User login
COVID-19: Thromboembolic events high despite prophylaxis
in a new large observational U.S. study.
“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview.
“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.
However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.
The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
Rates similar to other very sick patients
The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.
“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”
He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”
Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.
“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.
“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.
The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.
“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”
For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White.
Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.
Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.
Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.
Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.
“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.
“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”
Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.
“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
ARDS biggest risk factor
Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.
“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”
They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.
“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.
“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.
The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
Wait for randomized trials
In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.
Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.
“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”
He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.
“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.
This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.
A version of this article originally appeared on Medscape.com.
in a new large observational U.S. study.
“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview.
“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.
However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.
The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
Rates similar to other very sick patients
The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.
“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”
He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”
Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.
“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.
“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.
The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.
“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”
For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White.
Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.
Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.
Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.
Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.
“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.
“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”
Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.
“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
ARDS biggest risk factor
Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.
“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”
They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.
“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.
“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.
The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
Wait for randomized trials
In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.
Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.
“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”
He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.
“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.
This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.
A version of this article originally appeared on Medscape.com.
in a new large observational U.S. study.
“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview.
“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.
However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.
The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
Rates similar to other very sick patients
The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.
“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”
He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”
Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.
“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.
“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.
The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.
“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”
For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White.
Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.
Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.
Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.
Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.
“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.
“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”
Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.
“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
ARDS biggest risk factor
Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.
“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”
They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.
“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.
“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.
The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
Wait for randomized trials
In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.
Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.
“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”
He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.
“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.
This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.
A version of this article originally appeared on Medscape.com.
ASSET extension supports abatacept as treatment for diffuse cutaneous systemic sclerosis
“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.
To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.
Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.
All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.
Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.
Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.
Time to push forward with additional studies on abatacept
The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.
Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.
Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.
The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.
The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.
SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.
“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.
To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.
Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.
All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.
Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.
Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.
Time to push forward with additional studies on abatacept
The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.
Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.
Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.
The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.
The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.
SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.
“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.
To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.
Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.
All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.
Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.
Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.
Time to push forward with additional studies on abatacept
The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.
Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.
Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.
The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.
The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.
SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.
FROM THE LANCET RHEUMATOLOGY
An assessment of asthma drugs in pregnancy
Asthma effects about 10% of pregnant women worldwide. About 10% of these will have severe disease requiring oral corticosteroids. Brief reviews of asthma drugs are shown below.
The trade names (if available) and molecular weights (rounded to the nearest whole number) are shown in parentheses. Nearly all of these drugs will cross the placenta.
Beclomethasone (Beconase AQ) (539)
Either beclomethasone or budesonide was considered the inhaled steroids of choice for use during pregnancy, according to a position statement from a joint committee of the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology published in 2000. Although the drug is teratogenic in animals, no human reports associating the use of inhaled beclomethasone with human congenital anomalies have been found.
Benralizumab (Fasenra) (150,000)
There is no published human pregnancy data. Based on studies in monkeys, the drug crosses the placenta in the third trimester. It caused no fetal harm in monkeys when given throughout pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy. Health care providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/Fasenra.
Budesonide (Rhinocort) (431)
Either budesonide or beclomethasone was considered the inhaled steroids of choice for use during pregnancy in a position statement from a joint committee of ACOG and ACAAI published in 2000. Although the drug is teratogenic in animals, no human reports associating the use of inhaled beclomethasone with human congenital anomalies have been found.
Caffeine (194)
Although the amount of caffeine in commonly used beverages varies widely, caffeine consumption in pregnancy in moderate amounts does not pose a risk to the fetus. When used in moderation, no association with congenital malformations, spontaneous abortions, preterm birth, and low birth weight have been proven.
Ciclesonide (Alvesco) (541)
Ciclesonide is an inhaled corticosteroid. There is no published human pregnancy data but the molecular weight suggests that it will cross the placenta throughout pregnancy. The drug produced no defects in rats but caused fetal toxicity in rabbits. Although the risk may be low because it is inhaled, avoiding it in the first trimester should be considered (see dexamethasone).
Cromolyn sodium (490)
Cromolyn was available as a nasal spray and oral solution, but it is no longer available in the United States. It is poorly absorbed into the systemic circulation. Neither the human nor the animal data suggest a risk of embryo-fetal harm.
Dexamethasone (392)
This is a corticosteroid with potency similar to betamethasone. Because large epidemiologic studies have found positive associations between systemic corticosteroids and nonsyndromic orofacial clefts, it is best to avoid this agent in the first trimester. However, when used for the treatment of asthma, other studies have not found a significantly increased risk of maternal or fetal complications. The difference in these outcomes may be related to the systemic concentrations of the drug.
