Interferon Gamma-1b for Pulmonary Fibrosis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The recent trial of interferon gamma-1b for idiopathic pulmonary fibrosis, reported by Raghu et al. (Jan. 8 issue),1 is a major accomplishment, despite the disappointing results. One may wonder, however, whether the selected end points were optimal. A decline in the forced vital capacity by at least 10 percent of the predicted value seems a robust criterion, but the criterion for the difference between alveolar and arterial oxygen tension (P(A–a)O2), which accounted for 55 percent of the primary end-point events, is weak. Day-to-day variations in barometric pressure, the effective alveolar ventilation, and random errors in measurement can easily conspire to produce a rise of 5 mm Hg in the P(A–a)O2 without an important or lasting physiological change in the patient. In addition, the report is unclear about when "progression of disease" was determined. A sophisticated assessment of gas exchange might not be feasible in a large, multicenter trial, but other means of evaluation (e.g., a six-minute walk, measurement of oxyhemoglobin desaturation during light exercise, or even a full cardiorespiratory exercise test) might prove practicable and informative. Data on systemic markers of inflammation and collagen metabolism would be of supplementary interest. We hope that this study will pave the way for additional large-scale trials of treatment for idiopathic pulmonary fibrosis and similar difficult diseases, such as unremitting sarcoidosis.
A. Ross Hill, M.D.
State University of New York Downstate Medical Center
Brooklyn, NY 11203
ross.hill@downstate.edu
References
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-133.
To the Editor: Raghu et al. fail to mention pulmonary hypertension as one of the variables that may influence the quality of life and overall progression-free survival among patients with idiopathic pulmonary fibrosis. Pulmonary hypertension during exercise is common even during the early stages of idiopathic pulmonary fibrosis. When the vital capacity is less than 50 percent of the predicted value or the diffusing capacity for carbon monoxide falls below 45 percent of the predicted value, pulmonary hypertension at rest can be expected.1,2 In a multivariate analysis, King et al.3 found that survival among 87 patients with idiopathic pulmonary fibrosis was significantly related to evidence of pulmonary hypertension. It has been demonstrated that oxygen therapy at rest and during exercise improves pulmonary hemodynamics and probably improves exercise capacity and prognosis in such patients.4
Considering its key prognostic significance, I wonder whether the negative conclusions drawn by Raghu et al. would have been different if the two study groups in their trial had also been matched with respect to the presence or absence of pulmonary hypertension at base line.
Oren Fruchter, M.D.
Rambam Medical Center
Haifa 31096, Israel
oren_md@inter.net.il
References
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-664.
Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525.
King TE Jr, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025-1032.
Harris-Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marciniuk DD. Oxygen improves maximal exercise performance in interstitial lung disease. Am J Respir Crit Care Med 1994;150:1616-1622.
To the Editor: Raghu et al. conclude that interferon gamma-1b had no benefit for the treatment of idiopathic pulmonary fibrosis, but they may have underestimated its efficacy. There is an apparent discrepancy between the primary analysis of progression-free survival, which showed no benefit, and the mortality analysis, which suggested efficacy. This discrepancy may be due to a violation of the proportional-hazards assumption in the primary analysis, which is the assumption that the hazard ratio is constant over time.1 In Figure 1 of the article, the treatment effect appears to vary with time. During the first 150 days or so, the treatment group seemed to have an increased probability of disease progression or death, followed later by a decrease. This crossing of survival curves could indicate a violation of the proportional-hazards assumption. Consequently, this analysis could have obscured an overall benefit.
Moreover, the hazard ratio for death in the interferon gamma-1b group was 0.6, which suggests that the treatment had substantial efficacy. To conclude that there was no benefit because the P value was 0.08, instead of 0.05, seems overly conservative.2 Overall, the results appear to be most consistent with a survival benefit.
Mark D. Eisner, M.D., M.P.H.
University of California, San Francisco
San Francisco, CA 94143-0924
eisner@itsa.ucsf.edu
References
Hosmer DW Jr, Lemeshow S. Applied survival analysis: regression modeling of time to event data. New York: John Wiley, 1999.
Goodman SN. Toward evidence-based medical statistics. 1. The P value fallacy. Ann Intern Med 1999;130:995-1004.
