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Emerging Therapies for Interstitial Lung Disease

Emerging Therapies for Interstitial Lung Disease

Interstitial lung disease (ILD) encompasses a wide range of conditions and has significant direct and indirect costs for patients, insurance payers, and society. Although new drugs that reduce the progression of fibrosis have been developed for ILD with a progressive fibrotic phenotype, more work is needed to find therapies that abrogate the fibrotic process and treat patients with autoimmune-related ILD that does not respond to immunosuppressant drugs. This article discusses the risk factors, comorbidities, diagnosis, economic burden, and treatments for ILD, with a focus on progressive fibrosing and systemic sclerosis–related subtypes, based on recent Insights video interviews with Alicia M. Hinze, MD; Lisa H. Lancaster, MD; and Gary L. Johnson, MD, MBA. To watch the full interviews, visit

Interstitial lung disease (ILD) encompasses over 200 conditions and involves scarring or inflammation in a space (or potential space) between alveoli and capillaries or blood vessels, a unique area important for gas exchange and oxygenation, according to Lisa H. Lancaster, MD. She noted that ILD appears to have become more prevalent with time, although this increase may be in part related to improved diagnostic methods, such as imaging, that identify more subtle interstitial changes.

Lancaster also noted that because ILD includes a wide range of conditions, diagnosis of the particular type of ILD focuses on evaluation of the patient’s personal and family history, physical examination, laboratory testing, and imaging. Most cases of ILD are characterized by respiratory symptoms (eg, cough and dyspnea), specific abnormalities on chest radiography, typical changes on pulmonary function tests that would indicate decrease in lung volume, and microscopic patterns characteristic of inflammation and fibrosis.1 Lancaster noted that causes of ILD vary and include occupational and environmental factors, medications, medical conditions (particularly autoimmune conditions), and genetic propensity.

Alicia M. Hinze, MD, noted that rheumatologists may see patients with ILD to determine if an autoimmune disease is the underlying cause. “Sometimes they will [see a rheumatologist] in the setting of having some positive autoantibodies, and the rheumatologist is, again, asked to determine whether there may be an underlying autoimmune disease that may be driving some of the ILD process,” Hinze said. “This is particularly important as there are some patients [who] may have a pattern of disease that we call ‘nonspecific interstitial pneumonitis.’ And these patients, if it’s in the context of an autoimmune disease, may respond to immunosuppressant therapies.”

Lancaster added that pulmonologists are key and central figures in the management and diagnosis of ILD but pointed out that primary care physicians may be the first healthcare providers to diagnose ILD and coordinate care with local pulmonologists or an ILD center.


The different diagnoses and diseases categorized as ILD can make diagnosis challenging. Lancaster noted. “Some [patients] may have a mixture of inflammation coupled with fibrosis, and so teasing out that diagnosis is important.”

According to Lancaster, experts have begun to identify a progressive fibrotic phenotype, called progressive fibrosing–interstitial lung disease (PF-ILD; also called fibrosing-interstitial lung disease with progressive phenotype). Although idiopathic pulmonary fibrosis (IPF) is the classic example of PF-ILD, it characterizes multiple types of ILD with fibrosis, said Lancaster and Hinze.

“We are beginning to think [about PF-ILD] more categorically as a group rather than in specifics,” Lancaster explained. “[For example,] how do we treat that progressive fibrotic disease? Are the pathways that get to that progressive fibrotic disease similar enough that we can use similar antifibrotic therapies for their management?”

Hinze added that some patients with ILD related to systemic sclerosis have a progressive fibrotic phenotype, and this subset of patients will show progressive fibrosis on high-resolution computed tomography (CT) and pulmonary function testing that indicates increasing restrictive lung disease.

“Systemic sclerosis with ILD can change by definition,” Hinze said. “If [we] look strictly at whether there is ILD by high-resolution CT, we can see that there may be some bibasilar interstitial changes on high-res [resolution] CT in about 65% to 90% of patients, depending on the subset of patients that we’re looking at. However, not all ILD is going to progress to [cause] physiologic changes. There are patients in whom we can see a little bit of bibasilar interstitial fibrosis, but we may not see any changes on pulmonary function testing. Pulmonary function testing is really helping us understand what physiologic lung changes are being caused by the actual fibrosis itself.”