Dyphylline (254) + guaifenesin (198) (Difil-G Forte) (Dilex-G 400) (Dy-G)
This is an OTC liquid drug taken orally. It has not been studied in pregnant animals, and there is no published human pregnancy data. However, these bronchodilator agents probably can be classified as low risk for the embryo and fetus. Dyphylline alone has been removed from the market.
Fluticasone (539) + vilanterol (Breo Ellipta) (775)
Fluticasone is a corticosteroid and vilanterol is a long acting beta2-adrenergic agonist that are given by inhalation. The molecular weights suggest that the two agents will cross the placenta throughout pregnancy. The drug did not cause fetal harm in animals. There is no published human pregnancy data for this fixed combination.
Fluticasone (539) + umeclidinium (509) + vilanterol (Trelegy Ellipta) (776)
The combination of fluticasone (glucocorticoid), umeclidinium, and vilanterol (long-acting beta2-adrenergic agonists) is given by inhalation. The molecular weights suggest that the three agents will cross the placenta throughout pregnancy. Although the three-drug combination has not been studied in pregnant rats and rabbits, the individual agents did not cause embryo-fetal harm in these species. There is no evidence that these agents, when given by inhalation, will harm the human embryo and/or fetus. No published human pregnancy reports for this fixed combination have been located.
Formoterol + mometasone (Dulera Aerosol) (841 / 521)
This combination is an aerosol product. Formoterol is a long-acting beta2-adrenergic agonist and mometasone is a topical corticosteroid. There is no published human pregnancy data for this fixed combination. The molecular weights suggest that both drugs will cross the placenta throughout pregnancy. In animals given high oral doses, both were teratogenic.
Ipratropium (Atrovent) (430)
Inhaled ipratropium, an anticholinergic bronchodilator, is recommended for asthma in patients not responding adequately to other therapy. It was not teratogenic mice, rats, and rabbits. Although the human pregnancy data is limited, there is no evidence that the drug is hazardous to the fetus. It produces fewer systemic effects then atropine and may have an additive bronchodilatory effect to beta2 agonists.
Isoproterenol (211)
Isoproterenol is a sympathomimetic (bronchodilator) with beta-adrenergic effects that is given intravenously. No reports linking this agent with congenital defects have been located. The drug was not teratogenic in rats and rabbits but was in hamsters.
Levalbuterol (Xopenex HFA) (240)
Levalbuterol is the (R)-enantiomer of racemic albuterol. It is given by inhalation. No reports of its use in human pregnancy have been located. However, racemic albuterol is considered compatible in pregnancy, and there is no apparent reason not to classify levalbuterol the same way. The drug, when given orally, is teratogenic in animals. If levalbuterol is used in pregnancy for the treatment of asthma, health care professionals are encouraged to call the toll-free number (1-877-311-8972) for information about patient enrollment in an Organization of Teratology Specialists study.
Mepolizumab (Nucala) (149,000)
Mepolizumab is given by subcutaneous injection. It is not indicated for status asthmaticus. There is no published human pregnancy data but the molecular weight suggests that it will not cross the placenta in the first half of pregnancy. The drug did not cause defects in monkeys and mice. There is a pregnancy exposure registry that monitors pregnancy outcomes in women with asthma exposed to Nucala during pregnancy. Health care providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting www.mothertobaby.org/asthma.
Metaproterenol (521)
Metaproterenol, a selective beta2-adrenergic agonist, is a respiratory (bronchodilator) that is given orally. Use of this agent in pregnancy has not been linked with congenital defects. However, the drug is teratogenic in animals.
Methylprednisolone (Medrol) (374)
This is an oral glucocorticoid. The molecular weight suggests that it will cross the placenta throughout pregnancy. No reports relating to its use in human pregnancy or in pregnant animals have been located. However, teratogenicity is a potential problem (see below). If high doses of the drug are used in pregnancy, the newborn infants should be carefully observed for signs of hypoadrenalism. In addition, all corticosteroids increase calcium excretion.
Methylprednisolone acetate (Depo-Medrol) (417)
This is an injectable glucocorticoid. See below.
