Systemic sclerosis (SSc) is a rare chronic disease of unknown cause characterized by diffuse fibrosis, degenerative changes, and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus, lower GI 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 help with confirmation. Specific treatment is difficult, and emphasis is often on treatment of complications.
SSc 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. SSc can develop as part of mixed connective tissue disease.
Immunologic mechanisms and heredity (certain HLA subtypes) play a role in etiology. SSc-like syndromes can result from exposure to vinyl chloride, bleomycin, pentazocine, epoxy and aromatic hydrocarbons, contaminated rapeseed oil, or l-tryptophan.
Pathophysiology involves vascular damage and activation of fibroblasts; collagen and other extracellular proteins in various tissues are overproduced.
In SSc, the skin develops more compact collagen fibers in the reticular dermis, epidermal thinning, loss of rete pegs, 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.
SSc varies in severity and progression, ranging from generalized skin thickening with rapidly progressive and often fatal visceral involvement (SSc with diffuse scleroderma) 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 (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias). In addition, SSc can overlap with other autoimmune rheumatic disorders—eg, sclerodermatomyositis (tight skin and muscle weakness indistinguishable from polymyositis) and mixed connective tissue disease.
Symptoms and Signs
The most common initial symptoms and signs 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. 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.
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.
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, stricture, adenocarcinoma). Hypomotility of the small bowel causes anaerobic 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 CREST syndrome.
Lung involvement generally progresses indolently, with substantial individual variability, but is a common cause of death. Lung fibrosis 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.
Severe, often sudden renal disease (renal crisis) may occur, most commonly in the first 4 to 5 yr and in patients with diffuse scleroderma. It is usually heralded by sudden, severe hypertension with features of thrombotic microangiopathic hemolytic anemia.
SSc 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 can be obvious in patients with combinations of classic manifestations, such as Raynaud phenomenon, 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 do not rule it out.
Serum ANA and Scl-70 antibody should be obtained. ANA are present in ≥ 90%, often with an antinucleolar pattern. Antibody to centromeric protein (anticentromere antibody) occurs in the serum of a high proportion of patients with CREST syndrome and is detectable on the ANA. Scl-70 antigen is a DNA-binding protein sensitive to nucleases. Patients with diffuse scleroderma are more likely than those with CREST to have anti–Scl-70 antibodies. Rheumatoid factor also is positive in one third of patients.
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.
The course depends on the type of SSc but is unpredictable. Typically, progression is slow. Overall 10-yr survival is about 65%. Most patients with diffuse skin disease eventually develop visceral complications, which are the usual causes of death. Prognosis is poor if cardiac, pulmonary, or renal manifestations are present early. Heart failure may be intractable. Ventricular ectopy, even if asymptomatic, increases the risk of sudden death. Acute renal insufficiency, if untreated, progresses rapidly and causes death within months. Patients with CREST syndrome may have disease that is limited and 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.
No drug significantly influences the natural course of SSc overall, but various drugs are of value in treating specific symptoms or organ systems. NSAIDs can help arthritis but may cause GI problems. 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. Penicillamine, long used for treatment of skin thickening, has not shown clear efficacy in recent trials.
Various immunosuppressants, including methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide, may help pulmonary alveolitis. Successful lung transplantation has been reported. Epoprostenol (prostacyclin) and bosentan may be helpful for pulmonary hypertension. Ca channel blockers, such as nifedipine 20 mg po tid or as an extended-release formulation, 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, and sleeping with the head of the bed elevated. Esophageal strictures may require periodic dilation; gastroesophageal reflux may possibly require gastroplasty. Tetracycline 500 mg po bid or another broad-spectrum antibiotic can suppress overgrowth of intestinal flora and may alleviate malabsorption symptoms. Physiotherapy may help preserve muscle strength but is ineffective in preventing joint contractures. No treatment affects calcinosis.
For acute renal crisis, prompt treatment with an ACE inhibitor can dramatically prolong survival. BP is usually, but not always, controlled. The mortality rate of renal crisis remains high. If end-stage renal disease develops, it may be reversible, but dialysis and transplantation may be necessary.
Last full review/revision June 2013 by Rula A. Hajj-ali, MD
Content last modified October 2013