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MAUI, HAWAII – The latest practice guidelines on the diagnosis of interstitial lung disease issued by the American Thoracic Society and allied organizations recommend as the standard of care a review of all cases by a multidisciplinary team consisting of a pulmonologist, radiologist, and pathologist to ensure accurate diagnosis and classification.
That’s not good enough. A rheumatologist needs to routinely be involved in those multidisciplinary discussions as well, Aryeh Fischer, MD, asserted at the 2019 Rheumatology Winter Clinical Symposium.
Why? Because a rheumatologist’s input often leads to a change in diagnosis. And that change can have important prognostic and therapeutic implications.
“We want to distinguish the IPF [idiopathic pulmonary fibrosis] patients from everybody else. The most important thing with regards to therapy is to identify the IPF patient. The IPF patients are the only ones who are able to be treated with antifibrotic agents: pirfenidone or nintedanib. And we know that immunosuppression can make patients with IPF worse; their risks of hospitalization and mortality are higher on immunosuppression. But everybody else, including anyone with any of the autoimmune diseases along with ILD [interstitial lung disease] or any other causes of ILD, gets treated with immunosuppression,” explained Dr. Fischer, a rheumatologist with a special interest in autoimmune lung disease at the University of Colorado, Denver.
He cited a recent prospective blinded study in which 60 newly diagnosed ILD patients were evaluated separately by a multidisciplinary team comprising a pulmonologist, radiologist, and pathologist and once again with the involvement of a rheumatologist. The rheumatologic assessment reclassified 21% of patients from IPF – that is, lung disease unrelated to connective tissue disease (CTD) or exposure to asbestos, bird droppings, or other triggers – to ILD with connective tissue disease (CTD-ILD). And the number of patients classified as having ILD with autoimmune features without meeting full diagnostic criteria for a major CTD, a category that includes antisynthetase syndrome and IgG4-related ILD, jumped by 77%. Also, the investigators determined that adding a rheumatologist to the multidisciplinary team would have resulted in seven fewer bronchoscopies and one less surgical biopsy among this 60-patient cohort (J Rheumatol. 2018 Nov;45[11]:1509-14).
It’s not at all uncommon to identify a new occult CTD in patients presenting with ILD. Dr. Fischer noted that in a series of 114 consecutive patients evaluated at the interdisciplinary ILD program at Johns Hopkins University, Baltimore, 30% of them had a well-defined CTD, half of whom, or 15% of the total, were newly diagnosed with CTD by virtue of their ILD evaluation (Respir Med. 2009 Aug;103[8]:1152-8).
A CTD-ILD diagnosis has prognostic implications: Survival is significantly better than with IPF, with the exception of ILD with rheumatoid arthritis (RA-ILD), where the prognosis seems to be worse than for other forms of CTD-ILD and is more akin to that of IPF. Indeed, the risk of death is threefold higher in patients with RA-ILD than in those with RA without ILD. While the predominant pattern of lung injury in RA-ILD is usual interstitial pneumonia, marked by fibrosis and honeycombing, the predominant pattern in all other forms of CTD-ILD is nonspecific interstitial pneumonia.
A French study of 778 consecutive patients with ILD highlighted how common autoimmune disease is in the ILD population. Nearly one-third of the ILD patients had autoimmune disease: 22% had CTD-ILD and another 7% had interstitial pneumonia with autoimmune features, or IPAF (Respir Med. 2017 Feb;123:56-62).
Dr. Fischer was lead author of a report by a European Respiratory Society/American Thoracic Society task force that first put forth the term IPAF to describe ILD patients with subtle serologic, clinical, and/or morphologic findings that don’t rise to the level required for formal diagnosis of a defined CTD (Eur Respir J. 2015 Oct;46[4]:976-87).
IPAF is a research construct. Patients who fall into this category are the focus of ongoing prospective studies aimed at better understanding their prognosis and appropriate treatment.
