Juvenile Systemic Sclerosis 

Updated: Sep 18, 2017
Author: Donald A Person, MD, FAAP, FACR; Chief Editor: Harumi Jyonouchi, MD 

Overview

Practice Essentials

Systemic sclerosis (also scleroderma) is a chronic, autoimmune rheumatic disease affecting the skin and other organs. The hallmark of the disease is thickening/tightening of the skin and inflammation/scarring of various organs/body parts, leading to involvement of the lungs, kidneys, heart, intestinal system, and other areas. There is no cure for scleroderma but effective treatments for some features of the disease are available. The disease is relatively uncommon. About 75,000–100,000 people in the United States have the disease; most are women between the ages of 30 and 50 years. Twins and family members of those with scleroderma or other autoimmune connective tissue diseases, such as lupus, may have a slightly higher risk of developing scleroderma. Children can also get scleroderma, but the disease is different in children from that in adults. Although the underlying cause is unknown, research is shedding more light on the relationship between genes, the immune system and scleroderma. Research is also underway to find better treatments for scleroderma and, hopefully, one day a cure.

There are two main categories of scleroderma:

  1. Localized scleroderma affects skin, underlying connective tissues to a greater or lesser extent. Discolored, thickened patches of skin, termed morphea, may be so subtle as to escape the examiner's attention unless pointed out. When streaks/bands of thickened tissue involve a limb, it is termed linear scleroderma. Linear scleroderma involving the face, forehead, and scalp is termed “scleroderma en coup de sabre.” Diffuse cutaneous scleroderma without systemic involvement can occurr, but rarely.  
  2. Systemic scleroderma (systemic sclerosis), which is the most serious form of the disease, affects skin, muscles, bones, joints, blood vessels, lungs, kidneys, heart, and virtually all organs. Progressive systemic sclerosis is a rare, inexorably progressive disease that leads to an early death.

There is no known cause. Genetic factors and the immune system appear to be important in disease development and progression. Although exposure to certain chemicals and drugs may play a role in some children developing scleroderma, the vast majority of patients do not have a history of exposure to any suspicious toxins. It should be noted that as with other rheumatic diseases of childhood, cases with features of two or more conditions is not uncommon. Most overlap cases have features of scleroderma and dermatomyositis. In some children it may take years before a definitive diagnosis is possible. 

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 JSSc 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.

These inflammatory cells release cytokines, including transforming growth factor beta (TGF-β) and interleukin-1 (IL-1). Among its many 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 JSSc.

Epidemiology

Frequency

United States

JSSc is a rare childhood disorder, an orphan disease whose incidence is said to be approximately 0.05 per 100,000 children.[1] In addition, 5-10% of adult cases of systemic sclerosis arise before age 16 years, thus meeting the age criterion for JSSc. New criteria aimed at more uniformly defining JSSc will hopefully aid in better estimation of incidence and prevalence of the condition.

Mortality/Morbidity

Mortality rates in JSSc are reportedly lower than in adult systemic sclerosis. Five and 20-year survival rates for JSSc are 89% and 69%, respectively. This is likely a reflection of the increased incidence of simple morphea in children.

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 review of 153 patients, those who died had a significantly shorter time to diagnosis from onset of symptoms compared with patients that were still alive at follow-up 8.8 vs 23 months.[3] This demonstrates that those patients who eventually die due to complications of JSSc likely have a more aggressive form that is more quickly recognized due to the severity of symptoms. This is consistent with mortality rates of most studies that show most deaths from JSSc 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 digital ulcers. Arthralgias, arthritis, and muscle weakness may occur in as many as a quarter 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 JSSc, however in the senior author's experience children of color (African-American, Hispanic, Asian, and Pacific Islanders) made up the majority of patients followed in our clinics.

Sex

Females are affected more often than males, with an overall female-to-male ratio of approximately 3.6:1, much lower than the 15:1 female-to-male predominance seen in adults.

Age

By definition, the child must be younger than 17 years at the time of disease onset to the meet the criteria for JSSc. The youngest patient documented with JSSc was only a few months old at disease onset. The average age of onset is 8.1–8.8 years in the two largest published case series. Due to the rarity of this condition 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 in these studies were diagnosed almost 2 years later than the average child with juvenile systemic sclerosis.

Prognosis

Prognosis is dependent on the extent of the disease. Children with limited forms of the disease (eg, morphea) have an excellent prognosis both for function and life. The survival of JSSc 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.