Methylprednisolone sodium succinate (Solu-Medrol) (497)
Methylprednisolone is a glucocorticoid given parenterally. The molecular weight suggests that it will cross the placenta throughout pregnancy. As with other corticosteroids, the drug was teratogenic, at doses equivalent to the human dose, in mice, rats, and rabbits. If the drug is used in pregnancy, the newborn infant should be carefully observed for signs of hypoadrenalism. In addition, all corticosteroids increase calcium excretion.
Mometasone + formoterol (Dulera) (321 + 841)
Dulera is a combination product of mometasone (corticosteroid) and formoterol (beta2-adrenergic agonist). There is no published human data for Dulera but the molecular weights suggest that the drugs will cross the placenta. Oral doses of formoterol were not teratogenic in animals but were with mometasone. The limited human pregnancy data with formoterol did not suggest a risk of embryo/fetal harm, but there is no human pregnancy data for mometasone.
Montelukast (Singulair) (608)
Montelukast is a leukotriene receptor antagonist that is given orally. Although the human data are limited, the drug does not appear to cause harm to the embryo and/or fetus. The drug was not teratogenic in rats and rabbits. The manufacturer maintains a pregnancy registry for women exposed to montelukast. Health care professionals are encouraged to report pregnancy exposures to the registry by calling the toll-free number 1-800-986-8999.
Omalizumab (Xolair) (149,000)
Omalizumab is a recombinant DNA–derived humanized immunoglobulin (IgG1k) monoclonal antibody that is administered subcutaneously for patients with moderate to severe persistent asthma. In monkeys, the drug did not cause embryotoxicity or teratogenicity. The human pregnancy data is very limited but does not suggest an increased embryo-fetal risk.
Prednisone (Rayos) (358)
The use of oral prednisone appears to represent a small risk to the developing fetus. One of these risks appears to be orofacial clefts. The drug causes birth defects in rats, mice, rabbits, and hamsters. However, the available evidence supports its use to control various maternal diseases, one of which is asthma.
Reslizumab (Cinqair) (147,000)
Reslizumab is given intravenously. Even though the molecular weight is high, the drug crosses the placenta during pregnancy. In placebo-controlled studies, anaphylaxis occurred in 0.3% of patients receiving the drug. No adverse effects were observed when the drug was given to pregnant mice and rabbits.
Salmeterol (Serevent Diskus) (416)
Salmeterol is a long-acting beta2-adrenergic agonist that is given as an aerosol or dry powder for oral inhalation. Because the drug acts locally in the lung, plasma levels are very low or undetectable and are a result of swallowed salmeterol. The limited human pregnancy data does not suggest risk of embryo-fetal harm. High oral doses in animals were not teratogenic.
Theophylline (180)
Oral theophylline is a methylxanthine that is indicated for the treatment of symptoms of chronic asthma and other chronic lung diseases. According to ACOG, theophylline is not a preferred asthma therapy but considered an alternative agent. No published reports linking the use of theophylline with congenital defects have been located. However, the drug is teratogenic in mice, rats, and rabbits at doses close to the human dose.
Tiotropium (Spiriva Respimat) (490)
Tiotropium, an anticholinergic bronchodilator, is given by oral inhalation only. No reports describing the use of tiotropium during human pregnancy have been located. The animal data suggest low risk. However, because of its long elimination half-life (about 25 hours), use of tiotropium immediately before the diagnosis of an inadvertent pregnancy would most likely result in the exposure of a portion of organogenesis.
Triamcinolone (Kenalog-40) (435)
Triamcinolone is an inhaled corticosteroid with potency slightly greater than prednisone. Although the systemic use of the drug has a small absolute risk of oral clefts and fetal growth restriction, inhaled triamcinolone does not appear to cause embryo-fetal harm. The drug is teratogenic when given orally to animals.
Breastfeeding
It is not known if the above drugs are excreted into breast milk. Agents with relatively low molecular weights will probably be in milk. However, if the maternal levels are low, the amount in milk will probably be very small, if at all. Nevertheless, it is doubtful if any of these agents, even if they are excreted into milk, will have a harmful effect on a nursing infant.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at obnews@mdedge.com.
Asthma effects about 10% of pregnant women worldwide. About 10% of these will have severe disease requiring oral corticosteroids. Brief reviews of asthma drugs are shown below.
The trade names (if available) and molecular weights (rounded to the nearest whole number) are shown in parentheses. Nearly all of these drugs will cross the placenta.
Beclomethasone (Beconase AQ) (539)
Either beclomethasone or budesonide was considered the inhaled steroids of choice for use during pregnancy, according to a position statement from a joint committee of the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology published in 2000. Although the drug is teratogenic in animals, no human reports associating the use of inhaled beclomethasone with human congenital anomalies have been found.