The big three autoimmune diseases comorbid with ILD as reported by Dr. Fischer and coinvestigators in a study of 237 patients with an autoimmune phenotype in a Denver ILD clinic were scleroderma, present in 37%; rheumatoid arthritis, present in 18%; and myositis, with a prevalence of 11%. Another 24% had IPAF.
“There was surprisingly little SLE [3%], and not much Sjögren’s [6%],” he observed.
When pulmonologists come knocking on Dr. Fischer’s door asking if their patients with ILD have occult CTD, he finds it helpful to look for quantifiable specific extrathoracic features suggestive of rheumatologic disease, such as Raynaud’s, sclerodactyly, mechanic hands, and Gottron’s papules.
The ILD practice guidelines recently issued jointly by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society recommend that serologic evaluation for a long list of autoantibodies “should be performed even in the absence of signs or symptoms of connective tissue disease” (Am J Respir Crit Care Med. 2018 Sep 1;198[5]:e44-e68). Dr. Fischer indicated he has a problem with that recommendation since nonrheumatologists aren’t typically adept in interpreting the significance of autoantibodies.
“I will just tell you, I see a lot of patients for ILD evaluation, and autoimmune serologies often lead to more questions than answers. They always need to be considered within the clinical context,” the rheumatologist said.
High-resolution CT (HRCT) is the imaging method of choice for detecting ILD and classifying its severity. HRCT also holds clues for detection of CTD-ILD.
“There are no upper lung–predominant ILDs that really make you think CTD. Our diseases like the lower lung zones. We like to see multicompartment involvement. When you hear ‘airways and parenchymal,’ ‘pleural,’ ‘pericardial thickening,’ that sounds a lot like autoimmune disease,” according to Dr. Fischer.
Also, the presence of a dilated esophagus on HRCT is strongly suggestive of scleroderma, he added.
In the event a pathology report is available, it’s important to read the fine print. Secondary histopathologic features of CTD-ILD include extensive pleuritis, lymphoid aggregates with germinal center formation, dense perivascular collagen, and/or prominent plasmacytic infiltration.
While ILD can be the first manifestation of an underlying occult CTD, it’s also common for a patient with an established CTD to subsequently develop ILD.
Rheumatologists are no strangers to ambiguity, so it should come as no surprise that while audible bibasilar crackles on physical examination are strongly predictive of ILD, their absence doesn’t indicate absence of ILD. Similarly, dyspnea in a patient with established CTD can be tough to interpret, and absence of dyspnea doesn’t imply absence of ILD. If a patient with CTD is on immunosuppressive therapy, bronchoalveolar lavage is of value in ruling out infection.
When to order a surgical lung biopsy
“If you’re pretty sure your patient had a CTD and then you get a characteristic HRCT and there are no exposures to account for the imaging findings – if we have a scenario where it all fits – we often don’t biopsy. Biopsy usually means a 2-night hospital stay, and it’s reportedly associated with about a 1% mortality risk. And the clinical reality is the biopsy may not impact treatment. They’re going to give you azathioprine, mycophenolate, cyclophosphamide, or prednisone for the ILD and the extrathoracic disease irrespective of the ILD pattern,” the rheumatologist said.
He reserves surgical biopsy for patients with an atypical HRCT, those with known CTD and a possible alternative etiology for the ILD, such as exposure to asbestos or owning pet birds, and patients where he’s just not sure a CTD is actually present.
Treatment of CTD-ILD
“The available controlled efficacy data are limited to scleroderma-ILD, where cyclophosphamide and mycophenolate work a little bit. And that’s it. We don’t have good data to guide us on which agent for which CTD or ILD pattern, for how long, or what dose,” Dr. Fischer said. “We have good drugs for the joints, nothing for the lungs. Treatment is not evidence based. We initiate with high-dose steroids, switch to a steroid-sparing agent, we evaluate the response to treatment with surveillance every 3-6 months by 6-minute walking, lung function tests, and sometimes imaging, and we treat for a long time. Oftentimes stability equals success.”
That being said, it must be emphasized that not all CTD-ILD warrants treatment of the pulmonary disease. If the patient’s ILD is mild and indolent, clinical surveillance is often appropriate, he continued.
