Current Perspectives on the Treatment of Idiopathic Pulmonary Fibrosis

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1 Current Perspectives on the Treatment of Idiopathic Pulmonary Fibrosis Nicholas Walter, Harold R. Collard, and Talmadge E. King, Jr. San Francisco General Hospital, San Francisco, California The clinical course of idiopathic pulmonary fibrosis (IPF) is variable; however, the long-term survival in IPF is poor. Prednisone has been the mainstay of therapy since its release for clinical use in Recently, prednisone combined with azathioprine or cyclophosphamide has been used. A number of other drug combinations have been tried with prednisone (e.g., methotrexate, colchicine, penicillamine, or cyclosporine) but have failed or are not well tolerated by the patient. Few high quality, prospective, controlled clinical trials have been performed. Thus, there is no good evidence to support the routine use of any specific therapy in the management of IPF. Additional large clinical trials are needed to confirm the potential usefulness of the newer agents (e.g., IFN- 1b, pirfenidone, N-acetylcysteine, coumadin, bosentan, or etanercept). This article examines the body of evidence supporting the current therapies and reviews the newer agents being tested in patients with IPF. Keywords: clinical trials; drugs; idiopathic pulmonary fibrosis; interstitial lung diseases; lung transplant; treatment; usual interstitial pneumonia Despite 50 years of investigation, efficacious therapy for idiopathic pulmonary fibrosis (IPF) remains elusive, and considerable controversy exists as to when and how current treatments should be used. Patients with IPF continue to experience an inexorable progression to death, with lung transplantation being the only measure shown to prolong survival. Existing evidence about the treatment of IPF is difficult to interpret for several reasons. First, the literature is hampered by evolving case definitions and classification schemes. To varying degrees, most older studies included a heterogeneous group of interstitial lung diseases that are now understood to have markedly different natural histories and responses to therapy (1, 2). Because these were not studies of IPF as currently defined, the application of their results to contemporary patients with IPF is misleading. Second, methodologic problems (e.g., lack of precise, consistent histopathologic classification, and varying endpoints) and the paucity of adequately powered randomized placebocontrolled treatment trials have made evidence-based conclusions difficult. Amid this historically dismal therapeutic milieu, significant strides are being made toward the development of useful therapies. Improved understanding of the pathogenesis of IPF has identified promising molecular targets for rational drug development. In addition, refinement in the classification of interstitial lung disease and development of a precise definition of usual interstitial pneumonia (UIP), the histopathologic corollary of IPF, has enabled higher quality clinical trials. Also, progress has been made toward validating and standardizing outcome (Received in original form February 6, 2006; accepted in final form February 17, 2006) Correspondence and requests for reprints should be addressed to Talmadge E. King, Jr., M.D., San Francisco General Hospital, 1001 Potrero Avenue, Room 5H22, San Francisco, CA tking@medsfgh.ucsf.edu Proc Am Thorac Soc Vol 3. pp , 2006 DOI: /pats TK Internet address: measures. Thus, many new agents are being tested, some with suggestion of benefit. This article examines the body of evidence supporting current therapies and reviews the range of other agents being tested in patients with IPF. TRADITIONAL THERAPY: ANTIINFLAMMATORY AND IMMUNOMODULATORY AGENTS The hypothesis that IPF was an inflammatory alveolitis led to an emphasis on immunosuppression, initially with corticosteroids and later with the addition of cytotoxic and immunomodulatory agents, including azathioprine, chlorambucil, cyclophosphamide, cyclosporin, IFN- 1a, methotrexate, and D-penicillamine (3). There are no published randomized placebo-controlled trials of these agents. We discuss corticosteroids, azathioprine, cyclophosphamide, and colchicine in this article because the literature reporting the use of the other agents listed includes only case reports or small case series (Table 1) (4). Corticosteroids The evidence. Corticosteroids suppress neutrophil and lymphocyte migration into the lung, decrease the level of immune complexes, and alter alveolar macrophage function. Initially considered a measure of last resort, corticosteroid use evolved into accepted practice during the last 50 years despite the fact that no prospective placebo-controlled randomized trial has ever been performed. Many retrospective reviews and case series have been published. In some studies, transient objective clinical response was found in a small minority of patients with no survival benefit relative to untreated patients (5 32). However, these data are of poor quality as evidenced by a recent systematic review that found no high-quality prospective