OVERVIEW: What every practitioner needs to know

Are you sure your patient has scleroderma? What are the typical findings for this disease?

Scleroderma, or “tight skin,” is rare in childhood. It can be divided into 2 main forms: 1. Localized scleroderma, and 2. Juvenile systemic sclerosis. Localized scleroderma (LSc) , sometimes called morphea, is limited to the skin, fascia, or muscle. Juvenile systemic sclerosis (JSSc) involves multiple organ systems including the skin, GI tract, heart, and lungs.

The most common symptoms of scleroderma are skin changes from excess collagen deposition, with erythema, thickening, and atrophy.

What other disease/condition shares some of these symptoms?

1. Graft-versus-host disease

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2. Eosinophilic fasciitis

3. Juvenile dermatomyositis

4. Juvenile systemic lupus erythematosus

5. Trauma

What caused this disease to develop at this time?

  • The cause of scleroderma is not known.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • The diagnosis of LSc is clinical and not based on laboratory tests. The characteristic lesions are called morphea, which present with circumscribed patches of hardened skin.

  • In JSSc, patients may have signs of systemic involvement. A complete blood count may show anemia of chronic disease. Patients may also have elevated inflammatory markers, such as the erythrocyte sedimentation rate or C-reactive protein. Antinuclear antibodies (ANA) are present in most children with JSSc. More specific antibodies, such as anti-Scl-70 and anti-centromere, may also be present.

Would imaging studies be helpful? If so, which ones?

  • Imaging studies are not helpful for making the diagnosis of scleroderma, but can be helpful to monitor for complications. Barium swallow studies can identify slow transit due to GI involvement. Pulmonary function tests and high resolution CT scan of the lungs can identify signs of early interstitial lung disease.

If you are able to confirm that the patient has scleroderma, what treatment should be initiated?

  • For the localized disease of LSc, systemic therapy may not be needed. Physiotherapy and massage to maintain functional ability, joint function, and muscle strength are important. Patients may have intense pruritis around the involved skin, as sweat glands are trapped below layers of collagen. Emollients can be helpful to prevent drying of the skin.

  • For JSSc, treatment is directed towards the involved organ. No one immunosuppressive agent has been shown to be beneficial for the skin. The natural history of skin involvement is an initial inflammatory phase followed by atrophy and possible skin softening. If immunosuppressive therapy is started at this later stage, it may not have any impact.

  • For patients with Raynaud’s phenomenon, avoidance of cold and stress is important. Vasodilator therapy, with medications such as calcium channel blockers, are used widely and are effective in controlling symptoms. Other medications such as serotonin reuptake inhibitors have also been shown to be beneficial for Raynaud’s phenomenon. Patients with JSSc can progress to digital ulcerations. These can be treated with parenteral vasodilators such as prostaglandin or surgical procedures such as digital sympathectomy.

  • Musculoskeletal involvement in JSSc can be treated with physical therapy and anti-inflammatory agents. Patients with myositis may present with proximal muscle weakness and elevated muscle enzymes. These patients would benefit from immunosuppressive therapy such as glucocorticoids.

  • Pulmonary disease can present as inflammatory alveolitis or pulmonary hypertension. Because patients may not exhibit symptoms until significant lung disease is present, it is important to monitor patients every 6 months to 1 year with pulmonary function tests and echocardiogram for early disease. If alveolitis is identified, treatment includes glucocorticoids and immunosuppression with medications such as cyclophosphamide. Pulmonary hypertension can be treated with vasodilators such as endothelin receptor antagonists or phosphodiesterase-5 inhibitors.

  • Gastrointestinal disease can manifest as gastroesophageal reflux, dysmotility, or bacterial overgrowth. Treatment includes proton-pump inhibitors for reflux disease. Prokinetic agents such as erythromycin can be used for dysmotility.

  • Renal disease was the main cause of mortality in patients with JSSc prior to the addition of angiotensin-converting enzyme inhibitors. These medications are the mainstay of treatment for renal crisis, which manifests as hypertension and renal failure. Monitoring of blood pressure in patients with JSSc is important.

  • Sclerosis can occur in the heart, leading to conduction abnormalities and cardiomyopathy.

What are the adverse effects associated with each treatment option?

Immunosuppressive therapy can be associated with multiple side effects, including an increased risk of opportunistic infections, bone marrow suppression, kidney and liver disease, and an increased risk of malignancy. Careful monitoring of complete blood counts, comprehensive metabolic profiles, and urinalysis are needed every 1 to 3 months, depending on the medication being used.