More important than the pharmacotherapy available at present are adjunctive nonpharmacologic approaches: supplemental oxygen, pulmonary rehabilitation, treatment of comorbid GERD, immunizations, and addressing mental health issues related to these devastating diseases.
“We really don’t do these things well,” Dr. Fischer said.
On the horizon
An investigator-driven phase 2 clinical trial of the antifibrotic drug pirfenidone (Esbriet), now approved for IPF, is underway in patients with RA-ILD. Results of a trial of antifibrotic therapy in patients with scleroderma-ILD are due to be presented this year at EULAR. And a small study of antifibrotic therapy in patients with myositis-ILD is ongoing.
As for the biologics, there is a signal in the literature that tumor necrosis factor inhibitors may be associated with increased risk of rapidly progressive lung disease in patients with RA-ILD. An influential report from the British Society for Rheumatology Biologics Register on 299 patients with preexisting RA-ILD treated with anti-TNF therapy and 68 who received traditional disease-modifying antirrheumatic drugs showed that while mortality during follow-up was similar in the two groups, the proportion of deaths attributed to RA-ILD was 21% in the group on anti-TNF therapy, compared with only 7% in those on traditional DMARDs (Ann Rheum Dis. 2010 Jun;69[6]:1086-91).
Paul Emery, MD, rose from the audience at Dr. Fischer’s request to share his extensive experience with anti-TNF therapy and rituximab (Rituxan) in the setting of RA-ILD. When he was involved in several of the pivotal clinical trials of anti-TNF agents for RA he encountered a couple of cases of rapidly progressive ILD in patients on treatment.
“We had never before seen rapidly progressive ILD that didn’t respond to cyclophosphamide. Both patients died,” recalled Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
“Our experience is if you’ve got mild ILD – and if you look hard enough you can find it in many rheumatoids – TNF inhibitor therapy doesn’t affect it. But if there’s any hint of deterioration we move away from anti-TNF therapy. Our preference has been for rituximab,” he said.
Dr. Emery was senior author of the largest study to date of rituximab in patients with RA-ILD (Rheumatology [Oxford]. 2017 Aug 1;56[8]:1348-57). While he and his coinvestigators concluded that rituximab “appears to be an acceptable therapeutic choice for patients with RA-ILD,” Dr. Fischer didn’t find persuasive evidence from this relatively small retrospective observational study in which only 44 patients had lung data available.
“My own conclusion is evidence is lacking to support a role of rituximab for treating ILD in RA,” Dr. Fischer said.
He reported receiving research grants from Boehringer-Ingelheim and Corbus and serving as a consultant to a handful of other pharmaceutical companies.
MAUI, HAWAII – The latest practice guidelines on the diagnosis of interstitial lung disease issued by the American Thoracic Society and allied organizations recommend as the standard of care a review of all cases by a multidisciplinary team consisting of a pulmonologist, radiologist, and pathologist to ensure accurate diagnosis and classification.
That’s not good enough. A rheumatologist needs to routinely be involved in those multidisciplinary discussions as well, Aryeh Fischer, MD, asserted at the 2019 Rheumatology Winter Clinical Symposium.
Why? Because a rheumatologist’s input often leads to a change in diagnosis. And that change can have important prognostic and therapeutic implications.
“We want to distinguish the IPF [idiopathic pulmonary fibrosis] patients from everybody else. The most important thing with regards to therapy is to identify the IPF patient. The IPF patients are the only ones who are able to be treated with antifibrotic agents: pirfenidone or nintedanib. And we know that immunosuppression can make patients with IPF worse; their risks of hospitalization and mortality are higher on immunosuppression. But everybody else, including anyone with any of the autoimmune diseases along with ILD [interstitial lung disease] or any other causes of ILD, gets treated with immunosuppression,” explained Dr. Fischer, a rheumatologist with a special interest in autoimmune lung disease at the University of Colorado, Denver.