trials on which to base any recommendation (3). In older studies in which the definition of IPF was less specific (and the patient population, therefore, quite heterogeneous), corticosteroids alone were reported to result in physiologic or radiographic improvement in 15 to 30% of patients (16). However, many investigators now suspect that the subgroup of responders did not have IPF as we now define it but had nonspecific interstitial pneumonia, respiratory bronchiolitis associated interstitial lung disease, or desquamative interstitial pneumonia. This conclusion is consistent with the observation that the patients who respond to corticosteroids in these studies are younger and have more cellularity and less fibrosis on biopsy (33). This clinical and histopathologic description seems inconsistent with the IPF, where patients are typically older and demonstrate histopathologic evidence of fibrosis without significant inflammation (34). Adverse effects. When high-dose corticosteroids are used in trials, significant and often irreversible toxicity is consistently observed, including weight gain, hyperglycemia, osteoporosis, avascular necrosis, and gastrointestinal (GI) effects (13, 35, 36). Implications for practice. Only limited conclusions can be drawn from the uncontrolled prospective and retrospective studies performed to date. It is unclear that there is any survival advantage for patients treated with corticosteroids alone or in combination with other agents (see below). Current evidence

2 Walter, Collard, and King, Jr.: Treatment of IPF 331 TABLE 1. RESPONSE TO IMMUNOSUPPRESSIVE THERAPY IN CONTEMPORARY IDIOPATHIC PULMONARY FIBROSIS COHORTS* Reference Disease Therapy Study Design Outcome Douglas and colleagues, UIP Prednisone versus colchicine 22 patients prospectively treated with Two of the 22 prednisone treated 1997 (55) colchicine compared with patients had sustained 22 historical controls treated with improvements in DL CO, four of 22 had prednisone alone improved FVC Douglas and colleagues, UIP Prednisone versus colchicine Randomized trial of 26 patients; Of the group receiving prednisone 1998 (7) 12 received prednisone alone alone, none improved; 9 of 12 died or PFTs deteriorated; stability occurred in 2 of 12 Ziesche and colleagues, UIP Prednisolone versus IFN- 1b Randomized controlled trial of Deterioration in all patients treated with 1999 (65) 18 patients who had previously failed prednisolone alone immunosuppression; nine received prednisolone alone. Daniil and colleagues, UIP, NSIP Prednisone alone versus Retrospective case series; included UIP: 1 of 12 improved ( 15% rise in 1999 (8) prednisone and azathioprine 12 UIP patients were treated with FVC and/or DL CO ); 2 of 12 remained versus cyclophosphamide prednisolone alone (n 3) or stable; 9 of 12 deteriorated or died combined with azathioprine (n 3) or combined with cyclophosphamide (n 6) Nicholson and colleagues, UIP, NSIP, Prednisone versus prednisone and Retrospective case series; included In the UIP group: 3 of 28 improved 2000 (9) DIP, RBILD cyclophosphamide 28 UIP patients treated with ( 15% rise in FVC or DL CO ); prednisolone (n 10) or 19 remained stable; 8 declined prednisolone and cyclophosphamide (n 18) Zisman and colleagues, UIP Cyclophosphamide Prospective case series of 19 patients 1 of 19 improved ( 10 point drop in 2000 (38) who had previously failed to CRP score) respond to corticosteroids Douglas and colleagues, UIP Prednisone versus colchicine versus Retrospective review of 487 patients No difference in survival in treated and 2000 (13) no treatment untreated groups Riha, 2002 (78) UIP Corticosteroids versus Retrospective review of 27 patients No difference in survival compared with corticosteroids and treated with corticosteroids alone: no treatment cyclophosphamide versus no seven treated with corticosteroids treatment and cyclophosphamide and eight untreated Collard and colleagues, UIP Prednisone and Retrospective review of 164 patients; No difference in survival compared with 2004 (48) cyclophosphamide versus no 82 treated with prednisone and no treatment treatment cyclophosphamide; 82 untreated Demedts and colleagues, UIP Prednisone, azathioprine and Randomized trial comparing FVC: improvement ( 10% increase 2005 (45) N-acetylcysteine versus 71 patients treated with from baseline) occurred in 10% prednisone and azathioprine acetylcysteine plus standard acetylcysteine versus 12% of the therapy against 68 treated with standard therapy; 54% versus 37% standard therapy alone were stable; 37 versus 51% were worse ( 10% decrease from baseline). DL CO : improvement ( 15% increase from baseline) occurred in 12% acetylcysteine versus 5% of the standard therapy; 46 versus 44% were stable; 43 versus 51% were worse ( 15% decrease from baseline) Definition of abbreviations: CRP clinical, radiologic, physiologic score; DIP desquamative interstitial pneumonia; NSIP nonspecific interstitial pneumonia; PFTs pulmonary function tests; RBILD respiratory bronchiolitis associated interstitial lung disease; UIP usual interstitial pneumonia. * Restricted to studies that used currently accepted histologic