- Critical Care Associates
Shea, M.D., F.C.C.P.
What is Scleroderma?
Symptoms of Scleroderma
Types of Pulmonary Involvement
Diagnosing Interstitial Lung Disease (ILD)
Diagnosing Pulmonary Hypertension
Treatment of Scleroderma Lung Disease
Scleroderma affects about 14 out of every 1 million persons, worldwide, most frequently attacking women between the ages of 35 and 54. This high incidence in women during the childbearing years has led researchers to look for a pregnancy-related factor behind the development of scleroderma. Most recently, scientist at the National Institute of Allergy and Infectious Disease have found some evidence that leftover fetal cells, still circulating in the mothers bloodstream decades after pregnancy, may play some role in triggering the autoimmune changes behind scleroderma.
Scleroderma (also called systemic sclerosis) is a chronic autoimmune disorder, an illness in which immune defenses mistakenly attack the bodys own cells rather than protecting them from outside invaders. Scleroderma is a poorly understood illness that causes widespread hardening of the skin, especially on the hands and face. It may also damage the lungs, heart, kidneys, digestive tract, muscles, and joints.
In patients with scleroderma, scientists have identified abnormal immune proteins called autoantibodies, which are programmed to attack specific components of body cells. They have also found abnormal accumulations of protective T-cells (white blood cells that are part of the immune system) in the skin and elsewhere. In a mechanism that is still being defined, autoantibodies and /or T-cells somehow trigger damage to the bodys arterioles (the smallest arteries). These damaged arterioles leak fluid, which causes edema (swelling). They also release chemical factors which stimulate cells called fibroblasts to overproduce collagen (a fibrous protein). In the skin, abnormal fibroblast activity and collagen accumulation lead to thickening, hardening, and tightness, especially affecting skin on the hands and face. Elsewhere in the body, the autoimmune attack of scleroderma may damage: the digestive tract; the linings of joints; the outside sheaths of tendons; the muscles (including the heart muscle); portions of the heart which regulate heart rhythm; and the small blood vessels and urine-producing structures within the kidney.
Doctors classify scleroderma into different subtypes based on the specific area of the body which is most affected by autoimmune damage. For example, in limited cutaneous scleroderma, the skin is the primary target, while in diffuse cutaneous scleroderma, the damage not only affects the skin, but also the kidneys and other internal organs.
Symptoms vary from patient to patient and may include:
· Raynauds- An episodic tightening of small blood vessels in the fingers and/or toes, and sometimes in the tip of nose and earlobes. The affected extremity turns white and/or blue, and becomes cold and numb. This is then followed by a flush of redness as the extremity re-warms, often together with pain or tingling. Raynauds can be triggered by exposure to the cold or vibration, or by emotional stress.
· Skin symptoms- there may be swelling of the fingers, hands, forearms and face, sometimes the feet and lower legs will be affected. Then there is a skin thickening and tightness that may limit body movement. There can also be skin ulcers; areas of abnormal skin color (pigment too dark or too light); loss of hair; abnormal skin dryness, calcium deposits within the skin; and red spots caused by localized swelling of tiny blood vessels.
· Joints- may be joint pain, swelling, and stiffness, especially in the fingers and knees.
· Muscles- may be muscle weakness and abnormal thickening of muscle tendons.
· Digestive system- When scleroderma involves the esophagus, there may be a feeling of fullness or burning pain in the upper abdomen or behind the breast bone, together with difficulty swallowing or keeping down food. Other symptoms may include: bloating; lower abdominal pain; or difficulty controlling bowel movements.
· Heart- may be chest pain, abnormal heart rhythms, or heart failure.
· Kidneys- Kidney damages may lead to high blood pressure; headache; seizures; abnormally low urine output; and blood and/or abnormal proteins in the urine.
· Lungs- Shortness of breath, especially with exercise, and a dry cough that doesnt bring up mucus.
· Other symptoms- Dry eyes and mouth; sudden episodes of severe facial pain and impotence.