Vasodilator therapy used for treatment of Raynaud’s phenomenon and pulmonary hypertension can cause orthostasis, gum hypertophy, constipation, and bone marrow suppression.

What are the possible outcomes of scleroderma?

The prognosis for children with LSc depends on the extent of the lesion. For most patients with circumscribed morphea, the lesions self-resolve about 3 to 5 years after presentation. The major cause of poor outcome in patients with LSc is due to functional disability, not decreased survival.

For patients with JSSc, prognosis depends on the extent of organ involvement. The most common causes of death are related to cardiac, renal, or pulmonary disease. Compared with adults, children have a better prognosis, with 80% survival at 20 years after diagnosis.

What causes this disease and how frequent is it?

Children are thought to be only 3% of the total scleroderma population.

LSc is the most common type of scleroderma in children, with a reported incidence of 1 per 1 million.

The incidence of JSSc is low, with 0.3 cases per million children per year.

The cause of scleroderma is not known. Studies in adult Choctaw Native Americans found an increased prevalence of anti-topoisomerase antibodies in certain major histocompatibility complex (MHC) populations. However, this did not hold true in the Caucasian adult population.

No particular infectious agent has been associated with the development of scleroderma; however, it is hypothesized that the aberrant immune response seen in these patients may be triggered by a prior infection.

There were some initial reports of increased prevalence of scleroderma after exposure to silica or other products; however, this has not been shown in further studies.

How do these pathogens/genes/exposures cause the disease?

  • Not known

Other clinical manifestations that might help with diagnosis and management

What complications might you expect from the disease or treatment of the disease?

During the first 3 years from diagnosis, there is a rapid increase in skin sclerosis, followed by stabilization. Visceral disease can occur at any point in the presentation of JSSc. Mortality in scleroderma is secondary to these end organ complications. Pulmonary fibrosis from interstitial lung disease is one of the leading causes of death. Pulmonary hypertension can also be a significant problem in children with JSSc. Cardiac disease and fibrosis can lead to conduction defects and impaired ventricular function.

Are additional laboratory studies available; even some that are not widely available?

Skin biopsy can be helpful for the diagnosis of scleroderma, but is not necessary to make the diagnosis. Biopsy can show increased collagen deposition and an initial inflammatory reaction.

How can scleroderma be prevented?

There is no known prevention.

What is the evidence?

Zulian, F, Woo, P, Athreya, BH. “The Pediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for juvenile systemic sclerosis”. Arthritis Rheum. vol. 57. 2007. pp. 203-12. (This reference provides a classification schema for juvenile scleroderma.)

Martini, G, Foeldvari, I, Russo, R. “Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in an international database”. Arthritis Rheum. vol. 54. 2006. pp. 3971-8. (This reference reports on one of the largest case series describing outcomes in pediatric patients with scleroderma.)

Foeldvari, I, Nihtyanova, SI, Wierk, A, Denton, CP. “Characteristics of patients with juvenile onset systemic sclerosis in an adult single-center cohort”. J Rheumatol. vol. 37. 2010. pp. 2422-6. (This article compares pediatric and adult patients with scleroderma.)

Panigada, S, Ravelli, A, Silvestri, M. “HRCT and pulmonary function tests in monitoring of lung involvement in juvenile systemic sclerosis”. Pediatr Pulmonol. vol. 44. 2009. pp. 1226-34. (This paper outlines the progression of lung disease in JSSc.)

Tashkin, EP. “Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease”. N Engl J Med. vol. 354. 2006. pp. 2655-66. (This is one of the first placebo-controlled treatment studies in adults with SSc evaluating cyclophosphamide therapy in lung disease.)

Martini, G, Vittadello, F, Kasapçopur, O. “Factors affecting survival in juvenile systemic sclerosis”. Rheumatology (Oxford). vol. 48. 2009. pp. 119-22. (This paper outlines risk factors associated with decreased survival, such as diffuse skin disease.)

Ongoing controversies regarding etiology, diagnosis, treatment

There is controversy regarding treatment of the skin disease in LSc and JSSc. The natural history of skin involvement in both subtypes of scleroderma is an initial inflammatory phase, followed by increased collagen deposition, then atrophy. It is not clear whether immunosuppressive treatment makes a difference in skin outcomes because even without treatment, there is usually improved skin mobility and thinning over time.

Most rheumatologists agree that if diagnosed and treated in the early inflammatory stages, immunosuppressive therapy may be helpful to prevent more widespread involvement. However, it is not clear whether treatment affects the amount of skin involvement.