or radiographic criteria for case definition. Personal communication from Maurits Demedts (February 6, 2006). Adapted with permission from Reference 79. suggests that corticosteroid monotherapy is not indicated in the treatment of IPF (3, 37). IMMUNOMODULATORY AND ANTIFIBROTIC AGENTS Azathioprine The evidence. Azathioprine is a purine analog converted to mercaptopurine in body tissues. It inhibits adenine deaminase, which impairs the proliferation of cells, especially leukocytes and lymphocytes. A Cochrane Review identified three case-controlled or randomized controlled trials that evaluate azathioprine (4, 17, 35, 38). Most studies had design flaws (e.g., the studies were uncontrolled, had small numbers of subjects, failed to provide adequate primary or secondary outcome assessment, lacked adequate details to assess response, or included patients with conditions other than IPF) (14, 18, 20 23, 32). Raghu and colleagues compared 13 patients treated with high-dose prednisone and placebo versus 14 patients treated with an identical prednisone regimen and azathioprine (35). These cases were not explicitly identified as having IPF as currently defined; however, the inclusion criteria were similar to what is used today (39). At 1 yr, there was no significant difference in clinical measures or mortality. In a secondary analysis adjusted for age, the authors found that there was a marginally significant mortality benefit with azathioprine. Of two lesser-quality, earlier randomized controlled trials performed in a heterogeneous

3 332 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL population, one showed a marginal benefit of azathioprine (22) and the other showed no benefit (40). A limitation of the data on azathioprine is the lack of a no treatment arm in any of the trials. Without such an arm, it is impossible to know the true effect of azathioprine therapy. In the absence of no-treatment arms in the azathioprine trials, one can contrast the no-treatment arms of two recent large randomized clinical trials (41 43) to the prednisone plus azathioprine arm of the recently published European Idiopathic Pulmonary Fibrosis International Group Exploring NAC I Annual (IFIGENIA) study (44) (Figure 1). The prednisone and azathioprine group in the IFIGENIA trial (45) experienced a decline in FVC that was similar to that in the placebo group from the IFN trial (41) and the placebo group from the pirfenidone trial (43). Although it is not confirmative, this comparison suggests that prednisone plus azathioprine is no better than placebo in preserving lung function in patients with IPF. Adverse effects. The most common serious side effects of azathioprine involve blood elements, the GI system (e.g., nausea, vomiting, and loss of appetite), and liver toxicity. Other side effects encountered less frequently include fatigue, hair loss, joint pain, and diarrhea. An increased risk of malignancy has been reported, and azathioprine may be a teratogen. Implications for practice. Little evidence exists to justify the routine use of azathioprine in the management of IPF alone or as a steroid-sparing agent. Other forms of idiopathic interstitial pneumonias may show a better response to this agent; consequently, it is important to make an accurate diagnosis. Cyclophosphamide The evidence. Cyclophosphamide is an alkylating agent of the nitrogen mustard group. It is absorbed orally and activated in the liver to several cytotoxic compounds that suppress lymphocyte function. A number of nonrandomized small trials and case reports on idiopathic interstitial pneumonia suggested variable benefit with cyclophosphamide (17, 35, 38, 46). Most studies had design flaws (e.g., they were uncontrolled, had small numbers of subjects, failed to provide adequate primary or secondary outcome assessment, lacked adequate details to assess response, or included patients with conditions other than IPF) (14, 15, 18, 23, 26 32, 47). The best prospective data on cyclophosphamide are from Johnson and coworkers, who randomized 43 patients with idiopathic interstitial pneumonia to high-dose prednisolone versus low-dose prednisolone plus cyclophosphamide (17). In this early trial ( ), no distinction was made between UIP and other idiopathic interstitial pneumonias, and more than 20% of cases were associated with connective tissue disease. Subjects were switched to the alternative treatment regimen when they were perceived to have failed. Among this heterogeneous group, no difference in clinical markers or mortality was seen, although in a secondary analysis, when time to death or failure of first treatment regimen were analyzed as a single variable, a significant mortality benefit emerged. A retrospective review compared 82 patients with IPF treated with combination cyclophosphamide and prednisone with 82 untreated patients matched for age and FVC (48). All subjects had IPF as defined by the current American Thoracic Society criteria. The groups had similar baseline characteristics. There was no significant mortality difference. Median survival was 1,431 d in treated patients and 1,665 d in untreated patients (p 0.58). Subgroup