To the Editor: Raghu et al. report the results of a well-conducted trial and inhibit the initial enthusiasm about the use of interferon gamma-1b in the treatment of patients with idiopathic pulmonary fibrosis as previously reported by Ziesche et al.1 Two points in these studies will be important for future research. First, treatment with interferon gamma-1b had a better effect on survival among patients with a less impaired forced vital capacity at base line. Second, lung specimens from patients who had had a response to interferon gamma-1b in the past had overexpression of transforming growth factor 1 and connective-tissue growth factor and lacked interferon gamma-1b in their lung tissues.1 The question of whether interferon gamma-1b might be beneficial in subgroups of patients with idiopathic pulmonary fibrosis could be raised.
Immunomodulators may be useful in the treatment of idiopathic pulmonary fibrosis.2 The timing of treatment, however, is extremely important.3 The cytokine status of the patient could be crucial to the choice of an immunomodulatory agent and the patient's response to therapy. Assessing the cytokine profile in patients with idiopathic pulmonary fibrosis in lung specimens and correlating it with the serum level could be useful in future studies involving immunomodulatory agents.
Pelagia G. Tsoutsou, M.D.
Konstantinos I. Gourgoulianis, M.D.
University Hospital of Larissa
41 222 Larissa, Greece
pauletta24@hotmail.com
References
Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. 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;21:1264-1269.
Gross TG, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525.
Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345:340-350.
To the Editor: The study by Raghu et al. of interferon gamma-1b as treatment for idiopathic pulmonary fibrosis emphasizes the difficulty of treating this pernicious disease. Given the negative results of the study, I was surprised that Teirstein,1 commenting on the study in an editorial, does not recommend referral for lung transplantation as an important and early intervention. Because of the poor long-term prognosis for patients with this disease and the lack of effective medical therapies, transplantation should be the first treatment option for all eligible patients.2,3 I am equally surprised that Teirstein continues to recommend corticosteroids as frontline therapy. The often-quoted figure of a 30 percent rate of response to corticosteroids stems from studies that enrolled heterogeneous groups of patients with interstitial lung disease; in those studies, the criteria for idiopathic pulmonary fibrosis overlapped with those for other diseases that we now recognize as distinct and as having better prognoses; therefore, the results may not even apply to idiopathic pulmonary fibrosis.4 I agree that therapy instituted early in the course of disease may have increased potential to alter its natural history, but this hypothesis needs further validation through controlled studies before it serves as the basis for treatment recommendations.
Jason S. Vourlekis, M.D.
National Institutes of Health
Bethesda, MD 20892
vourlekj@mail.nih.gov
References
Teirstein AS. The elusive goal of therapy for usual interstitial pneumonia. N Engl J Med 2004;350:181-183.
Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525.
Thabut G, Mal H, Castier Y, et al. Survival benefits of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg 2003;126:469-475.
King TE Jr. Idiopathic interstitial pneumonias. In: Schwarz MI, King TE Jr, eds. Interstitial lung disease. 4th ed. Hamilton, Ont., Canada: B.C. Decker, 2003:701-86.
To the Editor: In his editorial on therapy for idiopathic pulmonary fibrosis, Teirstein points out that the currently available immunomodulatory therapeutic options for idiopathic pulmonary fibrosis, including the one best studied (interferon gamma-1b), are clearly inadequate to meet the expectations of both patients and doctors. However, he also reports that about one third of patients with idiopathic pulmonary fibrosis benefit from corticosteroid therapy. It should be noted that although limited evidence has been published for a few immunomodulatory agents in idiopathic pulmonary fibrosis, the authors of a recent systematic Cochrane Review were unable to find any level of evidence for the use of corticosteroid therapy in idiopathic pulmonary fibrosis.1 Considering that it is quite common that patients with this illness are treated for long periods with corticosteroids, which are associated with well-known risks of serious side effects, physicians should be aware that the most commonly used medication for idiopathic pulmonary fibrosis, prednisone, is also the medication with the lowest level of evidence for this use.
Luca Richeldi, M.D., Ph.D.
Policlinico Hospital
41100 Modena, Italy
References
Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;3:CD002880-CD002880.
