Question: I have been treating a patient with IPF for 9 months with prednisone/azathioprine. His lung function is relatively stable, but for the past 6 months he has been gaining weight (BMI 31) and his HbA1c is now 8.9. I received a call from his endocrinologist, a colleague at my medical center, who insists the prednisone is counterproductive. What is your recommendation?

Answer: Excellent question. Let's break it down into the component issues.

Is there good evidence for efficacy of prednisone/azathioprine in IPF?

The ATS consensus statement guideline from 2000 addresses the continuing ambiguity of this issue: "Optimal therapy for IPF is contentious. To date, most treatment strategies have been based on eliminating or suppressing the inflammatory component. No pharmacological therapy has been proven unequivocally to alter or reverse the inflammatory process of IPF. More importantly perhaps, little information has appeared supportive of the theory that the fibrotic process can be reversed."¹

The statement from 2000 still holds true today. What have we learned since the consensus statement came out? Several uncontrolled studies over the last several decades have had inconsistent results. Prospective trials continue to be rare. Flaherty and colleagues reported results of corticosteroid therapy on a multidimensional clinical/radiological/physiological score in 29 IPF patients.² A positive response was seen in 17% of patients while 31% remained stable and 52% were classified as nonresponders. A separate report from this group suggested that response to steroid therapy was not associated with a survival benefit; those remaining stable during short-term steroid therapy exhibited the best long-term prognosis.

The IFIGENIA study, a multicenter, multinational consortium reported the results of a trial combining N-acetyl cysteine (NAC 600 mg tid, an antioxidant with potential antifibrotic properties) with prednisone and azathioprine versus prednisone/azathioprine plus placebo. The group treated with combined immunosuppression and NAC exhibited a lesser decline in FVC (9%) and DL_CO (24%) after one year. Interestingly, the longitudinal change in FVC and DL_CO in NAC/immunosuppressive-treated patients in this trial was remarkably similar to the placebo-treated patients in the GIPF 001 gamma interferon study. A clear benefit of the NAC treatment was in the amelioration of myelotoxicity secondary to azathioprine. As there was no pure placebo arm, it is not clear what the effect of NAC is on the fibrotic aspect of this disease. This has led to controversial interpretation of the data.³ It will be difficult to draw conclusions on the effects of steroid therapy until randomized, placebo-controlled trials are done.

I do not treat patients with IPF with immunosuppressive therapy without strong indication of an autoimmune component with associated collagen vascular disease.

What is being done to address this?

We do not know if there is a benefit of prednisone/azathioprine treatment in IPF. The IPFnet is pursuing the PANTHER trial (Prednisone/azathioprine/NAC vs NAC vs Placebo), which may shed some light on the question. Since there is no prednisone/azathioprine arm without NAC, the answer to the prednisone/azathioprine efficacy question will be indirect. I think it is important that we fully enroll PANTHER to help settle the question of prednisone/azathioprine and NAC efficacy.

If prednisone/azathioprine is used, when is the effect evident?

When prednisone/azathioprine is called for, I recommend supplementing them with NAC. I also recommend a hard evaluation of the success or failure of therapy between 4 and 6 months with PFTs.

The ATS consensus statement is clear on this matter: "If responses are to occur with corticosteroids, improvement is usually noted within 3 months. After 3 months of corticosteroid therapy, objective clinical parameters are required to gauge response. Subjective improvement is not adequate to gauge response, because of placebo effects or mood-enhancing effects of corticosteroids."¹

In my opinion, failure to demonstrate a significant (≥ 10%) improvement in FVC or DL_CO is reason to discontinue these potentially toxic agents that have side effects such as poor glucose control.

How can the metabolic side effects of prednisone be managed?

Given your patient's stability, you are surely reticent to eliminate the immunosuppressive therapy. A cautious approach might be to reduce his corticosteroids, which could relieve the negative impact on his glycemic control. Dose adjustment and monitoring of his PFTs and glucose control should improve the situation.

1. American Thoracic Society. Idiopathic Pulmonary Fibrosis: Diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med. 2000;161:646-664.
2. Flaherty KR, Toews GB, Travis WD, et al. Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J. 2002;19:275-283.
3. Noth I, Martinez FJ. Recent advances in idiopathic pulmonary fibrosis. Chest. 2007:132:637-650.

Question: I read recently that pirfenidone was approved for IPF in Japan. What is this drug, what is its mechanism of action, and what is its status in the US?

Answer: Pirfenidone is an orally active compound that inhibits transforming growth factor beta. TGFβ is a key factor in collagen synthesis and extracellular matrix deposition, and an inhibitor is expected to have a positive therapeutic effect in fibrotic conditions such as IPF.¹

Pirfenidone's regulatory approval in Japan was based on two studies. Though Azuma et al did not find a significant difference in the primary endpoint between drug and placebo groups (difference in the change in the lowest oxygen saturation by pulse oximetry (SpO₂) during a 6-minute exercise test), they observed significantly fewer acute exacerbations in the group receiving drug, and the trial was terminated early.²

The second study looked at the rate of decline in forced vital capacity (FVC). In a randomized, double-blind phase 3 study, pirfenidone was associated with a significant reduction in the loss of FVC compared with placebo (P < 0.05). 267 patients were enrolled and randomized to placebo or to drug treatment groups. 2 doses of pirfenidone were tested, 1,200 and 1,800 mg/d. Patients receiving placebo lost 70-80 ml more vital capacity than those in the two treatment arms, and the difference was significant. Interestingly, the higher dose was not better than the lower dose. This study was presented in abstract form at the American Thoracic Society meeting in May 2008, but has not yet been published in a peer-reviewed journal. Based on preliminary studies, the most frequent side effects of pirfenidone include GI symptoms (mostly nausea, dyspepsia, anorexia, and vomiting), photosensitive skin rash, and fatigue.¹

In the US, two pirfenidone studies are under way. According to the sponsor InterMune, all patients in the CAPACITY trials are scheduled to complete their final study visit in November 2008. Preliminary results are anticipated in the first quarter of 2009. The primary endpoint in both CAPACITY trials is the absolute change in percent predicted FVC from baseline to week 72.³ We are eagerly awaiting the results of these trials. Since the drug has been fast tracked by the FDA, the regulatory process is expected to proceed quickly if the trials are positive.

