Unraveling Idiopathic Pulmonary Fibrosis


Vol. 16 •Issue 10 • Page 52
Unraveling Idiopathic Pulmonary Fibrosis

Interest in IPF grows as mortality rates climb.

“I can’t ride my bike around campus for that long anymore,” the college student told Mary Armanios, MD, an oncologist at Johns Hopkins University, Baltimore.

Little did Dr. Armanios know that this statement would lead her to unearth an important clue about a mysterious and fatal disease affecting 200,000 people in the U.S. The student had been seeing Armanios for aplastic anemia, which he developed at age nine. A CT scan revealed net-like white lines in his lower lungs — the classic scarring pattern of idiopathic pulmonary fibrosis.

IPF causes a hardening and deterioration of the lungs. In severe cases, the scarring can appear in chest scans as a honeycombing pattern. Symptoms include shortness of breath, a chronic dry and hacking cough, fatigue, weakness, discomfort in the chest, loss of appetite, and rapid weight loss.

Ten years ago, physicians hardly had a definition for the strange honeycombing phenomenon. Theories since focused on IPF as a chronic inflammatory disease, but most anti-inflammatory drugs aren’t effective at treating IPF.

Now that researchers are beginning to understand this disease, there’s more urgency than ever to develop a cure. Most patients only live for four to six years after diagnosis. Researchers are testing novel treatments, from thalidomide to Viagra to stem cells. Growing evidence suggests a genetic link.

Dr. Armanios suspected the student’s anemia and IPF were part of a hereditary syndrome called dyskeratosis congenita. IPF is the second-most common cause of death among patients with dyskeratosis congenita.

Tests revealed, in fact, that the young man harbored the same genetic mutation associated with the syndrome. As she pondered her young patient, Dr. Armanios wondered whether the potential for developing IPF could be written in his DNA.

Gene theory

To confirm her hypothesis, Dr. Armanios studied the DNA from 73 IPF patients with a family history of the disease. Vanderbilt University’s Familial IPF Registry, Nashville, Tenn., supplied the DNA.

Six of the IPF patients had mutations in the genes of their DNA that regulate the length of each chromosome. These lengtheners, called telomeres, cap the ends of each chromosome like the aglets of a shoelace. Without them, DNA strands would become shorter and shorter with each cell division, causing them to lose genetic information and eventually self-destruct. Mutant alleles can make this happen sooner.

The oncologist examined the family trees of each of the six people with mutant alleles to determine the inheritance patterns of IPF. Nineteen relatives were confirmed to have IPF, eight of whom carried mutant alleles.

Dr. Armanios also found seven people carried the mutation but displayed no symptoms of IPF. These people typically were 11 years younger than their relatives with IPF at the time of diagnosis. Dr. Armanios plans to follow up with the asymptomatic relatives to see if they develop IPF as they age.

The genetic mutation itself doesn’t cause IPF, Dr. Armanios said. Rather, the shortened telomeres resulting from the mutation cause lung deterioration. This distinction is important when considering how lifestyle affects a person’s genetic predisposition to the disease.

Dr. Armanios also plans to explore the effect of smoking on telomere length. Smoking causes damage to cells, provoking them to divide more often; therefore, smokers who have the mutant alleles may develop IPF earlier.

“We’re born with a finite number of cell divisions,” she said. “If you smoke, you might exhaust your cells’ capacity to divide earlier.”

The New England Journal of Medicine published her findings in March.1 Researchers from the University of Texas Southwestern Medical Center came up with similar findings a month later.

“We hope that, with this genetic clue, we can try to come up with more clever therapies that are targeted to the defects,” Dr. Armanios said.

First-rate team

But developing this type of therapy is a long way off. There still are no Food and Drug Administration-approved treatments on the market specifically for IPF. As physicians grapple with the trial-and-error therapies available today, a nationwide research consortium is exploring a combination of drugs they hope will take the guesswork out of the fatal lung disease.

The National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), established the IPF Network in 2005. Physicians in 12 states will conduct Phase III clinical trials for IPF treatments. The network will receive $37.5 million in NIH funding through 2010.

“When you put all those guys in the same room, you come up with probably the best strategies to tackle each problem,” said participant Joao de Andrade, MD, University of Alabama, Birmingham. “But you have 30 pulmonologists with very strong opinions. So it’s sometimes hard to conciliate that.”

The physicians were able to agree on the designs of two upcoming clinical trials, thanks to a moderator whose job is to keep members on task during meetings and teleconferences.

