eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Juvenile Systemic Sclerosis

Luke M Webb, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center
David J Schwartz, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center; Cecilia P Mikita, MD, MPH, Associate Program Director, Allergy-Immunology Fellowship, Assistant Professor of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Hospital Intern Director, Staff Allergist/Immunologist, Walter Reed Army Medical Center

Updated: Jul 20, 2009

Introduction

Background

Juvenile systemic sclerosis (JSSc) is a rare connective tissue disease of unknown etiology. Characteristic features include fibrosis of the skin, subcutaneous tissues, and internal organs as well as abnormalities of the vascular and immune systems occurring in children 16 and younger. This disease is one of the most severe rheumatologic conditions diagnosed in children.

Pathophysiology

One of the earliest processes thought to occur in juvenile systemic sclerosis is vascular injury. This results in upregulation of endothelial cell adhesion molecules, which facilitates local platelet aggregation and infiltration of inflammatory cells. This endothelial injury is manifested clinically as Raynaud phenomenon, pulmonary hypertension, and renovascular hypertension. Fibrosis is due to increased organ and dermal infiltration of lymphocytes, macrophages, eosinophils and mast cells.

These inflammatory cells release numerous cytokines, including transforming growth factor beta (TGF-β) and interleukin-1 (IL-1). Among its numerous effects, IL-1 is known to stimulate the release of platelet-derived growth factor, which stimulates fibroblasts to increase production and deposition of extracellular matrix components such as collagen, fibronectin, and glycosaminoglycans. This fibrosis may affect any organ of the body, most commonly the skin, GI tract, lungs, heart, kidneys, and musculoskeletal system.

Little is known about the role of the various autoantibodies, such as ANA, seen in almost all cases of juvenile systemic sclerosis, but their presence is suggestive of an autoimmune process underlying the aforementioned vascular injury and fibrosis. Resistance of lymphocytes to apoptosis seen in these patients is a potential mechanism for the persistence of autoreactive T cells in juvenile systemic sclerosis.

Frequency

United States

Juvenile systemic sclerosis is a rare childhood disorder. Foeldvari reported an incidence of approximately .05 per 100,000 children.¹  In addition, 5-10% of adult cases of systemic sclerosis arise before age 16 years, meeting the age criterion for juvenile systemic sclerosis. New criteria aimed at more uniformly defining juvenile systemic sclerosis will aid in better estimation of incidence and prevalence of juvenile systemic sclerosis.

Mortality/Morbidity

Mortality rates in juvenile systemic sclerosis are more optimistic than that seen in adult systemic sclerosis. Five year and 20 year survival rates in juvenile systemic sclerosis are 89% and 69-82.5%, respectively. 

The greatest morbidity and mortality is seen in those children who develop pulmonary, cardiac, and renal manifestations of the disease. A recently published report reveals that the most significant predictors of mortality at the time of diagnosis are pericarditis, elevated creatinine levels, and fibrosis on chest radiography.² The most common cause of early death in patients with juvenile systemic sclerosis is heart failure due to dilated cardiomyopathy, likely related to pulmonary hypertension and myocardial fibrosis. 

In a study of 153 patients with juvenile systemic sclerosis, those patients that succumbed to this disease had a significantly shorter time to diagnosis from onset of symptoms (8.8 mo) compared with patients that were still alive at follow-up (23 mo).³ This demonstrates that those patients who eventually die due to complications of juvenile systemic sclerosis likely have a more progressive form that is more quickly recognized by doctors due to the severity of symptoms. This is consistent with mortality rates of most studies that show most deaths from juvenile systemic sclerosis occur within the first 5 years after diagnosis.

Morbidity from the disease is seen in most patients in the form of fibrosis of the skin, which may lead to contractures and loss of mobility, and Raynaud phenomenon with associated pain and paresthesias, as well as occasional digital ulcers. Arthralgias, arthritis, and muscle weakness may occur in as many as 26% of patients, and a small number may experience dyspnea, weight loss and dysphagia as well.

Race

In the United States, adult systemic sclerosis is more common in blacks than in whites, with a ratio of 2:1. No specific demographic data are available for juvenile systemic sclerosis.

Sex

Females are more commonly affected than males in juvenile systemic sclerosis, with an overall female-to-male ratio of approximately 3.6:1. This is much lower than the 15:1 female-to-male predominance seen in adult systemic sclerosis.

Age

A child must be younger than 17 years at the time of disease onset to the meet the criteria for juvenile systemic sclerosis. The youngest patient documented with juvenile systemic sclerosis was only a few months old at disease onset. The average age of onset is 8.1-8.8 years in the two largest case series published on juvenile systemic sclerosis. Due to the rarity of this childhood disease and the subtle nature by which it can first appear, the average time from symptom onset to diagnosis is 1.9 years, taking as long as 12 years in some cases. Of note, children who died from juvenile systemic sclerosis in these 2 studies were diagnosed almost 2 years later than the average child with juvenile systemic sclerosis.

Clinical

History

Raynaud phenomenon is the most common finding at the time of diagnosis and is present in approximately 75% of patients. Cold exposure or stress may induce vasoconstriction with the attendant episodic pallor and cyanosis, followed by erythema. Other skin changes such as induration and sclerodactyly are the next most common symptoms. Skin changes are often subtle and may take months to years to evolve. Swelling and puffiness of the hands and fingers, polyarthralgia, or polyarthritis of the hands, fingers, feet, and toes are also early symptoms seen in patients that go on to develop juvenile systemic sclerosis. Most cases of Raynaud phenomenon are primary and unrelated to any connective tissue disease such as juvenile systemic sclerosis or systemic lupus erythematosus (SLE). 