He cited a recent prospective blinded study in which 60 newly diagnosed ILD patients were evaluated separately by a multidisciplinary team comprising a pulmonologist, radiologist, and pathologist and once again with the involvement of a rheumatologist. The rheumatologic assessment reclassified 21% of patients from IPF – that is, lung disease unrelated to connective tissue disease (CTD) or exposure to asbestos, bird droppings, or other triggers – to ILD with connective tissue disease (CTD-ILD). And the number of patients classified as having ILD with autoimmune features without meeting full diagnostic criteria for a major CTD, a category that includes antisynthetase syndrome and IgG4-related ILD, jumped by 77%. Also, the investigators determined that adding a rheumatologist to the multidisciplinary team would have resulted in seven fewer bronchoscopies and one less surgical biopsy among this 60-patient cohort (J Rheumatol. 2018 Nov;45[11]:1509-14).
It’s not at all uncommon to identify a new occult CTD in patients presenting with ILD. Dr. Fischer noted that in a series of 114 consecutive patients evaluated at the interdisciplinary ILD program at Johns Hopkins University, Baltimore, 30% of them had a well-defined CTD, half of whom, or 15% of the total, were newly diagnosed with CTD by virtue of their ILD evaluation (Respir Med. 2009 Aug;103[8]:1152-8).
A CTD-ILD diagnosis has prognostic implications: Survival is significantly better than with IPF, with the exception of ILD with rheumatoid arthritis (RA-ILD), where the prognosis seems to be worse than for other forms of CTD-ILD and is more akin to that of IPF. Indeed, the risk of death is threefold higher in patients with RA-ILD than in those with RA without ILD. While the predominant pattern of lung injury in RA-ILD is usual interstitial pneumonia, marked by fibrosis and honeycombing, the predominant pattern in all other forms of CTD-ILD is nonspecific interstitial pneumonia.
A French study of 778 consecutive patients with ILD highlighted how common autoimmune disease is in the ILD population. Nearly one-third of the ILD patients had autoimmune disease: 22% had CTD-ILD and another 7% had interstitial pneumonia with autoimmune features, or IPAF (Respir Med. 2017 Feb;123:56-62).
Dr. Fischer was lead author of a report by a European Respiratory Society/American Thoracic Society task force that first put forth the term IPAF to describe ILD patients with subtle serologic, clinical, and/or morphologic findings that don’t rise to the level required for formal diagnosis of a defined CTD (Eur Respir J. 2015 Oct;46[4]:976-87).
IPAF is a research construct. Patients who fall into this category are the focus of ongoing prospective studies aimed at better understanding their prognosis and appropriate treatment.
The big three autoimmune diseases comorbid with ILD as reported by Dr. Fischer and coinvestigators in a study of 237 patients with an autoimmune phenotype in a Denver ILD clinic were scleroderma, present in 37%; rheumatoid arthritis, present in 18%; and myositis, with a prevalence of 11%. Another 24% had IPAF.
“There was surprisingly little SLE [3%], and not much Sjögren’s [6%],” he observed.
When pulmonologists come knocking on Dr. Fischer’s door asking if their patients with ILD have occult CTD, he finds it helpful to look for quantifiable specific extrathoracic features suggestive of rheumatologic disease, such as Raynaud’s, sclerodactyly, mechanic hands, and Gottron’s papules.
The ILD practice guidelines recently issued jointly by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society recommend that serologic evaluation for a long list of autoantibodies “should be performed even in the absence of signs or symptoms of connective tissue disease” (Am J Respir Crit Care Med. 2018 Sep 1;198[5]:e44-e68). Dr. Fischer indicated he has a problem with that recommendation since nonrheumatologists aren’t typically adept in interpreting the significance of autoantibodies.
“I will just tell you, I see a lot of patients for ILD evaluation, and autoimmune serologies often lead to more questions than answers. They always need to be considered within the clinical context,” the rheumatologist said.
High-resolution CT (HRCT) is the imaging method of choice for detecting ILD and classifying its severity. HRCT also holds clues for detection of CTD-ILD.