Phase III trials

The PANTHER study for patients in the early stage of the disease will compare three commonly prescribed medications for treating IPF against a placebo. The drugs include prednisone, azathioprine, and N-acetylcysteine. Clinicians have never compared these drugs against a placebo before, said James Kiley, PhD, MS, director of the Division of Lung Diseases at the NHLBI.

Roughly 400 randomized patients will be treated for 60 weeks. Patients will be divided into three categories: those who take N-acetylcysteine only, those who take a combination of all three drugs, and those who take the placebo.

The STEP trial will evaluate the effectiveness of sildenafil citrate on patients with late-stage IPF. The study will last six months and already has begun in at least one university.

“They’re high-profile studies,” Dr. Kiley said. “They should influence practice.”

With NIH funding, investigators are free to explore the drug combinations without bias or pressure from pharmaceutical companies, said James E. Loyd, MD, Vanderbilt. NIH funding also makes it possible for researchers to study rare diseases such as IPF. Pharmaceutical companies that make widely prescribed and inexpensive drugs have little incentive to develop drugs for rare diseases, Dr. Loyd said.

Each site receives money based on how many patients it recruits, which serves as a built-in incentive for centers to meet recruitment goals, Dr. Kiley said. Centers are expected to contribute 20 to 30 patients for study.

As the IPF Network begins its first two trials, members are brainstorming a third study, possibly involving anticoagulants. Research has shown that damaged alveolar tissue creates a pro-clotting environment in the lungs of IPF patients.

“The clots are part of the scaffolding where fibroblasts can come and start producing collagen and eventually produce fibrosis of the lungs,” Dr. de Andrade said.

Stem cells

In still another pocket of IPF research, scientists from the University of Vermont, Burlington, are investigating whether stem cells can help regenerate lung tissue in IPF patients, according to Michael Rosenzweig, PhD, president and CEO of the Pulmonary Fibrosis Foundation, Chicago.

The foundation will partially fund the study, which will be performed on mice first. Baltimore-based Orisis Therapeutics has donated stem cells to the University of Vermont researchers, Dr. Rosenzweig said.

Stem cells have been used to regrow heart tissue. Physicians inject the cells in the groin with a stent, after which the stem cells migrate to the heart. To apply this process to the lungs, researchers first need to find an entryway to the lungs.

Scar tissue can’t be removed from the lungs, Dr. Rosenzweig said. “But by building new, healthy lung tissue, we can increase the viability of the lung and make it function better,” he said.

Chilling results

This year saw some exciting strides forward in IPF research. But patients felt a blow in March when drug maker InterMune abandoned its efforts to develop a treatment widely prescribed off-label for the lung disease. The company stopped its 826-subject trial of Actimmune after an interim analysis revealed the drug doesn’t prolong patients’ lives.

The FDA-approved Actimmune, a bioengineered form of interferon gamma, is used to treat chronic granulomatous disease and malignant osteopetrosis. But the drug was never OK’d to treat IPF. Still, physicians prescribed the drug off-label because it appeared to block scar formation in the lungs.

“We are in desperate need of something that treats this disease,” Dr. de Andrade said. “It was a setback.”

The results were chilling for the IPF community. Still, the information has been slow to reach some patients.

“Every once in a while, you’ll see a patient who still wants interferons as a possible therapy,” Dr. de Andrade said.

Other therapies for IPF include oxygen therapy, antibiotics for infection, corticosteroids such as prednisone, and some heart failure drugs. Lung transplants are an option, but few patients qualify, often because they’re too sick, according to Teresa Geiger, vice president of patient outreach and advocacy for the Coalition for Pulmonary Fibrosis, San Jose, Calif. Also complicating lung transplants, IPF patients on waiting lists can suffer dramatic turns for the worse in a period of three to six weeks.

“A transplant isn’t the answer,” Geiger said.

Elusive answers

With few answers, one thing is for certain: the growing body of IPF research has increased awareness among physicians.

“I’m getting more patients that have had the appropriate workup,” Dr. de Andrade said. “They come to me often times with diagnoses already. This didn’t happen in the past.”

A recent study by researchers from the National Jewish Medical and Research Center and the University of Colorado Health Sciences Center reflected this trend. IPF mortality rates have climbed steadily in recent years, according to the authors. One reason is that physicians are diagnosing patients with IPF more often.

The overall IPF mortality rate in 2003 was 50.8 per 1,000,000 people, accounting for 15,000 IPF deaths per year, and these numbers are expected to keep rising.2

For a list of references, look under the “From Print” toolbar on the left side of our home page at www.advanceweb.com/respmanager.

Lauren Meade is assistant editor of ADVANCE. She can be reached at lmeade@merion.com.

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