In patients with primary Raynaud phenomenon, common findings include bilateral involvement, no tissue necrosis, normal nail-fold capillaries, a normal erythrocyte sedimentation rate (ESR), and no autoantibodies. At least some of these features are expected in patients with Raynaud phenomenon secondary to juvenile systemic sclerosis, especially nail-fold capillary abnormalities and a positive ANA finding in addition to other skin findings proximal to the metacarpophalangeal and metatarsophalangeal joints. 

Systemic sclerosis requires organ or tissue involvement in addition to skin changes. This involvement may be manifested as dysphagia, gastroesophageal reflux, dyspnea, palpitations, arthritis, muscle weakness, and neuropathies.

Physical

• Cutaneous
  • Skin - Diffuse puffiness of the hands and feet, which may be followed by development of tautness of the skin 
  • Hyperpigmentation or hypopigmentation - Commonly misdiagnosed as vitiligo
  • Telangiectasias
  • Face - Pursed lips, flattened and lost facial folds and features, and difficulty opening the mouth and chewing
• Peripheral vascular
  • Raynaud phenomenon - Pallor, cyanosis, suffusion, and tingling of the fingers, which occurs abruptly and episodically (When the phenomenon is associated with a known cause [eg, scleroderma], it is termed Raynaud syndrome.)
  • Abnormal nailfold capillaroscopy - Hemorrhages, abnormal or dilated loops, megacapillaries, arborization, and avascular areas 
• GI
  • Esophageal dysmotility – Detected by newer diagnostic techniques in 90% of patients (Symptomatic dysphagia is seen in only 24% of patients.) 
  • Reflux - Seen in 30% of children (Some also develop significant weight loss and diarrhea, possibly due to malabsorption.) 
• Pulmonary
  • Interstitial pulmonary fibrosis, inflammatory alveolitis, and pulmonary hypertension either alone or in combination
  • Pulmonary hypertension and fibrosing alveolitis leading to interstitial pulmonary fibrosis (major complication and cause of death in juvenile systemic sclerosis)
• Cardiac
  • Heart failure - Most common cause of death in juvenile systemic sclerosis, although often complicated by concomitant pulmonary hypertension
  • Arrhythmias- Inflammatory and fibrotic processes such as pericarditis, myocardial fibrosis, and contraction band necrosis of coronary vessels
• Musculoskeletal
  • Sclerodactyly (ie, tightening of the skin over the fingers), often with a tapered appearance of the fingertips and flexion contractures, leading to a decreased ability to use the hands (This is seen in 46% of patients at the time of diagnosis and develops in 66% of patients over the course of the disease.)
    
    

    

    Photo of hands revealing sclerodactyly. This demonstrates the progression of disease over 7 years.

    
    
  • Digital tuft resorption - Observed on radiography, known as acro-osteolysis
  • Chronic myopathy - Mild weakness and minimal muscle enzyme elevations
  • Myositis - Not uncommon in systemic sclerosis, must be distinguished from other connective tissue diseases
  • Long-bone growth arrest and fibrotic bands that involve the joint capsule (in long-standing cases)
  • Contractures of the fingers and toes
  • Subcutaneous calcinosis - Seen in 19% of patients diagnosed with juvenile systemic sclerosis, usually involving extensor surfaces of both upper and lower extremities
  • Arthritis and arthralgias -More commonly seen in children with juvenile systemic sclerosis than in adult-onset disease
• Renal
  • Kidney involvement may be subtle, such as a slow rise in creatinine levels. 
  • Renal changes were reported in only 13% of cases of juvenile systemic sclerosis, but patients who develop proteinuria or hypertension are at increased risk of death.
  • The renal lesion is a slowly progressive vasculitis.
  • Intimal proliferation, medial thinning, and adventitial fibrosis, with decreased blood flow and glomerular function, characterize this disorder. 
• Neurological
  • Although seizures are rare in this population, 3% of patients with juvenile systemic sclerosis developed seizures at some time during their disease. 
  • Peripheral neuropathy, such as carpal tunnel syndrome, is also rare and is caused by fibrotic impingement of a nerve. 
  • Trigeminal neuropathy can also be seen in patients with facial skin involvement.

Causes

Juvenile systemic sclerosis is a condition with no known cause, but numerous conditions may be associated with cutaneous features that resemble scleroderma. Environmental exposures and other disease with sclerodermalike skin changes include the following:

• Toxic oil syndrome (eg, adulterated rapeseed oil)
• Eosinophilia myalgia syndrome (eg, contaminated L-tryptophan)
• Silica-associated and silicon-associated scleroderma
• Chemical-associated fibrosis (eg, bleomycin, vinyl chloride, pentazocine, other amines)
• Epoxy resin vapor
• Organic solvents (eg, benzene, xylene, toluene, methylene chloride, trichloroethylene, trichloroethane)
• Digital fibrosis in diabetes mellitus
• Scleromyxedema
• Carcinoid syndrome
• Eosinophilic fasciitis
• Porphyria cutanea tarda
• Acromegaly
• Werner syndrome (premature aging with sclerodermatous skin changes and subcutaneous calcifications)
• Hutchinson-Gilford syndrome (progeria)
• Rothmund syndrome, also termed Rothmund-Thompson syndrome or poikiloderma congenitale (atrophic, hyperpigmented, telangiectatic cutaneous plaques)
• Amyloidosis
• Lichen sclerosis et atrophicus (occasionally confused with sexual abuse in young females)

Differential Diagnoses

Other Problems to Be Considered

Many of the pediatric systemic rheumatic diseases, including dermatomyositis, systemic lupus erythematosus (SLE), systemic vasculitis, and juvenile rheumatoid arthritis (JRA), have numerous clinical features in common. These clinical similarities, in addition to the common laboratory findings that may be found among these diseases, can lead to diagnostic difficulties. Occasionally, even experienced rheumatologists may have some difficulty in making a definitive diagnosis.