Benralizumab (Fasenra) (150,000)
There is no published human pregnancy data. Based on studies in monkeys, the drug crosses the placenta in the third trimester. It caused no fetal harm in monkeys when given throughout pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy. Health care providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/Fasenra.
Budesonide (Rhinocort) (431)
Either budesonide or beclomethasone was considered the inhaled steroids of choice for use during pregnancy in a position statement from a joint committee of ACOG and ACAAI published in 2000. Although the drug is teratogenic in animals, no human reports associating the use of inhaled beclomethasone with human congenital anomalies have been found.
Caffeine (194)
Although the amount of caffeine in commonly used beverages varies widely, caffeine consumption in pregnancy in moderate amounts does not pose a risk to the fetus. When used in moderation, no association with congenital malformations, spontaneous abortions, preterm birth, and low birth weight have been proven.
Ciclesonide (Alvesco) (541)
Ciclesonide is an inhaled corticosteroid. There is no published human pregnancy data but the molecular weight suggests that it will cross the placenta throughout pregnancy. The drug produced no defects in rats but caused fetal toxicity in rabbits. Although the risk may be low because it is inhaled, avoiding it in the first trimester should be considered (see dexamethasone).
Cromolyn sodium (490)
Cromolyn was available as a nasal spray and oral solution, but it is no longer available in the United States. It is poorly absorbed into the systemic circulation. Neither the human nor the animal data suggest a risk of embryo-fetal harm.
Dexamethasone (392)
This is a corticosteroid with potency similar to betamethasone. Because large epidemiologic studies have found positive associations between systemic corticosteroids and nonsyndromic orofacial clefts, it is best to avoid this agent in the first trimester. However, when used for the treatment of asthma, other studies have not found a significantly increased risk of maternal or fetal complications. The difference in these outcomes may be related to the systemic concentrations of the drug.
Dyphylline (254) + guaifenesin (198) (Difil-G Forte) (Dilex-G 400) (Dy-G)
This is an OTC liquid drug taken orally. It has not been studied in pregnant animals, and there is no published human pregnancy data. However, these bronchodilator agents probably can be classified as low risk for the embryo and fetus. Dyphylline alone has been removed from the market.
Fluticasone (539) + vilanterol (Breo Ellipta) (775)
Fluticasone is a corticosteroid and vilanterol is a long acting beta2-adrenergic agonist that are given by inhalation. The molecular weights suggest that the two agents will cross the placenta throughout pregnancy. The drug did not cause fetal harm in animals. There is no published human pregnancy data for this fixed combination.
Fluticasone (539) + umeclidinium (509) + vilanterol (Trelegy Ellipta) (776)
The combination of fluticasone (glucocorticoid), umeclidinium, and vilanterol (long-acting beta2-adrenergic agonists) is given by inhalation. The molecular weights suggest that the three agents will cross the placenta throughout pregnancy. Although the three-drug combination has not been studied in pregnant rats and rabbits, the individual agents did not cause embryo-fetal harm in these species. There is no evidence that these agents, when given by inhalation, will harm the human embryo and/or fetus. No published human pregnancy reports for this fixed combination have been located.
Formoterol + mometasone (Dulera Aerosol) (841 / 521)
This combination is an aerosol product. Formoterol is a long-acting beta2-adrenergic agonist and mometasone is a topical corticosteroid. There is no published human pregnancy data for this fixed combination. The molecular weights suggest that both drugs will cross the placenta throughout pregnancy. In animals given high oral doses, both were teratogenic.
Ipratropium (Atrovent) (430)
Inhaled ipratropium, an anticholinergic bronchodilator, is recommended for asthma in patients not responding adequately to other therapy. It was not teratogenic mice, rats, and rabbits. Although the human pregnancy data is limited, there is no evidence that the drug is hazardous to the fetus. It produces fewer systemic effects then atropine and may have an additive bronchodilatory effect to beta2 agonists.
Isoproterenol (211)
Isoproterenol is a sympathomimetic (bronchodilator) with beta-adrenergic effects that is given intravenously. No reports linking this agent with congenital defects have been located. The drug was not teratogenic in rats and rabbits but was in hamsters.
