eMedicine Specialties > Rheumatology > Soft Tissue and Regional Rheumatic Disease

Localized Fibrosing Disorders - Linear Scleroderma, Morphea, and Regional Fibrosis

Mariana J Kaplan, MD, Assistant Professor, Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School

Updated: Dec 3, 2008

Introduction

Background

Localized fibrosing disorders include a spectrum of rare conditions that frequently begin in childhood. These lesions are characterized by circumscribed fibrotic areas involving different levels of the dermis, subcutis, and, sometimes, underlying soft tissue and bone. Although the clinical course of the disease is often benign, widespread lesions and disabling joint contractures may lead to significant complications.

Pathophysiology

Localized fibrosing disorders include several clinical and histopathological conditions that are similar to the skin involvement of systemic sclerosis, but the systemic features are absent. Localized fibrosing disorders can be classified into several subtypes that include morphea, generalized morphea, and linear scleroderma, in which facial involvement is termed en coup de sabre. Linear scleroderma and morphea can coexist in the same patient. Other fibrosing conditions mentioned in this article include retroperitoneal fibrosis, mediastinal fibrosis, and Dupuytren contracture.

Frequency

United States

The frequency of morphea ranges between 3.4 cases per million adults to 2.7 cases per 100,000 population, depending on the report.

International

No particular geographic distribution has been noted.

Mortality/Morbidity

• The clinical course of the disease is often benign, but widespread lesions and disabling joint contractures may lead to significant complications.
• Localized fibrosing disorders are only rarely life threatening, but they can severely affect quality of life, particularly in children.

Race

• Morphea seems to be more prevalent in whites than in blacks.

Sex

• Morphea is more common in women than in men, with a female-to-male ratio of 3-4:1.
• Morphea may appear or worsen during pregnancy.

Age

• Children are more likely than adults to develop localized forms of scleroderma. Because of the impact on growth, these lesions can result in major facial or limb asymmetry, flexion contractures, and disability.
• Linear scleroderma tends to affect children and adolescents.
• Morphea en plaque is more common in adults.

Clinical

History

The clinical presentation of morphea varies depending on the level of tissue involvement and extent of the lesions. The diagnosis is based more on physical examination than on history. Certain features, including localization of the lesions, help the clinician increase the index of suspicion for a specific diagnosis.

• A common feature of morphea is skin thickening.
• Internal organ involvement is not evident in most patients with morphea.
• Some patients present with associated arthralgias, foot and hand deformities, central nervous system abnormalities, intermittent abdominal pain, and periosteal erosions and osteolysis.
• Spina bifida is found in almost 33% of patients with morphea.
• Associated cutaneous pathologies include alopecia areata, vitiligo, dystrophy of the nails, and ichthyosis.
• Occasionally, localized morpheic lesions occur in the uninvolved skin of patients with progressive systemic sclerosis.
• Morphea has been reported in association with systemic lupus erythematosus, primary biliary cirrhosis, pemphigus, and dermatomyositis.