“There are no upper lung–predominant ILDs that really make you think CTD. Our diseases like the lower lung zones. We like to see multicompartment involvement. When you hear ‘airways and parenchymal,’ ‘pleural,’ ‘pericardial thickening,’ that sounds a lot like autoimmune disease,” according to Dr. Fischer.
Also, the presence of a dilated esophagus on HRCT is strongly suggestive of scleroderma, he added.
In the event a pathology report is available, it’s important to read the fine print. Secondary histopathologic features of CTD-ILD include extensive pleuritis, lymphoid aggregates with germinal center formation, dense perivascular collagen, and/or prominent plasmacytic infiltration.
While ILD can be the first manifestation of an underlying occult CTD, it’s also common for a patient with an established CTD to subsequently develop ILD.
Rheumatologists are no strangers to ambiguity, so it should come as no surprise that while audible bibasilar crackles on physical examination are strongly predictive of ILD, their absence doesn’t indicate absence of ILD. Similarly, dyspnea in a patient with established CTD can be tough to interpret, and absence of dyspnea doesn’t imply absence of ILD. If a patient with CTD is on immunosuppressive therapy, bronchoalveolar lavage is of value in ruling out infection.
When to order a surgical lung biopsy
“If you’re pretty sure your patient had a CTD and then you get a characteristic HRCT and there are no exposures to account for the imaging findings – if we have a scenario where it all fits – we often don’t biopsy. Biopsy usually means a 2-night hospital stay, and it’s reportedly associated with about a 1% mortality risk. And the clinical reality is the biopsy may not impact treatment. They’re going to give you azathioprine, mycophenolate, cyclophosphamide, or prednisone for the ILD and the extrathoracic disease irrespective of the ILD pattern,” the rheumatologist said.
He reserves surgical biopsy for patients with an atypical HRCT, those with known CTD and a possible alternative etiology for the ILD, such as exposure to asbestos or owning pet birds, and patients where he’s just not sure a CTD is actually present.
Treatment of CTD-ILD
“The available controlled efficacy data are limited to scleroderma-ILD, where cyclophosphamide and mycophenolate work a little bit. And that’s it. We don’t have good data to guide us on which agent for which CTD or ILD pattern, for how long, or what dose,” Dr. Fischer said. “We have good drugs for the joints, nothing for the lungs. Treatment is not evidence based. We initiate with high-dose steroids, switch to a steroid-sparing agent, we evaluate the response to treatment with surveillance every 3-6 months by 6-minute walking, lung function tests, and sometimes imaging, and we treat for a long time. Oftentimes stability equals success.”
That being said, it must be emphasized that not all CTD-ILD warrants treatment of the pulmonary disease. If the patient’s ILD is mild and indolent, clinical surveillance is often appropriate, he continued.
More important than the pharmacotherapy available at present are adjunctive nonpharmacologic approaches: supplemental oxygen, pulmonary rehabilitation, treatment of comorbid GERD, immunizations, and addressing mental health issues related to these devastating diseases.
“We really don’t do these things well,” Dr. Fischer said.
On the horizon
An investigator-driven phase 2 clinical trial of the antifibrotic drug pirfenidone (Esbriet), now approved for IPF, is underway in patients with RA-ILD. Results of a trial of antifibrotic therapy in patients with scleroderma-ILD are due to be presented this year at EULAR. And a small study of antifibrotic therapy in patients with myositis-ILD is ongoing.
As for the biologics, there is a signal in the literature that tumor necrosis factor inhibitors may be associated with increased risk of rapidly progressive lung disease in patients with RA-ILD. An influential report from the British Society for Rheumatology Biologics Register on 299 patients with preexisting RA-ILD treated with anti-TNF therapy and 68 who received traditional disease-modifying antirrheumatic drugs showed that while mortality during follow-up was similar in the two groups, the proportion of deaths attributed to RA-ILD was 21% in the group on anti-TNF therapy, compared with only 7% in those on traditional DMARDs (Ann Rheum Dis. 2010 Jun;69[6]:1086-91).
