Gastrointestinal Involvement

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Lung Fibrosis in Systemic Sclerosis

By Richard Silver, M.D., Professor of Medicine, Medical University of South Carolina (originally published in "Scleroderma Voice," 2004 Issue #1)

Richard Silver, M.D.

Editor's note: This is a long article. You can skip directly to the sections that interest you, by clicking on these links:

• Introduction
• Scleroderma Lung Disease Is Marked by Scarring of the Lungs
• Lung Fibrosis Usually Occurs in Systemic Sclerosis
• Diagnosing Lung Fibrosis
• Treating Scleroderma Lung Disease
• Conclusion
• Acknowledgements

Patients with systemic sclerosis often cough and experience a sensation of breathlessness with exertion, and these symptoms may be one of the earliest indicators that their disease is involving the lungs.

There may, however, be several other reasons for a patient to cough and experience shortness of breath. It is important for all potential causes to be investigated and if possible treated.

Keep in mind that if you experience shortness of breath or cough, it might be caused by a variety of other conditions and does not necessarily indicate lung fibrosis. For example, patients with weakness of the respiratory muscles or patients with heart disease might also experience breathlessness.

Anemia can also lead to shortness of breath.

And of course shortness of breath when walking long distances or climbing stairs might simply be due to poor physical conditioning.

In this brief review, I will provide some background information on normal lung function and how it may be disrupted in patients with scleroderma. Various tests that your rheumatologist and pulmonologist might order to evaluate your lungs will be described and, finally, some of the treatments to treat this serious complication of scleroderma will be discussed.

Figure 1. Respiration. Respiration involves the transport of air to and from the alveoli or air sacs.

Scleroderma Lung Disease Is Marked by Scarring of the Lungs
Scleroderma lung disease is categorized as an Interstitial Lung Disease (ILD). ILD refers to a broad category of lung diseases, of which scleroderma is one among nearly 150 conditions, marked by fibrosis or scarring of the lungs. The net result of the fibrosis is ineffective respiration or difficulty breathing.

The primary function of the respiratory system is to supply the blood with oxygen to be delivered throughout the body. The respiratory system does this through breathing (Figure 1).

Respiration and the exchange of carbon dioxide for oxygen is achieved through the mouth, nose, trachea, lungs, and diaphragm. The efficiency of this gas exchange depends in large part on the very close interface of the air we breathe with the blood flowing through the smallest blood vessels, the capillaries, in our lungs. This process occurs in the alveoli, or air sacs (Figure 2).

Figure 2. Normal Alveoli. Normal lung tissue showing multiple alveoli, with only a small amount of connective tissue separating the air from the capillaries containing red blood cells.

In scleroderma the efficiency of respiration may be impaired due to scarring in the alveoli (Figure 3). This leads to a sensation of breathlessness or, in medical terminology, dyspnea.

Lung Fibrosis Usually Occurs in Systemic Sclerosis
Lung fibrosis occurs in nearly all patients with systemic sclerosis. It does not occur in patients with localized scleroderma, e.g. morphea or linear scleroderma.

The extent of fibrosis is variable with mild scarring in some patients and more extensive scarring in others.

Depending on the severity of the condition, simple activities such as walking or talking on the phone may become difficult, and supplemental oxygen may be required in some cases.

Lung fibrosis may occur in patients with either the limited cutaneous form (CREST syndrome) or the diffuse cutaneous form of systemic sclerosis.

Figure 3. Scarred Alveoli. In scleroderma and other interstitial lung diseases, the alveoli are distorted and scarring or fibrosis thickens their walls.

For reasons that are not clear, severe lung scarring is seen more frequently in men and in African-American scleroderma patients.

Patients who have a positive blood test for the anti-Scl-70 antibody appear to be at highest risk for severe lung fibrosis.

Generally, lung fibrosis tends to occur early in the course of the illness, usually within the first 5 years from diagnosis. Routine monitoring for lung fibrosis is most important during this period of time or whenever a patient might experience shortness of breath or cough.

