Treatment of idiopathic pulmonary fibrosis: the rise and fall of corticosteroids.

After 50 years of clinical investigation, the role of corticosteroids in the treatment of idiopathic pulmonary fibrosis remains unclear (1). One conclusion, however, is unavoidable: meaningful clinical responses are rare (,30% of patients have objective evidence of improvement), improvement often occurs at substantial cost to the patient (side effects are common and lead to poorer quality of life), and survival is not improved (1,2). The study by Flaherty and coworkers (3) in this issue of The Green Journal illustrates many of these concepts well. Flaherty et al (3) report response to treatment, adverse effects, and survival in 41 patients with histopathologically proven idiopathic pulmonary fibrosis treated with corticosteroids. A significant response to treatment was defined as a drop of 10 or more points in a patient’s clinical-radiographic-physiologic disease severity score after 3 months of treatment (4). Eleven patients (27%) responded to corticosteroids. All patients had at least one side effect of the medication. Survival was 54%, at a mean follow-up of 3.3 years. Independent predictors of mortality were stable or an improved severity score at 3 months of therapy and a lower severity of pathologic fibrosis and cellularity at diagnosis. These results make several useful clinical points. They show that in as short a time as 3 months, a meaningful response to therapy can be assessed. In addition, the findings support the view that an initial response to therapy is a meaningful prognostic indicator (1). Finally, subgroup analysis of the mortality data suggests that patients with less severe disease, as measured by initial histopathology (less fibrosis and more cellularity), live longer. Whether this reflects improved responsiveness to therapy, a different underlying disease process, or is simply a result of lead-time bias is unclear, but the finding lends credence to the belief that earlier treatment leads to better outcomes (1). Unfortunately, methodologic issues question the conclusions that can be drawn from this study. First, uncertainty about the histologic pattern found in these patients complicates the interpretation of the results. Flaherty et al (3) did not clearly define idiopathic pulmonary fibrosis by the presence of usual interstitial pneumonia, and some of their patients likely had nonspecific interstitial pneumonia, a histopathologic subgroup known to have a better clinical course. Second, a substantial number of the patients enrolled in the early phases of this study had end-stage disease and died soon after entry into the study. Third, meaningful outcome measures in patients with idiopathic pulmonary fibrosis are poorly defined. Valuable measures should demonstrate or predict improvements in quality of life or mortality. A change in disease severity score does not necessarily mean symptomatic improvement. Although the score correlates reasonably well with the degree of lung fibrosis seen in open lung biopsy samples and although fibrosis is a known predictor of mortality, the score was not designed to predict survival (4). The finding by Flaherty et al that stability and improvement in the disease severity score were independent predictors of survival is important and deserves careful validation. Lastly, inferring a benefit of therapy from an uncontrolled study may not be valid. Patients who “respond” may have gotten better owing to the more benign natural history of their diseases, not because of corticosteroids. Such methodologic issues can be addressed only by randomized placebo-controlled trials with carefully defined samples of patients using validated clinical endpoints. Two recent changes have changed our understanding of idiopathic pulmonary fibrosis: its new definition (1) and the evolving hypothesis regarding its pathogenesis (5). The term idiopathic pulmonary fibrosis (also referred to as cryptogenic fibrosing alveolitis) has historically encompassed several histopathologically distinct patterns of idiopathic interstitial pneumonia that were thought to represent variations of the same fundamental theme—interstitial inflammation accompanied by varying degrees of fibrosis, either in the form of abnormal collagen deposition or a proliferation of fibroblasts capable of collagen synthesis (6). These four histopathologic patterns include usual interstitial pneumonia, desquamative interstitial pneumonia or respiratory bronchiolitis interstitial lung disease, nonspecific interstitial pneumonia, and acute interstitial pneumonia or Hamman-Rich disease (7). Recent studies have shown that the historically perplexing variation in presentation, corticosteroid responsiveness, and survival can be better explained by considering these as four separate entities (6 –12). Response to corticosteroids and survival for patients with usual interstitial pneumonia are much worse than for the other histopathologic subgroups, except for acute interAm J Med. 2001;110:326 –328. From the Department of Medicine, Veterans Affairs Medical Center, and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California. Requests for reprints should be addressed to Talmadge E. King, Jr., MD, San Francisco General Hospital, Room 5H22, 1001 Potrero Avenue, San Francisco, California 94110.