Antioxidant Therapy for Idiopathic Pulmonary Fibrosis

editorials www.nejm.org november 24, 2005 2285
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and remodeling of the lung parenchyma. The median survival of patients with the disease is about three years after diagnosis or five years after the onset of symptoms.
The pathological findings are those of usual interstitial pneumonia.1 In many instances, the diagnosis can be made when typical clinical and radiologic features are present.2-5 The classic radiologic features are a patchy pattern of peripheral “honeycombing” that is more prominent in the bases of the lungs, traction bronchiectasis, and the absence of prominent ground-glass opacity. When these findings are not present, a surgical biopsy of the lung is needed for diagnosis. A consensus statement on IPF from the American Thoracic Society–European Respiratory Society recommends therapy with prednisone and a cytotoxic agent, such as azathioprine. 6 However, there is little evidence that these agents alter the natural history of the disease. There may be some benefit from prednisone since it can help suppress cough in patients with this disease. However, there is no strong evidence supporting the clinical effectiveness of these treatments in patients with IPF. Indeed, since prednisone and cytotoxic agents do not benefit patients with IPF, it is reasonable to assume they cause harm, because each of these drugs is known to have substantial adverse effects. One of the side effects of prednisone is to promote physical deconditioning. This is especially important for patients with IPF, whose exercise capacity is already limited because of dyspnea. Cytotoxic agents probably cause injury, at some level, to all tissues of the body, in addition to their well-known myelotoxic effects. If a beneficial effect has been hard to demonstrate, why are these agents used to treat IPF? One reason may be a lack of specificity of the diagnosis in earlier studies. Many older studies included a related lung disorder, nonspecific interstitial pneumonia, under the diagnostic rubric we now consider as IPF. Nonspecific interstitial pneumonia can be associated with inflammation in the lung and can respond to drugs such as prednisone and azathioprine. Even though nonspecific interstitial pneumonia has been separated from IPF as a diagnostic entity, many clinicians continue to use prednisone and azathioprine as a treatment for IPF. Another reason for the use of these drugs is the lack of other effective therapies. A recent study suggested that pirfenidone might be useful as a therapy, but its effect as a single agent is not clear.7 Another study using interferon gamma showed no effect on the primary end point,8 although a subgroup analysis suggested an effect on early disease.
The effect of interferon gamma in patients with early disease is now under investigation. A number of other industry-supported trials are also under way. The National Heart, Lung, and Blood Institute recognized the need to develop therapies for the disease by establishing the IPF Clinical Research Network. The hope is that patients will be enrolled in these trials and therapies that are clearly effective will be forthcoming. Although the cause of IPF is not known, less emphasis is now placed on inflammation as a cause of the lung injury in this condition. Current hypotheses suggest that IPF results from repeated or ongoing episodes of acute lung injury that primarily affect peripheral areas of the lung.9 A related theory is that there may be an excess of type 2 helper T-cell (Th2) cytokines that facilitates the lung injury and fibrosis. These observations have kindled an interest in agents that may affect lung fibrosis and repair. In this issue of the Journal, Demedts et al.10 tested another therapy for IPF — antioxidant therapy. In this multicenter study, patients with IPF were randomly assigned to receive prednisone and azathioprine (the “standard of care”) or prednisone, azathioprine, and acetylcysteine. After one year of treatment, patients who received acetylcysteine, in addition to prednisone and azathioprine, had significantly better preserved vital capacity and diffusing capacity for carbon monoxide (DlCO). A substantial number of patients dropped out of the study, and differences in vital capacity and DlCO after one year were relatively small and were probably not clinically significant; the effect on the outcome of the patients who withdrew from the study is Antioxidant! Therapy for Idiopathic Pulmonary Fibrosis Gary W. Hunninghake, M.D.