Risk factors associated with ILD include older age, exposure to environmental toxins (eg, asbestos, silica, or dust from metal and wood), farmer’s lung, gastroesophageal reflux disease (GERD), smoking history, radiation, and chemotherapy.1 Hinze noted that several autoimmune diseases are also associated with ILD, including scleroderma, rheumatoid arthritis, dermatomyositis, antisynthetase syndrome, Sjögren’s syndrome, and occasionally lupus. “There are some patients who have overlapping phenotypes where they do not fit into a specific category, but they may have overlapping features that can also develop [into] ILD,” Hinze explained.

Lancaster noted that many comorbidities are associated with ILD, typically pulmonary hypertension, coronary artery disease, GERD, and obstructive sleep apnea. Although obstructive sleep apnea has long been identified as a comorbidity in chronic obstructive pulmonary disease (COPD), Lancaster said that its high frequency in patients with lung disease, particularly IPF, has become increasingly recognized.

“Assessing sleep in patients with IPF is important because we’re assessing their breathing during one-third of their day,” Lancaster said. She estimated that 50% to 88% of patients with IPF have obstructive sleep apnea and suggested that the associated oxygen desaturations may be proinflammatory and profibrotic, although she stated that further study is needed to elucidate the relationship between obstructive sleep apnea and the development of IPF or other progressive fibrotic phenotypes of ILD.


Because ILD encompasses over 200 diseases, the differential diagnosis similarly varies broadly and relies on a good history of environmental exposures and any signs or symptoms that may corroborate autoimmune disease, said Hinze. “When talking to patients who may be found to have ILD on high-res [resolution] CT or who were presenting with symptoms of shortness of breath and found to have ILD, we will go through a detailed history all the way back to whether they may have [had] any exposure, such as coal, or whether they have a pet bird at home,” Hinze said.

To evaluate for autoimmune diseases that may be driving ILD, Hinze often asks patients whether they have color changes in their fingers in response to cold (a possible sign of Raynaud’s syndrome), stiffness in their joints in the morning (which may indicate inflammatory arthritis), or skin changes such as rashes or skin thickening (which may indicate systemic sclerosis).

Regarding diagnostic tools, Hinze identified high-resolution CT as the optimal modality for visual evaluation and pulmonary function testing for identifying reductions in forced vital capacity (FVC) and diffusing capacity for carbon dioxide and evaluating for clinically relevant reductions in lung function with ILD. “The high-resolution CT and pulmonary function testing [are] the key features that we use in terms of examination and imaging parameters and procedures to define the level of ILD and how it’s affecting the patient,” Hinze explained.

However, she noted that these findings must be looked at in context with other symptoms the patient may be experiencing as underlying pulmonary hypertension can also lead to a reduction in diffusing capacity for carbon dioxide. “It’s a complex evaluation. We use first, a clinical examination, [and] second, patient history of dyspnea,” Hinze added.

Gary L. Johnson, MD, MBA, shared that the focus of insurance payers in cost management for ILD is on management of pharmaceuticals, and they generally do not have specified algorithms for diagnostic criteria or preferences for a workup. “We leave that pretty much entirely up to the practicing physician,” he said.

According to Hinze, the point at which patients seek care varies greatly. Some patients seek care when they experience shortness of breath, and subsequent lung function tests or imaging show abnormalities suggestive of ILD. “If they’re presenting with dyspnea, these patients will often then go see a pulmonologist who will further evaluate the ILD and potential drivers,” she said.

Alternatively, she said that some patients present with signs of autoimmune disease which then prompts a workup for ILD based on their risk factors. “With scleroderma, for example, there are certain subsets [of patients] who are more at risk for ILD,” she said. “In subsets in which I know clinically, or by laboratory, that they are at higher risk for ILD, I may go looking more intently for it in order to detect it so that we may better monitor it over time to determine [the] need for treatment.”

Hinze added that a multidisciplinary approach is essential for diagnosis and treatment of ILD, particularly for patients with ILD related to autoimmune disease. “The pulmonologist and the rheumatologist work together closely because the rheumatologist also assesses other features of autoimmune disease that may also require treatment, such as immunosuppression therapies,” she said. “We want to ensure that not only is the patient’s lung disease being treated and managed, but also that we are addressing other features of the autoimmune disease that may require immunosuppression.”

She also stated that the severity of ILD varies widely. Some patients with scleroderma have radiographic evidence of ILD with normal pulmonary function tests and minimal symptoms, while others have mild dyspnea and slight changes in lung function that can be monitored before implementing immunosuppressive therapies. For patients who have scleroderma-associated ILD that progresses quickly, however, Hinze said that prompt therapeutic intervention is warranted. “[We] try to assess where the patient is at, the level of symptoms that they are having, and the timing of when it is best to implement therapies,” she said.

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