Overlap syndromes are well described and mentioned in this topic because systemic sclerosis, dermatomyositis, SLE, systemic vasculitis, and systemic JRA (ie, Still disease) have been previously noted in various combinations within pediatric patients or in the evolution of any single rheumatic disease of childhood.

Establishing a specific diagnosis is important for prognosis and treatment. In some patients, a specific diagnosis may take months to years to establish. With recent attempts at better defining diagnostic criteria for juvenile systemic sclerosis (JSSc), the elapsed time between onset of symptoms and diagnosis will hopefully decrease. Some of the most challenging pediatric rheumatologic diseases to differentiate include those that overlap between scleroderma and dermatomyositis. Systemic vasculitis may mimic almost any of the other systemic rheumatic diseases.

Workup

Laboratory Studies

In juvenile systemic sclerosis (JSSc), as in many of the systemic rheumatic diseases, inflammation early in systemic disease may be associated with anemia, thrombocytosis and possibly eosinophilia. Therefore, obtaining routine CBC counts and erythrocyte sediment rates (ESRs) is prudent. Other early studies may include a urinalysis, chemistry survey, and ANA tests. These tests help to establish baseline values before the introduction of potentially toxic medications (see Medication).

• Early in the course of the disease, few, if any, laboratory finding abnormalities may be present. Later, mild anemia with slight thrombocytosis may be evident. Regular monitoring of these values may be warranted when a diagnosis of systemic sclerosis is suspected.
• The ESR is often normal or only mildly elevated in patients with juvenile systemic sclerosis. The largest published case series showed elevation of ESR in 34% of patients. 
• Peripheral eosinophilia should alert the clinician to one of the variants of scleroderma.
• Hematuria, proteinuria, and cellular casts are an ominous sign in patients with juvenile systemic sclerosis and may represent impending renal insufficiency.
• Survey chemistry findings are useful in monitoring disease activity and drug-associated toxicities.
• Rheumatoid factor (RF) is present in 17% of patients with juvenile systemic sclerosis, slightly less than the 25% of those with adult-onset disease.
• Immunologic tests are often helpful in patients with juvenile systemic sclerosis. Patients often have a positive ANA finding on nucleolar staining. The precise frequency is debated, but most experts estimate that between 81-97% of patients with juvenile systemic sclerosis have positive ANA findings. Antinucleolar staining (one cause of a speckled ANA pattern) is observed almost exclusively in adult and pediatric systemic sclerosis. Some of the other autoantibodies suggestive of systemic sclerosis or scleroderma that have been described include those listed below. However, note that as many as one third of patients who are diagnosed with juvenile systemic sclerosis and have positive ANA findings do not have any of the more specific autoantibodies, including the following: 
  • Anti-SCL 70 - Specific for topoisomerase I, found in 28-34% of cases
  • Anti–RNA polymerase
  • Anti-centromere - Only found in 7-8% of juvenile systemic sclerosis cases compared with 21-23% of adults systemic sclerosis cases
  • Antifibrillarin
  • Anti-PM-Scl
  • Anti-RNA polymerase I or II
• Contrary to findings in adult disease, the presence of anti-topoisomerase I and anti-RNA polymerase III antibodies are not associated with poorer survival in juvenile systemic sclerosis.
• In one third of cases, quantitative immunoglobulin levels may demonstrate a mild to modest immunoglobulin G (IgG) hypergammaglobulinemia. This nonspecific polyclonal gammopathy is detectable in many chronic inflammatory and systemic rheumatic diseases. Complement levels are normal in most cases. Test results for circulating immunocomplexes are usually negative.

Imaging Studies

• Although once commonly obtained in patients with juvenile systemic sclerosis, barium swallow with small bowel follow-through has been replaced by esophageal manometry.
• High-resolution thin-cut CT (HRCT) of the lungs has been helpful in making the diagnosis and in following the progress of diffuse interstitial pneumonitis and pulmonary fibrosis in patients with juvenile systemic sclerosis.

Other Tests

• Nailfold capillaroscopy may reveal changes prior to the onset of systemic symptoms. The changes noted on nailfold capillaroscopy in patients with Raynaud phenomenon include abnormal capillary dilation (resulting from vasculopathy) or loss of nailfold capillaries.
• Although HRCT remains the imaging study of choice when monitoring patients with juvenile systemic sclerosis for early evidence of interstitial pneumonitis and pulmonary fibrosis, the diffusing capacity of the lung for carbon monoxide (DLCO) test is the most sensitive for detecting early evidence of pulmonary fibrosis.  
• Although skin biopsies have been useful in assessing patients with systemic sclerosis for years, the results are not specific and must always be correlated with clinical features. Tests for collagen synthesis have not been consistently helpful, and their performance and interpretation requires the expertise of a research laboratory.
• Esophageal manometry is currently the study of choice for diagnosis of esophageal involvement in patient with juvenile systemic sclerosis.