analysis found no difference in mortality when limited to cases with presumed earlier disease (FVC 60% predicted) or when limited to only surgical biopsy-proven cases. This finding was similar to that found in a smaller retrospective study of patients with IPF treated with corticosteroids and cytotoxics versus untreated patients (49). Adverse effects. In addition to increasing the risk of infection, cyclophosphamide is associated with myelosuppression, hepatotoxicity, hemorrhagic cystitis, and increased risk for several cancers (50). In a recent small prospective trial of cyclophosphamide in patients with IPF, 68% experienced adverse effects, and discontinuation was required in 47% (38). Cyclophosphamide has been associated with the development of interstitial lung disease (51). Implications for practice. No evidence exists to justify the routine use of cyclophosphamide in the management of IPF alone or as a steroid-sparing agent. There are significant potential side effects. As with azathioprine, other forms of interstitial lung diseases may show a better response to this agent. Figure 1. Vital capacity (VC) at 6, 9, and 12 mo, as compared with baseline. Values for VC are shown as percentages of the predicted value. The prednisone/azathioprine (Pred/Aza) data are from the Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine (NAC) I Annual (IFIGENIA) trial (45). The placebo (IFN- trial) data were derived from the placebo group of the IFN- trial (41, 42). The patients in the placebo group of the IFN- trial were previously treated with a total corticosteroid dose of 1,800 mg or greater within the preceding 2 yr and were permitted to continue taking prednisone ( 15 mg/d) if the dosage remained stable. The placebo (Pirfenidone trial) data were derived from the placebo group of the Pirfenidone trial (101). Of the 107 patients evaluated for efficacy of pirfenidone, 92 had not received prior treatment with corticosteroids; thus, the majority of enrolled patients were corticosteroid naive (43). The data were estimated by taking the mean VC for the placebo group in the full analysis set (VC, 2.5; n 35) and calculating the percent change at 6 and 9 mo. There was a marginal decline in VC from baseline at 6 mo in the placebo group ( 0.08 L; 3.2%) and at 9 mo ( 0.13 L; 5.2%). Data from References 41, 43, and 44.

4 Walter, Collard, and King, Jr.: Treatment of IPF 333 Colchicine The evidence. Colchicine inhibits collagen formation from fibroblasts and may increase collagen degradation. It also suppresses the release of alveolar-macrophage derived growth factor and fibronectin by alveolar macrophages from patients with pulmonary fibrosis. Numerous in vitro and animal model studies have suggested that colchicine may slow the fibrotic process (52, 53). Several clinical studies have failed to show a significant difference in the rate of decline of lung function or improvement in survival when patients were treated with colchicine (with or without corticosteroids) (7, 12, 13, 54 56). In a retrospective intent-to-treat analysis, Douglas and coworkers found no evidence to suggest that colchicine was different from no therapy with respect to survival in the treatment of IPF/UIP (13). The best prospective controlled clinical trial (7) showed that colchicine was no more effective as a treatment than prednisone, with no significant difference in outcomes (e.g., survival, pulmonary function), although the colchicine seems to be safer and better tolerated. Adverse effects. Side effects that may be encountered include nausea, vomiting, abdominal pain, and diarrhea. Implications for practice. No evidence exists to justify the routine use of colchicine in the management of IPF. NOVEL THERAPIES The pathophysiology of IPF is believed by many to be predominantly a disorder of fibroproliferation rather than inflammation (57). This may explain the poor response in this disease to therapies aimed at decreasing inflammation. Recent emphasis has been on targeting the molecular events that are believed to perpetuate and sustain the fibrotic process in IPF. Data have offered hints of benefit but have failed to show clear and significant clinical efficacy (Table 2). Here we address the state of the evidence for several promising therapeutic prospects. N-Acetylcysteine The evidence. Acetylcysteine is a sulfhydryl substance that functions as a powerful antioxidant and cellular detoxifying agent. It is proposed that an oxidant/antioxidant imbalance is involved in alveolar epithelial cell injury and thereby contributes to progressive fibrosis in IPF (58). Acetylcysteine, a precursor of the major antioxidant glutathione, was shown to restore depleted pulmonary glutathione levels and to improve lung function in patients with fibrotic lung disease (59). A recent multicenter randomized trial, the IFIGENIA study, tested acetylcysteine with azathioprine and high-dose corticosteroids versus azathioprine and high-dose corticosteroids alone in a population with rigorously established IPF (45). N-acetylcysteine (Fluimucil) was given as 600-mg effervescent tablets three times daily. This is three to nine times the