Physical

• Plaque morphea: Superficial morphea are often confined to the dermis (see Images 1-2) and occasionally to the superficial panniculus. Subsets include morphea en plaque, guttate morphea, keloid morphea, lichen sclerosus et atrophicus, and atrophoderma of Pasini and Pierini.
  • Morphea en plaque: This is the most prevalent form of this group. It involves only 1 or 2 anatomic sites, usually the trunk. The disease is characterized by one or more circular areas of induration, usually larger than 1 cm in diameter, with varying degrees of pigment changes. An erythematous or violaceous halo (lilac ring), which is often evident during early disease, corresponds with an inflammatory state. As the disease progresses, the skin becomes sclerotic. As the inflammation subsides, the center of the lesion becomes whitish. After months to years, the skin softens and becomes atrophic, and a residual area of hypopigmentation or hyperpigmentation might occur. Distinctive borders usually separate the plaques from the normal surrounding skin.
  • Guttate morphea: This subset usually occurs on the upper trunk. Typically, it presents as multiple oval lesions between 2-10 mm in diameter. The lesions often manifest as faint erythema, followed by mild induration and hypopigmentation or hyperpigmentation.
  • Keloid morphea: This presents as nodules that resemble keloids in the presence of typical morphea.
  • Lichen sclerosus et atrophicus: This is characterized by shiny white plaques often preceded by violaceous discoloration of the skin. This subset has a predilection for the anogenital area and has an increased association with autoimmune-related diseases (eg, vitiligo, alopecia areata).
  • Atrophoderma of Pasini and Pierini: This presents as asymptomatic, hyperpigmented atrophic patches with well-demarcated "cliff drop borders" on the trunk. No pronounced inflammatory or sclerotic changes are present. The course is chronic, with spontaneous resolution usually after 10 years.
• Generalized morphea
  • This occurs when individual plaques of morphea become confluent lesions.
  • It can affect more than 2 anatomic sites, including the upper trunk, breasts, abdomen, and upper thighs.
  • Arms, legs, face, neck, and scalp may also be involved.
  • Bullae may develop in localized areas, particularly around the abdomen.
  • Keratoses and calcinosis may occur.
  • Contractures may occur in limbs, and mobility may be restricted.
• Bullous morphea
  • This is characterized by tense subepidermal bullae in the presence of typical morphea or morphea profunda.
  • The lesions can occur on the face, neck, trunk, or extremities and may be superficial or extend deep into the dermis.
• Linear scleroderma: This is characterized by one or more linear streaks and induration that can involve dermis, subcutaneous tissue, muscle, and bone. It occurs on the extremities, face, or scalp of children and adolescents. It is subdivided into subgroups including linear scleroderma, lesions en coup de sabre, and progressive hemifacial atrophy (Parry-Romberg syndrome).
  • Linear scleroderma: This is characterized by discrete linear induration that primarily affects the extremities. In more than 90% of patients, the involvement is unilateral. Linear scleroderma is complicated by deformities, joint contractures, and severe limb atrophy. The process can affect the growth of bony structures.
  • Lesions en coup de sabre: If the face or scalp is affected with linear scleroderma, the involvement is often compared to a stroke from a sword (sabre). The lesions start with contractions and firmness of the skin over the affected area. Then, an ivory, irregular, sclerotic plaque with hyperpigmentation at the edge develops.
  • Progressive hemifacial atrophy (Parry-Romberg syndrome): This subtype results in hemiatrophy of the face. The primary lesions occur in the subcutaneous tissue, muscle, and bone. The disease usually begins in the first 2 decades of life.
• Deep morphea: This primarily involves the deep dermis, subcutaneous tissue, fascia, or superficial muscle. The lesions are more diffuse than in linear scleroderma and do not demonstrate a linear pattern. Subtypes include subcutaneous morphea, morphea profunda, disabling pansclerotic morphea of childhood, and eosinophilic fasciitis.
  • Subcutaneous morphea: It primarily involves the panniculus or subcutaneous tissue. The onset of sclerosis is usually rapid, occurring during a period of several months. This is a more of an inflammatory condition than other types of morphea.
  • Morphea profunda: The entire skin feels thickened, bound down, and taut. Patients develop deep sclerosis of the skin. Onset usually occurs before age 14 years. The extensor aspect of the extremities and trunk develops sclerotic plaques that extend deep into the subcutaneous tissue, fascia, muscle, and bone. The lilac ring is usually absent.
  • Disabling pansclerotic morphea of childhood: This is an aggressive and mutilating variant of morphea. It is characterized by generalized, full-thickness involvement of the trunk, extremities, face, and scalp. The fingertips and toes are usually spared.
  • Eosinophilic fasciitis: This condition is characterized by a painful peau d'orange appearance involving the extremities, proximal to the hands and feet. The fascia is the predominant level of involvement. The natural course is not well defined, but patients seem to spontaneously regress or remain unchanged for years.
• Regional fibrosing disorders
  • Mediastinal fibrosis is characterized by excessive perinodal fibrotic proliferation that invades and destroys normal mediastinal structures. It can coexist with retroperitoneal fibrosis. It is considered the most serious late complication of remote Histoplasma capsulatum infection. Tuberculosis has been considered another triggering agent. Mediastinal hemorrhage and methysergide use also can trigger mediastinal fibrosis.
    • Patients with mediastinal fibrosis can present with pleuritic chest pain, malaise, and pain and stiffness in the thoracic spine. Other symptoms include dyspnea, cough, hemoptysis, and superior vena caval obstruction. The fibrotic process may accrue over prolonged periods and may extend within the lumina of critical mediastinal structures to produce complete occlusion. Patients may develop severe stenosis of the trachea, carina, or mainstem bronchi.
    • An accentuated pulmonic component of the second heart sound, wheezing, and localized murmur are among the most common physical findings. Thoracotomy may be required for histologic diagnosis. Successful superior vena cava bypass surgery has been described. Corticosteroid therapy has been effective in some reported cases.
  • Retroperitoneal fibrosis, or Ormond disease, is a rare inflammatory fibrosing disorder that leads to compression of the ureter, vena cava, nerves, and aorta. The disorder is about twice as common in males as in females, and the peak age at onset is in the fifth and sixth decades of life. The course is usually slowly progressive in nature.
    • Low back pain is the most common symptom. Weight loss and fever are common. The most common clinical presentation of retroperitoneal fibrosis is renal dysfunction due to obstruction of the ureters. The retroperitoneal involvement may spread to the deep structures in the pelvis. Patients with retroperitoneal fibrosis can present with upper gastrointestinal bleeding and ascites due to complications of portal hypertension. Some patients may present with signs and symptoms of pulmonary hypertension associated with pulmonary arterial and venous obstruction.
    • Retroperitoneal fibrosis has been associated with the use of certain medications, including methysergide, ergotamine, pergolide (withdrawn from US market March 29, 2007), hydralazine, and methyldopa. Associated diseases include atherosclerotic disease of the aorta (abdominal aortic aneurysm), systemic lupus erythematosus, vasculitis, scleroderma, biliary cirrhosis, and malignancy.
    • Laboratory abnormalities are nonspecific, including an elevated erythrocyte sedimentation rate. The diagnosis is often suggested by findings of intravenous pyelography. Ultrasonography, CT scanning, and MRI are useful, showing a fibrotic paraaortic mass (see Image 3). Gallium scintigraphy may help assess activity of inflammation. Multiple deep biopsies may be required to distinguish this condition from malignancy.
    • Surgical treatment is often highly successful. Steroid therapy may be useful in the cases detected before significant obstruction has occurred. Azathioprine, cyclophosphamide, and tamoxifen have been used as well, with apparent success. The long-term outlook is fairly good if the disease is recognized early before irreversible obstructive lesions have occurred. Most deaths are secondary to renal failure.
  • Dupuytren contracture consists of a thickening and shortening of the palmar fascia. Thick, cordlike superficial fibrous tissue, which can be felt in the palm, causes a contracture, usually of the fourth finger. The fifth, third, and second fingers are involved in decreasing order of frequency. Initial lesions might show dimpling or puckering of the skin over the involved fascia. Dupuytren contracture occurs predominantly in whites and is more common in Europe. The condition is 5 times more common in men. A gradual increase in incidence occurs with age. An association with diabetes and liver disease has been reported.