More than 95% of patients with scleroderma have both Raynauds and skin thickening. Those with limited cutaneous scleroderma tend to have the red spots caused by localized swelling of tiny blood vessels (85%), digestive problems involving the esophagus (80%), joint symptoms (70%), lung symptoms (70%), muscle weakness (50%), and heart failure (30%).
About 10% to 15% of people with scleroderma develop severe lung disease during the course of their illness.
Two main clinical manifestations of lung involvement in scleroderma are:
Fibrosing alveolitis occurs in more than three-quarters of patients with scleroderma, and vascular disease in at least 10 percent and possibly many more.
the incidence of pulmonary hypertension has varied from 10 to 80 percent. It occurs most frequently as an isolated pulmonary complication, but can be secondary to pulmonary fibrosis. Pulmonary hypertension is typically subclinical for many years until the on-going arterial damage results in the new onset of dyspnea.
There are also a number of less common manifestations of pulmonary involvement in scleroderma. This may include pleural disease, aspiration pneumonia, bronchiectasis, spontaneous pneumothorax, drug-associated pneumonitis, and neoplasm.
Diagnosing scleroderma is based on your symptoms and on the skin changes seen during physical examination. Skin biopsies and blood test may be obtained. Blood tests are used to measure the levels of autoantibodies; immunoglobulins, especially Ig G; and rheumatoid factor (RF). If scleroderma affects internal organs such as the heart, lungs, or digestive organs, other more specialized testing may be necessary.
The most common symptoms of interstitial lung disease in scleroderma are fatigue, breathlessness on exertion (and eventually at rest), and a dry cough. Chest pain is infrequent and hemoptysis (coughing up blood) is rare. The most frequent finding on physical examination is what is called bilateral basal crepitations. This is a crackling sound heard in both bases of the lungs.
The following tests are used to diagnose and assess the severity and prognosis of scleroderma lung disease:
· Chest x-rays- this would show symmetric, basal, reticulonodular shadowing. Chest x-rays are an insensitive indicator of fibrosing alveolitis and is used as an initial screen to detect established findings and/or rule out secondary infection or aspiration because of esophageal involvement.
· Pulmonary Function Tests- there are many patients with mild symptoms and normal chest x-rays who have ILD. In these patients a diagnosis can be established with PFTs and HRCT. A reduction in the single breath diffusion capacity for carbon monoxide (DLCO) is the earliest detectable functional correlate of lung disease in scleroderma; it is present in over 70 percent of patients with systemic sclerosis, including those who have no pulmonary symptoms and unremarkable chest. A pronounced reduction in DLCO in ILD (less than 65 percent of normal) is usually associated with a restrictive pattern on PFTs. Normal lung volumes in this setting are suggestive of pure vascular disease.
Measurement of the alveolar-arterial oxygen difference during exercise appears to be another sensitive indicator of lung disease in scleroderma.
· High resolution CAT Scan (HRCT)- this can demonstrate the character and distribution of fine structural abnormalities that may not be visible on chest x-rays. The earliest change is usually a narrow, often ill-defined, subpleural crescent of increased density in the posterior segments of both lower lobes. With progressive disease, the shadowing often takes on a reticulonodular appearance and also becomes associated with fine honeycomb air spaces, and then large cystic air spaces. It is important to perform scans while lying face downward and upward, especially in subtle cases. This will eliminate radiographic changes resulting from gravity-induced vascular and interstitial pooling in the dependant areas.
· Bronchoalveolar Lavage (BAL)- this procedure is done during a bronchoscopy, using a bronchoscope to view the lungs. The extent of disease defined by HRCT within a lavaged lobe also correlates with the predominant type of inflammatory cells obtained by BAL of that lobe.
· Lymphocytes are present in excess before involvement is detectable by HRCT.
· Eosinophils appear as the lung becomes involved.
· Neurophils predominate when at least the disease process affects 50 percent of the lavaged lobe.
