Corey D. Kershaw, MD, FCCP

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.