Causes

• The causes of localized fibrosing disorders are unknown.
• Suggested causes include genetic, infectious, and autoimmune mechanisms. Neoplasms, infections, trauma, aortic aneurysms, and ergot have been associated with retroperitoneal fibrosis.
  • Autoantibodies are frequently seen in localized scleroderma, particularly antinuclear antibodies and antibodies to single-stranded DNA and histones.
  • Environmental agents (eg, L-tryptophan, vinyl chloride, bleomycin, methysergide, ergot, bromocriptine, radiation) can cause a morphealike picture. Methysergide is also associated with the development of retroperitoneal fibrosis. Other drugs that can trigger this condition include phenacetin, hydralazine, and propranolol.
  • Infections (eg, varicella, measles, Epstein-Barr virus, borreliosis) may precede the onset of morphea. H capsulatum infection has been associated with the development of mediastinal fibrosis.
  • Vaccination (bacille Calmette-Guérin [BCG]) has also been reported to precede the onset of morphea, and trauma has been considered a possible triggering event in these conditions.

Differential Diagnoses

Acromegaly
Graft Versus Host Disease
Lipodystrophy, Localized

Other Problems to Be Considered

Acrodermatitis chronica atrophicans
Bleomycin exposure
Bromocriptine exposure
Carcinoid syndrome
Panniculitis
Ergot exposure
Localized lipoatrophies
Methysergide exposure
Phenylketonuria
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes)
Poikiloderma
Porphyria cutanea tarda
Scleredema
Scleromyxedema
Vitamin K injection

Workup

Laboratory Studies

• Currently, no reliable laboratory markers are available for assessing disease activity.
• Antinuclear antibodies can be detected in 46-80% of patients with morphea. The most common pattern is homogeneous, but this is nonspecific.
• The erythrocyte sedimentation rate may be increased in eosinophilic fasciitis, in some forms of linear and localized morphea, and in mediastinal and retroperitoneal fibrosis.
• A polyclonal gammopathy may occur in patients with morphea or eosinophilic fasciitis.

Imaging Studies

• Computed tomographic scanning and magnetic resonance imaging of the chest and abdomen are helpful in evaluating patients with mediastinal and retroperitoneal fibrosis, respectively.

Procedures

• A biopsy of the lesion is considered the criterion standard.
• For plaque, generalized, and bullous morphea, a deep punch biopsy is often sufficient.
• For linear and deep forms of morphea, an excisional biopsy of the skin including the dermis, panniculus, and fascia is preferred.
• Biopsies of fibrotic lesions of the mediastinum and retroperitoneum are useful in establishing a diagnosis in regional fibrosing disorders and for ruling out infection or malignancy.

Histologic Findings

• Dermal fibrosis characterizes the cutaneous lesions of both local and systemic forms of scleroderma.
• The lesion seen in localized sclerosing conditions is characterized by infiltration of lymphocytes, mast cells, plasma cells, and eosinophils with excess collagen deposition extending into the dermis, the subcutaneous fat, and, in some forms, deeper structures.
• The focus of morphea seems to be collagen fibers, which become altered with thickening and hyalinization.
• The histology of mediastinal and retroperitoneal fibrosis consists of foci of chronic inflammatory infiltrates at the periphery of the lesion with lymphocytes and macrophages and a central region of fibrosis.