The authors reply: The primary end point in our trial was defined as the first occurrence of the following: an increase of 5 mm Hg or more in the P(A–a)O2 gradient at rest, a decrease of 10 percent or more in the predicted forced vital capacity, or death. These primary end points were chosen on the basis of the best available data at the time of initiation of the trial.1 We agree with Dr. Hill that the criterion relating to the P(A–a)O2 gradient was suboptimal. A change of 5 mm Hg or more in the P(A–a)O2 gradient alone accounted for 62 percent of progression events in the trial. Therefore, the P(A–a)O2 gradient may not be a reliable measure of disease progression, and our use of it could have substantially underpowered the analysis. We appreciate Dr. Hill's suggestions as well as those of Drs. Tsoutsou and Gourgoulianis and Dr. Fruchter, all of whom note other ways to improve the understanding of the treatment effect.
We agree with Dr. Eisner that the conclusion that the treatment was of no benefit, though accurate by statistical convention (P>0.05), is conservative and fails to recognize a potentially important clinical benefit.2 The lack of a safe and effective therapy and the dismal prognosis for patients with idiopathic pulmonary fibrosis make survival a critically important outcome. Survival was both a component of our primary end point and a prespecified secondary end point. Consequently, our finding of a 41 percent relative reduction in the risk of death in the overall population of patients treated with interferon gamma-1b (P=0.08), coupled with the significant improvements in survival found in subanalyses of treatment-adherent patients (P=0.02) and patients with a lesser degree of impairment in lung function at base line (P=0.04), clearly warrants further investigation. Accordingly, a confirmatory trial has been initiated.
We also agree with Dr. Eisner that the proportional-hazards assumption was violated in the analysis of progression-free survival. However, the Cox proportional-hazards model must be used as it was prespecified. It should be noted that the proportional-hazards assumption was not violated in the intention-to-treat analysis of survival time.
We disagree with the recommendations made in the editorial that accompanied our study.2 Prednisone should not be used as the sole treatment for idiopathic pulmonary fibrosis.1,3 Furthermore, lung transplantation should be considered early in the clinical course and not as a last resort.4
Future therapy for idiopathic pulmonary fibrosis should be based on data from controlled clinical trials. Therefore, we recommend that clinicians encourage eligible patients with idiopathic pulmonary fibrosis to enroll in clinical trials of new therapeutic agents or treatment regimens, including trials of interferon gamma-1b.
Ganesh Raghu, M.D.
University of Washington
Seattle, WA 98195
Talmadge E. King, Jr., M.D.
University of California, San Francisco
San Francisco, CA 94110
References
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-664.
Teirstein AS. The elusive goal of therapy for usual interstitial pneumonia. N Engl J Med 2004;350:181-183.
Mapel DW, Samet JM, Coultas DB. Corticosteroids and the treatment of idiopathic pulmonary fibrosis: past, present, and future. Chest 1996;110:1058-1067.
Mogulkoc N, Brutsche MH, Bishop PW, Greaves SM, Horrocks AW, Egan JJ. Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation. Am J Respir Crit Care Med 2001;164:103-108.
The editorialist replies: Vourlekis correctly raises two important questions regarding the treatment of usual interstitial pneumonia: the role of lung transplantation and the lack of conclusive evidence in support of corticosteroid therapy. In my editorial, I refer to lung transplantation as the treatment of last resort, rather than the primary treatment. The authors of a recent study report a median waiting time of 555 days for patients with idiopathic pulmonary fibrosis after registration on the list for lung transplantation; 31 percent of these patients died awaiting transplantation.1 While patients are waiting for up to two years for a new lung, how should we treat them? As I state in my editorial and as Vourlekis emphasizes, there are no controlled studies that support the efficacy of any drug therapy for idiopathic fibrosis. The reported 10 to 30 percent rate of success with corticosteroids probably includes patients with relatively corticosteroid-responsive pneumonias. However, responses to corticosteroids do occur in biopsy-proven usual interstitial pneumonia, corticosteroids are recommended in the consensus statement on pulmonary fibrosis issued by the American Thoracic Society and the European Respiratory Society,2 and responses have been reported in several publications.3,4
Finally, although the new pathological classification of the spectrum of idiopathic pneumonitis has greatly improved the indications for corticosteroid therapy, there remains an unknown, but not insignificant, number of patients in whom radiologists and even pathologists have difficulty differentiating usual interstitial pneumonia from the other fibrosing entities. Even open-lung biopsy may yield specimens that differ from subsequent whole-lung autopsy tissue. Thus, it is difficult to be dogmatic about the efficacy or lack of efficacy of any therapy. Although most patients with usual interstitial pneumonia will eventually die of the disease, corticosteroid therapy and lung transplantation help some. Unfortunately, good therapy for usual interstitial pneumonia remains elusive.
