclosporin A or glyburide

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May cause or exacerbate congestive heart failure, anemia, liver impairment (LFTs must be checked at baseline and thereafter monthly), pulmonary veno-occlusive disease harmful to fetus


Ambrisentan (Letairis)

Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure. Because of the risks of hepatic injury and teratogenic potential, only available through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).

Adult

5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab

Pediatric

Not established

Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg, cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19 inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin and hematocrit values (monitor at baseline, 1 mo, and then periodically)

Phosphodiesterase type 5 inhibitor, peripheral vasodilator

These agents may increase vasodilation in the pulmonary vascular bed.


Sildenafil (Revatio)

Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting PDE-5. This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output.

Adult

20 mg PO tid; adjust dose in liver or renal failure

Pediatric

Not established

Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%

Documented hypersensitivity, concomitant nitrate use

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Headache; flushing; pyrexia; myalgias; insomnia; diarrhea; dyspepsia; gastritis; paresthesias; visual disturbances; MI; stroke; arrhythmias; hypotension; cerebrovascular, pulmonary, retinal, or subarachnoid hemorrhage; anterior ischemic optic neuropathy

More on Scleroderma

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Differential Diagnoses & Workup: Scleroderma
Treatment & Medication: Scleroderma
Follow-up: Scleroderma
Multimedia: Scleroderma
References
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Further Reading

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Keywords

scleroderma, systemic sclerosis, proximal scleroderma, diffuse cutaneous scleroderma, limited cutaneous scleroderma, diffuse systemic scleroderma, progressive systemic sclerosis, hard skin, skin tightening, skin tightness, sclerodactyly, bibasilar pulmonary fibrosis, Raynaud phenomenon, Raynaud's phenomenon, pulmonary hypertension, calcinosis, esophageal dysmotility, telangiectasias, CREST, juvenile-onset systemic sclerosis

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Contributor Information and Disclosures

Author

Sergio A Jimenez, MD, Director, The Scleroderma Center; Co-Director, Jefferson Institute of Molecular Medicine; Director, Division of Connective Tissue Diseases; Professor of Medicine, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University
Sergio A Jimenez, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Society for Biochemistry and Molecular Biology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Patrick M Cronin, DO, FACR, Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital
Patrick M Cronin, DO, FACR is a member of the following medical societies: American College of Rheumatology, American Osteopathic Association, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Andrew Koenig, 
Andrew Koenig is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, and American Osteopathic Association
Disclosure: Nothing to disclose.

Marie Spevak O'Brien, DO, Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group
Marie Spevak O'Brien, DO is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association, American Osteopathic Association, International Society for Clinical Densitometry, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

John Varga, MD, Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University
John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical Research, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

 
 
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