Levalbuterol (Xopenex HFA) (240)
Levalbuterol is the (R)-enantiomer of racemic albuterol. It is given by inhalation. No reports of its use in human pregnancy have been located. However, racemic albuterol is considered compatible in pregnancy, and there is no apparent reason not to classify levalbuterol the same way. The drug, when given orally, is teratogenic in animals. If levalbuterol is used in pregnancy for the treatment of asthma, health care professionals are encouraged to call the toll-free number (1-877-311-8972) for information about patient enrollment in an Organization of Teratology Specialists study.
Mepolizumab (Nucala) (149,000)
Mepolizumab is given by subcutaneous injection. It is not indicated for status asthmaticus. There is no published human pregnancy data but the molecular weight suggests that it will not cross the placenta in the first half of pregnancy. The drug did not cause defects in monkeys and mice. There is a pregnancy exposure registry that monitors pregnancy outcomes in women with asthma exposed to Nucala during pregnancy. Health care providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting www.mothertobaby.org/asthma.
Metaproterenol (521)
Metaproterenol, a selective beta2-adrenergic agonist, is a respiratory (bronchodilator) that is given orally. Use of this agent in pregnancy has not been linked with congenital defects. However, the drug is teratogenic in animals.
Methylprednisolone (Medrol) (374)
This is an oral glucocorticoid. The molecular weight suggests that it will cross the placenta throughout pregnancy. No reports relating to its use in human pregnancy or in pregnant animals have been located. However, teratogenicity is a potential problem (see below). If high doses of the drug are used in pregnancy, the newborn infants should be carefully observed for signs of hypoadrenalism. In addition, all corticosteroids increase calcium excretion.
Methylprednisolone acetate (Depo-Medrol) (417)
This is an injectable glucocorticoid. See below.
Methylprednisolone sodium succinate (Solu-Medrol) (497)
Methylprednisolone is a glucocorticoid given parenterally. The molecular weight suggests that it will cross the placenta throughout pregnancy. As with other corticosteroids, the drug was teratogenic, at doses equivalent to the human dose, in mice, rats, and rabbits. If the drug is used in pregnancy, the newborn infant should be carefully observed for signs of hypoadrenalism. In addition, all corticosteroids increase calcium excretion.
Mometasone + formoterol (Dulera) (321 + 841)
Dulera is a combination product of mometasone (corticosteroid) and formoterol (beta2-adrenergic agonist). There is no published human data for Dulera but the molecular weights suggest that the drugs will cross the placenta. Oral doses of formoterol were not teratogenic in animals but were with mometasone. The limited human pregnancy data with formoterol did not suggest a risk of embryo/fetal harm, but there is no human pregnancy data for mometasone.
Montelukast (Singulair) (608)
Montelukast is a leukotriene receptor antagonist that is given orally. Although the human data are limited, the drug does not appear to cause harm to the embryo and/or fetus. The drug was not teratogenic in rats and rabbits. The manufacturer maintains a pregnancy registry for women exposed to montelukast. Health care professionals are encouraged to report pregnancy exposures to the registry by calling the toll-free number 1-800-986-8999.
Omalizumab (Xolair) (149,000)
Omalizumab is a recombinant DNA–derived humanized immunoglobulin (IgG1k) monoclonal antibody that is administered subcutaneously for patients with moderate to severe persistent asthma. In monkeys, the drug did not cause embryotoxicity or teratogenicity. The human pregnancy data is very limited but does not suggest an increased embryo-fetal risk.
Prednisone (Rayos) (358)
The use of oral prednisone appears to represent a small risk to the developing fetus. One of these risks appears to be orofacial clefts. The drug causes birth defects in rats, mice, rabbits, and hamsters. However, the available evidence supports its use to control various maternal diseases, one of which is asthma.
Reslizumab (Cinqair) (147,000)
Reslizumab is given intravenously. Even though the molecular weight is high, the drug crosses the placenta during pregnancy. In placebo-controlled studies, anaphylaxis occurred in 0.3% of patients receiving the drug. No adverse effects were observed when the drug was given to pregnant mice and rabbits.
Salmeterol (Serevent Diskus) (416)
Salmeterol is a long-acting beta2-adrenergic agonist that is given as an aerosol or dry powder for oral inhalation. Because the drug acts locally in the lung, plasma levels are very low or undetectable and are a result of swallowed salmeterol. The limited human pregnancy data does not suggest risk of embryo-fetal harm. High oral doses in animals were not teratogenic.
Theophylline (180)
Oral theophylline is a methylxanthine that is indicated for the treatment of symptoms of chronic asthma and other chronic lung diseases. According to ACOG, theophylline is not a preferred asthma therapy but considered an alternative agent. No published reports linking the use of theophylline with congenital defects have been located. However, the drug is teratogenic in mice, rats, and rabbits at doses close to the human dose.