Histologic Findings

• Early in the course of systemic sclerosis, an inflammatory reaction with subintimal vascular proliferation and an infiltration of round cells often goes unrecognized. After a varying length of time, fibrosis follows this reaction. Fibrosis characterizes the final common pathway in systemic sclerosis.
• In the skin, thinning of the epidermis occurs, with loss of rete pegs as collagens and accumulation of other matrix proteins in the dermis. Early studies made use of this feature to quantitate dermal thickness in skin biopsies and relate the degree of fibrosis with disease severity.
• Arteriolar and capillary endothelial proliferation precedes fibrosis in the visceral organs. Prognosis is related to the intensity and rapidity of fibrosis in the lungs, heart, GI tract, and kidney. Finally, atrophy ensues, and vital function is compromised.
• Humoral and cellular immunity both contribute to the pathology of systemic sclerosis, but the intimate details remain to be elucidated. The complex relationships among immune, vascular, and fibrotic perturbations may help explain the difficulties encountered in the treatment of patients with systemic sclerosis.

Treatment

Medical Care

General recommendations on the pharmacologic management of juvenile systemic sclerosis (JSSc) is difficult; no drug has been shown to have unequivocal benefit in the pediatric or adult form of the disease. The treatment of children with chronic disease is multifaceted and also requires attention to general health measures including; nutrition, rest, maximizing school attendance, and exercise. Treating a child with systemic sclerosis requires a team approach, ideally including a nurse educator, physical therapist, occupational therapist, nutritionist, and social worker. No treatment or combination of medical or surgical treatments has proven unequivocally efficacious in juvenile systemic sclerosis. However, therapeutic strategies have been developed that are directed toward the individual patient and the organ systems involved in that patient.

Given the lack of consensus that existed regarding the pharmaceutical management of juvenile systemic sclerosis, an European League Against Rheumatism (EULAR) task force, which included pediatric rheumatologists and representatives of patients who had juvenile systemic sclerosis, was developed. In 2007, this group attempted to establish some treatment recommendations for the treatment of juvenile systemic sclerosis. The group established a final set of 14 recommendations. Among experts in the field, a consensus of greater than 85% was reached on 9 of these 14 recommendations.⁴

• Meta-analysis on dihydropyridine-type antagonist and prostanoids indicated that nifedipine and intravenous iloprost reduce both the severity and frequency of Raynaud phenomenon attacks in patients with juvenile systemic sclerosis. Dihydropyridine-type antagonist (eg, nifedipine) should be considered first-line therapy for juvenile systemic sclerosis–associated Raynaud phenomenon. Intravenous (IV) prostanoids (eg, iloprost) should be used to treat severe Raynaud phenomenon.
• Two randomized clinical trials have demonstrated that intravenous prostanoid (particularly iloprost) are effective in healing digital ulcers.
• Despite some conflicting data and its known toxicity, cyclophosphamide should be considered for the treatment of juvenile systemic sclerosis–related interstitial lung disease. As with the use of cyclophosphamide in other conditions (juvenile systemic lupus erythematosus [SLE]), in order to prevent hemorrhagic cystitis, adequate hydration and frequent voiding must be emphasized.
• Glucocorticoids (most commonly prednisone), have few indications in treating juvenile systemic sclerosis. The use of glucocorticoids in treating juvenile systemic sclerosis–associated myositis, arthritis, and tenosynovitis, may be indicated. However, several studies have demonstrated a higher incidence of renal crisis in patients with juvenile systemic sclerosis treated with glucocorticoids emphasizes; thus, careful monitoring of blood pressure and renal function is needed in these patients.
• ACE inhibitors and angiotensin receptor blockers (ARBs) are considered to be the most effective and safest treatment option for long term management of hypertension, renal insufficiency, and renal crisis in patients with juvenile systemic sclerosis.
• Methotrexate has been shown to improve a clinical monitoring scale known as the skin score in early diffuse systemic sclerosis in adults. Although studies in children are not currently available, expert opinion suggests that methotrexate would be the treatment of choice for skin manifestations of juvenile systemic sclerosis, particularly in the earlier phases of the disease.
• Recommendations for treatment of GI manifestations of juvenile systemic sclerosis include proton pump inhibitors (PPIs), including omeprazole for preventing or treating gastroesophageal reflux symptoms. Prokinetic agents for treating symptoms related to motility disturbances. Finally, rotating antibiotics to include doxycycline and ciprofloxacin to decreased bacterial overgrowth which can lead to malabsorption.
• Interstitial lung disease associated with juvenile systemic sclerosis is a major therapeutic challenge. Treatment recommendations made by the EULAR group also included recommendations for treatment of pulmonary artery hypertension associated with juvenile systemic sclerosis. Randomized clinical trials have demonstrated improved exercise tolerance in patients with pulmonary artery hypertension with the use of several medications, including bosentan, sitaxsentan, and sildenafil. Despite the emerging evidence that these medications may benefit these patients, many experts in the field have called for further pediatric trials before making general recommendations regarding these medications in pulmonary artery hypertension secondary to juvenile systemic sclerosis.
• Additional treatment considerations are as follows:
  • Vascular therapy may take on several forms and is not necessarily pharmacologic. Early on, Raynaud phenomenon may respond to avoidance of tobacco, cold exposure, and vasoconstricting medications.
  • Biofeedback has been helpful in some patients with the development of tissue ischemia of digital tip ulcers. Local management of digital ulcers is indicated.
  • The arthritis of systemic sclerosis may respond to nonsteroidal anti-inflammatory drugs (NSAIDs) but to a lesser extent than the arthritis associated with other connective tissue diseases.