Paul Emery, MD, rose from the audience at Dr. Fischer’s request to share his extensive experience with anti-TNF therapy and rituximab (Rituxan) in the setting of RA-ILD. When he was involved in several of the pivotal clinical trials of anti-TNF agents for RA he encountered a couple of cases of rapidly progressive ILD in patients on treatment.
“We had never before seen rapidly progressive ILD that didn’t respond to cyclophosphamide. Both patients died,” recalled Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
“Our experience is if you’ve got mild ILD – and if you look hard enough you can find it in many rheumatoids – TNF inhibitor therapy doesn’t affect it. But if there’s any hint of deterioration we move away from anti-TNF therapy. Our preference has been for rituximab,” he said.
Dr. Emery was senior author of the largest study to date of rituximab in patients with RA-ILD (Rheumatology [Oxford]. 2017 Aug 1;56[8]:1348-57). While he and his coinvestigators concluded that rituximab “appears to be an acceptable therapeutic choice for patients with RA-ILD,” Dr. Fischer didn’t find persuasive evidence from this relatively small retrospective observational study in which only 44 patients had lung data available.
“My own conclusion is evidence is lacking to support a role of rituximab for treating ILD in RA,” Dr. Fischer said.
He reported receiving research grants from Boehringer-Ingelheim and Corbus and serving as a consultant to a handful of other pharmaceutical companies.
MAUI, HAWAII – The latest practice guidelines on the diagnosis of interstitial lung disease issued by the American Thoracic Society and allied organizations recommend as the standard of care a review of all cases by a multidisciplinary team consisting of a pulmonologist, radiologist, and pathologist to ensure accurate diagnosis and classification.
That’s not good enough. A rheumatologist needs to routinely be involved in those multidisciplinary discussions as well, Aryeh Fischer, MD, asserted at the 2019 Rheumatology Winter Clinical Symposium.
Why? Because a rheumatologist’s input often leads to a change in diagnosis. And that change can have important prognostic and therapeutic implications.
“We want to distinguish the IPF [idiopathic pulmonary fibrosis] patients from everybody else. The most important thing with regards to therapy is to identify the IPF patient. The IPF patients are the only ones who are able to be treated with antifibrotic agents: pirfenidone or nintedanib. And we know that immunosuppression can make patients with IPF worse; their risks of hospitalization and mortality are higher on immunosuppression. But everybody else, including anyone with any of the autoimmune diseases along with ILD [interstitial lung disease] or any other causes of ILD, gets treated with immunosuppression,” explained Dr. Fischer, a rheumatologist with a special interest in autoimmune lung disease at the University of Colorado, Denver.
He cited a recent prospective blinded study in which 60 newly diagnosed ILD patients were evaluated separately by a multidisciplinary team comprising a pulmonologist, radiologist, and pathologist and once again with the involvement of a rheumatologist. The rheumatologic assessment reclassified 21% of patients from IPF – that is, lung disease unrelated to connective tissue disease (CTD) or exposure to asbestos, bird droppings, or other triggers – to ILD with connective tissue disease (CTD-ILD). And the number of patients classified as having ILD with autoimmune features without meeting full diagnostic criteria for a major CTD, a category that includes antisynthetase syndrome and IgG4-related ILD, jumped by 77%. Also, the investigators determined that adding a rheumatologist to the multidisciplinary team would have resulted in seven fewer bronchoscopies and one less surgical biopsy among this 60-patient cohort (J Rheumatol. 2018 Nov;45[11]:1509-14).
It’s not at all uncommon to identify a new occult CTD in patients presenting with ILD. Dr. Fischer noted that in a series of 114 consecutive patients evaluated at the interdisciplinary ILD program at Johns Hopkins University, Baltimore, 30% of them had a well-defined CTD, half of whom, or 15% of the total, were newly diagnosed with CTD by virtue of their ILD evaluation (Respir Med. 2009 Aug;103[8]:1152-8).
