Interstitial Lung Disease in Systemic Sclerosis

Interstitial lung disease (ILD) is a devastating and significant cause of death in patients with a rare type of scleroderma called systemic sclerosis (SSc). Affecting about 20 people per million in the United States annually, systemic sclerosis is an autoimmune disease which can potentially affect multiple organs of the gastrointestinal, cardiac, renal, and pulmonary systems (1). SSc is characterized by hardening of the skin and internal organs due to disease-specific autoantibodies and overproduction of collagen. Interstitial lung disease in systemic sclerosis encompasses numerous disorders that can result in transformation and damage to the tissues of the lung parenchyma and can result in diminishment of respiratory function (2). Various forms of ILD can manifest during several disease processes, but ILD in systemic sclerosis is particularly worrisome because it has the highest mortality rate of all autoimmune rheumatic disorders (2).

No standard criteria exist for SSc-ILD diagnosis. The general consensus of medical professionals is that the initial diagnosis of SSc-ILD should be determined by the completion of a pulmonary function test (PFT), a high resolution computed tomography (HRCT) scan, a six-minute walk test, and a dyspnea measurement using the Borg index (2). The two major complaints of patients with SSc-ILD are dyspnea during exertion and a nonproductive cough. The most common symptom of ILD that can be assessed during physical examination is fine crackles heard at the lung bases during auscultation (4). Forced vital capacity (FVC), which measures lung volume, the diffusing capacity of the lung for carbon monoxide (DLCO), which measures how easily oxygen diffuses from alveoli into the bloodstream, and total lung capacity (TLC) are key tests performed during the PFT that help diagnose ILD (3). A decrease in FVC, TLC, and DLCO are signs of a restrictive respiratory defect. The FVC and DLCO values are proportional with the severity of disease, with a declining DLCO being the most pertinent marker of mortality (5). An HRCT scan of the lungs is the preferred noninvasive method of aiding in the diagnosis of SSc-ILD. The detailed HRCT scan can detect scarring and inflammation of the lungs, and show the distribution of abnormalities that might not be visible using chest x-rays (6). In some cases, the severity of lung inflammation needs to be assessed by a surgical lung biopsy or a bronchoalveolar lavage (BAL) (3). The BAL fluid sample can give valuable insight about the character of pulmonary infiltrates and the extent of inflammation within the lungs (7).

Interstitial lung disease is common in SSc and is the foremost cause of scleroderma-related deaths. Much of the pathogenesis of ILD in SSc is problematic and unknown. In some SSc-ILD patients, the ILD develops early and rapidly in the disease onset and can remain stable for years. In other patients with SSc-ILD, the ILD will continually progress. The development and progression of SSc-ILD encompasses abnormalities of the immune and circulatory systems (2). The errant response of the immune system can lead to an increase of inflammatory response that can progress to an increased deposition of collagen and lung fibrosis. The dense collagen destroys capillaries and the fibrosis obliterates the alveolar walls, which impedes the lungs’ function of gas exchange (8).

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Prevention of lung injury becomes the primary course of treatment because there is no cure for SSc-ILD and no treatment exists that can counter the effects of ILD. The progression of ILD in systemic sclerosis is dependent on the amount of fibrosis and the extent of tissue injury that occurs due to attack by the immune system. Therefore, a combination of anti-fibrotic and immunosuppressant drugs are employed to combat SSc-ILD (2). A variety of pharmaceutical and alternative therapies are available, but most of them are low to moderately effective, short-term, and have potentially adverse side effects (2).

The most widely studied drug used to treat SSc-ILD is the immunosuppressive drug cyclophosphamide (Cytoxan). The functionality of cyclophosphamide in treating SSc-ILD is uncertain due to the toxicity and the differing data regarding efficacy (9). When used with prednisone, a significant improvement in FVC and mortality was noted (5). The effects of cyclophosphamide are significant when compared to other drugs used to combat SSc-ILD. Although its effects are beneficial, the adverse reactions must be noted. In some studies, it has been proven to cause malignancy, hematologic, infectious, urologic, and reproductive disorders (7).

Systemic sclerosis patients with early stage ILD who cannot take cyclophosphamide can take azathioprine as alternate immunosuppressant. Azathioprine is normally administered with prednisone for patients with deteriorating lung function and worsening symptoms (9). Azathioprine is less effective than cyclophosphamide, but is advantageous as a maintenance drug used to stabilize lung function in patients who have completed a course of cyclophosphamide (9).

Penicillamine possesses immunosuppressive properties and inhibits collagen synthesis. It has been used since the 1960’s in scleroderma treatment. Patients using this drug have seen an improvement in alveolitis and an increase of DLCO but not the FVC.

Mycophenolate mofetil has been used to control organ transplant rejection but is now being used more frequently to treat SSc-ILD. Anti-fibrotic effects, stability of lung function, and an improvement in VC have been noted in patients taking mycophenolate mofetil (2, 10). When compared with other immunosuppressive treatments, mycophenolate mofetil shows a lesser occurrence of pulmonary fibrosis and a higher survival rate (5).

When pharmaceutical treatments fail to stop the deterioration of lung function, patients with severe SSc-ILD may consider lung transplantation as an option. Studies have determined that lung transplantation is a viable option for patients with end-stage SSc-ILD because pulmonary function and mortality rates improved (11).

Hematopoietic stem cell transplantation (HSCT) following immunosuppressive therapy is a treatment option that could become more prevalent in the future. The goal of HSCT is to modify the immune system in order to eliminate the erroneous inflammatory response causing the SSc-ILD symptoms (12).

Systemic sclerosis (SSc) patients who have interstitial lung disease (ILD) have an increased mortality rate. Restrictive lung disease develops in SSc-ILD patients within the first two years of disease onset, and the largest decline in FVC occurs during the first three years (5, 9). The estimated 5-year survival of SSc-ILD patients is 85% (13). Patients with mild to moderate SSc-ILD have a nine-year survival rate of 72% while patients with severe SSc-ILD have a nine-year survival rate of 30% (9). Recently, an algorithm correlating the HRCT with the FVC was developed by Goh et al. to predict the extent of disease and patient mortality for patients with SSc-ILD (5).

The trigger for disease onset remains unknown, but advances in treatment of SSc-ILD have progressed. Wide-ranging tests are necessary in order to assess the presence and severity of SSc-ILD. Pharmaceutical and therapeutic advancements need to be developed to prevent or improve the effects of inflammation and fibrosis of the lungs, and extensive treatment trials are needed for new medications and therapies in order to measure their efficacy. The progression of SSc-ILD can vary greatly among patients, but with better understanding of SSc-ILD, improvements can be made to better the quality of life and survival rate of patients stricken with this disease.

Jason Cartledge is a student at the University of Alabama at Birmingham and the winner of our 2013 Student Writing Contest. Read more about him here.


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13. Wells AU, Cullinan P, Hansell DM et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. American Journal of Respiratory Critical Care Medicine. 149(6), 1583-1590 (1994).

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