If linear scleroderma involves the child's dominant hand there may be significant writing restriction and note-taking in the classroom may be compromized. Arrested leg growth, seen in linear scleroderma may result in significant gait disturbances and orthotics in the form of lifts or inserts may be required. Severe scleroderma en coup de sabre involvement of the child's face has led to severe depression, sometimes with sucidal ideation. Fortunately rare, progressive systemic sclerosis is a slowly developing, progressive condition, which, when it involves the esophagus, lungs, kidney, etc. leads inexoriably to death. 

The most common causes of death are secondary to complications of cardiac, renal, or pulmonary involvement and failure. A study by Martini et al studied 134 patients with JSSc.[4] 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.

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

There is almost no information available concerning patient education in JSSc. If the rheumatologist is fortunate enough to have a multidisciplinary team available including a nurse, social worker, physical therapist, occupational therapist, and nutritionist then the development of a self-help group may be possible. A small pilot study involving adult women in Sweden suggests that this approach appears to be useful. Skin care and pain were common concerns of the patients in that study.[5]

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

 

Presentation

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 (JSSc). Most cases of Raynaud phenomenon are primary and unrelated to any connective tissue disease.

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 JSSc, especially nail-fold capillary abnormalities and a positive ANA 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

See the list below:

  • Skin - Diffuse puffiness of the hands and feet, which may be followed by development of tautness of the skin (hide-bound)

  • Hyperpigmentation/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

See the list below:

  • Raynaud phenomenon - Pallor, cyanosis, suffusion, and tingling of the fingers, which occurs abruptly and episodically (When the phenomenon is associated with a known cause scleroderma, SLE, RA], it is termed Raynaud syndrome.)

  • Abnormal nailfold capillaroscopy - Hemorrhages, abnormal or dilated loops, megacapillaries, arborization, and avascular areas

GI

See the list below:

  • Esophageal dysmotility – Detected by newer diagnostic techniques in 90% of patients (Symptomatic dysphagia is seen in only 24% of patients.)

    Esophagram revealing dysmotility. Esophagram revealing dysmotility.
  • Reflux - Seen in 30% of children (Some also develop significant weight loss and diarrhea, possibly due to malabsorption.)

Pulmonary

See the list below:

  • Interstitial pulmonary fibrosis, inflammatory alveolitis, and pulmonary hypertension either alone or in combination (See the image below.)

    Chest radiograph revealing diffuse, coarse interst Chest radiograph revealing diffuse, coarse interstitial marking with bilateral lower lobe bronchiectasis.
  • Pulmonary hypertension and fibrosing alveolitis leading to interstitial pulmonary fibrosis (major complication and cause of death in juvenile systemic sclerosis) (See the image below.)

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

Cardiac

See the list below:

  • Heart failure - Most common cause of death in JSSc, often complicated by concomitant pulmonary hypertension

  • Arrhythmias- Inflammatory and fibrotic processes such as pericarditis, myocardial fibrosis, fibrosis of the conduction system, and contraction band necrosis of coronary vessels

Musculoskeletal

See the list below:

  • 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. See the image below.)

    Photo of hands revealing sclerodactyly. This demon 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

See the list below:

  • Kidney involvement may be subtle, such as a slow rise in creatinine levels.

  • Renal changes were reported in only 13% of cases of JSSc, but patients who develop proteinuria or hypertension are at increased risk of death.

  • The renal lesion is a slowly progressive vasculitis with sclerosis.

  • Intimal proliferation, medial thinning, and adventitial fibrosis, with decreased blood flow and glomerular function, characterize this disorder.

Neurological

See the list below:

  • Although seizures are rare in this population, 3% of patients with JSSc 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

JSSc is a condition of unknown etiology, but numerous conditions may be associated with cutaneous features that resemble classical skin changes typical of scleroderma. Environmental exposures and other disease with scleroderma-like skin changes include the following:

  • Toxic oil syndrome (adulterated rapeseed oil)

  • Eosinophilia myalgia syndrome (contaminated L-tryptophan)[6]  

  • Silica-associated and silicon-associated scleroderma

  • Chemical-associated/induced fibrosis (bleomycin, vinyl chloride, pentazocine, other amines)

  • Epoxy resin vapor

  • Organic solvents (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 (sometimes misdiagnosed as sexual abuse in young girls)

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.

 

DDx

Diagnostic Considerations

Many of the pediatric systemic rheumatic diseases, including: dermatomyositis, systemic lupus erythematosus (SLE), vasculitis syndromes, and juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), 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 (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 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.