Surgical Care

Because involvement in patients with juvenile systemic sclerosis widely varies, surgical management must be individualized.

• Surgery to release contractures is occasionally indicated, and a few patients benefit from the surgical release of entrapped nerves.
• Emergency life-saving surgery in patients with juvenile systemic sclerosis who have a ruptured viscus may be required.
• Amputation should be considered only in extreme cases and if no other therapeutic options have proven effective.  
• Sympathectomy as a treatment of the peripheral vascular disease has been abandoned.

Consultations

The treatment of severe, chronic and debilitating pediatric diseases such as juvenile systemic sclerosis requires a team approach. 

• The pediatric rheumatologist team leader must be a specialist experienced in the care of patients with juvenile systemic sclerosis.
• The team should also include a pediatric gastroenterologist, pediatric nephrologist, and pediatric pulmonologist.
• The team should also include a nurse educator, occupational therapist, physical therapist, nutritionist, and social worker.
• Telemedicine may play a role in long-distance consultation and treatment of patients with juvenile systemic sclerosis who reside far from full-service institutions.
• Recent experimental therapies that necessitate other consultations, such as stem cell, renal, and lung transplantation, are beyond the scope of this discussion.

Medication

Calcium channel blocking agents

These agents are helpful in treating patients who develop tissue ischemia of digital tip ulcers. Dihydropyridine calcium channel blockers (eg, nifedipine, nicardipine) have more pronounced peripheral vasodilatory effect.

Nifedipine (Adalat, Procardia)

Effective in vasospastic conditions.
Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.

Dosing

Adult

20-30 mg PO bid; not to exceed 120 mg/d; alternatively, use the sustained-release product qd

Pediatric

Not established, limited data suggest 10 mg PO bid

Interactions

Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2 blockers (eg, cimetidine) may increase toxicity

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

May cause lower extremity edema; allergic hepatitis has occurred but is rare

Nicardipine (Cardene)

For IV use when PO route is not possible.
Individualized slow IV infusion at a concentration of 0.1 mg/mL with constant infusion; blood pressure falls within min (50% decrease in 45 min)

Dosing

Adult

5 mg/h IV continuous infusion initially (concentration = 0.1 mg/mL); may titrate upward by increments of 2.5 mg/h to desired effect; not to exceed 15 mg/h

Pediatric

3-5 mg/h IV continuous infusion initially; safety and efficacy not established

Interactions

Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2-receptor blockers (eg, cimetidine) may increase toxicity; may increase cyclosporine levels

Contraindications

Documented hypersensitivity; PVD; symptomatic hypotension; advanced aortic stenosis

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

To be administered in an intensive/critical care setting

ACE inhibitors

Previously, hypertensive renal crisis was the most dreaded complication of systemic sclerosis. However, with the development of the ACE inhibitors (eg, captopril, enalapril), the prognosis of such patients has improved remarkably.

Captopril (Capoten)

Prevents conversion of angiotensin I to angiotensin II (a potent vasoconstrictor), resulting in lower aldosterone secretion.

Dosing

Adult

25-50 mg PO bid/tid

Pediatric

0.5-6 mg/kg/d PO divided q8h; safety and efficacy not established

Interactions

NSAIDs may reduce hypotensive effects of captopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases captopril levels; probenecid may increase captopril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity; renal impairment; previous angioedema with other ACE inhibitors

Precautions

Pregnancy

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

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Enalapril (Vasotec)

Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Dosing

Adult

5-40 mg/d PO qd or divided bid

Pediatric

0.15-0.5 mg/kg/d PO divided q12-24h
Safety and efficacy not established in children

Interactions

NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity; angioedema

Precautions

Pregnancy

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

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Angiotensin Ii Receptor Antagonist

Consider these agents if unable to use ACE inhibitors for hypertension, renal insufficiency, and renal crisis.

Losartan (Cozaar)

Nonpeptide angiotensin II–receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors. Does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors. Less effective in patients with scleroderma than with primary Raynaud phenomenon. May modify some serum markers of vascular damage and possibly modulate some of the underlying tissue damage in scleroderma.

Dosing

Adult

50 mg PO qd initially; not to exceed 100 mg/d

Pediatric

<6 years: Not established
>6 years: 0.7 mg/kg PO qd, not to exceed 50 mg/d; adjust dose according to blood pressure response

Interactions

May increase digoxin, lithium, and allopurinol levels; probenecid may increase losartan levels; coadministration with diuretics, increase hypotensive effects; NSAIDs may reduce hypotensive effects of losartan; may increase risk of hyperkalemia if taken concurrently with potassium supplements or other potassium-sparing diuretics

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

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

Precautions

Caution in patients with unilateral or bilateral renal artery stenosis

Nonsteroidal anti-inflammatory agents

These agents are used to treat the arthritis of systemic sclerosis. They have analgesic, antiinflammatory, and antipyretic activities. Their mechanism of action is not known, but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also occur (eg, inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, various cell-membrane functions).