Tiotropium (Spiriva Respimat) (490)
Tiotropium, an anticholinergic bronchodilator, is given by oral inhalation only. No reports describing the use of tiotropium during human pregnancy have been located. The animal data suggest low risk. However, because of its long elimination half-life (about 25 hours), use of tiotropium immediately before the diagnosis of an inadvertent pregnancy would most likely result in the exposure of a portion of organogenesis.
Triamcinolone (Kenalog-40) (435)
Triamcinolone is an inhaled corticosteroid with potency slightly greater than prednisone. Although the systemic use of the drug has a small absolute risk of oral clefts and fetal growth restriction, inhaled triamcinolone does not appear to cause embryo-fetal harm. The drug is teratogenic when given orally to animals.
Breastfeeding
It is not known if the above drugs are excreted into breast milk. Agents with relatively low molecular weights will probably be in milk. However, if the maternal levels are low, the amount in milk will probably be very small, if at all. Nevertheless, it is doubtful if any of these agents, even if they are excreted into milk, will have a harmful effect on a nursing infant.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at obnews@mdedge.com.
Asthma effects about 10% of pregnant women worldwide. About 10% of these will have severe disease requiring oral corticosteroids. Brief reviews of asthma drugs are shown below.
The trade names (if available) and molecular weights (rounded to the nearest whole number) are shown in parentheses. Nearly all of these drugs will cross the placenta.
Beclomethasone (Beconase AQ) (539)
Either beclomethasone or budesonide was considered the inhaled steroids of choice for use during pregnancy, according to a position statement from a joint committee of the American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma, and Immunology published in 2000. Although the drug is teratogenic in animals, no human reports associating the use of inhaled beclomethasone with human congenital anomalies have been found.
Benralizumab (Fasenra) (150,000)
There is no published human pregnancy data. Based on studies in monkeys, the drug crosses the placenta in the third trimester. It caused no fetal harm in monkeys when given throughout pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to the drug during pregnancy. Health care providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/Fasenra.
Budesonide (Rhinocort) (431)
Either budesonide or beclomethasone was considered the inhaled steroids of choice for use during pregnancy in a position statement from a joint committee of ACOG and ACAAI published in 2000. Although the drug is teratogenic in animals, no human reports associating the use of inhaled beclomethasone with human congenital anomalies have been found.
Caffeine (194)
Although the amount of caffeine in commonly used beverages varies widely, caffeine consumption in pregnancy in moderate amounts does not pose a risk to the fetus. When used in moderation, no association with congenital malformations, spontaneous abortions, preterm birth, and low birth weight have been proven.
Ciclesonide (Alvesco) (541)
Ciclesonide is an inhaled corticosteroid. There is no published human pregnancy data but the molecular weight suggests that it will cross the placenta throughout pregnancy. The drug produced no defects in rats but caused fetal toxicity in rabbits. Although the risk may be low because it is inhaled, avoiding it in the first trimester should be considered (see dexamethasone).
Cromolyn sodium (490)
Cromolyn was available as a nasal spray and oral solution, but it is no longer available in the United States. It is poorly absorbed into the systemic circulation. Neither the human nor the animal data suggest a risk of embryo-fetal harm.
Dexamethasone (392)
This is a corticosteroid with potency similar to betamethasone. Because large epidemiologic studies have found positive associations between systemic corticosteroids and nonsyndromic orofacial clefts, it is best to avoid this agent in the first trimester. However, when used for the treatment of asthma, other studies have not found a significantly increased risk of maternal or fetal complications. The difference in these outcomes may be related to the systemic concentrations of the drug.
Dyphylline (254) + guaifenesin (198) (Difil-G Forte) (Dilex-G 400) (Dy-G)
This is an OTC liquid drug taken orally. It has not been studied in pregnant animals, and there is no published human pregnancy data. However, these bronchodilator agents probably can be classified as low risk for the embryo and fetus. Dyphylline alone has been removed from the market.
Fluticasone (539) + vilanterol (Breo Ellipta) (775)
Fluticasone is a corticosteroid and vilanterol is a long acting beta2-adrenergic agonist that are given by inhalation. The molecular weights suggest that the two agents will cross the placenta throughout pregnancy. The drug did not cause fetal harm in animals. There is no published human pregnancy data for this fixed combination.
