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Systemic Sclerosis

(Scleroderma)

By

Alana M. Nevares

, MD, The University of Vermont Medical Center

Last full review/revision Feb 2020| Content last modified Feb 2020
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Topic Resources

Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus, lower gastrointestinal tract, lungs, heart, and kidneys). Common symptoms include Raynaud phenomenon, polyarthralgia, dysphagia, heartburn, and swelling and eventually skin tightening and contractures of the fingers. Lung, heart, and kidney involvement accounts for most deaths. Diagnosis is clinical, but laboratory tests support the diagnosis and aid in prognostication. Specific treatment is difficult, and emphasis is often on treatment of complications.

Systemic sclerosis is about 4 times more common among women than men. It is most common among people aged 20 to 50 and is rare in children.

Classification

Systemic sclerosis is classified as

  • Limited systemic sclerosis (CREST syndrome)

  • Generalized systemic sclerosis (with diffuse skin involvement)

  • Systemic sclerosis sine scleroderma

In limited systemic sclerosis (CREST syndrome—calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), patients develop skin tightening over the face and distal to the elbows and knees and may also have gastroesophageal reflux disease. This type is characterized by slow progression and is often complicated by pulmonary hypertension.

In generalized systemic sclerosis with diffuse skin involvement, patients have Raynaud phenomenon and gastrointestinal (GI) complications. This type typically evolves rapidly. Interstitial lung disease and scleroderma renal crisis are the major complications.

In systemic sclerosis sine scleroderma, patients have systemic sclerosis–related antibodies and visceral manifestations of the disease but no skin tightening.

Etiology

Immunologic mechanisms and heredity (certain human leukocyte antigen subtypes) play a role in etiology. Systemic sclerosis–like syndromes have been associated with vinyl chloride, bleomycin, pentazocine, epoxy and aromatic hydrocarbons, contaminated rapeseed oil, or L-tryptophan.

Pathophysiology

Pathophysiology involves vascular damage and activation of fibroblasts; collagen and other extracellular proteins in various tissues are overproduced.

In systemic sclerosis, the skin develops more compact collagen fibers in the reticular dermis, epidermal thinning, loss of rete pegs (epithelial extensions that project into the underlying connective tissue), and atrophy of dermal appendages. T cells may accumulate, and extensive fibrosis in the dermal and subcutaneous layers develops. In the nail folds, capillary loops dilate and some microvascular loops are lost. In the extremities, chronic inflammation and fibrosis of the synovial membrane and surfaces and periarticular soft tissues occur.

Esophageal motility becomes impaired, and the lower esophageal sphincter becomes incompetent; gastroesophageal reflux and secondary strictures can develop. The intestinal muscularis mucosa degenerates, leading to pseudodiverticula in the colon and ileum. Interstitial and peribronchial fibrosis or intimal hyperplasia of small pulmonary arteries can develop; if long-standing, pulmonary hypertension can result. Diffuse myocardial fibrosis or cardiac conduction abnormalities occur. Intimal hyperplasia of interlobular and arcuate arteries can develop within the kidneys, causing renal ischemia and hypertension.

Systemic sclerosis varies in severity and progression, ranging from generalized skin thickening with rapidly progressive and often fatal visceral involvement (diffuse systemic sclerosis) to isolated skin involvement (often just the fingers and face) and slow progression (often several decades) before visceral disease develops. The latter form is termed limited cutaneous scleroderma or CREST syndrome. In addition, systemic sclerosis can overlap with other autoimmune rheumatic disorders—eg, sclerodermatomyositis (tight skin and muscle weakness indistinguishable from autoimmune myositis) and mixed connective tissue disease.

Symptoms and Signs

The most common initial symptoms and signs of systemic sclerosis are Raynaud phenomenon and insidious swelling of the distal extremities with gradual thickening of the skin of the fingers. Polyarthralgia is also prominent. GI disturbances (eg, heartburn, dysphagia) or respiratory complaints (eg, dyspnea) are occasionally the first manifestations.

Skin and nail manifestations

Swelling of the skin is usually symmetric and progresses to induration. It may be confined to the fingers (sclerodactyly) and hands, or it may affect most or all of the body. The skin eventually becomes taut, shiny, and hypopigmented or hyperpigmented; the face becomes masklike; and telangiectases may appear on the fingers, chest, face, lips, and tongue. However, in some patients, skin can soften to variable degrees. Subcutaneous calcifications may develop, usually on the fingertips (pulps) and over bony eminences. Digital ulcers are common, especially on the fingertips, overlying the finger joints, or over calcinotic nodules. Abnormal capillary and microvascular loops in the nails can be seen with an ophthalmoscope or dissecting microscope.

Skin Manifestations of Systemic Sclerosis

Joint manifestations

Polyarthralgias or mild arthritis can be prominent. Flexion contractures may develop in the fingers, wrists, and elbows. Friction rubs may develop over the joints, tendon sheaths, and large bursae.