Treatment

Medical Care

• Most patients with plaque morphea experience spontaneous remission and require no specific treatment. Treatment depends entirely on the severity of the findings. Intralesional injections of corticosteroids might be helpful in early stages.
  • The progression of Dupuytren contracture varies, ranging from little or no change over many years to rapid progression and complete flexion contracture of one or more digits.
  • The treatment of mediastinal and retroperitoneal fibrosis has not been well studied, although corticosteroids, immunosuppressive agents, and tamoxifen appear to be effective.
• If the lesions spread (as in generalized morphea), anti-inflammatory or immunosuppressive medications may be indicated.
• Although numerous therapeutic agents have been used for morphea, treatment remains unsatisfactory.
• Daily antimalarial agents may be beneficial, especially when lesions are highly inflammatory.
• In linear scleroderma and deep morphea, aggressive treatment, including systemic corticosteroids, may be necessary. Topical corticosteroids may also be useful.
• Occasionally, other disease-modifying agents, including d-penicillamine, azathioprine, sulfasalazine, methotrexate, and cyclophosphamide, are necessary to control a severe inflammatory process.
• Plasmapheresis may be useful in some patients, but no randomized controlled trials have been published.
• Reports indicate that patients with severe localized scleroderma have been treated successfully with psoralen plus ultraviolet light of the A wave length (PUVA) bath photochemotherapy.¹
  • Low-dose UVA1 phototherapy can be highly effective for sclerotic plaques, even in patients with advanced localized fibrosing disorders with rapidly evolving lesions despite conventional therapy.
  • Patients are usually irradiated with 20 J/cm² UVA1 for 12 weeks, with a cumulative UVA1 dose of 600 J/cm².
• A recent study reported that occlusive treatment with tacrolimus ointment can be useful in localized scleroderma.² Imiquimod has also been suggested as a potential treatment for morphea and fibromatoses, but more studies are needed.³

Surgical Care

• Tendon-lengthening procedures and surgical release of joint contractures are sometimes necessary.
• Amputation may be necessary as a consequence of severe flexural deformity.
• Often, patients with en coup de sabre or Parry-Romberg syndrome require surgical reconstruction of the face and scalp.
• Reports indicate that en coup de sabre lesions have been repaired effectively with a combination of an expanded skin flap and a hydroxyapatite implant.
• When actual contractures occur in Dupuytren contracture, surgical intervention is desirable. Limited fasciotomy is effective in most instances. More radical procedures, including amputation, are necessary in rare cases. Palmar fasciotomy is a useful and more benign procedure. Surgical management is often required to treat the complications of both retroperitoneal and mediastinal fibrosis.

Consultations

• Patients with the linear and deep types of morphea require physical therapy to prevent joint deformities and skin contractures. Heat treatment and massage might be helpful.
• Psychotherapy for people with deformities and disfiguration is very important.
• Early evaluation by a reconstructive or plastic surgeon is important for patients with en coup de sabre lesions or Parry-Romberg disease.
• Evaluation by a hand surgeon may be indicated in patients with Dupuytren contracture for consideration of releasing the contractures.
• Surgical consultation may be considered in patients with mediastinal and retroperitoneal fibrosis if obstructive lesions occur.

Activity

• Physical therapy is very important for patients prone to develop joint and muscle contractures and deformities. Joint mobility should be maintained.

Medication

Glucocorticoids can be used systemically, topically in ointment form, or under occlusive dressings. Diluted triamcinolone acetonide suspension of 1:3 to 1:5 given by intralesional injection has been suggested. Repeated infiltrations are recommended every 3-4 weeks. Ointments containing heparin or heparinoids may also be helpful.

Linear scleroderma in children has effectively been treated with oral calcitriol. The use of phenytoin has been advocated, especially for linear morphea. Long-term treatment with oral p-aminobenzoate has been suggested, but the results are unclear.

Topical tocoretinate for 6 months to 3 years may be beneficial for treating skin sclerosis.⁴ The following agents have been reported to be beneficial in morphea: d-penicillamine, corticosteroids, phenytoin, aminobenzoate potassium, dimethyl sulfoxide, vitamin E, disodium edetate, sulfasalazine, cyclofenil, methotrexate, colchicine, antimalarials, azathioprine, griseofulvin, penicillin, chlorambucil, cyclophosphamide, etretinate, isotretinoin, and interferon alfa and gamma.

No treatment seems to alter the natural course of localized scleroderma, but reports indicate that moderate doses of systemic or locally injected corticosteroids, d-penicillamine, and photochemotherapy with 8-methoxypsolaren have been helpful in decreasing the degree of inflammation and fibrosis.

Antimalarials

These agents have anti-inflammatory properties and inhibit multiple functions of phagocytes, including reactive oxygen species release.

Hydroxychloroquine (Plaquenil)

Treats malaria, rheumatoid arthritis, systemic lupus erythematosus, and juvenile chronic arthritis. Use in localized fibrosing disorders has not been well characterized, but several reports indicate some efficacy. Response to antimalarials is slow, so it can take up to 6 months for full effect.