Alvin S. Teirstein, M.D.
Mount Sinai Medical Center
New York, NY 10029
References
Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung transplantation. Chest 2002;122:233-238.
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-664.
Gay SE, Kazerooni EA, Toews GB, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:1063-1072.
Flaherty 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;110:278-282.
A. Ross Hill, M.D.
State University of New York Downstate Medical Center
Brooklyn, NY 11203
ross.hill@downstate.edu
References
Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125-133.
To the Editor: Raghu et al. fail to mention pulmonary hypertension as one of the variables that may influence the quality of life and overall progression-free survival among patients with idiopathic pulmonary fibrosis. Pulmonary hypertension during exercise is common even during the early stages of idiopathic pulmonary fibrosis. When the vital capacity is less than 50 percent of the predicted value or the diffusing capacity for carbon monoxide falls below 45 percent of the predicted value, pulmonary hypertension at rest can be expected.1,2 In a multivariate analysis, King et al.3 found that survival among 87 patients with idiopathic pulmonary fibrosis was significantly related to evidence of pulmonary hypertension. It has been demonstrated that oxygen therapy at rest and during exercise improves pulmonary hemodynamics and probably improves exercise capacity and prognosis in such patients.4
Considering its key prognostic significance, I wonder whether the negative conclusions drawn by Raghu et al. would have been different if the two study groups in their trial had also been matched with respect to the presence or absence of pulmonary hypertension at base line.
Oren Fruchter, M.D.
Rambam Medical Center
Haifa 31096, Israel
oren_md@inter.net.il
References
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-664.
Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525.
King TE Jr, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025-1032.
Harris-Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marciniuk DD. Oxygen improves maximal exercise performance in interstitial lung disease. Am J Respir Crit Care Med 1994;150:1616-1622.
To the Editor: Raghu et al. conclude that interferon gamma-1b had no benefit for the treatment of idiopathic pulmonary fibrosis, but they may have underestimated its efficacy. There is an apparent discrepancy between the primary analysis of progression-free survival, which showed no benefit, and the mortality analysis, which suggested efficacy. This discrepancy may be due to a violation of the proportional-hazards assumption in the primary analysis, which is the assumption that the hazard ratio is constant over time.1 In Figure 1 of the article, the treatment effect appears to vary with time. During the first 150 days or so, the treatment group seemed to have an increased probability of disease progression or death, followed later by a decrease. This crossing of survival curves could indicate a violation of the proportional-hazards assumption. Consequently, this analysis could have obscured an overall benefit.
Moreover, the hazard ratio for death in the interferon gamma-1b group was 0.6, which suggests that the treatment had substantial efficacy. To conclude that there was no benefit because the P value was 0.08, instead of 0.05, seems overly conservative.2 Overall, the results appear to be most consistent with a survival benefit.
Mark D. Eisner, M.D., M.P.H.
University of California, San Francisco
San Francisco, CA 94143-0924
eisner@itsa.ucsf.edu
References
Hosmer DW Jr, Lemeshow S. Applied survival analysis: regression modeling of time to event data. New York: John Wiley, 1999.
Goodman SN. Toward evidence-based medical statistics. 1. The P value fallacy. Ann Intern Med 1999;130:995-1004.
To the Editor: Raghu et al. report the results of a well-conducted trial and inhibit the initial enthusiasm about the use of interferon gamma-1b in the treatment of patients with idiopathic pulmonary fibrosis as previously reported by Ziesche et al.1 Two points in these studies will be important for future research. First, treatment with interferon gamma-1b had a better effect on survival among patients with a less impaired forced vital capacity at base line. Second, lung specimens from patients who had had a response to interferon gamma-1b in the past had overexpression of transforming growth factor 1 and connective-tissue growth factor and lacked interferon gamma-1b in their lung tissues.1 The question of whether interferon gamma-1b might be beneficial in subgroups of patients with idiopathic pulmonary fibrosis could be raised.
