Treatment of idiopathic pulmonary fibrosis: the rise and fall of corticosteroids
2001; Elsevier BV; Volume: 110; Issue: 4 Linguagem: Inglês
10.1016/s0002-9343(01)00622-2
ISSN1555-7162
AutoresHarold R. Collard, Talmadge E. King,
Tópico(s)Occupational exposure and asthma
ResumoAfter 50 years of clinical investigation, the role of corticosteroids in the treatment of idiopathic pulmonary fibrosis remains unclear (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar, 2Mapel D.W. Samet J.M. Coultas D.B. Corticosteroids and the treatment of idiopathic pulmonary fibrosis. Past, present, and future.Chest. 1996; 110: 1058-1067Crossref PubMed Scopus (130) Google Scholar). The study by Flaherty and coworkers (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) in this issue of The Green Journal illustrates many of these concepts well.Flaherty et al (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) 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 (4Watters L.C. King T.E. Schwarz M.I. et al.A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis.Am Rev Respir Dis. 1986; 133: 97-103Crossref PubMed Scopus (249) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar).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 (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) 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 (4Watters L.C. King T.E. Schwarz M.I. et al.A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis.Am Rev Respir Dis. 1986; 133: 97-103Crossref PubMed Scopus (249) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar) and the evolving hypothesis regarding its pathogenesis (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar). 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 (6Myers J.L. NSIP, UIP, and the ABCs of idiopathic interstitial pneumonias.Eur Respir J. 1998; 12: 1003-1004Crossref PubMed Scopus (29) Google Scholar). 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 (7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar). 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 (6Myers J.L. NSIP, UIP, and the ABCs of idiopathic interstitial pneumonias.Eur Respir J. 1998; 12: 1003-1004Crossref PubMed Scopus (29) Google Scholar, 7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar, 8Bjoraker J.A. Ryu J.H. Edwin M.K. et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (970) Google Scholar, 9Daniil Z.D. Gilchrist F.C. Nicholson A.G. et al.A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 1999; 160: 899-905Crossref PubMed Scopus (373) Google Scholar, 10Travis W.D. Matsui K. Moss J. Ferrans V.J. Idiopathic nonspecific interstitial pneumonia prognostic significance of cellular and fibrosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia.Am J Surg Pathol. 2000; 24: 19-33Crossref PubMed Scopus (514) Google Scholar, 11Nagai S. Kitaichi M. Itoh H. et al.Idiopathic nonspecific interstitial pneumonia/fibrosis comparison with idiopathic pulmonary fibrosis and BOOP.Eur Respir J. 1998; 12: 1010-1019Crossref PubMed Scopus (342) Google Scholar, 12Nicholson A.G. Colby T.V. Dubois R.M. et al.The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 2000; 162: 2213-2217Crossref PubMed Scopus (456) Google Scholar). Response to corticosteroids and survival for patients with usual interstitial pneumonia are much worse than for the other histopathologic subgroups, except for acute interstitial pneumonia (8Bjoraker J.A. Ryu J.H. Edwin M.K. et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (970) Google Scholar, 9Daniil Z.D. Gilchrist F.C. Nicholson A.G. et al.A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 1999; 160: 899-905Crossref PubMed Scopus (373) Google Scholar, 12Nicholson A.G. Colby T.V. Dubois R.M. et al.The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 2000; 162: 2213-2217Crossref PubMed Scopus (456) Google Scholar, 13Carrington C.B. Gaensler E.A. Coutu R.E. et al.Natural history and treated course of usual and desquamative interstitial pneumonia.N Engl J Med. 1978; 298: 801-809Crossref PubMed Scopus (597) Google Scholar). Because of its distinct clinical course, the American Thoracic Society has redefined the diagnostic criteria for idiopathic pulmonary fibrosis to require the histopathologic presence of usual interstitial pneumonia (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). This is an important semantic change that emphasizes the relevance of histopathology.The prevailing pathophysiologic theory holds that an initial inflammatory process eventually leads to widespread parenchymal fibrosis and progressive decline in pulmonary function. This model seems to hold true for many of the corticosteroid-responsive interstitial lung diseases (eg, desquamative