Gastrointestinal manifestations

Esophageal dysfunction is the most frequent visceral disturbance and occurs in most patients. Dysphagia (usually retrosternal) usually develops first. Acid reflux can cause heartburn and stricture. Barrett esophagus occurs in one third of patients and predisposes to complications (eg, adenocarcinoma). Hypomotility of the small bowel causes bacterial overgrowth that can lead to malabsorption. Air may penetrate the damaged bowel wall and be visible on x-rays (pneumatosis intestinalis). Leakage of bowel contents into the peritoneal cavity can cause peritonitis. Distinctive wide-mouthed diverticula can develop in the colon. Biliary cirrhosis may develop in patients with limited systemic sclerosis (CREST syndrome).

Cardiopulmonary manifestations

Lung involvement generally progresses indolently, with substantial individual variability, but is a common cause of death. Lung fibrosis and interstitial lung disease are common and can impair gas exchange, leading to exertional dyspnea and restrictive disease with eventual respiratory failure. Acute alveolitis (potentially responsive to therapy) can develop. Esophageal dysfunction can lead to aspiration pneumonia. Pulmonary hypertension may develop, as can heart failure, both of which are poor prognostic findings. Pericarditis with effusion or pleurisy can occur. Cardiac arrhythmias are common.

Renal manifestations

Severe, often sudden renal disease (scleroderma renal crisis) may occur, most commonly in the first 4 to 5 years in patients who usually have diffuse scleroderma and the RNA polymerase III antibody. It is often heralded by sudden, severe hypertension with features of thrombotic microangiopathic hemolytic anemia. It can also occur without acute hypertension or in systemic sclerosis sine scleroderma, and therefore clinical suspicion is required to make the diagnosis. Corticosteroid use is a risk factor for development of scleroderma renal crisis.

Diagnosis

  • Clinical criteria

  • Antibody testing

Systemic sclerosis should be considered in patients with Raynaud phenomenon, typical musculoskeletal or skin manifestations, or unexplained dysphagia, malabsorption, pulmonary fibrosis, pulmonary hypertension, cardiomyopathies, or conduction disturbances. Diagnosis of systemic sclerosis sine scleroderma should be considered in patients who have unexplained visceral findings (eg, pulmonary hypertension). Diagnosis of systemic sclerosis can be obvious in patients with combinations of classic manifestations, such as Raynaud phenomenon (with abnormal nail-fold capillary findings), dysphagia, and tight skin. However, in some patients, the diagnosis cannot be made clinically, and confirmatory laboratory tests can increase the probability of disease but their absence does not exclude it.

Antinuclear antibodies (ANA) are present in 90% of patients, often with an antinucleolar pattern. Rheumatoid factor is positive in one third of patients. Antibody to centromeric protein (anticentromere antibody) occurs in the serum of a high proportion of patients with limited disease. Patients with generalized (diffuse) systemic sclerosis are more likely than those with limited disease to have anti-Scl-70 (topoisomerase I) antibodies. RNA polymerase III is associated with generalized systemic sclerosis, scleroderma renal crisis, and cancer. U3 RNP (fibrillarin) antibody is also associated with diffuse disease. The most cost-effective way to test for antibodies is to test for ANA, anti-Scl-70, and anticentromere antibodies first; if results are negative, testing for other antibodies should be considered based on clinical manifestations.

To help establish the diagnosis, clinicians can also consult the American College of Rheumatology (ACR)/European League Against Rheumatism's (EULAR) classification criteria for systemic sclerosis.

ACR/EULAR criteria for systemic sclerosis include the following features:

  • Skin thickening of the fingers of both hands

  • Fingertip lesions (eg, ulcers, pitting scars)

  • Telangiectasia

  • Abnormal nail-fold capillaries (eg, ectatic blood vessels, dropout areas) on capillaroscopy examination (eg, seen with an ophthalmoscope or dissecting microscope)

  • Pulmonary arterial hypertension and/or interstitial lung disease

  • Raynaud phenomenon

  • Systemic sclerosis–related autoantibodies (anticentromere, anti–Scl-70, anti–RNA polymerase III)

These criteria are weighted, in some cases according to subcriteria, and added to generate a score. Scores above a certain threshold are classified as definite systemic sclerosis.

If lung involvement is suspected, pulmonary function testing, chest CT, and echocardiography can begin to define its severity. Acute alveolitis is often detected by high-resolution chest CT.

