SEATTLE—In the 1950s, corticosteroids were introduced as first-line therapy for idiopathic pulmonary fibrosis (IPF). Today, most clinicians continue to prescribe corticosteroids for IPF patients although evidence of their effectiveness in relieving symptoms or prolonging survival is lacking. In fact, there has never been a prospective, randomized, placebo-controlled trial using corticosteroids in this population.

At this year’s International Conference of the American Thoracic Society in Seattle, two experts—Talmadge E. King, Jr, MD, and Ganesh Raghu, MD—debated whether corticosteroids should be administered to patients with IPF.[1] Dr. King submitted that IPF is a fibroproliferative, not an inflammatory, disease, and hence corticosteroids should not be given. Dr. Raghu countered that although IPF has some fibroproliferative properties, it also has inflammatory elements, and therefore corticosteroids may be helpful. Both agreed on the difficulty of diagnosing IPF and the need for further research regarding treatment.

WHAT IS IPF?

Before selecting treatment, you first have to decide what IPF is, said Dr. King, a Professor of Medicine at the University of California, San Francisco. In 2000, the American Thoracic Society and the European Respiratory Society issued a joint statement recommending that the term idiopathic pulmonary fibrosis be reserved for “the clinical condition characterized by progressive dyspnea, cough, restrictive lung disease, and the histopathological pattern of usual interstitial pneumonia [UIP].”[2]

One of the main purposes for establishing a histological pattern of UIP is to rule out other interstitial pneumonias, which often have a much better treatment response. In the past, said Dr. King, many lung biopsy specimens thought to show UIP really represented other interstitial pneumonias.

A 1998 review by Katzenstein and Myers[3] showed that UIP can be histopathologically defined. The presence of fibroblastic foci on a lung biopsy specimen, along with collagen deposition or honeycomb changes, indicates that fibrosis is ongoing. “You have areas of fibroblastic foci right next to scarred lung; almost always you see microscopic honeycombing even if you did not see radiographic honeycombing on chest x-ray or high-resolution computed tomography,” said Dr. King.

The difficulty in diagnosis may help to explain the variability in response to therapy. Patients with nonspecific interstitial pneumonia (NSIP, which often cannot be differentiated from UIP or other interstitial pneumonias) are the ones who respond to corticosteroids, Dr. King observed.

WHAT PREDICTS SURVIVAL?

Dr. King and colleagues conducted a study of 238 patients with IPF/UIP using the most recent definition and found that patients who are older at presentation generally have worse outcomes.[4] Survival is also decreased if lung function and/or gas exchange has declined to less than 50% at presentation. Paradoxically, the ability to continue smoking correlates with better survival.

Response to therapy, while seeming to indicate improved outcomes, is short-lived (six to 12 months). At about 10 years, Dr. King noted, survival falls dramatically, regardless of the initial response to treatment. In general, levels of inflammation or fibrosis have little impact on outcome, but patients with a lot of fibroblastic foci fare worse than do those with less fibrosis. Patients who are younger and seem to improve with treatment probably have something other than IPF/UIP, he said. “IPF has a horrible prognosis, much worse than anything else we see,” concluded Dr. King.

CORTICOSTEROIDS DON’T WORK

When corticosteroids first came into use for interstitial lung disease, “the rationale was that they were going to treat the inflammation, slow the fibroblastic proliferation, and prevent irreversible fibrosis,” said Dr. King. But very high doses were given, causing severe adverse effects in many patients. Even at lower doses, corticosteroids do not alter long-term survival. However, some patients experience a precipitous decline in health status when taken off therapy, even if the corticosteroids had not improved their condition. Thus, what, if any, effect the drugs have on IPF remains unclear, Dr. King admitted.

According to Dr. King, the initial hypothesis was that in interstitial pneumonia, inflammation leads to fibrosis. However, there is now a lot of evidence against inflammation playing a pivotal role: It is not present on biopsy specimens, and in animal models, epithelial injury in the absence of inflammation can cause fibrosis.

