eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Juvenile Systemic Sclerosis: Treatment & Medication

Author: Luke M Webb, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center
Coauthor(s): 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
Contributor Information and Disclosures

Updated: Jul 20, 2009

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.

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

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

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

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

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 its beneficial effect.

Methotrexate (Folex PFS, 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

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%).

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.

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.

• Search for CME/CE on This Topic »

• Factors Affecting Survival in Juvenile Systemic Sclerosis