1. Walter N, Collard HR, and King TE, Jr. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:330-338.
2. 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.
3. www.clinicaltrials.gov NCT00287729 and NCT00287716.

Question: I understand that there is no evidence supporting the use of corticosteroid and cyclophosphamide therapy for patients with confirmed IPF. However, in some cases the diagnosis is not definitive and therefore this therapy might be beneficial for the patient. What are the critical diagnostic findings that should guide the decision on immunosuppressive therapy when IPF is suspected but not confirmed?

Answer: The lack of evidence for efficacy of corticosteroids and additional immunosuppression in IPF suggests that this approach should not be taken in cases of confirmed IPF. The IPFnet is conducting a trial of prednisone/azathioprine/N-acetyl cysteine vs
N-acetyl cysteine vs Placebo, which may furnish indirect evidence for prednisone/azathioprine efficacy.¹ Your question is about other diseases that present like IPF that might be appropriately treated with immunosuppressive therapy.

This question has to be divided into a few parts:

• How do we recognize an autoimmune disease?
• Is immunosuppression effective for autoimmune disease?
• How long should immunosuppression be tried?

Usually a diagnosis of indefinite IPF results from an "atypical" CT scan without evidence of honeycombing. In the studies that looked at the utility of HRCT for definitive diagnosis, NSIP was difficult to distinguish from IPF. Kinder et al proposed that a positive autoantibody test in a patient with pulmonary symptoms suggests Undifferentiated Connective Tissue Disease or autoimmune disorder.^2,3,4 They found that these cases mostly were NSIP. This type of patient would be a candidate for immunosuppressive therapy. These patients should be treated cautiously with immunosuppression because of the side effects. Positive biopsy evidence and high autoantibody titers are suggestive of autoimmunity, where immunosuppression could be appropriate. There should be confident diagnosis of autoimmune disease to proceed with this course. As with IPF, the diagnosis of autoimmune diseases is not trivial. Regional ILD centers are sources of expertise that should be utilized for difficult cases.

In the largest review of NSIP cases by an ATS project group the impact of treatment on overall survivorship was deemed to be "very good." Thus, steroids and immunosuppression is a reasonable option for patients with NSIP.⁵

Because of the side effects of immunosuppressive therapy, it is important to limit the exposure. This is especially true if the treatment is not proving efficacious. I compare my patients' PFTs at baseline and at 3-6 months of treatment. If there are not appreciable improvements, I withdraw therapy. If the PFTs improve, continuation of has to be guided by balancing the risks and benefits for the individual patient.

1. Noth I, Martinez F. Recent advances in idiopathic pulmonary fibrosis. Chest. 2007;132:637-650.
2. Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest. 2003;124:1215-1223.
3. 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. Chest. 1999;116:1168-1174.
4. Kinder B, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176:691-697.
5. Travis WD, Hunninghake GW, King TE Jr, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008;177:1338-1347.

Question: I have a patient with biopsy-proven IPF who has been monitored with a yearly CT scan and has developed a 2 cm solitary pulmonary nodule. It does not appear spiculated. How aggressive should I be in treating this patient?

Answer: Lung cancer in IPF presents a proverbial "rock and a hard place" quandary, and is not uncommon. Le Jeune recently found that the rate of lung cancer in IPF patients is almost 5 times higher than in the population at large.¹

Two things should be considered in evaluating how hard the "rocks" are. The first is that somewhere between 60 and 80% of patients with IPF will die of IPF but that also means that 20-40% will die of something else. A significant cause of death in this population is lung cancer, for which we have recognized therapies. A resection has the potential of being curative. But the combination of IPF and lung cancer poses heightened risk. Aubry et al reported that the mean survival of patients with IPF was 2.3 years from diagnosis but only 1.6 years for patients with IPF and lung cancer.²

The second key is, of course, the severity of the underlying interstitial disease and its influence on surgical outcome. Patients with IPF have high postoperative pulmonary morbidity and mortality, with ARDS being the primary concern. IPF patients with ARDS have a lower preoperative %FVC than those without postoperative ARDS.³ While the morbidity and mortality of patients with IPF is high, the surgical success in treating lung cancer in patients with IPF is similar to the success rate in patients without IPF, as reflected by similar rates of disease-free survival.⁴

Therefore the approach in a patient with a solitary pulmonary nodule and IPF is really no different than with patients with a nodule and in other lung diseases such as emphysema. The pros and cons of surgery have to be carefully discussed with the patient. If the patient is a reasonable candidate for a resection, the work up should be done as expeditiously as possible, as it would for any solitary pulmonary nodule.

1. Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R. The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med. 2007;101:2534-2540.
2. Aubry MC, Myers JL, Douglas WW, et al. Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin Proc. 2002;77:763-770.
3. Kushibe K, Kawaguchi T, Takahama M, Kimura M, Tojo T, Taniguchi S. Operative indications for lung cancer with idiopathic pulmonary fibrosis. Thorac Cardiovasc Surg. 2007;55:505-508.
4. Kawasaki H, Nagai K, Yoshida J, Nishimura M, Nishiwaki Y. Postoperative morbidity, mortality, and survival in lung cancer associated with idiopathic pulmonary fibrosis. J Surg Oncol. 2002;81:33-37.