A significant number of children with an underlying systemic rheumatic diathesis evolve over time fulfilling diagnostic criteria for different rheumatic diseases at any point in time. The current author has cared for children with definite acute rheumatic fever (ARF) that evolved to pauciarticular JRA, then to polyarticular JRA, and finally to SLE. Others began as localized myositis that evolved to polymyositis, then to dermatomyositis, to scleroderma, then to JSSc. Still others started as JRA and evolved to SLE, then to systemic vasculitis, then to aplastic anemia, and then to death from lymphoblastic lymphoma.

Differential Diagnoses

 

Workup

Laboratory Studies

In juvenile systemic sclerosis (JSSc) as in many of the systemic rheumatic diseases, inflammation 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.

  • Complete metabolic panel (CMP) 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 JSSc. Patients often have a positive ANA (with a speckled staining pattern, most commonly nucleolar). The precise frequency is debated, but most experts estimate that between 81-97% of patients with JSSc have a positive ANA. Antinucleolar staining is observed almost exclusively in adult and pediatric patients with 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 JSSc 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

    • Anti-fibrillarin

    • 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 JSSc.

  • 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 immune complexes 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 high resolution computed tomography (HRCT) remains the imaging study of choice when monitoring patients with JSSc for early evidence 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.

Procedures

Diagnostic procedures are dictated by the patient's signs and symptoms.

There are no routine procedures indicated.

 

Treatment

Approach Considerations

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 (renal crisis, cardiac and/or respiratory failure, surgical emergencies).

Other treatments should be accomplished in ambulatory care units or at home whenever possible without sacrificing patient safety.

Outpatient Care

Outpatient care needs to be individualized and independent activities of daily living, good nutrition, exercise, and a healthy and positive attitude should be stressed. .

The importance of continued schooling and independent living cannot be overemphasized.

 

Medical Care

Pharmacologic management of juvenile systemic sclerosis (JSSc) has been abysmal. The treatment of children with chronic rheumatic disease is multifaceted and 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 JSSc. 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 exists regarding any pharmaceutical management of JSSc, the European League Against Rheumatism (EULAR) task force, which included pediatric rheumatologists and representatives of patients with JSSc, was convened and in 2007, attempted to establish some treatment recommendations. 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.[7]

  • 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 JSSc. Dihydropyridine-type antagonist (nifedipine) should be considered first-line therapy for juvenile systemic sclerosis–associated Raynaud phenomenon. Intravenous (IV) prostanoids (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 JSSc–related interstitial lung disease. As with the use of cyclophosphamide in other conditions (childhood 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 (clinical trials stopped worldwide because of liver injury), 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.

  • On December 10, 2010, Pfizer announced that sitaxsentan (also known as sitaxsentan; brand name of Thelin) is being withdrawn in regions where it is approved (the European Union, Canada, and Australia). Additionally, clinical trials for sitaxsentan are being discontinued worldwide. This decision was based on a review of safety information from clinical trials and post marketing reports of life-threatening idiosyncratic risk for liver injury.

  • 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 is no longer used.

Consultations

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

  • The pediatric rheumatologist team leader must be a specialist experienced in the care of patients with JSSc.

  • The team should also include a pediatric gastroenterologist, pediatric nephrologist, pediatric cardiologist, 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 JSSc who reside far from full-service institutions.

  • Recent experimental therapies that necessitate other consultations, such as stem cell, renal, cardiac, and lung transplantation, are beyond the scope of this discussion. The author does not recommend organ transplantation in any child with JSSc.

 

Medication

Medication Summary

As is the case with the treatment of many chronic diseases of childhood, treatment of adolescents and young adults with JSSc is often 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.

Calcium Channel Blocking Agents

Class Summary

These agents are helpful in treating patients who develop tissue ischemia of digital tip ulcers. Dihydropyridine calcium channel blockers (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.

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)

ACE Inhibitors

Class Summary

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.

Enalapril (Vasotec)

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

Angiotensin II Receptor Antagonist

Class Summary

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.

Nonsteroidal Anti-inflammatory Agents (NSAIDs)

Class Summary

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.

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.

Immunosuppressive Agents

Class Summary

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.

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 minimal beneficial effect.

Methotrexate (Rheumatrex, MTX, Trexall)

Antimetabolite used for immunomodulatory therapy.

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.

Immune Globulin

Class Summary

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, Gamunex, 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%).

Prostacyclin Analogues

Class Summary

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 Remodulin (treprostinil). 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, 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.

Gastric Acid Secretion Inhibitor

Class Summary

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 weeks to treat and relieve symptoms of active duodenal ulcers. May use for up to 8 wk to treat all grades of erosive esophagitis.