Prognosis

Overall 10-year survival is 92% for limited systemic sclerosis and is 65% for diffuse systemic sclerosis. Predictors of early mortality include male sex, late onset, diffuse disease, pulmonary arterial hypertension, and renal crisis (1). The course depends on the type of disease (generalized vs limited) and antibody profiling but can be unpredictable. Patients with diffuse skin disease tend to have a more aggressive clinical course and eventually develop visceral complications (usually within the first 3 to 5 years), which, if severe, can lead to death. Heart failure may be intractable. Ventricular ectopy, even if asymptomatic, increases the risk of sudden death. Patients with limited systemic sclerosis (CREST syndrome) may have disease that is nonprogressive for long periods; visceral changes (eg, pulmonary hypertension caused by vascular disease of the lung, a peculiar form of biliary cirrhosis) eventually develop, but the course is often remarkably benign.

Prognosis reference

  • 1. Hao Y, Hudson M, Baron M, et al: Early mortality in a multinational systemic sclerosis inception cohort. Arthritis Rheumatol 69(5):1067–1077, 2017. doi: 10.1002/art.40027.

Treatment

  • Treatment directed at symptoms and dysfunctional organs

No drug significantly influences the natural course of systemic sclerosis overall, but various drugs are of value in treating specific symptoms or organ systems. Corticosteroids may be helpful if there is overt myositis or mixed connective tissue disease but may predispose to renal crisis and thus are used only if necessary.

Various immunosuppressants, including methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide, may help pulmonary alveolitis. Mycophenolate mofetil is effective for the treatment of interstitial lung disease (1) and is the standard of care in some specialized centers. Successful lung transplantation has been reported. Epoprostenol (prostacyclin) and bosentan may be helpful for pulmonary hypertension.

Calcium channel blockers, such as long-acting oral nifedipine (eg, 30 to 120 mg a day), may help Raynaud phenomenon but may worsen gastric reflux. Bosentan, sildenafil, tadalafil, and vardenafil are other alternatives for severe Raynaud phenomenon. Patients should dress warmly, wear mittens, and keep their head warm. IV infusions of prostaglandin E1 (alprostadil) or epoprostenol or sympathetic blockers can be used for digital ischemia.

Reflux esophagitis is relieved by frequent small feedings, high-dose proton pump inhibitors, sleeping with the head of the bed elevated, and not lying supine within 3 hours of the last meal. Esophageal strictures may require periodic dilation; gastroesophageal reflux may possibly require gastroplasty. Oral ciprofloxacin 500 mg 2 times a day or the combination of metronidazole (500 mg 3 times a day) and trimethoprim/sulfamethoxazole double strength (1 tablet 2 times a day) for 7 to 10 days or another broad-spectrum antibiotic can suppress overgrowth of intestinal flora and may alleviate symptoms of small intestine bacterial overgrowth, such as bloating, flatulence, and diarrhea.

Physiotherapy may help preserve muscle strength but is ineffective in preventing joint contractures.

No treatment has clear benefit in treating calcinosis.

For acute renal crisis, a medical emergency, prompt treatment with an angiotensin-converting enzyme inhibitor can dramatically prolong survival. The mortality rate of renal crisis remains high, but the crisis is often reversible if treatment is prompt. Dialysis may be necessary, but the need for dialysis may be temporary. Renal transplantation is a feasible option in patients who develop end-stage renal disease.

Recent evidence showed that autologous hematopoietic stem cell transplantation in early generalized systemic sclerosis increases survival after the first year more than does IV cyclophosphamide; however, mortality was higher during the first year. This may become an option in the future for select patients (2).

Some experts encourage periodic screening for pulmonary hypertension with pulmonary function testing and/or echocardiography every 1 to 2 years, depending on symptoms.

Treatment references

  • 1. Tashkin DP, Roth MD, Clements PJ, et al: Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir Med 4(9):708–719, 2016. doi: 10.1016/S2213-2600(16)30152-7.

  • 2. van Laar JM, Farge D, Sont JK, et al: Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: A randomized clinical trial. JAMA 311(24):2490–2498, 2014. doi: 10.1001/jama.2014.6368.

Key Points

  • Key findings in systemic sclerosis include skin and joint changes, Raynaud phenomenon, and esophageal changes, but life-threatening effects may involve organs such as the lungs, heart, or kidneys.

  • Consider the diagnosis if patients have Raynaud phenomenon, typical musculoskeletal or skin manifestations, or unexplained dysphagia, malabsorption, interstitial lung disease and pulmonary fibrosis, pulmonary hypertension, cardiomyopathies, or conduction disturbances.

  • Test for ANA, Scl-70 (topoisomerase I), and anticentromere antibodies.

  • Because there is no clear disease-modifying therapy, direct treatment at involved organs.

Drugs Mentioned In This Article

Drug Name Select Trade
CYTOXAN (LYOPHILIZED)
CILOXAN, CIPRO
CELLCEPT
FLAGYL
No US brand name
OTREXUP
FLOLAN
IMURAN
CAVERJECT, EDEX, MUSE
TALWIN
ADALAT CC, PROCARDIA
LEVITRA
VIAGRA
CIALIS
TRACLEER
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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