and nonspecific interstitial pneumonia, hypersensitivity pneumonitis, eosinophilic pneumonia, sarcoidosis, and cryptogenic organizing pneumonia), but only for a minority, if any, of the patients with usual interstitial pneumonia. Recent insight into the pathophysiology of usual interstitial pneumonia provides a potential explanation for this difference. There is little evidence that inflammation is more prominent in early disease, and it is unclear whether it is relevant for the development of the fibrotic process (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar, 7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar). Rather, Selman et al (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar) have proposed that usual interstitial pneumonia is a model of abnormal wound healing in the lung that results from multiple, microscopic sites of ongoing alveolar epithelial injury and activation. This leads to the formation of patchy areas of fibroblast/myofibroblast foci. Fibroblast/myofibroblast migration and proliferation, decreased myofibroblast apoptosis, and increased activity of, and response to, fibrogenic cytokines (eg, transforming growth factor beta-1, tumor necrosis factor-alpha, platelet-derived growth factor, and insulin-like growth factor) characterize these sites of injury and abnormal repair. In addition, there appears to be an absence of appropriate reepithelialization and impaired extracellular matrix remodeling, leading to basement membrane disruption, angiogenesis, and fibrosis (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar, 7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar). Such a fibroproliferative model, lacking a major inflammatory component, may explain the poor response to anti-inflammatory therapies such as corticosteroids.Is the treatment of patients with idiopathic pulmonary fibrosis thus doomed to frustration and failure? The answer is most emphatically “no.” There is hope on the horizon. The recent shift in focus from inflammatory to fibroproliferative processes has generated interest in agents aimed at arresting fibrosis. The results of a phase II, open-label study evaluating the antifibrotic drug pirfenidone showed that it was well tolerated. Its use enabled discontinuation or tapering of prednisone and immunomodulatory therapy without loss of lung function (14Raghu G. Johnson W.C. Lockhart D. Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone results of a prospective, open-label phase II study.Am J Respir Crit Care Med. 1999; 159: 1061-1069Crossref PubMed Scopus (449) Google Scholar). A pilot study found significantly better lung function at 12 months in patients treated with both interferon gamma-1b and low-dose prednisolone when compared with prednisolone alone (15Ziesche R. Hofbauer E. Wittmann K. et al.A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 1999; 341: 1264-1269Crossref PubMed Scopus (580) Google Scholar). The results of a phase II trial of a third agent, interferon beta-1a, are due soon. All of these studies rely on the careful clinical and histopathologic diagnosis of idiopathic pulmonary fibrosis. Many other promising agents are being studied, including relaxin, suramin, endothelin-1, lovastatin, antisense therapy, survanta, keratinocyte growth factor, and inhibitors of angiotensin-converting enzyme (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar).So what is a practicing physician to do? It seems clear that knowledge of the underlying histopathology is useful in most patients, as it allows more accurate prognosis, makes stopping corticosteroid therapy easier in patients who are unlikely to benefit, and allows clinicians to consider enrolling patients in clinical studies of new therapies. The American Thoracic Society has recommended that initial therapy for idiopathic pulmonary fibrosis involve both corticosteroids and immunomodulatory agents (either cyclophosphamide or azathioprine) for 6 months; a rise in the disease severity or substantial side effects of treatment should lead to cessation or modification of therapy (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). Flaherty et al (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) suggest that the efficacy of corticosteroid therapy can be assessed within a shorter period (90 days), and decisions about continuation of therapy can then be made. Patients who fail standard therapy should be enrolled in clinical studies of new therapies and, if eligible, referred for lung transplant evaluation. After 50 years of clinical investigation, the role of corticosteroids in the treatment of idiopathic pulmonary fibrosis remains unclear (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar, 2Mapel D.W. Samet J.M. Coultas D.B. Corticosteroids and the treatment of idiopathic pulmonary fibrosis. Past, present, and future.Chest. 