Dosing

Adult

200-400 mg PO qd

Pediatric

6-7 mg/kg PO qd or divided bid; not to exceed 400 mg/d

Interactions

Hydroxychloroquine may increase levels of digoxin and reduce levels of praziquantel

Contraindications

Documented hypersensitivity; retinal or visual field changes

Precautions

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

Requires careful ophthalmologic screening at baseline and q6-12mo to identify early retinal damage; psoriasis, porphyria, hepatic dysfunction, G-6-PD deficiency

Corticosteroids

These agents have potent anti-inflammatory and immunosuppressive properties. They inhibit lymphocyte proliferation and delayed-type hypersensitivity and cause changes in WBC traffic and Fc receptor suppression.

Prednisone (Orasone, Deltasone, Sterapred)

Constitutes main therapy for multiple inflammatory and autoimmune disorders including vasculitis, systemic lupus erythematosus, inflammatory myopathies, and polymyalgia rheumatica. May be useful in localized and regional fibrosing disorders by inhibiting inflammatory response.

Dosing

Adult

5-60 mg/d PO, depending on severity of symptoms; taper as manifestations resolve

Pediatric

0.5-2 mg/kg/d PO; taper as manifestations resolve

Interactions

May cause water and salt retention; exacerbates hypertension increasing requirement for antihypertensive drugs in hypertensive patients; may aggravate hyperglycemia increasing requirement or hypoglycemic agents in diabetic patients; metabolism may be increased by drugs that induce hepatic microsomal enzymes requirements including phenytoin, phenobarbital, carbamazepine and rifampin, thus increasing the corticosteroid requirements

Contraindications

Documented hypersensitivity; severe bacterial, viral, or fungal infections; active peptic ulcer disease; diabetes mellitus

Precautions

Pregnancy

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

Precautions

Toxicities include weight gain, dyspepsia, mood changes, infection, peptic ulcer disease, hypertension, diabetes mellitus, osteoporosis, avascular necrosis, cataracts, glaucoma, myopathy and skin changes; growth retardation in children; abrupt discontinuation may result in adrenal crisis

Triamcinolone (Aristocort)

Can be helpful in inhibiting inflammation and fibrosis in localized fibrosing conditions. Repeated administrations might be necessary.

Dosing

Adult

Topical: Apply thin film bid/tid to response
Intralesional: Suspension of 1:3-1:5 given by intralesional injection suggested; repeated infiltrations are recommended q3-4wk

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; fungal, viral, and bacterial skin infections

Precautions

Pregnancy

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

Precautions

A percentage of topical drug might be absorbed systemically; if application is repeated, there may be some systemic effects of the corticosteroids

Immunosuppressives/disease-modifying antirheumatic drugs

These agents have anti-inflammatory and immunosuppressive properties. Some drugs may have antifibrotic effects.

D-Penicillamine (Cuprimine)

Used to treat rheumatoid arthritis and shown to have some benefit in systemic sclerosis. Its mode of action is unknown, but seems to modulate the immune system via sulfhydryl exchange reactions in various cells.

Dosing

Adult

125-250 mg/d PO, increase 250 mg q2-3mo prn, not to exceed 1 g/d PO
Medication must be taken in morning, with an empty stomach; wait at least 2 h before ingesting any food

Pediatric

20-30 mg/kg/d PO divided qid

Interactions

Antacids (magnesium-aluminum hydroxides) reduce bioavailability; may reduce digoxin concentrations; oral iron substantially reduces plasma penicillamine concentration, with reduced therapeutic response

Contraindications

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

Precautions

Pregnancy

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

Precautions

Caution with concomitant use with other nephrotoxic drugs or administration of drugs or other substances that inhibit or induce CYP3A enzyme systems (systemic formulations); do not use simultaneously with cyclosporine (systemic formulations); hyperkalemia may develop; do not use potassium-sparing diuretics during therapy (systemic formulations); increases risk of lymphoma and other malignancies; increases risk of varicella-zoster virus infection, herpes simplex virus infection, or eczema herpeticum (topical); insulin-dependent posttransplant diabetes mellitus may develop (systemic formulations); limited data with pediatric kidney transplantation patients (systemic formulations)
May cause hypertension, myocardial hypertrophy (systemic formulations); minimize or avoid natural or artificial sunlight exposure (topical); neurotoxicity and nephrotoxicity may develop (systemic formulations); not recommended in patients with Netherton syndrome (topical); risk of anaphylactic reaction (injection); susceptibility to infection; vaccinations may be less effective; use of live vaccines should be avoided during therapy

Azathioprine (Imuran)

Purine analog and derivative of 6-mercaptopurine. Has immunosuppressive effects by inhibiting purine synthesis in cells. Used for treating systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and inflammatory myopathies and preventing allograft rejection.

Dosing

Adult

2-3 mg/kg/d PO in single or divided dose
Starting dose: 1 mg/kg/d PO; increase depending on clinical and hematologic response and toxicity

Pediatric

Administer as in adults

Interactions

Allopurinol may increase toxicity of azathioprine, and a dosage adjustment is necessary; azathioprine may reduce effects of warfarin

Contraindications

Documented hypersensitivity; systemic infections and severe cytopenias

Precautions

Pregnancy

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

Precautions

Nausea and vomiting, leukopenia, thrombocytopenia, anemia, infection, abnormal liver function tests may occur

Sulfasalazine (Azulfidine)

Sulfonamide derivative with anti-inflammatory properties. Useful for treating rheumatoid arthritis, spondyloarthropathies, and inflammatory bowel disease. Effects on localized fibrosing conditions are not well characterized.