A CTD-ILD diagnosis has prognostic implications: Survival is significantly better than with IPF, with the exception of ILD with rheumatoid arthritis (RA-ILD), where the prognosis seems to be worse than for other forms of CTD-ILD and is more akin to that of IPF. Indeed, the risk of death is threefold higher in patients with RA-ILD than in those with RA without ILD. While the predominant pattern of lung injury in RA-ILD is usual interstitial pneumonia, marked by fibrosis and honeycombing, the predominant pattern in all other forms of CTD-ILD is nonspecific interstitial pneumonia.
A French study of 778 consecutive patients with ILD highlighted how common autoimmune disease is in the ILD population. Nearly one-third of the ILD patients had autoimmune disease: 22% had CTD-ILD and another 7% had interstitial pneumonia with autoimmune features, or IPAF (Respir Med. 2017 Feb;123:56-62).
Dr. Fischer was lead author of a report by a European Respiratory Society/American Thoracic Society task force that first put forth the term IPAF to describe ILD patients with subtle serologic, clinical, and/or morphologic findings that don’t rise to the level required for formal diagnosis of a defined CTD (Eur Respir J. 2015 Oct;46[4]:976-87).
IPAF is a research construct. Patients who fall into this category are the focus of ongoing prospective studies aimed at better understanding their prognosis and appropriate treatment.
The big three autoimmune diseases comorbid with ILD as reported by Dr. Fischer and coinvestigators in a study of 237 patients with an autoimmune phenotype in a Denver ILD clinic were scleroderma, present in 37%; rheumatoid arthritis, present in 18%; and myositis, with a prevalence of 11%. Another 24% had IPAF.
“There was surprisingly little SLE [3%], and not much Sjögren’s [6%],” he observed.
When pulmonologists come knocking on Dr. Fischer’s door asking if their patients with ILD have occult CTD, he finds it helpful to look for quantifiable specific extrathoracic features suggestive of rheumatologic disease, such as Raynaud’s, sclerodactyly, mechanic hands, and Gottron’s papules.
The ILD practice guidelines recently issued jointly by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society recommend that serologic evaluation for a long list of autoantibodies “should be performed even in the absence of signs or symptoms of connective tissue disease” (Am J Respir Crit Care Med. 2018 Sep 1;198[5]:e44-e68). Dr. Fischer indicated he has a problem with that recommendation since nonrheumatologists aren’t typically adept in interpreting the significance of autoantibodies.
“I will just tell you, I see a lot of patients for ILD evaluation, and autoimmune serologies often lead to more questions than answers. They always need to be considered within the clinical context,” the rheumatologist said.
High-resolution CT (HRCT) is the imaging method of choice for detecting ILD and classifying its severity. HRCT also holds clues for detection of CTD-ILD.
“There are no upper lung–predominant ILDs that really make you think CTD. Our diseases like the lower lung zones. We like to see multicompartment involvement. When you hear ‘airways and parenchymal,’ ‘pleural,’ ‘pericardial thickening,’ that sounds a lot like autoimmune disease,” according to Dr. Fischer.
Also, the presence of a dilated esophagus on HRCT is strongly suggestive of scleroderma, he added.
In the event a pathology report is available, it’s important to read the fine print. Secondary histopathologic features of CTD-ILD include extensive pleuritis, lymphoid aggregates with germinal center formation, dense perivascular collagen, and/or prominent plasmacytic infiltration.
While ILD can be the first manifestation of an underlying occult CTD, it’s also common for a patient with an established CTD to subsequently develop ILD.
Rheumatologists are no strangers to ambiguity, so it should come as no surprise that while audible bibasilar crackles on physical examination are strongly predictive of ILD, their absence doesn’t indicate absence of ILD. Similarly, dyspnea in a patient with established CTD can be tough to interpret, and absence of dyspnea doesn’t imply absence of ILD. If a patient with CTD is on immunosuppressive therapy, bronchoalveolar lavage is of value in ruling out infection.
