Emerging Therapies for Interstitial Lung Disease - AJMC.com Managed Markets Network

Emerging Therapies for Interstitial Lung Disease - AJMC.com Managed Markets Network
Targeting CD146-HIF-1α Feedback Signals May Prevent PH Development, Study Suggests - Pulmonary Hypertension News
Cystic fibrosis in children: Causes, symptoms, and treatment - Medical News Today

Posted: 19 Aug 2019 12:00 AM PDT

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 ajmc.com/insights.

OVERVIEW OF INTERSTITIAL LUNG DISEASE

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.

TYPES AND RISKS OF ILD

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.

DIAGNOSIS 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.

Targeting CD146-HIF-1α Feedback Signals May Prevent PH Development, Study Suggests - Pulmonary Hypertension News

Posted: 23 Aug 2019 05:00 AM PDT

Disrupting the vascular remodeling feedback signaling loop mediated by CD146-HIF-1α can effectively prevent the development of pulmonary hypertension (PH) in mice, a study found.

This suggests that medicines that could target CD146-HIF-1α signals may represent a potential strategy to treat pulmonary arterial hypertension (PAH) and other similar disorders in humans, the researchers said.

The study, "CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension," was published in Nature Communications.

PAH is a type of PH that is characterized by the narrowing of the pulmonary arteries. This restricts blood flow through the lungs, and causes blood pressure to rise (hypertension).

The narrowing of arteries is caused by a process called vascular remodeling, which involves thickening of pulmonary arterial walls, increased muscularity, and the uncontrolled growth of pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms of vascular remodeling remain, to some extent, unclear.

In low-oxygen environments (hypoxia), the body naturally constricts the pulmonary arterial walls to better distribute blood flow locally. This increases the efficiency of gas exchange between blood and air. A protein called hypoxia-inducible factor 1-alpha, or HIF-1α, is responsible for activating the genes that regulate this process.

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Chronic hypoxia is known as a cause of vascular remodeling leading to PH, which is accompanied by the aberrant activation of HIF-1α. There is evidence that the activation of this protein is enhanced by an interaction with another protein called CD146, which i is commonly present on the surface of smooth muscle cells (SMCs).

Chinese researchers now investigated the relationship between HIF-1α and CD146. Their focus was uncovering the process of HIF-1α-guided vascular remodeling, which could potentially lead to promising PAH treatment strategies.

First, the investigators demonstrated that increased levels of CD146 protein are associated with the severity of PH development. This was done by examining lung tissue samples over time collected from mice and rats with hypoxia-induced PH. In particular, the protein was found to be mainly present in PASMCs in remodeled pulmonary arterial walls.

Higher CD146 levels also were found to be linked to an increase in right ventricular systolic pressure. CD146 was localized to PASMCs in remodeled pulmonary arteries from PH lung samples.

Next, the team found that hypoxia-induced HIF-1α activation could trigger this increase in CD146 levels in PASMCs. When they exposed human PASMCs to different oxygen levels, the amount of CD146 was found to also rise proportionally to oxygen concentration, in a dose- and time-dependent manner. Indeed, this process was only mediated by HIF-1α. The team showed that HIF-1α was able to directly bind the DNA sequence that controls CD146 protein production.

With further experiments, researchers were able to demonstrate that the accumulation of CD146, in turn, promoted an increase in HIF-1α through a second mediator called NF-κB.

Overall, under a hypoxia status, CD146 and HIF-1α could cross-regulate each other through a feedback loop. An increase in HIF-1α led to more CD146, which generated more HIF-1α, and so on, contributing to impaired response of PASMCs and vasculature remodeling.

Expanding on these results, the team showed that disrupting CD146-HIF-1α signals in SMCs — by genetically preventing CD146 production — would inhibit the process of pulmonary vascular remodeling in mice. Consistently, the mice that were lacking CD146 also showed reduced amounts of HIF-1α in their lungs. These results confirm that CD146 is essential for the activity of HIF-1α that is responsible for vascular remodeling.

Finally, when the team treated PH mice with an antibody that blocks CD146 activity, the animals were protected from vascular remodeling when exposed to chronic hypoxia. These animals showed improved lung function, reduced vascular wall thickness and muscularization, and improved cardiac function in comparison with untreated mice with hypoxia-induced PH.

All of these results together strongly suggest that targeting the cross-regulation feedback loop of CD146-HIF-1α represents a possible strategy for the treatment of PH by directly reducing the effects of vascular remodeling.

The researchers expand on this conclusion.

"Our study reveals a causative role of CD146-HIF-1α axis in pulmonary vascular remodeling. From a clinical perspective, our findings should greatly facilitate the development of potential anti-remodeling therapies for PH, and perhaps other vascular remodeling disorders," the said.

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Cystic fibrosis in children: Causes, symptoms, and treatment - Medical News Today

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