usual approved dose of acetylcysteine (44). Although both groups showed lower FVC and Dl CO after 12 mo of treatment, the rate of decline was significantly lower in the N-acetylcysteine group. The magnitude of the difference was modest: There was a 9% relative reduction in the decline of FVC and a 24% relative reduction in the decline of Dl CO. These changes are of uncertain clinical significance. No mortality benefit was seen. Adverse effects. The most common adverse effects of acetylcysteine include nausea, vomiting, and other GI complaints. Rarely, rash with or without fever may occur. In the recent trial, no significant additional toxicity was seen with the addition of acetylcysteine, and acetylcysteine seemed to protect against azathioprine-induced myelotoxicity (44). Implications for practice. Because the IFIGENIA trial did not have a no treatment group, it is impossible to establish whether N-acetylcysteine in combination with prednisone and azathioprine is better than no treatment. The implications for clinical practice remain unclear. Additional studies of N-acetylcysteine need to be performed before it can be routinely recommended as therapy for IPF. However, if one is considering prednisone and azathioprine therapy for patients with IPF, the addition of N-acetylcysteine should be considered because of its mitigating effects on the myelotoxicity of azathioprine. Pirfenidone The evidence. Pirfenidone is a novel compound shown in vitro to inhibit transforming growth factor- (TGF- ), a key stimulus of collagen synthesis and extracellular matrix accumulation. In animal models, it ameliorates bleomycin-induced pulmonary fibrosis (60). Two uncontrolled, open-label studies of oral pirfenidone have been published (61, 62). Raghu and coworkers studied the drug in 54 patients with IPF and suggested that it may help to stabilize lung function (61). Nagai and colleagues studied eight patients with IPF (two others had associated systemic sclerosis). They showed that at 12 mo, no significant deterioration in chest radiographic scores and Pa O2 occurred, and the drug was well tolerated. Pirfenidone may slow the progression of lung impairment in patients with pulmonary fibrosis due to Hermansky-Pudlak syndrome (63). A recent randomized phase II trial in which pirfenidone was compared with placebo generated encouraging data (64). The authors did not find a significant difference in the primary endpoint (change in lowest oxygen saturation on 6- min walk test over 6 or 9 mo) in the full cohort. There was benefit observed among a prespecified subset of patients who were less hypoxemic with exercise at the start of the trial. At 6 and 9 mo, the treated patients experienced improvement in exercise-induced hypoxemia, but the magnitude of the benefit was small ( 3% oxygen saturation). It is unclear whether this primary outcome measure is meaningful. Among the secondary endpoints, the rate of decline in VC at 9 mo was significantly lower in the pirfenidone group. There was no significant difference in total lung capacity, Dl CO, and resting Pa O2. Acute exacerbations of IPF were seen only in the placebo group (14%). Based on this finding, the trial was stopped by the Data Safety Monitoring Board. Adverse effects. Side effects were observed in up to 90% of the patients treated with pirfenidone. The most frequent side effects of pirfenidone include GI symptoms (mostly nausea, dyspepsia, anorexia, and vomiting), photosensitive skin rash, and fatigue. Other potential side effects include diarrhea, constipation, itching, dry skin, hyperpigmentation, headache, and weakness. Implications for practice. Pirfenidone in not available in the United States or Europe. The current data suggest that pirfenidone has the potential to stabilize or improve lung function, which has implications for improving the quality of life and survival of patients with IPF. The suggestion that pirfenidone prevents acute exacerbations of IPF should be evaluated in larger studies. IFN- 1b The evidence. IFN- 1b is an endogenous cytokine considered to play a key role in down-regulating expression of TGF-, which limits fibroblast proliferation and collagen synthesis. Ziesche and colleagues undertook a small open-label trial in patients with less advanced pulmonary disease that was not clearly defined as IPF. This study showed significant improvement in a variety of clinical markers (65). Subsequently, a large-scale multicenter, randomized, placebo-controlled trial was completed in which 330 patients with confirmed IPF that had failed to respond to a