Naproxen (Aleve, Naprosyn, Anaprox)

Anti-inflammatory of the arylacetic acid group of derivatives with good benefit-risk ratio. PO-administrated drugs with a half-life of 12 h.

Dosing

Adult

500-750 mg PO bid

Pediatric

<2 years: Not established
>2 years: 15-20 mg/kg/d PO divided bid; not to exceed 1 g/d

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

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

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

Precautions

Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Ibuprofen (Motrin, Ibuprin)

Anti-inflammatory of the propionic acid group with good benefit-risk ratio. PO-administrated drugs with a half-life of 2-3 h, respectively.

Dosing

Adult

800 mg PO tid/qid

Pediatric

20-40 mg/kg/d PO divided tid/qid; not to exceed 2.4 g/d

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding

Precautions

Pregnancy

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

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

Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Immunosuppressive agents

Interstitial lung disease associated with systemic sclerosis is a major therapeutic challenge. Treatment with high-dose corticosteroids, methotrexate, and cyclophosphamide has shown variable response among different patients. Slower-acting antirheumatic drug or disease-modifying antirheumatic drugs (eg, penicillamine) have been used for their anti-inflammatory and anticollagen effects.

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.

Dosing

Adult

1000-1500 mg IV every mo; infuse over 1 h

Pediatric

30 mg/kg IV every mo; not to exceed 1000-1500 mg every mo; infuse over 1 h

Interactions

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

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

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

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; if the patient's renal function permits, good prehydration is indicated; close observation during infusion is indicated by physician

Penicillamine (Cuprimine, Depen)

The fact that penicillamine interferes with collagen cross-linking in vitro is the oft-quoted basis for its use in systemic sclerosis.
Retrospective studies using historic controls suggested its beneficial effect.

Dosing

Adult

Up to 500 mg/d PO

Pediatric

125-500 mg PO qd

Interactions

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

Contraindications

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

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

Thrombocytopenia, agranulocytosis, and aplastic anemia may occur

Methotrexate (Folex PFS, Trexall)

Antimetabolite used for immunomodulatory therapy.

Dosing

Adult

15-25 mg PO in divided doses on 1 d each wk

Pediatric

2.5-25 mg PO in divided doses on 1 d each wk

Interactions

PO aminoglycosides may decrease absorption and blood levels of concurrent PO methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX
Coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

Contraindications

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

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or upon risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems
Discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Prednisone (Deltasone, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dosing

Adult

5-80 mg/d PO; not to exceed 100 mg/d

Pediatric

1-2 mg/kg/d PO; not to exceed 80-100 mg/d

Interactions

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

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

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

Immune Globulin

This agent is purified preparation of gamma globulin. It is derived from large pools of human plasma and comprises 4 subclasses of antibodies, approximating the distribution of human serum. It is used for immune modulation.

Immune globulin intravenous (Carimune NF, Sandoglobulin, Famunex, Privigen)

Neutralize circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).

Dosing

Adult

Depends on indication, 100-1000 mg/kg/dose IV q4wk

Pediatric

Depends on indication, 100-2000 mg/kg/dose IV q4wk

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)

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

Check serum IgA before IVIG (if IgA deficient, use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease;
laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Prostacyclin analogues

Prostacyclins, specifically epoprostenol, are indicated for the long-term treatment of pulmonary hypertension associated with scleroderma disease. They may also reduce pain and the occurrence of digital ulcerations. Additionally, prostacyclins may improve lesion scores and ischemic lesion scores. Other prostacyclin analogues being investigated for use in systemic sclerosis include an orally administered prostacyclin (beraprost), iloprost (Ventavis), and subcutaneously administered treprostinil (Remodulin). Iloprost and treprostinil are currently US Food and Drug Administration (FDA)-approved for pulmonary artery hypertension. Iloprost is available as an aerosolized inhaled agent, but an intravenous form is currently under investigation.

Epoprostenol (Flolan)

Analogue of PGI2 has potent vasodilatory properties, immediate onset of action, and half-life of approximately 5 min. Potent pulmonary and systemic vasodilator. In addition to vasodilator properties, contributes to inhibition of platelet aggregation and plays role in inhibition of smooth muscle proliferation. Requires permanent, tunnelized central venous catheter together with portable infusion pump for IV administration. Indicated for long-term IV treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients in whom conventional therapy does not produce an adequate response.

Dosing

Adult

0.5-4 ng/kg/min IV initially; may gradually increase dose as tolerated (typical incremental increase is by 2 ng/kg/min)
Target dose in first 2-4 wk is approximately 5-10 ng/kg/min; ultimately, may require doses as high as 200 ng/kg/min

Pediatric

Administer as in adults

Interactions

Coadministration with anticoagulants may increase bleeding risk because of shared effects on platelet aggregation (although typically coadministered with anticoagulants to reduce thromboembolic risk); additional blood pressure reduction may occur with other drugs that lower BP (eg, diuretics, antihypertensive agents, other vasodilators)

Contraindications

Documented hypersensitivity; CHF with severe LV dysfunction; long-term use in patients who develop pulmonary edema during initiation

Precautions

Pregnancy

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

Precautions

Abrupt withdrawal, interruptions in delivery, or large dose reductions may precipitate rebound pulmonary hypertension; dose-limiting adverse effects include nausea, vomiting, headache, and hypotension; unless contraindicated, coadminister with anticoagulants to reduce risk of thromboembolism

Gastric Acid Secretion Inhibitor

This agent is indicated for prevention or treatment of gastroesophageal reflux disease.