Diagnosing Lung Fibrosis
When should you be concerned about possible scleroderma lung fibrosis? Breathlessness is the most common symptom and warrants thorough evaluation.

Cough may be another common symptom of lung fibrosis. The cough may worsen with exertion and usually there is little or only scant clear sputum. A cough that produces much sputum or blood warrants further evaluation because it may indicate infection or

another pulmonary problem. Your rheumatologist or pulmonologist will conduct a battery of tests designed to diagnose scleroderma lung fibrosis and to exclude other potential causes of breathlessness and cough.

In addition to a complete history and physical examination, at which time your physician will inquire about your exercise capacity, symptoms such as breathlessness and cough, and listen with a stethoscope to your lungs and heart, a number of tests might be performed to determine the presence of lung fibrosis and to estimate the degree of impairment.

A list of such tests, all of which might not be required for your particular evaluation, is shown in Table 1.

Blood Oxygen Saturation
The overall efficiency of respiration can be estimated by measuring the amount of oxygen (O2 satur-ation) in your blood. This can be performed by directly measuring oxygen in a sample of arterial blood (ABG, arterial blood gases), or it can be estimated by using an instrument called an oximeter, which fits on the finger, earlobe, or forehead.

The oximeter method is preferred in most cases since it is noninvasive, but sometimes it does not work well due to reduced blood circulation to the fingers or earlobe.

The blood gas test is not recommended for most patients since it requires an arterial puncture and can precipitate severe vasospasm (Raynaud’s phenomenon).

Figure 4. Patient undergoing pulmonary function tests (PFTs).

Pulmonary Function Tests
Pulmonary Function Tests (PFTs) are a group of tests that are noninvasive and usually performed as an outpatient.

To perform PFTs, you are required to breathe into a tube via a mouthpiece (Figure 4). Some scleroderma patients may not be able to accommodate a standard mouthpiece, but an adapter or pediatric mouthpiece can be used.

Analysis of pulmonary function tests such as the Forced Vital Capacity (FVC, the total amount of air you can blow out forcefully) and the Diffusion Capacity for Carbon Monoxide (DLCO, a measure of how well oxygen diffuses into your blood) will help your physician determine the presence and severity of restriction of the lungs.

Restriction is the characteristic abnormality in scleroderma, leading to a decrease (below 80% predicted) in the FVC and DLCO.

PFTs can also detect other lung abnormalities such as obstruction of the airways; the latter may be due to emphysema or chronic obstructive pulmonary disease (COPD) often related to cigarette smoking. PFTs should be performed as part of a baseline evaluation and repeated sequentially, especially during the first 5 years of disease or whenever dyspnea worsens.

Chest X-Ray
Radiographic imaging studies are part of the initial evaluation and subsequent follow-up of the scleroderma patient complaining of shortness of breath.

Figure 5. High resolution computed tomographic scan (HRCT) showing areas of early inflammation and fibrosis.

High Resolution Computed Tomography of Chest (HRCT)
A routine chest x-ray may demonstrate fibrosis, but it is not a very sensitive test for detecting early or mild disease.

Most patients will require additional testing with a high resolution computed tomographic (HRCT) scan. This noninvasive scan provides images of multiple slices through the lung from top (apex) to bottom (base) and can even detect subclinical ILD, i.e. inflammation or fibrosis that occurs before the development of shortness of breath (Figure 5).

Much more needs to be learned about the interpretation of HRCT scans, but this technology has enabled earlier diagnosis of lung disease and is being used to monitor the progress of fibrosis and impact of treatment.

Bronchoscopy with Bronchoalveolar Lavage (BAL)
Bronchoscopy with broncho-alveolar lavage (BAL) is a more invasive test that also may provide information about the degree of inflammation in the lungs. Inflammation or alveolitis is believed to occur before lung fibrosis.