Fluticasone (539) + umeclidinium (509) + vilanterol (Trelegy Ellipta) (776)
The combination of fluticasone (glucocorticoid), umeclidinium, and vilanterol (long-acting beta2-adrenergic agonists) is given by inhalation. The molecular weights suggest that the three agents will cross the placenta throughout pregnancy. Although the three-drug combination has not been studied in pregnant rats and rabbits, the individual agents did not cause embryo-fetal harm in these species. There is no evidence that these agents, when given by inhalation, will harm the human embryo and/or fetus. No published human pregnancy reports for this fixed combination have been located.
Formoterol + mometasone (Dulera Aerosol) (841 / 521)
This combination is an aerosol product. Formoterol is a long-acting beta2-adrenergic agonist and mometasone is a topical corticosteroid. There is no published human pregnancy data for this fixed combination. The molecular weights suggest that both drugs will cross the placenta throughout pregnancy. In animals given high oral doses, both were teratogenic.
Ipratropium (Atrovent) (430)
Inhaled ipratropium, an anticholinergic bronchodilator, is recommended for asthma in patients not responding adequately to other therapy. It was not teratogenic mice, rats, and rabbits. Although the human pregnancy data is limited, there is no evidence that the drug is hazardous to the fetus. It produces fewer systemic effects then atropine and may have an additive bronchodilatory effect to beta2 agonists.
Isoproterenol (211)
Isoproterenol is a sympathomimetic (bronchodilator) with beta-adrenergic effects that is given intravenously. No reports linking this agent with congenital defects have been located. The drug was not teratogenic in rats and rabbits but was in hamsters.
Levalbuterol (Xopenex HFA) (240)
Levalbuterol is the (R)-enantiomer of racemic albuterol. It is given by inhalation. No reports of its use in human pregnancy have been located. However, racemic albuterol is considered compatible in pregnancy, and there is no apparent reason not to classify levalbuterol the same way. The drug, when given orally, is teratogenic in animals. If levalbuterol is used in pregnancy for the treatment of asthma, health care professionals are encouraged to call the toll-free number (1-877-311-8972) for information about patient enrollment in an Organization of Teratology Specialists study.
Mepolizumab (Nucala) (149,000)
Mepolizumab is given by subcutaneous injection. It is not indicated for status asthmaticus. There is no published human pregnancy data but the molecular weight suggests that it will not cross the placenta in the first half of pregnancy. The drug did not cause defects in monkeys and mice. There is a pregnancy exposure registry that monitors pregnancy outcomes in women with asthma exposed to Nucala during pregnancy. Health care providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting www.mothertobaby.org/asthma.
Metaproterenol (521)
Metaproterenol, a selective beta2-adrenergic agonist, is a respiratory (bronchodilator) that is given orally. Use of this agent in pregnancy has not been linked with congenital defects. However, the drug is teratogenic in animals.
Methylprednisolone (Medrol) (374)
This is an oral glucocorticoid. The molecular weight suggests that it will cross the placenta throughout pregnancy. No reports relating to its use in human pregnancy or in pregnant animals have been located. However, teratogenicity is a potential problem (see below). If high doses of the drug are used in pregnancy, the newborn infants should be carefully observed for signs of hypoadrenalism. In addition, all corticosteroids increase calcium excretion.
Methylprednisolone acetate (Depo-Medrol) (417)
This is an injectable glucocorticoid. See below.
Methylprednisolone sodium succinate (Solu-Medrol) (497)
Methylprednisolone is a glucocorticoid given parenterally. The molecular weight suggests that it will cross the placenta throughout pregnancy. As with other corticosteroids, the drug was teratogenic, at doses equivalent to the human dose, in mice, rats, and rabbits. If the drug is used in pregnancy, the newborn infant should be carefully observed for signs of hypoadrenalism. In addition, all corticosteroids increase calcium excretion.
Mometasone + formoterol (Dulera) (321 + 841)
Dulera is a combination product of mometasone (corticosteroid) and formoterol (beta2-adrenergic agonist). There is no published human data for Dulera but the molecular weights suggest that the drugs will cross the placenta. Oral doses of formoterol were not teratogenic in animals but were with mometasone. The limited human pregnancy data with formoterol did not suggest a risk of embryo/fetal harm, but there is no human pregnancy data for mometasone.