When to order a surgical lung biopsy
“If you’re pretty sure your patient had a CTD and then you get a characteristic HRCT and there are no exposures to account for the imaging findings – if we have a scenario where it all fits – we often don’t biopsy. Biopsy usually means a 2-night hospital stay, and it’s reportedly associated with about a 1% mortality risk. And the clinical reality is the biopsy may not impact treatment. They’re going to give you azathioprine, mycophenolate, cyclophosphamide, or prednisone for the ILD and the extrathoracic disease irrespective of the ILD pattern,” the rheumatologist said.
He reserves surgical biopsy for patients with an atypical HRCT, those with known CTD and a possible alternative etiology for the ILD, such as exposure to asbestos or owning pet birds, and patients where he’s just not sure a CTD is actually present.
Treatment of CTD-ILD
“The available controlled efficacy data are limited to scleroderma-ILD, where cyclophosphamide and mycophenolate work a little bit. And that’s it. We don’t have good data to guide us on which agent for which CTD or ILD pattern, for how long, or what dose,” Dr. Fischer said. “We have good drugs for the joints, nothing for the lungs. Treatment is not evidence based. We initiate with high-dose steroids, switch to a steroid-sparing agent, we evaluate the response to treatment with surveillance every 3-6 months by 6-minute walking, lung function tests, and sometimes imaging, and we treat for a long time. Oftentimes stability equals success.”
That being said, it must be emphasized that not all CTD-ILD warrants treatment of the pulmonary disease. If the patient’s ILD is mild and indolent, clinical surveillance is often appropriate, he continued.
More important than the pharmacotherapy available at present are adjunctive nonpharmacologic approaches: supplemental oxygen, pulmonary rehabilitation, treatment of comorbid GERD, immunizations, and addressing mental health issues related to these devastating diseases.
“We really don’t do these things well,” Dr. Fischer said.
On the horizon
An investigator-driven phase 2 clinical trial of the antifibrotic drug pirfenidone (Esbriet), now approved for IPF, is underway in patients with RA-ILD. Results of a trial of antifibrotic therapy in patients with scleroderma-ILD are due to be presented this year at EULAR. And a small study of antifibrotic therapy in patients with myositis-ILD is ongoing.
As for the biologics, there is a signal in the literature that tumor necrosis factor inhibitors may be associated with increased risk of rapidly progressive lung disease in patients with RA-ILD. An influential report from the British Society for Rheumatology Biologics Register on 299 patients with preexisting RA-ILD treated with anti-TNF therapy and 68 who received traditional disease-modifying antirrheumatic drugs showed that while mortality during follow-up was similar in the two groups, the proportion of deaths attributed to RA-ILD was 21% in the group on anti-TNF therapy, compared with only 7% in those on traditional DMARDs (Ann Rheum Dis. 2010 Jun;69[6]:1086-91).
Paul Emery, MD, rose from the audience at Dr. Fischer’s request to share his extensive experience with anti-TNF therapy and rituximab (Rituxan) in the setting of RA-ILD. When he was involved in several of the pivotal clinical trials of anti-TNF agents for RA he encountered a couple of cases of rapidly progressive ILD in patients on treatment.
“We had never before seen rapidly progressive ILD that didn’t respond to cyclophosphamide. Both patients died,” recalled Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
“Our experience is if you’ve got mild ILD – and if you look hard enough you can find it in many rheumatoids – TNF inhibitor therapy doesn’t affect it. But if there’s any hint of deterioration we move away from anti-TNF therapy. Our preference has been for rituximab,” he said.
Dr. Emery was senior author of the largest study to date of rituximab in patients with RA-ILD (Rheumatology [Oxford]. 2017 Aug 1;56[8]:1348-57). While he and his coinvestigators concluded that rituximab “appears to be an acceptable therapeutic choice for patients with RA-ILD,” Dr. Fischer didn’t find persuasive evidence from this relatively small retrospective observational study in which only 44 patients had lung data available.
“My own conclusion is evidence is lacking to support a role of rituximab for treating ILD in RA,” Dr. Fischer said.
He reported receiving research grants from Boehringer-Ingelheim and Corbus and serving as a consultant to a handful of other pharmaceutical companies.
REPORTING FROM RWCS 2019