5 334 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL TABLE 2. POTENTIAL DRUG TREATMENTS FOR IDIOPATHIC PULMONARY FIBROSIS Agent Biological Rationale and Safety Description of Studies Bosentan Endothelin-1, an amino acid secreted by endothelial and Phase II trial recently completed. Preliminary reports are that smooth muscle cells, has diffuse vasoactive, mitogenic there was no effect on the primary outcome of 6-min walk and immunomodulatory effects. It is shown to but that there were trends toward improvement in the up-regulate production of TGF- and to have independent prespecified combined outcome of death or time to stimulatory effects on fibroblasts. treatment failure. On the basis of these data, a phase III Bosentan is an endothelin ET(A/B) receptor antagonist. trial of bosentan is expected to be initiated. Captopril, losartan Angiotensin II is a vasoactive peptide with fibroblast mitogenic Ongoing trial at the National Institute of Respiratory Diseases, (Cozaar) effects (80 82). Angiotensin II mediated fibroblast Mexico (86). proliferation seems to be linked to autocrine production No significant effect on mortality in a retrospective study (87). of transforming growth factor- 1 (80). Inhibits the angiotensin-converting enzyme and completely abrogates Fas-induced apoptosis in human alveolar epithelial cells (83). Inhibits fibroblast proliferation in vitro and reduces the fibrotic lung response in vivo (84, 85). Cyclosporin Exerts an inhibitory effect on T cells. It is known to suppress The few published reports on the use of cyclosporin in delayed-type hypersensitivity, allograft rejection, and interstitial lung disease have been anecdotal and less antibody response to T-cell dependent antigens. than encouraging (88 90). Etanercept (Enbrel) Etanercept is a TNF- antagonist. A phase II trial is ongoing. TNF- is a cytokine with varied but primarily mitogentic effects on fibroblast differentiation and collagen synthesis. Imatinib mesylate Inhibitor of several protein-tyrosine kinases that are believed A phase II trial is underway in the United States. (Gleevec) to play a role in the proliferation of tumor cells and mesenchymal cells, such as lung fibroblasts. Inhibits expression of PDGF signal transduction, which in animal models reduces fibroproliferative responses. IFN- 1a In vitro, shown to reduce fibroblast migration and proliferation. Randomized clinical trials in the United States and Canada Inhibits collagen production by fibroblasts. failed to show any benefit (91, 92). Keratinocyte growth factor Induce type II pneumocytes proliferation (Abnormally Intravenous, not FDA-approved or commercially available. (Repifermin) stimulated alveolar epithelial cells may play a deleterious Has been unsuccessful in acute lung injury when given after role increasing intraalveolar antifibrinolytic activity and the fibrotic insult (93, 94). secreting fibrogenic cytokines.) Phase II trials for chronic cutaneous ulcers, mucositis, Promotes reepithelialization in various wound models without ulcerative colitis (Human Genome Sciences) (95). inducing scarring or fibrosis (82). Lovastatin Blocks the formation of granulation tissue by induction of No improvement in survival in retrospective study (87). fibroblast apoptosis in vitro and in vivo (96). Mycophenolate mofetil Impairs lymphocyte function by blocking purine biosynthesis The few published reports on the use of mycophenolate (CellCept) via inhibition of the enzyme inosine monophosphate mofetil in interstitial lung disease have been anecdotal dehydrogenase. and less than encouraging. D-penicillamine Inhibits collagen synthesis by interfering with collagen Limited studies have not shown efficacy in idiopathic cross-linking. pulmonary fibrosis. Suppression of T-cell function. Most studies had design flaws (uncontrolled, failed to provide adequate primary or secondary outcome assessment, lacked adequate details to assess response; included patients with conditions other than idiopathic pulmonary fibrosis) (12, 19 21, 24, 97, 98). Pentoxifylline A methylxanthine derivative that decreases TNF- synthesis. Has been studied in the treatment of alcoholic hepatitis in Inhibits hepatic stellate cell proliferation and collagen humans. synthesis in vitro and in a rat model of secondary biliary fibrosis. Sirolimus (Rapamune, A macrocyclic triene antibiotic. Randomized clinical trial in patients with lung fibrosis rapamycin) Immunosuppressive (used in transplantation) and underway in Australia. antiproliferative properties. Inhibits stellate cell proliferation, which could attenuate the potential fibrotic response in patients with recurrent liver disease. Suramin A synthetic compound that has been used to treat nematode infestations. Inhibits the effect of numerous profibrotic growth factors (99). In rabbits, delays wound healing and prevents hypertrophic scarring after eye surgery (100). Definition of abbreviations: FDA Food and Drug Administration; PDGF platelet-derived growth factor; TNF tumor necrosis factor. course of corticosteroids were randomized to subcutaneous IFN- 1b or placebo (41). No significant differences were noted in the primary outcome of progression-free survival or the secondary outcomes of pulmonary function or quality of life. Nonetheless, exploratory analysis suggested that there may be benefit worth exploring with future trials. For subjects with FVC greater than 55% predicted, there were significantly fewer death seen in the IFN- 1b patients (4.8 vs. 16.4% in the placebo group); a similar finding was seen for the group with a Dl CO greater than 30% predicted (3.4 vs. 13.2% of placebo). Patients with more severe disease do not seem to benefit from treatment with IFN- 1b (41, 66).

