Systemic Sclerosis (SSc)

At a Glance

Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology that affects the skin, blood vessels, muscles, joints, and a variety of internal organs, such as the digestive tract, heart, lungs, and kidneys. The major characteristics of this disease are immunologic abnormalities, vascular damage, and excessive diffuse fibrosis. Often, the primary finding is thickening and tightening of the skin, which can progress to visceral involvement, leading to renal failure, cardiac failure, pulmonary insufficiency, or intestinal malabsorption.

SSc should be differentiated from “localized scleroderma,” a much more indolent disease that is characterized only by distinct skin lesions on the hands and face that rarely, if ever, spread throughout the body or cause serious complications. It can manifest either as oval-shaped patches of skin with purple borders and pale centers (morphea) or as bands or streaks of hardened skin on one or both arms or legs or on the forehead (linear scleroderma).

There are two main clinical types of SSc: limited and diffuse disease. In limited SSc, the affected skin is found predominantly distally to the knees and elbow, and complications are mainly limited to pulmonary hypertension and ischemic digital loss. A form of limited SSc that is manifested by calcinosis, Raynaud’s phenomenon, esophageal dismotility, sclerodactyly, and teleangiectasia is called CREST syndrome. Diffuse SSc is a much more aggressive disease that is characterized by organ involvement and a different pattern of affected skin localized on the proximal portion of extremities and trunk.

Patients with SSc have a variety of skin symptoms. The typical finding is skin tightness and mask-like appearance of the face. Skin hardness, thickening, or stiffness can also be seen and felt on the fingers, hands, and forearms. Skin discoloration is also a frequent symptom. Some areas of skin appear abnormally light or dark, reddish, or scaly with visibly dilated blood vessels (telangiectasies). There is often substantial, severe, and recurrent itching of the skin. These patients frequently report that their fingers or toes turn color in response to hot and cold temperatures or during emotional distress (Raynaud’s phenomenon). Raynaud’s phenomenon, usually the first symptom of systemic sclerosis, is caused by episodes of vasospasm. Although some patients with Raynaud’s phenomenon may not develop the entire spectrum of triphasic color changes (pallor, dusky cyanosis, and red engorgement), most have digital pallor in response to cold or stress.

Occasionally, patients notice the presence of small, white lumps beneath the skin, which sometimes ooze a white toothpaste-like substance (calcinosis). It is not uncommon to find sores (ulcers) on the fingertips or toes. Because of the resorption of the fingertips, the fingers become spindle-shaped (sclerodactyly). Hair loss is another common finding.

Bone and muscle symptoms of SSc include pain, stiffness and swelling of fingers and joints, numbness and pain in the feet, and joint contractures. Joint mobility, especially of the small joints of the hand, may be restricted because of calcinosis or skin thickening. Patients may develop muscle weakness (myopathy) and arthritis.

SSc patients often complain about breathing problems; dry, nonproductive cough; shortness of breath (first on exertion and subsequently at rest); and wheezing. Pulmonary function testing demonstrates some impairment in lung function in almost all patients with diffuse SSc, even in the absence of radiographic changes or exertional dyspnea. In more advanced disease, pulmonary complications can lead to aspiration pneumonia, pulmonary hemorrhage, and pneumothorax.

Sometimes palpitations, atypical chest pain, fatigue, and pulmonary hypertension occur, which can develop into right-sided heart failure. Cardiovascular complications include myocardial fibrosis, conduction defects, pericarditis, and pericardial effusion.

Digestive tract problems, which are not uncommon, are caused by decreased gastrointestinal (GI) motility, followed by progressive fibrosis and scarring. Patients frequently suffer from heartburn and difficulty swallowing (dysphagia), first with solids, then liquids. Chest pains are sometimes reported as well. Other GI symptoms include bloating after meals, constipation, diarrhea, nausea, vomiting, weight loss, abdominal cramps, and fecal incontinence. In case of severe complications, such as pneumatosis cystoides intestinalis (gas pockets in the bowel wall), wide-mouthed diverticula in the colon and esophagus, and liver febrosis, patients can become profoundly malnourished. Upper gastrointestinal bleeding and iron deficiency anemia can occasionally develop.