1996; 110: 1058-1067Crossref PubMed Scopus (130) Google Scholar). The study by Flaherty and coworkers (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) in this issue of The Green Journal illustrates many of these concepts well. Flaherty et al (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) 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 (4Watters L.C. King T.E. Schwarz M.I. et al.A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis.Am Rev Respir Dis. 1986; 133: 97-103Crossref PubMed Scopus (249) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). 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 (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) 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 (4Watters L.C. King T.E. Schwarz M.I. et al.A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis.Am Rev Respir Dis. 1986; 133: 97-103Crossref PubMed Scopus (249) Google Scholar). 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 (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar) and the evolving hypothesis regarding its pathogenesis (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar). 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 (6Myers J.L. NSIP, UIP, and the ABCs of idiopathic interstitial pneumonias.Eur Respir J. 1998; 12: 1003-1004Crossref PubMed Scopus (29) Google Scholar). 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 (7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar). 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 (6Myers J.L. NSIP, UIP, and the ABCs of idiopathic interstitial pneumonias.Eur Respir J. 1998; 12: 1003-1004Crossref PubMed Scopus (29) Google Scholar, 7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar, 8Bjoraker J.A. Ryu J.H. Edwin M.K. et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (970) Google Scholar, 9Daniil Z.D. Gilchrist F.C. Nicholson A.G. et al.A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 1999; 160: 899-905Crossref PubMed Scopus (373) Google Scholar, 10Travis W.D. Matsui K. Moss J. Ferrans V.J. Idiopathic nonspecific interstitial pneumonia prognostic significance of cellular and fibrosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia.Am J Surg Pathol. 2000; 24: 19-33Crossref PubMed Scopus (514) Google Scholar, 11Nagai S. Kitaichi M. Itoh H. et al.Idiopathic nonspecific interstitial pneumonia/fibrosis comparison with idiopathic pulmonary fibrosis and BOOP.Eur Respir J. 1998; 12: 1010-1019Crossref PubMed Scopus (342) Google Scholar, 12Nicholson A.G. Colby T.V. Dubois R.M. et al.The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 2000; 162: 2213-2217Crossref PubMed Scopus (456) Google Scholar). Response to corticosteroids and survival for patients with usual interstitial pneumonia are much worse than for the other histopathologic subgroups, except for acute interstitial pneumonia (8Bjoraker J.A. Ryu J.H. Edwin M.K. et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 1998; 157: 199-203Crossref PubMed Scopus (970) Google Scholar, 9Daniil Z.D. Gilchrist F.C. Nicholson A.G. et al.A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 1999; 160: 899-905Crossref PubMed Scopus (373) Google Scholar, 12Nicholson A.G. Colby T.V. Dubois R.M. et al.The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis.Am J Respir Crit Care Med. 2000; 162: 2213-2217Crossref PubMed Scopus (456) Google Scholar, 13Carrington C.B. Gaensler E.A. Coutu R.E. et al.Natural history and treated course of usual and desquamative interstitial pneumonia.N Engl J Med. 1978; 298: 801-809Crossref PubMed Scopus (597) Google Scholar). Because of its distinct clinical course, the American Thoracic Society has redefined the diagnostic criteria for idiopathic pulmonary fibrosis to require the histopathologic presence of usual interstitial pneumonia (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). This is an important semantic change that emphasizes the relevance of histopathology. The prevailing pathophysiologic theory holds that an initial inflammatory process eventually leads to widespread parenchymal fibrosis and progressive decline in pulmonary function. This model seems to hold true for many of the corticosteroid-responsive interstitial lung diseases (eg, desquamative and nonspecific interstitial pneumonia, hypersensitivity pneumonitis, eosinophilic pneumonia, sarcoidosis, and cryptogenic organizing pneumonia), but only for a minority, if any, of the patients with usual interstitial pneumonia. Recent insight into the pathophysiology of usual interstitial pneumonia provides