6 Walter, Collard, and King, Jr.: Treatment of IPF 335 Adverse effects. The most frequent side effects include flulike symptoms such as fever, headache, muscle soreness, malaise, fatigue, and chills. Acetaminophen ( 500 mg) or ibuprofen ( 400 mg with food) taken at the time of injection lessens these side effects. Other side effects reported include diarrhea, vomiting, nausea, abdominal pain, injection site erythema or tenderness, and depression. Acute respiratory failure and diffuse alveolar damage has been reported after IFN- therapy (67). Implications for practice. The implications for clinical practice remain unclear. Current evidence does not justify the routine use of IFN- 1b in the management of IPF. The results of a second ongoing randomized, double-blind, placebo-controlled, multinational phase 3 study are awaited. Anticoagulation The evidence. It is proposed that inflammation and vascular injury in IPF may result in a prothrombotic state that leads to additional morbidity. This hypothesis was recently tested in a nonblinded trial in which 56 patients with IPF were randomized to prednisolone alone or prednisolone and anticoagulation (with coumadin as an outpatient and with intravenous dalteparin when hospitalized) (68). The authors found a significant improvement in survival at 3 yr (35% survival in the nonanticoagulant group compared with 63% in the anticoagulant group). Although the incidence of acute exacerbation was not different between the groups, the mortality associated with acute exacerbation was lower in the anticoagulant group (15 deaths in 21 acute exacerbations vs. two deaths in 11 acute exacerbations). Several methodologic issues raise concern for the study s applicability to a typical IPF population. The incidence of acute exacerbation was higher than is typical (64% in the placebo group), and the median survival of the placebo group (399 d) was lower than is seen in contemporary IPF cohorts. There may have been selection bias toward more advanced and rapidly progressive disease, perhaps because these patients were recruited on initial hospitalization. Another concerning feature is the withdrawal of 26% of patients in the anticoagulant group after randomization but before initiating treatment. Because the study did not use an intention-to-treat analysis, randomization is threatened. It is conceivable that the patients who withdrew were more ill and would have had higher mortality. Finally, the mechanism of the beneficial effect of anticoagulation therapy for IPF is not known (69). Adverse effects. No serious complications, such as bleeding, were observed with the anticoagulant agents in the recent trial. Implications for practice. Current practice should not change on the basis of this single small study, but the results remain encouraging, and larger scale trials should be initiated. Lung Transplant The evidence. Lung transplant is the only therapy shown to prolong survival in advanced IPF, although the post-transplant 5-yr survival for patients with IPF is approximately 40% (70). Patients with IPF are often referred late in the course of their disease. The median wait for transplantation is approximately 46 mo; consequently, patients with IPF have the highest death rate among the diagnostic groups on the transplant waiting list ( 30% of patients with IPF who are listed die before receiving a transplant). Indications and choice of procedure. Appropriate timing for referral to transplant is controversial given the variable course of IPF and lack of validated prognostic measures. Failure to respond to medical treatment, worsening exercise-induced desaturation, resting hypoxemia, or a sustained downward trend in vital capacity should prompt consideration of lung transplantation. Single-lung transplantation has been the standard procedure for patients with IPF and has produced good results. Implications for practice. Early referral for transplant evaluation should be considered even before the response to initial medical therapy has been determined. Thus, it is reasonable to refer for transplant evaluation at the time of initial diagnosis (71). ADDITIONAL MANAGEMENT ISSUES Acute Exacerbations in IPF Patients with IPF may suffer acute deterioration secondary to infections, pulmonary embolism, pneumothorax, or heart failure (72). However, it is increasingly apparent that acute exacerbations or an accelerated phase of rapid clinical decline without an identifiable cause characterizes the clinical course of IPF and is associated with a poor prognosis (43, 69, 73 76). The rate of these acute exacerbations ranges from 10 to 57%, apparently depending on the length of follow-up (43, 69, 76). The risk factors for acute exacerbations of IPF are unknown. During these episodes, the histopathologic pattern of acute lung injury (diffuse alveolar damage) is often found on the background of UIP (69, 73, 74). Definition. Acute exacerbation is generally defined by worsening of dyspnea within a few weeks ( 1 mo); newly developing diffuse radiographic opacities; worsening hypoxemia (a decrease in Pa O2 of 10 mm Hg or Pa O2 /Fi O2 300); and absence of infectious pneumonia, heart failure, and sepsis (43, 69, 76). Implications for practice. Better understanding and management of these episodes seem to be critical to reducing the death rate in IPF. Because of the clinical presentation, patients are usually treated with broad-spectrum antibiotics