Exploring Key Unmet Needs in Idiopathic Pulmonary Fibrosis

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Noble is a pulmonologist at Cedars-Sinai iand chief of its lung institute. Frohna is the chief medical officer of Endeavor BioMedicines, a company developing therapies for fibrotic disease and cancer. Their wide-ranging discussion of idiopathic pulmonary fibrosis (IPF) covered diagnosis and treatment and differences between IPF and progressive pulmonary fibrosis.

Presenting symptoms
and epidemiology

The presenting symptoms with IPF and PPF are remarkably similar, said Noble, and the two main ones are exertional breathlessness and a dry, hacking cough. “Not all patients have it, but it is a symptom that can bring them to medical attention,” he noted. Older people may sometimes chalk up the exertional breathlessness from IPF and PPF to getting older, Noble said. “Perhaps they’ve retired recently. They’re a bit out of shape,” he said. “They attribute that breathlessness with exertion, particularly going upstairs. ‘Who doesn’t get short of breath when you go upstairs?’ ” But that belief can lead to a delay in diagnosis, Noble noted. Similarly, many older people have heart disease, so general practitioners are likely to consider heart disease before IPF and PPF.

Most patients are older than 65 when they are diagnosed, and that is especially true for IPF, Noble said. “It’s essentially a disease of aging,” he observed, noting that that patients younger than 50 are rare and have a familial form of the disease. Men are affected more often than women for reasons that are not completely understood; Noble said up to 75% of IPD patients are men. The disease also disproportionately affects White individuals, he said.

Most patients have smoked in the past, although Noble said in his experience, very few are current smokers. Exposure to the particulate matter found in urban environments also leads to the development of IPF, Noble said, while PPF generally occurs in the setting of an autoimmune disease. Noble said there is a “genetic underpinning” to many cases of IPF and that mutations in the telomerase genes have been associated with IPF.

Differences between IFP and PPF

PPF can stem from a number of autoimmune diseases, classically rheumatoid arthritis, but also mixed connective tissue disease, scleroderma, Sjogren’s syndrome and antisynthetase syndrome. PPF typically has a more indolent course than IFP. Intervention prior to use of an antifibrotic drug often can slow the course of the disease and sometimes even improve the patient’s condition, according to Noble. As a result, the mortality rate is much better for PPF than it is for IPF, Noble said. But as PPF gets worse, it can start to behave clinically like IPF, he said, and those PPF patients will need a lung transplant. Between one-quarter and one-third of patients with PPF will eventually need a lung transplant, according to Noble.

Noble said it is important to distinguish IPF from PPF, partly because cytotoxic agents such as azathioprine, an immunosuppressive agent that is sometimes used to treat rheumatoid arthritis, can do more harm than good in patients with IPF while judicious use of immunosuppression can be effective in patients with rheumatoid arthritis with pulmonary fibrosis, he said.

Diagnosis

IPF is, ultimately, a diagnosis of exclusion, Noble said. PPF and chronic hypersensitivity pneumonitis need to be ruled out. Chronic hypersensitivity pneumonitis is caused by exposure to pet birds, mold and down feathers. Noble said there are also some medications that can cause pulmonary fibrosis, including nitrofurantoin used to treat urinary tract infections, and amiodarone, used to treat ventricular arrhythmia. High-resolution chest CT scans are very helpful in making a diagnosis. Sometimes the high-resolution scans are done for other reasons and show peripheral and reticular opacities. Noble said the IPF diagnosis can be made when a scan shows a pattern of traction bronchiectasis, which pulmonologists sometimes call honeycomb changes, in the absence of another explanation for the changes in the lungs.

Prognosis and chances of needing a
lung transplant

The gender-age-physiology (GAP) index developed at the University of California, San Francisco, is helpful in assessing a patient and making a prognosis, Noble said. “When patients come to me, they all want to know one thing. ‘What’s going to happen: What does the future hold?’ ” Noble said. The GAP is a composite score that includes measures of lung function such as forced vital capacity as well as results of the 6-minute walk test and pulse oximetry.

Noble says that if patients’ forced vital capacity and results of their 6-minute walk test remain stable and, more importantly, if their oxygen saturation with exertion remains above 88%, “that is a very good prognostic factor that you won’t need to go for a lung transplant.”

Acute exacerbations

When a patient experiences an abrupt change in symptoms — they are much more breathless on exertion; they are coughing more; if they’re on oxygen, their oxygen saturation drops — they should be seen by a pulmonologist on an urgent basis, Noble said. “A diagnosis of acute exacerbation in patients with IPF or PPF is very concerning because patients can progress to the point of respiratory failure, and sometimes patients succumb,” he said. Common respiratory infections, such as the flu or COVID-19, can also cause worsening of symptoms. A high-resolution CT scan helps a pulmonologist sift through possible causes and arrive at a diagnosis, said Noble, who mentioned that bronchoalveolar lavage can also aid in diagnosis.

Noble said that treatment of acute exacerbations is “not well established.” Once an infection is excluded, patients will typically be treated with oral prednisone. Patients who are more ill may be treated with intravenous steroids. Frohna mentioned that some patients are also treated with cyclosporine or cyclophosphamide.

Getting evaluated for a lung transplant may also be appropriate for some patients, Noble said, so if they are a transplant candidate, they are “plugged into a lung transplant program.”

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Treatment

Nintedanib, sold as Ofev, and pirfenidone, sold as Esbriet, are antifibrotic agents. They were approved as treatments for IPF in 2014 and have had other indications added since. Frohna noted that because they don’t stabilize the disease but merely slow down its progression, “it is paramount to get the patient started on one of these agents as soon as possible.”

If a patient doesn’t tolerate one of them, then clinicians will switch the patient to the other one. Frohna said some centers are looking at using them in combination. There is also a push, he said, to research whether nintedanib might be effective in only some subtypes of PPF.Side effects are a problem with both agents, observed Frohna. Up to one-third of patients stop taking them because of their side effects, he said.

Partly for that reason, drug developers are working to find other IPF and PFF treatment drugs, and Frohna said several are in late-stage trials. But IPF drug developmenthas suffered setbacks in recent years with several promising candidates faltering in later stage trials.

Multidisciplinary approach

Patients with IPF or PFF often have other conditions that need treatment and management, Frohna said, so it is best to take a multidisciplinary approach to their care. Some of the other conditions include obesity, high blood pressure, diabetes and sleep apnea, he said.

Pulmonary fibrosis can tip people into depression, Frohna noted. “People become isolated. They don’t do or aren’t able to do the things that they previously enjoyed. They’re not as social. They’re not as mobile,” he said. Many people have gastroesophageal reflux disease that can be treated with antacids or proton pump inhibitors.

Clinicians also need to consider a variety of nonpharmacologic approaches, ranging from support groups to pulmonary training that can help with breathing to advice on weight management, Frohna said.