Dr. King hypothesized that IPF is not an inflammatory disorder but a fibroproliferative one. This has led to the study of antifibrotic agents. Interferon-gamma caused tremendous excitement because of suggestions that it improved outcomes in patients with corticosteroid-resistant IPF, said Dr. King. But in a randomized placebo-controlled study of 330 patients with IPF who were corticosteroid nonresponders, there was no benefit among those with severe disease. However, interferon-gamma treatment had a greater impact on survival in patients with less severe lung-function impairment.

… SOMETIMES THEY DO

“Corticosteroids seem to make a difference,” countered Dr. Raghu, a Professor of Medicine (Pulmonary/Critical Care) at the University of Washington in Seattle. In 1982, Dr. Raghu and colleagues began a randomized, double-blind, placebo-controlled trial in 27 patients with newly diagnosed IPF.[5] No patient had ever received corticosteroids. Group 1 received prednisone plus placebo; group 2 was given prednisone plus azathioprine. The prednisone dosage was identical in both groups (10 to 20 mg/d). The primary end point was survival at five years, and the secondary end point was a measurable change in any lung function test at one year.

Patients were followed for a mean of nine years. There was no significant difference in lung function at one year, and no difference in survival was seen at that time. After one year, however, survival was improved in group 2, showing a marginally significant survival advantage with combined therapy.

No additional studies of this combined regimen have been published. Thus, it is still unclear whether both groups benefited from the corticosteroids or whether azathioprine truly has additive value. In the absence of evidence, clinicians can only weigh hypotheses. But given the lack of alternative therapies and the grim prognosis that IPF patients face, corticosteroids are worth considering, Dr. Raghu suggested.

One strong argument for corticosteroid administration, he said, is the difficulty in establishing a diagnosis of IPF. For example, a three-month trial of the drugs can help establish a diagnosis in patients with atypical features of interstitial pneumonia, especially when histologic findings are unavailable or nondiagnostic. “If the patients improve or remain stable, the diagnosis is likely to be NSIP versus UIP. If they deteriorate, the diagnosis is likely to be IPF.”

Another argument for corticosteroid use, Dr. Raghu posited, is that both inflammation and fibrosis are present in IPF patients. Furthermore, both processes are ongoing, although they may vary in intensity, severity, and frequency; therefore, patients’ conditions continue to deteriorate because the injury is still occurring. Cytokines involved with inflammation decrease with the administration of corticosteroids. There is a direct inhibition of agents involved in both the inflammatory response and fibrosis, he said.

A third argument in favor of corticosteroid administration is that IPF does not always occur in isolation. “You can have NSIP and UIP in the same lung,” Dr. Raghu proposed. “IPF is a morphologically heterogeneous disorder,” he said, and it is the NSIP and early UIP components that are responding to treatment (with corticosteroids) and that are blocking the cytokines implicated in the pathogenesis of pulmonary fibrosis.

ACUTE EXACERBATIONS OF IPF

A significant number of IPF patients have acute exacerbations (ie, acute worsening of breathlessness associated with new infiltrates on chest imaging studies). Patients who suffer these acute exacerbations most commonly display diffuse alveolar damage or organizing pneumonia, on top of the UIP pattern. Because many patients die during these episodes, they should receive aggressive treatment with corticosteroids.

For acute exacerbations, Dr. Raghu uses pulsed intravenous methylprednisolone, given as 1 g/d for the first three or four days and then he decreases the dosage to around 40 to 60 mg/d over the next few days. Dr. Raghu stressed that this regimen is based only on anecdotal observations and that there is no evidence specifying a particular dosage.

Drs. King and Raghu agreed that in patients with newly diagnosed IPF, clinicians should discuss the option of lung transplantation and strongly encourage these patients to enter clinical trials. The bottom line is that in IPF/UIP corticosteroids may help—or they may not.

“There is a point in patients with IPF/ UIP where nothing that we currently have will work,” said Dr. King. Therefore, instituting therapy early is important.

—Gale Jurasek

References
1. King TE Jr, Raghu G. Pro/con: Corticosteroids should not be used in the treatment of UIP/IPF. Presented at: annual meeting of the American Thoracic Society; May 18, 2003; Seattle, Wash.
2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med. 2000;161:646-664.
3. Katzenstein AA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157:1301-1315.
4. King TE Jr, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med. 2001;164:1171-1181.
5. Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis. 1991;144:291-296.

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