Omeprazole (Prilosec)

Decreases gastric acid secretion by inhibiting the parietal cell H⁺/K⁺ -ATPase pump. Used for up to 4-8 wk to treat and relieve symptoms of active duodenal ulcers. May use for up to 8 wk to treat all grades of erosive esophagitis.

Dosing

Adult

20 mg PO qd

Pediatric

<1 year: Not established
>1 year:
5-10 kg: 5 mg PO qd
10-20 kg: 10 mg PO qd
>20 kg: 20 mg PO qd

Interactions

May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin, and phenytoin

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

Bioavailability may increase in the elderly

Follow-up

Further Inpatient Care

• Patients with juvenile systemic sclerosis (JSSc) are admitted to the hospital on a limited basis, and then only to treat critical care emergencies, often in an ICU (eg, renal crisis, impending respiratory failure, surgical emergencies).
• Other treatments should be accomplished in ambulatory care units or at home whenever possible without sacrificing patient safety.

Further Outpatient Care

• Outpatient care needs to be individualized.
• Stress independent activities of daily living, good nutrition, and a healthy and positive attitude.
• Monitor medication and admit patients to the hospital only for definitive medical or surgical treatment.
• The team (see Medical Care) is integral to the outpatient care of a child with systemic sclerosis.
• The importance of continued schooling and independent living cannot be overemphasized.

Inpatient & Outpatient Medications

• As with the treatment of many chronic diseases, treatment of adolescents and young adults with juvenile systemic sclerosis may be complicated by poor compliance. Individual responsibility is encouraged and emphasized by the team, particularly the nurse educator and social worker.
• Further, appropriate support should be provided for family members and caregivers.  School attendance, independence, and compliance with medication and exercise programs need to be encouraged and reinforced.

Transfer

• The expertise of an experienced pediatric rheumatologist is required.

Deterrence/Prevention

• Idiopathic disease is not preventable.
• Conditions that resemble juvenile systemic sclerosis secondary to toxins or metabolic perturbations may be quite amenable to preventive principles.

Complications

• Complications include subcutaneous calcinosis, esophageal dysfunction to the point of malnutrition, and wasting.
• Serious hypertension is an indication of advancing renal disease, and hypertensive crises occasionally occur.
• For more information about the potential lethal effects of pulmonary artery hypertension, see Pulmonary Hypertension, Eisenmenger Syndrome; Pulmonary Hypertension, Persistent Newborn; and Pulmonary Hypertension, Idiopathic.

Prognosis

• Although a severely debilitating disease with significant morbidity and mortality, the prognosis of children with systemic sclerosis appears to be better than in adult patients with systemic sclerosis.
• The survival of juvenile systemic sclerosis at 5 years, 10 years, 15 years, and 20 years after diagnosis is 89%, 80-87.4%, 74-87.4%, and 69-82.5%, respectively. These survival rates are significantly higher than those reported in patients with adult-onset systemic sclerosis.
• The most common causes of death are secondary to complications of cardiac, renal, or pulmonary involvement. A recent study by Martini et al studied 134 patients with juvenile systemic sclerosis.⁵ All patients who died had a diffuse form of the disease, with rapid progression and early signs of internal organ involvement, suggesting two courses: a more rapid course and a slow course with lower mortality.
• As discussed above, regular and frequent monitoring of cardiac, renal, and pulmonary function are critical while caring for this patient population. However, further research is still required to better define disease activity so that a standardized approach to treatment of this disease may be established.

Patient Education

• As with all chronic disease, systemic sclerosis requires continual reinforcement of education concerning adequate nutrition, independent mobility, and control of potential adverse effects of medication.

Miscellaneous

Medicolegal Pitfalls

• Issues of missed diagnosis (commonly another rheumatic disease) and obtaining informed consent for sometimes heroic therapies (leading to wrongful death litigation) constitute the major legal pitfalls. For this reason, experienced specialists are essential in the diagnosis and treatment of patients with systemic sclerosis.
• These patients require a treatment team with a pediatric rheumatologist as team leader and case manager.

Multimedia

Media file 1: An 8-year-old girl with overlap syndrome with evolution to progressive systemic sclerosis (PSS).

Media file 2: Photo of hands revealing sclerodactyly. This demonstrates the progression of disease over 7 years.

Media file 3: Chest radiograph revealing diffuse, coarse interstitial marking with bilateral lower lobe bronchiectasis.

Media file 4: Axial CT scan of the chest of a 15-year-old female adolescent with progressive systemic sclerosis (PSS).

Media file 5: Esophagram revealing dysmotility.

References

1. Behrman R, et al. Systemic Sclerosis. In: Nelson Textbook of Pediatrics. 17^th ed. 2004:817-9.

2. Johnson SR, Swiston JR, Swinton JR, Granton JT. Prognostic factors for survival in scleroderma associated pulmonary arterial hypertension. J Rheumatol. Aug 2008;35(8):1584-90. [Medline].

3. Martini G, Foeldvari I, Russo R, Cuttica R, Eberhard A, Ravelli A. Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in an international database. Arthritis Rheum. Dec 2006;54(12):3971-8. [Medline].