Dosing

Adult

1 g PO qd/qid; not to exceed 3 g/d

Pediatric

<2 years: Do not administer
>2 years: 40-60 mg/kg/d PO divided bid/tid
Maintenance: 30 mg/kg/d PO in divided doses

Interactions

Reduces digoxin concentrations; concurrent methenamine can result in crystalluria; inhibits metabolism of warfarin

Contraindications

Documented hypersensitivity to salicylates or sulfas; porphyria; intestinal or urinary tract obstructions

Precautions

Pregnancy

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

Precautions

Caution in renal or hepatic function impairment, allergy, or aspirin-sensitive asthma, G-6-PD deficiency, blood dyscrasias

Methotrexate (Rheumatrex)

This drug reversibly inhibits dihydrofolate reductase; limits the availability of 1-carbon fragments necessary for synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. Extensively used for cancer treatment, rheumatoid arthritis, psoriasis, and as a steroid-sparing agent in various autoimmune conditions.

Dosing

Adult

In autoimmune conditions: 7.5-25 mg/wk PO/SC as single dose; folic acid supplementation is usually given concomitantly

Pediatric

5-15 mg/m²/wk PO/SC as single dose

Interactions

Oral tetracyclines and aminoglycosides reduce methotrexate absorption by 30-50%; antimalarials may reduce methotrexate levels; binding resins may reduce methotrexate levels; omeprazole and penicillins may increase methotrexate levels; etretinate increases risk of hepatotoxicity
Cyclosporine reduces methotrexate excretion and may increase toxicity; trimethoprim/sulfamethoxazole also inhibits folate metabolism, thus potentiating methotrexate toxicity

Contraindications

Liver or renal dysfunction, alcohol abuse, preexisting profound bone marrow depression, certain pulmonary diseases

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBC count, LFTs, BUN, and creatinine at regular intervals, usually every mo at the initiation of therapy; monitor for cough or shortness of breath for possibility of pneumonitis

Cyclophosphamide (Cytoxan, Neosar)

Synthetic nitrogen mustard alkylating agent used for treating severe lupus complications, vasculitis, refractory rheumatoid arthritis, scleroderma lung disease, and myopathies. Its role in localized forms of fibrosis has not been well characterized. It is indicated only for severe inflammatory lesions that do not respond to other agents.

Dosing

Adult

0.5-2 mg/kg/d PO

Pediatric

1-2.5 mg/kg/d PO

Interactions

Long-term high-dose phenobarbital therapy may increase metabolism to its active metabolite increasing toxicity; inhibits cholinesterase activity for up to 10 days after an intravenous dose which can potentiate the effect of succinylcholine chloride

Contraindications

Documented hypersensitivity; suppressed bone marrow function; infections; prostatic hyperplasia; lower urinary tract obstruction; previous history of hemorrhagic cystitis

Precautions

Pregnancy

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

Precautions

Toxicities include nausea and vomiting, leukopenia, thrombocytopenia, anemia, infection, alopecia, hemorrhagic cystitis, infertility, teratogenicity, and risk of malignancy

Colchicine

Inhibits microtubule formation in leukocytes and decreases joint inflammation. Drug has no direct analgesic properties. Useful in gout, skin vasculitis, and Behçet disease. Has been advocated to have an antifibrotic effect with potential therapeutic implications in generalized or localized fibrosing disorders.

Dosing

Adult

0.6-1.8 mg PO qd in divided doses

Pediatric

Children: Not established
Adolescents: Administer as in adults

Interactions

Sympathomimetic agent toxicity and effect of CNS depressants are significantly increased with colchicine

Contraindications

Documented hypersensitivity; serious gastrointestinal, renal, hepatic, and cardiac disorders, blood dyscrasias

Precautions

Pregnancy

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

Precautions

Older patients, children, and lactation; may induce ileal vitamin B-12 malabsorption; can cause a peripheral neuritis, diarrhea, malaise, nausea, vomiting, alopecia, and dermatitis; monitor patients for cytopenias

Tacrolimus (Prograft, Protopic)

Used to treat atopic dermatitis and for prophylaxis of renal and kidney transplant rejection.

