Correspondence
Interferon Gamma-1b for the Treatment of Idiopathic Pulmonary Fibrosis
N Engl J Med 2000; 342:974-975March 30, 2000
- Article
To the Editor:
Ziesche et al. (Oct. 21 issue)1 report the findings of a preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. Given that there is no successful medical therapy for idiopathic pulmonary fibrosis, with only lung transplantation holding promise for long-term survival, the authors deserve credit for performing this pilot project. Unfortunately, their findings do not justify the enthusiasm that this article has generated in the media and among people with this disease.
First, it is unclear that the patients studied had idiopathic pulmonary fibrosis.2 The disease is uncommon; consequently, most centers are unable to enroll 18 patients over the course of a 22-month period. The incidence of cigarette smoking — a risk factor for idiopathic pulmonary fibrosis3 that also has an effect on survival — was not reported. An important consideration is the fact that the criteria used to define the features of idiopathic pulmonary fibrosis histopathologically and on high-resolution computed tomography are unclear and incomplete.2,4 Therefore, it is likely that some of the cases represent forms of idiopathic interstitial pneumonia — particularly, nonspecific interstitial pneumonia or chronic cryptogenic organizing pneumonia.
Second, the outcome and duration of survival among the patients in the study by Ziesche et al. are atypical.5 Standard treatment for more than six months was not effective, and seven patients required oxygen therapy (five at enrollment and two during the treatment phase). Since patients with idiopathic pulmonary fibrosis invariably have progressive disease, the absence of more severe disease in any of these patients is very unusual, especially given that there were three to seven years of follow-up.
Third, the treatment outcome was not clinically significant.2 An increase of 10 percent in total lung capacity (or at least an increase of about 200 ml) is required for an improvement to be considered clinically significant. Thus, there was no clinically significant change in the total lung capacity in either the control group or the treatment group. The data on gas exchange are also problematic. Presumably, all arterial-blood gas measurements were made while the patients were breathing room air. It is difficult to compare the results of maximal exercise testing in a serial fashion, because the level of work performed must be controlled for. Since the methods used for the exercise study are not described, such a comparison is not possible. Even if we assume the outcome to be positive (stabilization in the face of previous worsening), similar short-term improvements have been reported with other agents. However, once treatment is tapered or stopped, the disease progresses, and with longer follow-up, treatment is shown to have had no effect on survival.
The promising preliminary data of Ziesche et al. should be viewed with caution. The use of interferon gamma-1b in clinical practice must await additional study. It should also be noted that in the accompanying editorial,6 du Bois reports that there is an ongoing study of the efficacy of interferon alfa for the treatment of idiopathic pulmonary fibrosis. I am not aware of this study; however, I am chair of the advisory committee of a multicenter study of interferon beta-1a for the treatment of idiopathic pulmonary fibrosis, sponsored by Biogen (Cambridge, Mass.). I receive a consulting fee for this role.
6 ReferencesTalmadge E. King, Jr., M.D.
San Francisco General Hospital, San Francisco, CA 941101
Ziesche R ,Hofbauer E ,Wittmann K ,Petkov V ,Block L-H . 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;341:1264-1269
Full Text | Web of Science | Medline2
Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement
Web of Science | Medline3
Baumgartner KB ,Samet JM ,Stidley CA ,Colby TV ,Waldron JA . Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997;155:242-248
Web of Science | Medline4
Katzenstein ALA ,Myers JL . Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301-1315
Web of Science | Medline5
Bjoraker JA ,Ryu JH ,Edwin MK , et al. Prognostic significance of histopathologic subsets of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199-203
Web of Science | Medline6
du Bois RM . Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis. N Engl J Med 1999;341:1302-1304
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Although our study was conducted between 1996 and 1998, the survey of patients with idiopathic pulmonary fibrosis from various European countries had begun in 1994, which allowed enough time for the enrollment of our patients. All the patients were nonsmokers. We carefully considered the diagnostic criteria for idiopathic pulmonary fibrosis, taking into account the definition used by the pathology department of the Mayo Clinic.1 In addition to established histopathological characterization of fibrotic lesions, we attempted to characterize the genes involved in the development of fibrotic lesions. Given our experience, we are convinced that, in addition to conventional procedures, the diagnosis of idiopathic pulmonary fibrosis must include molecular biologic assessment of fibrotic lesions to make sure that features compatible with the biologic changes at the cellular level are present that coincide with the clinical picture of the disease. Moreover, in addition to using the various exclusion criteria, we selected only patients whose condition did not respond to sufficient immunosuppressive therapy, which makes differential diagnoses, such as nonspecific interstitial pneumonia, rather unlikely.