and corticosteroids. Often, mechanical ventilation is required but is usually not successful, with a hospital mortality rate of 78% in one study (76). In patients who survive, a recurrence of acute exacerbation is common and usually results in death (76). Improving Quality of Life in Patients with IPF Research focused on quality of life in IPF has been limited (77). A recent systematic review found that, in addition to the effect on physical health, general health, energy level, respiratory symptoms, and level of independence were impaired in patients with IPF (77). Implications for practice. In addition to drug therapy for IPF, there is much that can be done in the way of supportive therapy that will ease the breathlessness that accompanies this condition. Pulmonary rehabilitation and education programs can help in teaching patients how to breathe more efficiently and to perform their activities of daily living with less breathlessness. Often, supplemental oxygen therapy is required to treat the hypoxemia that is usually worsened by exercise. Early treatment of chest infections is required. Smoking must be discontinued because the effects of tobacco aggravate the shortness of breath. The stress of the illness can often be helped by joining a support group where members share common experiences and problems. CONCLUSIONS Based on the evidence available, few can imagine that corticosteroids and cytotoxic agents would be accepted were they introduced today as a novel therapy for IPF. Nonetheless, the view that these agents are the standard of care has inhibited the initiation of truly placebo-controlled trials (i.e., with a no-therapy arm). Modern trials are frequently performed in patients who have failed to improve with corticosteroids or are designed to test a novel agent against a corticosteroid and cytotoxic regimen. Consequently, a toxic therapy without meaningful evidence of

7 336 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL benefit has been adopted as the standard to which other therapies are added. Several points regarding corticosteroid and cytotoxic therapy in IPF are clear. First, there is no evidence to suggest that immunosuppression improves mortality. Second, the vast majority of patients with IPF do not respond to treatment with corticosteroids and cytotoxic agents and suffer significant side effects from the therapy. Third, in the absence of a placebo-controlled trial of corticosteroids and cytotoxic agents, it is impossible to ascertain whether the small subgroup of patients who respond to this therapy is real or represents variation in the natural history of disease. For now, clinicians continue to confront a practical problem: What therapy should be recommended to patients with IPF? Patients and clinicians are faced with four options: (1) no treatment, (2) traditional therapy with corticosteroids and cytotoxic agents, (3) participation in a clinical trial of an investigational agent, and (4) off-label use of investigational agents. There is no evidenced-based answer to this issue. The only treatment proven effective in prolonging survival is lung transplantation. The lack of alternative efficacious therapy in the treatment of IPF is not an argument in favor of the continued use of immunosuppression in the management of IPF, and neither is the fact that it is the historical standard of care. The medical literature is replete with examples of non evidenced-based toxic therapies being widely used because of anecdotal evidence and conventional wisdom only to be found through prospective trials to be harmful. It seems clear that a prospective randomized trial of corticosteroids and cytotoxic agents compared with no therapy is the only way this question will be answered. Clinical trials of this and other therapies for IPF are the hope for a better tomorrow in the treatment of this disease. RECOMMENDATIONS 1. No specific drug treatment recommendations can be made. 2. Treatment of IPF with corticosteroids alone should not be considered a standard of therapy. 3. Treatment of IPF with corticosteroids and cytotoxic agents is of unproven benefit and causes substantial morbidity; combined therapy should not be routinely prescribed. 4. Agents such as coumadin, N-acetylcysteine, IFN- 1b, pirfenidone, bosentan, or etanercept show promise, but there is insufficient evidence to recommend their general use. 5. Efforts must be made to better understand and manage the acute events that seem to be a harbinger of death in patients with IPF. 6. Appropriate patients should receive pulmonary rehabilitation and oxygen therapy. 7. All suitable patients should be referred for lung transplant evaluation at the time of diagnosis. Conflict of Interest Statement : N.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.R.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.E.K. has served on advisory boards for Actelion (compensation in 2003, $11,725; in 2004, $9,940; in 2005, $15,000); for InterMune (compensation in 2003, $21,000; in 2004, $15,000, in 2005, $20,000); for GlaxoSmithKline (compensation in 2004, $12,625; in 2005, $10,000); and has served as a consultant for Nektar, Alexza, AstraZeneca, Biogen, Centocor, Fibrogen, Genzyme, Human Genome Sciences, Merck, and CoTherix. Compensation from these institutions did not exceed $10,000 per company per year in any one of the preceding 3 yr. 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