Immunomodulators may be useful in the treatment of idiopathic pulmonary fibrosis.2 The timing of treatment, however, is extremely important.3 The cytokine status of the patient could be crucial to the choice of an immunomodulatory agent and the patient's response to therapy. Assessing the cytokine profile in patients with idiopathic pulmonary fibrosis in lung specimens and correlating it with the serum level could be useful in future studies involving immunomodulatory agents.
Pelagia G. Tsoutsou, M.D.
Konstantinos I. Gourgoulianis, M.D.
University Hospital of Larissa
41 222 Larissa, Greece
pauletta24@hotmail.com
References
Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. 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;21:1264-1269.
Gross TG, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525.
Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001;345:340-350.
To the Editor: The study by Raghu et al. of interferon gamma-1b as treatment for idiopathic pulmonary fibrosis emphasizes the difficulty of treating this pernicious disease. Given the negative results of the study, I was surprised that Teirstein,1 commenting on the study in an editorial, does not recommend referral for lung transplantation as an important and early intervention. Because of the poor long-term prognosis for patients with this disease and the lack of effective medical therapies, transplantation should be the first treatment option for all eligible patients.2,3 I am equally surprised that Teirstein continues to recommend corticosteroids as frontline therapy. The often-quoted figure of a 30 percent rate of response to corticosteroids stems from studies that enrolled heterogeneous groups of patients with interstitial lung disease; in those studies, the criteria for idiopathic pulmonary fibrosis overlapped with those for other diseases that we now recognize as distinct and as having better prognoses; therefore, the results may not even apply to idiopathic pulmonary fibrosis.4 I agree that therapy instituted early in the course of disease may have increased potential to alter its natural history, but this hypothesis needs further validation through controlled studies before it serves as the basis for treatment recommendations.
Jason S. Vourlekis, M.D.
National Institutes of Health
Bethesda, MD 20892
vourlekj@mail.nih.gov
References
Teirstein AS. The elusive goal of therapy for usual interstitial pneumonia. N Engl J Med 2004;350:181-183.
Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525.
Thabut G, Mal H, Castier Y, et al. Survival benefits of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg 2003;126:469-475.
King TE Jr. Idiopathic interstitial pneumonias. In: Schwarz MI, King TE Jr, eds. Interstitial lung disease. 4th ed. Hamilton, Ont., Canada: B.C. Decker, 2003:701-86.
To the Editor: In his editorial on therapy for idiopathic pulmonary fibrosis, Teirstein points out that the currently available immunomodulatory therapeutic options for idiopathic pulmonary fibrosis, including the one best studied (interferon gamma-1b), are clearly inadequate to meet the expectations of both patients and doctors. However, he also reports that about one third of patients with idiopathic pulmonary fibrosis benefit from corticosteroid therapy. It should be noted that although limited evidence has been published for a few immunomodulatory agents in idiopathic pulmonary fibrosis, the authors of a recent systematic Cochrane Review were unable to find any level of evidence for the use of corticosteroid therapy in idiopathic pulmonary fibrosis.1 Considering that it is quite common that patients with this illness are treated for long periods with corticosteroids, which are associated with well-known risks of serious side effects, physicians should be aware that the most commonly used medication for idiopathic pulmonary fibrosis, prednisone, is also the medication with the lowest level of evidence for this use.
Luca Richeldi, M.D., Ph.D.
Policlinico Hospital
41100 Modena, Italy
References
Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003;3:CD002880-CD002880.
The authors reply: The primary end point in our trial was defined as the first occurrence of the following: an increase of 5 mm Hg or more in the P(A–a)O2 gradient at rest, a decrease of 10 percent or more in the predicted forced vital capacity, or death. These primary end points were chosen on the basis of the best available data at the time of initiation of the trial.1 We agree with Dr. Hill that the criterion relating to the P(A–a)O2 gradient was suboptimal. A change of 5 mm Hg or more in the P(A–a)O2 gradient alone accounted for 62 percent of progression events in the trial. Therefore, the P(A–a)O2 gradient may not be a reliable measure of disease progression, and our use of it could have substantially underpowered the analysis. We appreciate Dr. Hill's suggestions as well as those of Drs. Tsoutsou and Gourgoulianis and Dr. Fruchter, all of whom note other ways to improve the understanding of the treatment effect.
