Acetylcysteine in Pulmonary Fibrosis
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《新英格兰医药杂志》
To the Editor: In their recent study, Demedts et al. (Nov. 24 issue)1 report a significant difference in bone marrow toxic effects between the acetylcysteine treatment group (4 percent) and the placebo group (13 percent) (P=0.03). They postulate that this may be due to the augmentation of glutathione biosynthesis induced by acetylcysteine.
Treatment with azathioprine is known to give rise to leukopenia in up to 27 percent of patients and thrombocytopenia in up to 5 percent.2 It is recognized that persons with low levels of activity of the enzyme thiopurine methyltransferase are at increased risk of bone marrow toxic effects, and consequently many physicians perform an analysis of thiopurine methyltransferase (TPMT) activity before the initiation of azathioprine therapy.3
In the Methods section of the study, Demedts et al. mention that all patients underwent laboratory tests; however, further detail is not given. It could be that the observed differences in bone marrow toxic effects are related to TPMT activity in the study population.
James H.K. Hull, M.R.C.P.
Frimley Park Hospital
Frimley GU16 7UJ, United Kingdom
jiminio@doctors.org.uk
References
Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242.
Huskisson EC. Azathioprine. Clin Rheum Dis 1984;10:325-332.
Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-537.
To the Editor: Demedts et al. suggest that in patients with idiopathic pulmonary fibrosis, acetylcysteine slows the deterioration of vital capacity and single-breath carbon monoxide diffusing capacity by showing a statistically significant difference in the absolute change from baseline as compared with 12 months post-treatment. The changes are small, and although statistically significant, they do not show how many patients actually benefit from the effect of acetylcysteine. To illustrate this point, it would be useful to present the histograms that compare the treatment group and the placebo group in terms of the numbers of patients who have changes from baseline in the outcome measures; these histograms would be similar to those used for the presentation of the results of the National Emphysema Treatment Trial in the Journal.1
Tudor P. Toma, M.D.
Angshu Bhowmik, M.D.
Raja Rajakulasingam, M.D.
Homerton University Hospital NHS Trust
London E9 6SR, United Kingdom
References
Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:2059-2073.
The authors reply: The point raised by Dr. Hull with regard to the value of a TPMT analysis before initiation of azathioprine therapy is well taken. We did not evaluate TPMT activity in our study because it is not recommended by the American Thoracic Society–European Respiratory Society International Consensus1 on which the study treatment was based. It is unlikely that the lower rate of myelotoxic effects among patients receiving acetylcysteine than among those receiving placebo is due to differences in TPMT activity between the two groups. It seems possible that randomization led to an equal distribution of TPMT mutations between the groups.
Dr. Toma and colleagues suggest that histograms be used to compare the changes between baseline and month 12 with regard to vital capacity and carbon monoxide diffusing capacity among patients receiving acetylcysteine or placebo. In our post hoc analysis of categorical changes, 37 percent of patients receiving acetylcysteine and 51 percent of those receiving placebo had a deterioration in vital capacity of more than 10 percent or 0.2 liter (P=0.22). In similar fashion, 43 percent of patients receiving acetylcysteine and 51 percent of those receiving placebo had a deterioration in diffusing capacity of more than 15 percent or 1 mmol per minute per kilopascal (P=0.17). The loss of vital capacity over the course of one year in patients receiving placebo (including those patients who died) was similar to that reported in other trials among patients with idiopathic pulmonary fibrosis2,3 (Table 1). These results further support a direct beneficial effect of acetylcysteine, albeit small, rather than merely a prevention of azathioprine toxic effects, and would support an argument against the consideration expressed in the editorial that accompanied our article.5
Table 1. Change in Vital Capacity in Treatment Trials in Patients with Idiopathic Pulmonary Fibrosis.
Maurits Demedts, M.D.
Katholieke Universiteit Leuven
B-3000 Leuven, Belgium
maurits.demedts@uz.kuleuven.ac.be
Roland Buhl, M.D.
Klinikum der Johannes-Gutenberg-Universit?t
D-55131 Mainz, Germany
Ulrich Costabel, M.D., Ph.D.