The new england journal of medicine n engl j med 353;21 www.2286 nejm.org november 24, 2005 not known. The administration of acetylcysteine had no effect on survival. The investigators stated that the rationale for this study was provided by a number of earlier observations showing that patients with IPF have depleted levels of glutathione in the lung and that this depletion can be corrected by treating patients with acetylcysteine. This observation is not unique to IPF and is found in many chronic inflammatory disorders. Glutathione is an important antioxidant in all tissues and is crucial for many aspects of cell metabolism and survival (Fig. 1). Tissues that are depleted of glutathione are more susceptible to injury. Uptake of cysteine by cells is a rate-limiting step for the synthesis of glutathione. Ace- Figure 1.!Synthesis!of!Glutathione. Glutathione is synthesized from three amino acids: l-glutamine, l-cysteine, and l-glycine. Absolute levels of glutathione and the ratio of glutathione to glutathione disulfide are crucial for the maintenance of normal cell metabolism and survival. One function of glutathione is to detoxify a wide variety of reactive oxygen species that are generated within and outside of cells. During this detoxification process, glutathione is converted to glutathione disulfide. Under normal conditions, glutathione disulfide can be reconverted to glutathione, preserving both normal levels of glutathione and the ratio of glutathione to glutathione disulfide. In some conditions of acute or chronic stress, the ratio of glutathione to glutathione disulfide cannot be maintained, and glutathione disulfide is exported from cells. In addition, synthesis cannot proceed fast enough to replenish cellular stores of glutathione. Associated with this process is a depletion of a pool of other mixed antioxidant thiols. This depletion results in altered cell metabolism and injury. The synthesis of glutathione can be accelerated by the administration of acetylcysteine, which crosses cell membranes easily and can be converted to l-cysteine. Uptake of l-cysteine is an important rate-limiting step for the synthesis of glutathione. Acetylcysteine increases the pool of other antioxidant thiols that also protect cells from injury. editorials n engl j med 353;21 www.nejm.org november 24, 2005 2287 tylcysteine is used to increase the production of glutathione because it crosses cell membranes easily and can be converted to cysteine. The drug also increases the pool of other mixed antioxidant thiols. These other reduced thiols can also protect cells from injury. The use of acetylcysteine to prevent acute liver injury in the setting of an acetaminophen overdose has been well demonstrated. Acetaminophen, in large doses, generates a profound oxidant stress in liver tissue that depletes glutathione and other antioxidant thiols. When levels of these thiols drop below a critical level, there may be an explosive onset of liver injury. Acetylcysteine prevents this liver injury by maintaining adequate cellular levels of glutathione and other antioxidant thiols. What can we conclude from the study by Demedts et al.? One obvious conclusion is that acetylcysteine is directly beneficial as a therapy for IPF. However, another conclusion should also be considered. It is possible that the combination of prednisone and azathioprine is toxic to patients with IPF. If this were true, then it would be likely that the effects of acetylcysteine in this study are explained by the drug’s prevention of the toxic effects of prednisone and azathioprine. It is known that azathioprine depletes liver tissue of glutathione and that acetylcysteine can, in some settings, prevent liver injury. 11,12 In support of the latter hypothesis is the observation in the study by Demedts et al. that there were fewer myelotoxic effects in the group of patients with IPF who received acetylcysteine. Thus, it is not clear from this study whether the drug has direct beneficial effects on IPF or whether it prevents the toxic effects of prednisone and azathioprine. Therefore, a prospective study comparing prednisone and azathioprine with placebo is needed to address this issue. If a new study showed toxic effects or no effect of prednisone and azathioprine, investigators conducting studies of new therapies for IPF would be liberated from the use of this “standard of therapy,” and patients would be freed from exposure to these potentially toxic drugs. It is not clear how this study will affect the treatment of IPF. Since there are no therapies that are clearly effective for IPF, many physicians and patients will find the use of acetylcysteine to be very seductive. In many ways, if it were ultimately shown to be effective, it would be an ideal drug (i.e., beneficial with few side effects). Also, acetylcysteine is available without prescription. It is hoped that these observations will not prevent the design of a new study that evaluates whether acetylcysteine directly benefits patients with IPF. For now, physicians caring for patients with this disease should encourage their participation in clinical trials. There are still too many unresolved questions to continue to treat patients by guesswork. From the Department of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304. [Erratum, Am J Respir Crit Care Med 2002;166:426.] Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164:193-6. Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003;124:1215-23. Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest 1999;116:1168-74. Lynch DA, David Godwin J, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 2005;172:488-93. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 2000;161:646-64. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-7. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med 2004;25:409-19. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-25. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-42. Menor C, Fernandez-Moreno MD, Fueyo JA, et al. Azathioprine acts upon rat hepatocyte mitochondria and stress-activated protein kinases leading to necrosis: protective role of N-acetyl-Lcysteine. J Pharmacol Exp Ther 2004;311:668-76. Lee AU, Farrell GC. Mechanism of azathioprine-induced injury to hepatocytes: roles of glutathione depletion and mitochondrial injury. J Hepatol 2001;35:756-64. Copyright © 2005 Massachusetts Medical Society.