a potential explanation for this difference. There is little evidence that inflammation is more prominent in early disease, and it is unclear whether it is relevant for the development of the fibrotic process (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar, 7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar). Rather, Selman et al (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar) have proposed that usual interstitial pneumonia is a model of abnormal wound healing in the lung that results from multiple, microscopic sites of ongoing alveolar epithelial injury and activation. This leads to the formation of patchy areas of fibroblast/myofibroblast foci. Fibroblast/myofibroblast migration and proliferation, decreased myofibroblast apoptosis, and increased activity of, and response to, fibrogenic cytokines (eg, transforming growth factor beta-1, tumor necrosis factor-alpha, platelet-derived growth factor, and insulin-like growth factor) characterize these sites of injury and abnormal repair. In addition, there appears to be an absence of appropriate reepithelialization and impaired extracellular matrix remodeling, leading to basement membrane disruption, angiogenesis, and fibrosis (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar, 7Katzenstein A.L.A. Myers J.L. Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification.Am J Respir Crit Care Med. 1998; 157: 1301-1315Crossref PubMed Scopus (1170) Google Scholar). Such a fibroproliferative model, lacking a major inflammatory component, may explain the poor response to anti-inflammatory therapies such as corticosteroids. Is the treatment of patients with idiopathic pulmonary fibrosis thus doomed to frustration and failure? The answer is most emphatically “no.” There is hope on the horizon. The recent shift in focus from inflammatory to fibroproliferative processes has generated interest in agents aimed at arresting fibrosis. The results of a phase II, open-label study evaluating the antifibrotic drug pirfenidone showed that it was well tolerated. Its use enabled discontinuation or tapering of prednisone and immunomodulatory therapy without loss of lung function (14Raghu G. Johnson W.C. Lockhart D. Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone results of a prospective, open-label phase II study.Am J Respir Crit Care Med. 1999; 159: 1061-1069Crossref PubMed Scopus (449) Google Scholar). A pilot study found significantly better lung function at 12 months in patients treated with both interferon gamma-1b and low-dose prednisolone when compared with prednisolone alone (15Ziesche R. Hofbauer E. Wittmann K. et al.A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 1999; 341: 1264-1269Crossref PubMed Scopus (580) Google Scholar). The results of a phase II trial of a third agent, interferon beta-1a, are due soon. All of these studies rely on the careful clinical and histopathologic diagnosis of idiopathic pulmonary fibrosis. Many other promising agents are being studied, including relaxin, suramin, endothelin-1, lovastatin, antisense therapy, survanta, keratinocyte growth factor, and inhibitors of angiotensin-converting enzyme (5Selman M. King Jr, T.E. Pardo A. Idiopathic pulmonary fibrosis progress in understanding its pathogenesis and implications for therapy.Ann Intern Med. 2001; 134: 136-151Crossref PubMed Scopus (1528) Google Scholar). So what is a practicing physician to do? It seems clear that knowledge of the underlying histopathology is useful in most patients, as it allows more accurate prognosis, makes stopping corticosteroid therapy easier in patients who are unlikely to benefit, and allows clinicians to consider enrolling patients in clinical studies of new therapies. The American Thoracic Society has recommended that initial therapy for idiopathic pulmonary fibrosis involve both corticosteroids and immunomodulatory agents (either cyclophosphamide or azathioprine) for 6 months; a rise in the disease severity or substantial side effects of treatment should lead to cessation or modification of therapy (1American Thoracic SocietyIdiopathic pulmonary fibrosis diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (981) Google Scholar). Flaherty et al (3Flaherty KR, Toews GB, Lynch JP III, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med. 2001;110:XXX–XXX.Google Scholar) suggest that the efficacy of corticosteroid therapy can be assessed within a shorter period (90 days), and decisions about continuation of therapy can then be made. Patients who fail standard therapy should be enrolled in clinical studies of new therapies and, if eligible, referred for lung transplant evaluation.
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