Dosing

Adult

Atopic dermatitis: Apply thin layer of 0.03% or 0.1% ointment to affected areas bid
Kidney transplant rejection prophylaxis: 0.2 mg/kg/d PO divided q12h
Kidney transplant rejection prophylaxis: 0.03-0.05 mg/kg/d continuous IV infusion; convert to PO formulation as soon as possible
Liver transplant rejection prophylaxis: 0.03-0.05 mg/kg/d continuous IV infusion; convert to PO formulation as soon as possible
Liver transplant rejection prophylaxis: 0.1-0.15 mg/kg/d PO divided q12h

Pediatric

Atopic dermatitis (ages 2-15 y): Apply thin layer of 0.03% ointment to affected areas bid
Liver transplant rejection prophylaxis: 0.03-0.05 mg/kg/d continuous IV infusion
Liver transplant rejection prophylaxis: 0.15-0.2 mg/kg/d PO divided q12h

Interactions

Caution with drugs associated with renal dysfunction, including aminoglycoside, amphotericin B, cisplatin, and others (can enhance nephrotoxicity); concentrations may be increased in presence of diltiazem, nicardipine, nifedipine, verapamil, clotrimazole, fluconazole, itraconazole, ketoconazole, clarithromycin, erythromycin, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, cyclosporine, danazol, methylprednisolone, and protease inhibitors; concentrations may decrease when administered with carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin

Contraindications

Documented hypersensitivity to tacrolimus products or hydrogenated castor oil (IV formulation)

Precautions

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

Shown to cross placenta and may cause neonatal hyperkalemia and renal dysfunction in pregnancy (ointment may be used during pregnancy only if benefits to mother outweigh risks to fetus)
Renal insufficiency; monitor CBC count and urinalysis q1-2mo; toxicity is common, including pruritic and urticarial rash, nausea, dysgeusia, and stomatitis; can cause proteinuria and different forms of renal disease; can cause thrombocytopenia, neutropenia, and aplastic anemia; reports indicate that different autoimmune diseases have been triggered by this drug (eg, myasthenia gravis, inflammatory myopathies, Goodpasture syndrome)

Topical Skin Product

Agents such as imiquimod may induce mediators of immune processes.

Imiquimod (Aldara)

Topical antiviral agent. Induces secretion of interferon alpha and other cytokines; mechanism of action is unknown.

Dosing

Adult

Actinic keratosis: Apply 5% cream to defined treatment area 2 times/wk hs for 16 wk; leave on skin for 8 h
Superficial basal cell carcinoma: Apply 5% cream to defined treatment area 5 times/wk hs for 6 wk; leave on skin for 8 h
Venereal warts: Apply 5% cream to affected area hs for 3 times/wk for up to 16 wk; leave on skin for 6-10 h

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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

Has not been evaluated for treatment of urethral, intravaginal, cervical, rectal, or intra-anal human papillomavirus disease; pediatric patients (safety and efficacy in patients <18 y have not been studied); avoid eye contact with topical product; if severe local skin reactions occur, the cream should be removed by washing the treatment area with soap and water; treatment can be resumed after the reaction has subsided; topical administration is not recommended until genital/perianal tissue is healed from any previous drug or surgical treatment; inflammatory conditions of the skin; may weaken condoms and vaginal diaphragms; thus, concurrent use is not recommended; safety and efficacy not established for basal cell nevus syndrome or xeroderma pigmentosum

Follow-up

Further Outpatient Care

• Periodic follow-up is recommended to detect early spread of lesions or other chronic complications.

Deterrence/Prevention

• Early evaluation for prevention and treatment of joint and muscle contractures and deformities is important.
• Cases that involve children with severe facial deformities should be referred to a plastic surgeon early for prompt evaluation and consultation about possible treatment.

Complications

• Joint contractures, deformities, and severe limb atrophy can occur in patients with linear scleroderma.
  • Severe atrophy of underlying muscle and bone also can occur.
  • Disabling pansclerotic morphea of childhood can include claw deformity of the hands.
  • Arthralgias, osteoporosis, flexion contractures, and other bone changes are common.
• A 1.5- to 7-cm leg length discrepancy occurs in 20% of patients with linear scleroderma.
• Psychosocial problems related to adjusting to deformities and disfiguration can occur.
• Loss of eyebrow or eyelashes, ptosis, pseudooculomotor palsy, uveitis, asymmetry of the tongue, and altered dentition and dental caries can occur in patients with morphea en coup de sabre.
• Overt seizures may occur in patients with Parry-Romberg syndrome.
• Aplastic anemia, thrombocytopenia, and hemolytic anemia have been reported in patients with eosinophilic fasciitis.
• Intense pain may be present, particularly in disabling pansclerotic morphea of children and in en coup de sabre lesions, probably due to cutaneous nerve involvement.
• In patients with generalized morphea, contractures may occur in limbs, and mobility may be restricted. Marked chest wall involvement may cause difficulty in breathing due to constriction of the thorax.
• In patients with mediastinal and retroperitoneal fibrosis, complications are related to obstruction of vascular structures, bronchi, or ureters.
• Complications in Dupuytren contracture are related to progressive hand deformities.

Prognosis

• In general, localized and regional fibrosing disorders carry a good prognosis.
• Plaquelike lesions tend to improve with time. The duration of the activity usually is 3-5 years, but some lesions persist longer.
• Residual pigmentation persists long term in about one-third of the patients.
• Linear lesions tend to persist longer than plaque lesions.
• Contractures may limit joint movements and may lead to clawing of the hands.
• Facial hemiatrophy persists.
• Individuals with the severe inflammatory subtypes, en coup de sabre linear scleroderma, or Parry-Romberg disease can have severe functional limitations.
• In mediastinal and retroperitoneal fibrosis, the prognosis is related to the amount of irreversible obstruction.