Renal involvement in scleroderma is considered a poor prognostic factor and can be fatal. The most important kidney complication of scleroderma is scleroderma renal crisis, which is characterized by malignant hypertension, hyperreninemia, azotemia, microangiopathic hemolytic anemia, hematuria, and proteinuria. Renal crisis leads to rapidly progressive rental failure. Patients at greatest risk for scleroderma renal crisis are those with rapidly progressive diffuse skin fibrosis, antecedent use of glucocorticoids, presence of RNA polymerase III antibody, and those with a new onset pericardial effusion.

Other symptoms of SSc include signs of hypothyroidism, sicca symptoms (dry eyes and mouth), carpal tunnel syndrome, trigeminal neuralgia, and erectile dysfunction in men.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Initial testing should include a complete blood count (CBC), ESR, complete metabolic panel, muscle enzymes, thyroid function tests, rheumatoid factor, immunoglobulin testing, C-reactive protein, serologic testing for autoantibodies, and urinalysis. These tests often reveal increased ESR, thrombocytopenia, microangiopathic hemolytic anemia, hypergammaglobulinemia, positive rheumatoid factor, presence of autoantibodies, increased creatine phosphokinase levels in patients with muscle involvement, and increased urea and creatinine levels in patients with kidney involvement.

Serologic testing for autoantibodies can be helpful in diagnosing and classifying systemic sclerosis and in determinating disease prognosis. However, none of the serologic tests are sensitive enough to independently exclude disease. The various autoantibodies in SSc are not closely related to the pathogenesis of the disease.

Antinuclear antibody (ANA) is positive in 60-80% of patients with scleroderma; therefore, negative results do not exclude the diagnosis of SSc. With repeated investigations during the course of the disease, they have been found in approximately 98% of affected individuals.

Three ANA species are currently used to identify distinctive clinical entities in SSc: anti-DNA-topoisomerase I (ATA or Scl-70) antibodies, antibodies recognizing one or more centromere proteins (ACA), and antibodies to RNA-polymerase III (ARNAP III). When tested by indirect immunofluorescence, they show specific nuclear staining patterns. Each of these ANAs can be detected in roughly 20-25% of patients, and they are generally considered mutually exclusive. The main three antibodies are highly disease-specific, are important for the early diagnostics of the specific type of SSc and the initiation of the appropriate therapy, and might, in the future, be used to determine the clinical activity of the disease and monitor a patient’s response to immunological therapies.

ATA correlates with diffuse cutaneous SSc. ATA-positive patients are associated with the highest frequency of pulmonary interstitial fibrosis. This group of patients has intermediate risk with respect to cumulative survival times, frequencies of diffuse SSc, and renal involvement.

ACAs are found in roughly 60-80% of patients with limited SSc, only rarely in patients with diffuse SSc, and are nearly mutually exclusive with ATA. In combination with Raynaud’s phenomenon, they predict the evolution of SSc. ACA are closely associated with CREST-syndrome. The ACA group has the best prognosis of the three, with the longest cumulative survival times and the lowest frequency of diffuse SSc, pulmonary involvement, and renal disease.

ARNAP III reflects the worst prognosis. Patients with anti-RNAP III antibodies exhibit the greatest risk of diffuse SSc, the highest mean maximum skin sickness score, the shortest cumulative survival times, and the greatest likelihood of renal involvement compared with patients in either of the other two groups.

In addition to the ANAs, anti-histone antibodies can be found in patients with SSc, but they are not characteristic of the disease. Antithyroid antibodies are sometimes detected as well and are associated with signs of hypothyroidism.

Additional tests may include skin biopsy, chest x-ray, CT scan of the lungs, echocardiogram, and pulmonary function tests. Skin biopsy is not usually necessary but is characteristic. Initially, there is a perivascular mononuclear infiltrate predominantly composed of CD4+ and CD8+ T-cells. The epidermis shows signs of atrophy, whereas in the dermis there is excessive presence of ground substance and some odd-looking endothelial cells. This is followed by deposits of collagen later in the disease and development of fibrosis.

What Lab Results Are Absolutely Confirmatory?

There are no absolutely confirmatory laboratory tests.