We agree with Dr. Eisner that the conclusion that the treatment was of no benefit, though accurate by statistical convention (P>0.05), is conservative and fails to recognize a potentially important clinical benefit.2 The lack of a safe and effective therapy and the dismal prognosis for patients with idiopathic pulmonary fibrosis make survival a critically important outcome. Survival was both a component of our primary end point and a prespecified secondary end point. Consequently, our finding of a 41 percent relative reduction in the risk of death in the overall population of patients treated with interferon gamma-1b (P=0.08), coupled with the significant improvements in survival found in subanalyses of treatment-adherent patients (P=0.02) and patients with a lesser degree of impairment in lung function at base line (P=0.04), clearly warrants further investigation. Accordingly, a confirmatory trial has been initiated.
We also agree with Dr. Eisner that the proportional-hazards assumption was violated in the analysis of progression-free survival. However, the Cox proportional-hazards model must be used as it was prespecified. It should be noted that the proportional-hazards assumption was not violated in the intention-to-treat analysis of survival time.
We disagree with the recommendations made in the editorial that accompanied our study.2 Prednisone should not be used as the sole treatment for idiopathic pulmonary fibrosis.1,3 Furthermore, lung transplantation should be considered early in the clinical course and not as a last resort.4
Future therapy for idiopathic pulmonary fibrosis should be based on data from controlled clinical trials. Therefore, we recommend that clinicians encourage eligible patients with idiopathic pulmonary fibrosis to enroll in clinical trials of new therapeutic agents or treatment regimens, including trials of interferon gamma-1b.
Ganesh Raghu, M.D.
University of Washington
Seattle, WA 98195
Talmadge E. King, Jr., M.D.
University of California, San Francisco
San Francisco, CA 94110
References
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-664.
Teirstein AS. The elusive goal of therapy for usual interstitial pneumonia. N Engl J Med 2004;350:181-183.
Mapel DW, Samet JM, Coultas DB. Corticosteroids and the treatment of idiopathic pulmonary fibrosis: past, present, and future. Chest 1996;110:1058-1067.
Mogulkoc N, Brutsche MH, Bishop PW, Greaves SM, Horrocks AW, Egan JJ. Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation. Am J Respir Crit Care Med 2001;164:103-108.
The editorialist replies: Vourlekis correctly raises two important questions regarding the treatment of usual interstitial pneumonia: the role of lung transplantation and the lack of conclusive evidence in support of corticosteroid therapy. In my editorial, I refer to lung transplantation as the treatment of last resort, rather than the primary treatment. The authors of a recent study report a median waiting time of 555 days for patients with idiopathic pulmonary fibrosis after registration on the list for lung transplantation; 31 percent of these patients died awaiting transplantation.1 While patients are waiting for up to two years for a new lung, how should we treat them? As I state in my editorial and as Vourlekis emphasizes, there are no controlled studies that support the efficacy of any drug therapy for idiopathic fibrosis. The reported 10 to 30 percent rate of success with corticosteroids probably includes patients with relatively corticosteroid-responsive pneumonias. However, responses to corticosteroids do occur in biopsy-proven usual interstitial pneumonia, corticosteroids are recommended in the consensus statement on pulmonary fibrosis issued by the American Thoracic Society and the European Respiratory Society,2 and responses have been reported in several publications.3,4
Finally, although the new pathological classification of the spectrum of idiopathic pneumonitis has greatly improved the indications for corticosteroid therapy, there remains an unknown, but not insignificant, number of patients in whom radiologists and even pathologists have difficulty differentiating usual interstitial pneumonia from the other fibrosing entities. Even open-lung biopsy may yield specimens that differ from subsequent whole-lung autopsy tissue. Thus, it is difficult to be dogmatic about the efficacy or lack of efficacy of any therapy. Although most patients with usual interstitial pneumonia will eventually die of the disease, corticosteroid therapy and lung transplantation help some. Unfortunately, good therapy for usual interstitial pneumonia remains elusive.
Alvin S. Teirstein, M.D.
Mount Sinai Medical Center
New York, NY 10029
References
Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung transplantation. Chest 2002;122:233-238.
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-664.
Gay SE, Kazerooni EA, Toews GB, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998;157:1063-1072.
Flaherty 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;110:278-282.