BAL is performed by a pulmonologist, usually as an outpatient and with conscious sedation. One or more segments of the lungs are washed with a sterile salt water solution that is then recovered and analyzed for the types of cells and proteins in the alveoli or air sacs (Figure 6). BAL should be performed only at specialized centers capable of analyz-ing and interpreting the results.

Figure 6. Bronchoalveolar lavage (BAL) allows sampling of cells and proteins from the lower airways and alveoli.

Lung Biopsy
Lung biopsy is often recommended to help diagnose various types of ILD, but it is required less often among scleroderma patients in whom the diagnosis is more straightforward.

The lung can be biopsied at the time of bronchoscopy (transbronchial lung biopsy), but only a small amount of lung tissue is obtained and it is often insufficient for diagnosis.

When needed for diagnosis, a biopsy via a surgical incision or a scope (thoracoscopic) is preferable to the bronchoscopic approach.

Other Tests of Lung Function
To exclude other causes of breathlessness, additional tests required in some but not all cases might include a ventilation/perfusion lung scan, an echocardiogram, a cardiopulmonary exercise test, a cardiac stress test, and a cardiac catheterization.

Treating Scleroderma Lung Disease
Treatment of scleroderma lung disease depends on the extent of lung fibrosis, degree of activity of the inflammation (alveolitis), and degree of respiratory impairment. Obviously, these factors will vary among patients and may change over time for an individual patient. Thus, no single treatment can be recommended.

The general approach is to identify the presence of alveolitis and then attempt to suppress it with anti-inflammatory medications (steroids usually) and immuno-suppressant medications.

High doses of steroids, e.g. prednisone, are generally avoided because high doses have been associated with severe kidney disease (scleroderma renal crisis).

Lower doses of prednisone (20 mg daily or less) are often used and seem to be safe and in some cases effective.

In addition to low doses of prednisone, an immuno-suppressant medication such as cyclo-phosphamide is often used for patients with increasing breathlessness and evidence of alveolitis.

A multicenter, randomized clinical trial known as the Scleroderma Lung Study (SLS) recently closed enrollment with more than 160 scleroderma patients. When analysis has been completed, the SLS should provide valuable information regarding the safety and effectiveness of cyclophosphamide therapy for scleroderma patients with lung fibrosis.

Another clinical trial, BUILD2 (Bosentan Use in Interstitial Lung Disease), is designed to determine the safety and usefulness of the drug bosentan (Tracleer) for lung fibrosis in scleroderma patients.

BUILD2 is currently enrolling patients and, if interested, you should contact your rheumatologist or pulmonologist for details and to see if you might qualify to participate. [See p. 24 for more about the BUILD2 study. —Editor]

Other drugs that are potentially anti-fibrotic are also being studied for scleroderma and may prove to be effective in preventing or improving lung fibrosis.

Vaccinations for the influenza virus and pneumococcal pneumonia (Pneumovax) are recommended for most patients with any degree of lung impairment.

Prevention or treatment of gastroesophogeal reflux is also important to avoid additional lung damage.

Regular exercise, sometimes prescribed as part of a pulmonary rehabilitation program, may be recommended as well.

Supplemental oxygen may be required when exercising or at rest, for those patients whose lung fibrosis leads to significant impairment in providing oxygen to the tissues.

Lung transplantation has been performed in some scleroderma patients, but only a few specialized centers have significant experience in such transplants for scleroderma patients.

Conclusion
Although lung fibrosis remains a serious complication, we are fortunate now to have a number of useful tests to enable earlier diagnosis.

It is also heartening to see a greater interest in potential new therapies, with more opportunities than ever for patient participation in clinical trials. Through such studies, one day we will have more effective and safer medications to treat scleroderma lung fibrosis.

Acknowledgments
The author gratefully acknowledges the input of his patients Amy Parrish, Ed Tapley, and George Tweedy, as well as the advice of his colleagues at MUSC.

Dr. Silver is the recipient of research funding from the Scleroderma Foundation, NIAMS, and NHLBI.