These observations suggest that different inflammatory cells are involved at different stages of the disease. BAL is used to evaluate diffuse lung disease, to sample cells and noncellular material from the lower respiratory tract. Patients with fibrosing alveolitis typically have elevated numbers of granulocytes, particularly neutrophils and eosinophils. Excess lymphocytes and an increase in mast cells also may be seen in some patients. BAL has been demonstrated as a prognostic value, for example, patients with persistent alveolitis had a greater deterioration in pulmonary function than those without findings of alveolitis.
For these reasons, BAL is performed at presentation in all patients with evidence of scleroderma lung disease.
Pulmonary hypertension is a potentially fatal complication of scleroderma. On chest x-rays it is characterized by an enlarged pulmonary artery and attenuation of the smaller vessels. Dyspnea is the most common symptom, but as many as one-third of patients are asymptomatic. Pulmonary hypertension may be suspected if the pulmonary function tests show an isolated marked decrease in DLCO, in the absence of significant restrictive ventilatory abnormalities. Pulmonary vascular disease in scleroderma is associated with both histologic and functional abnormalities. On histologic examination, pulmonary arteries of all sizes show marked intimal and medial hyperplasia, producing an onion skin appearance similar to that in the kidney in scleroderma renal disease. The pulmonary vasculature also appears to be abnormally reactive, with significant pulmonary vasoconstriction occurring on exposure to cold.
There is no noninvasive method that is highly sensitive for the diagnosis of early pulmonary hypertension. Doppler echocardiography is useful in the presence of tricuspid regurgitiation, a setting in which pulmonary artery pressures can be estimated. Echocardiography done on patients with scleroderma accurately predicted pulmonary hypertension, which was subsequently confirmed by right heart catheterization.
All of these tests for ILD and pulmonary hypertension are repeated yearly if the results are normal and the patient remains asymptomatic. Bronchoalveolar lavage in symptomatic patients or those with an abnormality is done on the initial evaluation.
There has not been any evidence of any drug that alters the course of the lung disease in scleroderma. The apparent failure of therapy may be the ineffectiveness of currently available drugs, the fact that scleroderma is a spectrum of disease with a variable rate of progression, and the fact that pulmonary involvement has usually been identified at an established or late stage. Once extensive lung fibrosis is present, the best response to treatment that can be expected in most patients is stabilization of the disease; significant improvement in lung function will not be obtained at this advanced stage. Stabilization should not be regarded as a failed treatment.
With HRCT and BAL to recognize early inflammatory disease and to predict outcome, prospective studies are urgently needed to establish the correct role for drugs already in use and to analyze new agents.
Many drugs have been used to treat scleroderma lung disease in the past. The major drugs that are currently used are D-penicillamine, corticosteroids, and cyclophosphamide.
Penicillamine- this is an inhibitor of both collagen synthesis and crosslinking, and possesses immunosppressive properties. It has been used in scleroderma since the early 1960s. The major improvement has been an increase in the diffusing capacity for carbon monoxide (DLCO). Long-term administration of penicillamine was associated with a significant increase in DLCO (predicted values rose from 76 to 87 percent of predicted) versus little or no improvement in the control group (76 to 79 percent). Monitoring disease responsiveness to penicillamine by BAL showed a decline in BAL lymphocyte content and an improvement in alveolitis.
Corticosteroids and cyclophosphamide- The most widely used drug in pulmonary scleroderma has been corticosteroids. Corticosteroids may also be more effective if given in combination with cyclophosphamide. A study, which consisted of 30 patients with biopsy evidence of fibrosing alveolitis, was giving the following treatment regimen with results. The treatment regimens included high-dose prednisone alone (60 mg/day, which was then tapered after one month), and low-dose prednisone (20 mg every other day) plus cyclophosphamide. Thirteen of the patients (43 percent) responded to therapy; a response was defined as more than a 15 percent improvement in either FVC or DLCO over pretreatment values that was sustained for one year.
The optimal approach to therapy for the lung disease in scleroderma remains uncertain. The presence of alveolitis early in the disease, the ability to recognize it rapidly, plus the knowledge that the greatest decline in FVC occurs in the first two years of the disease indicate that future studies must not only be controlled and prospective, but also targeted at the early active stage.