Ruhrlandklinik
D-45239 Essen-Heidhausen, Germany
for the IFIGENIA Study Group
References
Idiopathic 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;161:646-664.
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.
Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-1047.
Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242.
Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2285-2287.
Treatment with azathioprine is known to give rise to leukopenia in up to 27 percent of patients and thrombocytopenia in up to 5 percent.2 It is recognized that persons with low levels of activity of the enzyme thiopurine methyltransferase are at increased risk of bone marrow toxic effects, and consequently many physicians perform an analysis of thiopurine methyltransferase (TPMT) activity before the initiation of azathioprine therapy.3
In the Methods section of the study, Demedts et al. mention that all patients underwent laboratory tests; however, further detail is not given. It could be that the observed differences in bone marrow toxic effects are related to TPMT activity in the study population.
James H.K. Hull, M.R.C.P.
Frimley Park Hospital
Frimley GU16 7UJ, United Kingdom
jiminio@doctors.org.uk
References
Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242.
Huskisson EC. Azathioprine. Clin Rheum Dis 1984;10:325-332.
Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-537.
To the Editor: Demedts et al. suggest that in patients with idiopathic pulmonary fibrosis, acetylcysteine slows the deterioration of vital capacity and single-breath carbon monoxide diffusing capacity by showing a statistically significant difference in the absolute change from baseline as compared with 12 months post-treatment. The changes are small, and although statistically significant, they do not show how many patients actually benefit from the effect of acetylcysteine. To illustrate this point, it would be useful to present the histograms that compare the treatment group and the placebo group in terms of the numbers of patients who have changes from baseline in the outcome measures; these histograms would be similar to those used for the presentation of the results of the National Emphysema Treatment Trial in the Journal.1
Tudor P. Toma, M.D.
Angshu Bhowmik, M.D.
Raja Rajakulasingam, M.D.
Homerton University Hospital NHS Trust
London E9 6SR, United Kingdom
References
Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:2059-2073.
The authors reply: The point raised by Dr. Hull with regard to the value of a TPMT analysis before initiation of azathioprine therapy is well taken. We did not evaluate TPMT activity in our study because it is not recommended by the American Thoracic Society–European Respiratory Society International Consensus1 on which the study treatment was based. It is unlikely that the lower rate of myelotoxic effects among patients receiving acetylcysteine than among those receiving placebo is due to differences in TPMT activity between the two groups. It seems possible that randomization led to an equal distribution of TPMT mutations between the groups.
Dr. Toma and colleagues suggest that histograms be used to compare the changes between baseline and month 12 with regard to vital capacity and carbon monoxide diffusing capacity among patients receiving acetylcysteine or placebo. In our post hoc analysis of categorical changes, 37 percent of patients receiving acetylcysteine and 51 percent of those receiving placebo had a deterioration in vital capacity of more than 10 percent or 0.2 liter (P=0.22). In similar fashion, 43 percent of patients receiving acetylcysteine and 51 percent of those receiving placebo had a deterioration in diffusing capacity of more than 15 percent or 1 mmol per minute per kilopascal (P=0.17). The loss of vital capacity over the course of one year in patients receiving placebo (including those patients who died) was similar to that reported in other trials among patients with idiopathic pulmonary fibrosis2,3 (Table 1). These results further support a direct beneficial effect of acetylcysteine, albeit small, rather than merely a prevention of azathioprine toxic effects, and would support an argument against the consideration expressed in the editorial that accompanied our article.5
Table 1. Change in Vital Capacity in Treatment Trials in Patients with Idiopathic Pulmonary Fibrosis.
Maurits Demedts, M.D.
Katholieke Universiteit Leuven
B-3000 Leuven, Belgium
maurits.demedts@uz.kuleuven.ac.be
Roland Buhl, M.D.
Klinikum der Johannes-Gutenberg-Universit?t
D-55131 Mainz, Germany
Ulrich Costabel, M.D., Ph.D.
Ruhrlandklinik
D-45239 Essen-Heidhausen, Germany
for the IFIGENIA Study Group
References
Idiopathic 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;161:646-664.
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.
Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-1047.
Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242.
Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2285-2287.