Miscellaneous

Medicolegal Pitfalls

• Distinguish localized scleroderma from systemic sclerosis in early stages.

Special Concerns

• In children, lesions can have a major impact on growth and result in major facial or limb asymmetry, flexion contractures, and disability.

Multimedia

Media file 1: This photograph shows morphea en plaque on the trunk of a patient. There is a distinctive border separating the plaque from the surrounding normal skin (reproduced with permission of Mayo Clinic Proceedings).

Media file 2: This photograph shows generalized morphea on the trunk of a patient (reproduced with permission from Mayo Clinic Proceedings).

Media file 3: CT scan of the abdomen showing the typical paraaortic mass of retroperitoneal fibrosis.

References

1. Todd DJ, Askari A, Ektaish E. PUVA therapy for disabling pansclerotic morphoea of children. Br J Dermatol. Jan 1998;138(1):201-2. [Medline].

2. Mancuso G, Berdondini RM. Localized scleroderma: response to occlusive treatment with tacrolimus ointment. Br J Dermatol. Jan 2005;152(1):180-2. [Medline].

3. Namazi MR. Imiquimod: a potential weapon against morphea and fibromatoses. J Drugs Dermatol. Jul-Aug 2004;3(4):362-3. [Medline].

4. Mizutani H, Yoshida T, Nouchi N, et al. Topical tocoretinate improved hypertrophic scar, skin sclerosis in systemic sclerosis and morphea. J Dermatol. Jan 1999;26(1):11-7. [Medline].

5. Dehen L, Roujeau JC, Cosnes A, et al. Internal involvement in localized scleroderma. Medicine (Baltimore). Sep 1994;73(5):241-5. [Medline].

6. Eguchi T, Harii K, Sugawara Y. Repair of a large "coup de sabre" with soft-tissue expansion and artificial bone graft. Ann Plast Surg. Feb 1999;42(2):207-10. [Medline].

7. Falanga V, Medsger TA Jr, Reichlin M, et al. Linear scleroderma. Clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med. Jun 1986;104(6):849-57. [Medline].

8. Ghersetich I, Teofoli P, Benci M, et al. Localized scleroderma. Clin Dermatol. Apr-Jun 1994;12(2):237-42. [Medline].

9. Gilkeson GS, Allen NB. Retroperitoneal fibrosis. A true connective tissue disease. Rheum Dis Clin North Am. Feb 1996;22(1):23-38. [Medline].

10. Jablonska S, Blaszczyk M. Sclerodermalike diseases. Clin Dermatol. Jul-Sep 1994;12(3):437-48. [Medline].

11. Kerscher M, Volkenandt M, Gruss C, et al. Low-dose UVA phototherapy for treatment of localized scleroderma. J Am Acad Dermatol. Jan 1998;38(1):21-6. [Medline].

12. Mathisen DJ, Grillo HC. Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg. Dec 1992;54(6):1053-7; discussion 1057-8. [Medline].

13. Peterson LS, Nelson AM, Su WP. Classification of morphea (localized scleroderma). Mayo Clin Proc. Nov 1995;70(11):1068-76. [Medline].

14. Schachter RK. Localized scleroderma. Curr Opin Rheumatol. Dec 1989;1(4):505-11. [Medline].

15. Schumacher HR. Multifocal fibrosclerosis. In: Cecil Textbook of Medicine. WB Saunders Co; 2000:1561-62.

16. Varga J, Kahari VM. Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and related fibrosing disorders. Curr Opin Rheumatol. Nov 1997;9(6):562-70. [Medline].

Keywords

localized fibrosing disorders, linear scleroderma, morphea, regional fibrosis, localized scleroderma, systemic sclerosis, generalized morphea, en coup de sabre, retroperitoneal fibrosis, mediastinal fibrosis, Dupuytren contracture, morphea en plaque, plaque morphea, guttate morphea, keloid morphea, lichen sclerosus et atrophicus, atrophoderma of Pasini and Pierini, bullous morphea, deep morphea, subcutaneous morphea, morphea profunda, disabling pansclerotic morphea of childhood, eosinophilic fasciitis

Contributor Information and Disclosures

Author

Mariana J Kaplan, MD, Assistant Professor, Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School
Mariana J Kaplan, MD is a member of the following medical societies: American Association of Immunologists, American College of Rheumatology, American Federation for Medical Research, American Medical Association, Central Society for Clinical Research, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Medical Editor

Kristine M Lohr, MD, MS, Program Director, Professor, Department of Internal Medicine, Division of Rheumatology and Women's Health, University of Kentucky School of Medicine
Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Medical Women's Association
Disclosure: Nothing to disclose.

Pharmacy Editor

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

Managing Editor

Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Lawrence H Brent, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, and American College of Rheumatology
Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching

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; West Penn Allegheny Health System None Board membership

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