4. [Guideline] Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. May 2009;68(5):620-8. [Medline].

5. [Best Evidence] Martini G, Vittadello F, Kasapcopur O, et al. Factors affecting survival in juvenile systemic sclerosis. Rheumatology (Oxford). Feb 2009;48(2):119-22. [Medline].

6. Black CM, Denton CP. Therapy of Systemic Sclerosis. In: Van de Putte LBA, Furst DE, Williams HJ, van Riel PLCM, eds. Therapy of Systemic Rheumatic Disorders. 1998:495-545.

7. Bottoni CR, Reinker KA, Gardner RD. Scleroderma in childhood: a 35-year history of cases and review of the literature. J Pediatr Orthop. Jul-Aug 2000;20(4):442-9. [Medline].

8. Foeldvari I. Current developments in pediatric systemic sclerosis. Curr Rheumatol Rep. Apr 2009;11(2):97-102. [Medline].

9. Foeldvari I. Scleroderma in children. Curr Opin Rheumatol. Nov 2002;14(6):699-703. [Medline].

10. Foeldvari I. Systemic sclerosis in childhood. Rheumatology (Oxford). Oct 2006;45 Suppl 3:iii28-9. [Medline].

11. Foti R, Leonardi R, Rondinone R, Di Gangi M, Leonetti C, Canova M. Scleroderma-like disorders. Autoimmun Rev. Feb 2008;7(4):331-9. [Medline].

12. Hoeper MM. Pulmonary hypertension in collagen vascular disease. Eur Respir J. 2002;19: 571 - 576.

13. Kaal SE, van Den Hoogen FH, de Jong EM. Systemic sclerosis: new insights in autoimmunity. Proc Soc Exp Biol Med. Oct 1999;222(1):1-8. [Medline].

14. LeRoy EC. Pathogenesis of Systemic Sclerosis (scleroderma). In: Koopman WJ, ed. Arthritis and Allied Conditions. 1997:1481-90.

15. Levy BD. Eicosanoids in scleroderma: lung disease hangs in the balance. Arthritis Rheum. Dec 2005;52(12):3693-7. [Medline].

16. Nagaya N. Drug therapy of primary pulmonary hypertension. Am J Cardiovasc Drugs. 2004;4(2):75-85. [Medline].

17. Poormoghim H, Lucas M, Fertig N. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum. Feb 2000;43(2):444-51. [Medline].

18. Rosenkranz ME, Agle LM, Efthimiou P, Lehman TJ. Systemic and localized scleroderma in children: current and future treatment options. Paediatr Drugs. 2006;8(2):85-97. [Medline].

19. Russo RA, Katsicas MM. Clinical characteristics of children with Juvenile Systemic Sclerosis: follow-up of 23 patients in a single tertiary center. Pediatr Rheumatol Online J. May 1 2007;5:6. [Medline].

20. Silver RM. Variant forms of scleroderma. In: Koopman WJ, ed. Arthritis and Allied Conditions. 1997:1465-80.

21. Steen V. Advancements in diagnosis of pulmonary arterial hypertension in scleroderma. Arthritis Rheum. Dec 2005;52(12):3698-700. [Medline].

22. Vancheeswaran R, Black CM, David J, et al. Childhood-onset scleroderma: is it different from adult-onset disease. Arthritis Rheum. Jun 1996;39(6):1041-9. [Medline].

23. Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin North Am. Feb 2008;34(1):239-55; ix. [Medline].

24. Zulian F, Martini G. Childhood systemic sclerosis. Curr Opin Rheumatol. Nov 2007;19(6):592-7. [Medline].

25. [Guideline] Zulian F, Woo P, Athreya BH, Laxer RM, Medsger TA Jr, Lehman TJ. The Pediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for juvenile systemic sclerosis. Arthritis Rheum. Mar 15 2007;57(2):203-12. [Medline].

Keywords

 juvenile systemic sclerosis, JSSc, scleroderma, Scl, progressive systemic sclerosis, PSS, progressive pulmonary fibrosis, cutaneous sclerosis, linear scleroderma, en coup de sabre, morphea, CREST syndrome, calcinosis, Raynaud phenomenon, Raynaud's phenomenon, Raynaud's, esophageal hypomotility, sclerodactyly, telangiectasia, dermatosclerosis, sclerosis corii, sclerosis cutanea, connective tissue disease, connective tissue disease, pericarditis, dilated cardiomyopathy, polyarthralgia, polyarthritis, systemic lupus erythematosus, SLE, gastroesophageal reflux, vitiligo, heart failure, treatment, diagnosis

Contributor Information and Disclosures

Author

Luke M Webb, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center
Luke M Webb, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, and American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

David J Schwartz, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center
David J Schwartz, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association
Disclosure: Nothing to disclose.

Cecilia P Mikita, MD, MPH, Associate Program Director, Allergy-Immunology Fellowship, Assistant Professor of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Hospital Intern Director, Staff Allergist/Immunologist, Walter Reed Army Medical Center
Cecilia P Mikita, MD, MPH is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Medical Editor

Ann O'Neill Shigeoka, MD †, Former Clinical Associate Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine
Ann O'Neill Shigeoka, MD † is a member of the following medical societies: American Federation for Medical Research, Clinical Immunology Society, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals
David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Completion of this review was greatly aided by the expertise and groundwork laid by the previous author of this article, Donald Person, MD. The authors are deeply indebted to his work on prior versions of this topic.

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