The outcome, progression, and duration of idiopathic pulmonary fibrosis vary considerably. In our trial, patients with advanced fibrosis were excluded. The apparently better outcome of the patients in our study is explained by the strict enrollment criteria. Response to interferon gamma-1b decreases with greater duration of breathlessness at rest and other severe symptoms.
The treatment outcome was clinically significant in that there was a mean increase in total lung capacity of about 500 ml (or about 9 percent) per patient. Consequently, with a total lung capacity ranging from 4 to 6 liters, as was the case for the patients in our study, the improvement achieved by treatment with interferon gamma-1b is clinically important. Data on gas exchange were obtained while the patients were at rest and after maximal exertion, on the assumption that an improvement in gas exchange under both conditions would indicate a reduction of diffusion barriers. It should be noted that such an improvement was observed in all the patients who received treatment with interferon gamma-1b at rest and in seven of the nine patients after maximal exertion.
We tried to take a new approach to unravel the underlying disturbance of the cell biology in the development of fibrotic lesions in patients with idiopathic pulmonary fibrosis. We believe that the characterization of the genes involved in the inflammatory changes due to idiopathic pulmonary fibrosis is essential for understanding the pathology of idiopathic pulmonary fibrosis and provides the rationale for treatment with interferon gamma-1b.
1 ReferencesRolf Ziesche, M.D.
Lutz-Henning Block, M.D.
University of Vienna Medical School, A-1090 Vienna, Austria1
Ryu JH ,Colby TV ,Hartman TE . Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc 1998;73:1085-1101
CrossRef | Web of Science | Medline
To the Editor:
King addresses the issue of the selection of patients for research on idiopathic pulmonary fibrosis and the clinical significance of treatment outcomes. His observations underscore the need for further carefully targeted studies.
The final paragraph of my editorial should have referred to the ongoing study of interferon beta-1a, not interferon alfa. I look forward to the results of this study.
R.M. du Bois, M.D.
Royal Brompton Hospital, London SW3 6NP, United Kingdom- Citing Articles (9)
Citing Articles
1
Ross C. KLINGSBERG, Steven E. MUTSAERS, Joseph A. LASKY. (2010) Current clinical trials for the treatment of idiopathic pulmonary fibrosis. Respirology 15:1, 19-31
CrossRef2
Robert Matthew KOTTMANN, Christopher M. HOGAN, Richard P. PHIPPS, Patricia J. SIME. (2009) Determinants of initiation and progression of idiopathic pulmonary fibrosis. Respirology 14:7, 917-933
CrossRef3
Eleni G. Tzortzaki, Katerina M. Antoniou, Maria I. Zervou, Irini Lambiri, Anastassios Koutsopoulos, Nikolaos Tzanakis, Maria Plataki, George Maltezakis, Demosthenes Bouros, Nikolaos M. Siafakas. (2007) Effects of antifibrotic agents on TGF-β1, CTGF and IFN-γ expression in patients with idiopathic pulmonary fibrosis. Respiratory Medicine 101:8, 1821-1829
CrossRef4
Demosthenes Bouros, Katerina M Antoniou, Argyris Tzouvelekis, Nikolaos M Siafakas. (2006) Interferon-γ 1b for the treatment of idiopathic pulmonary fibrosis. Expert Opinion on Biological Therapy 6:10, 1051-1060
CrossRef5
Annick Clement, Alexandra Henrion-Caude, Brigitte Fauroux. (2004) The pathogenesis of interstitial lung diseases in children. Paediatric Respiratory Reviews 5:2, 94-97
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Efsevia Albanis, Rifaat Safadi, Scott L. Friedman. (2003) Treatment of hepatic fibrosis: Almost there. Current Gastroenterology Reports 5:1, 48-56
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Pinak S. Acharya, David A. Zisman. (2001) Antifibrotic Therapy for Idiopathic Pulmonary Fibrosis. Clinical Pulmonary Medicine 8:6, 327-334
CrossRef8
Robert Baughman, Fortune Alabi. (2001) Current Opinion in Pulmonary Medicine 7:5, 309
CrossRef9
Stephen J. Oliver. (2000) The Th1/Th2 paradigm in the pathogenesis of scleroderma, and its modulation by thalidomide. Current Rheumatology Reports 2:6, 486-491
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