Montelukast (Singulair) (608)
Montelukast is a leukotriene receptor antagonist that is given orally. Although the human data are limited, the drug does not appear to cause harm to the embryo and/or fetus. The drug was not teratogenic in rats and rabbits. The manufacturer maintains a pregnancy registry for women exposed to montelukast. Health care professionals are encouraged to report pregnancy exposures to the registry by calling the toll-free number 1-800-986-8999.
Omalizumab (Xolair) (149,000)
Omalizumab is a recombinant DNA–derived humanized immunoglobulin (IgG1k) monoclonal antibody that is administered subcutaneously for patients with moderate to severe persistent asthma. In monkeys, the drug did not cause embryotoxicity or teratogenicity. The human pregnancy data is very limited but does not suggest an increased embryo-fetal risk.
Prednisone (Rayos) (358)
The use of oral prednisone appears to represent a small risk to the developing fetus. One of these risks appears to be orofacial clefts. The drug causes birth defects in rats, mice, rabbits, and hamsters. However, the available evidence supports its use to control various maternal diseases, one of which is asthma.
Reslizumab (Cinqair) (147,000)
Reslizumab is given intravenously. Even though the molecular weight is high, the drug crosses the placenta during pregnancy. In placebo-controlled studies, anaphylaxis occurred in 0.3% of patients receiving the drug. No adverse effects were observed when the drug was given to pregnant mice and rabbits.
Salmeterol (Serevent Diskus) (416)
Salmeterol is a long-acting beta2-adrenergic agonist that is given as an aerosol or dry powder for oral inhalation. Because the drug acts locally in the lung, plasma levels are very low or undetectable and are a result of swallowed salmeterol. The limited human pregnancy data does not suggest risk of embryo-fetal harm. High oral doses in animals were not teratogenic.
Theophylline (180)
Oral theophylline is a methylxanthine that is indicated for the treatment of symptoms of chronic asthma and other chronic lung diseases. According to ACOG, theophylline is not a preferred asthma therapy but considered an alternative agent. No published reports linking the use of theophylline with congenital defects have been located. However, the drug is teratogenic in mice, rats, and rabbits at doses close to the human dose.
Tiotropium (Spiriva Respimat) (490)
Tiotropium, an anticholinergic bronchodilator, is given by oral inhalation only. No reports describing the use of tiotropium during human pregnancy have been located. The animal data suggest low risk. However, because of its long elimination half-life (about 25 hours), use of tiotropium immediately before the diagnosis of an inadvertent pregnancy would most likely result in the exposure of a portion of organogenesis.
Triamcinolone (Kenalog-40) (435)
Triamcinolone is an inhaled corticosteroid with potency slightly greater than prednisone. Although the systemic use of the drug has a small absolute risk of oral clefts and fetal growth restriction, inhaled triamcinolone does not appear to cause embryo-fetal harm. The drug is teratogenic when given orally to animals.
Breastfeeding
It is not known if the above drugs are excreted into breast milk. Agents with relatively low molecular weights will probably be in milk. However, if the maternal levels are low, the amount in milk will probably be very small, if at all. Nevertheless, it is doubtful if any of these agents, even if they are excreted into milk, will have a harmful effect on a nursing infant.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at obnews@mdedge.com.
Novel treatments under study for chronic graft-versus-host disease in allo-HCT
Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.
However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.
According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”
The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”
In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”
For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.
Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.
Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.
The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.
In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.
In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”
Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”
Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.
However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.
According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”
The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”
In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”
For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.
Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.
Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.
The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.
In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.
In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”
Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”
Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.
However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.
According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”
The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”
In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”
For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.
Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.
Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.
The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.
In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.
In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”
Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”
Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
FROM ALF 2020
Be among the first to commit to AGA Giving Day
Our patients face racial health disparities daily, leading to inequalities in care and poorer health outcomes.
At this important moment in history, the AGA Research Foundation is uniquely qualified to push forward innovative research in health disparities in gastroenterology. With donations from AGA members to our new initiative called AGA Giving Day, we can provide researchers with a secure source of funding that helps understand the causes of known health disparities, understand why the disparity exists, and develop interventions to reduce and eliminate health disparities.
The AGA Research Foundation invites you to support AGA Giving Day today through Dec. 3. Contributors will be recognized as supporters of our fight to achieve equity and eradicate disparities in digestive diseases.
Learn more at gastro.org/agagivingday.
ginews@gastro.org
Our patients face racial health disparities daily, leading to inequalities in care and poorer health outcomes.
At this important moment in history, the AGA Research Foundation is uniquely qualified to push forward innovative research in health disparities in gastroenterology. With donations from AGA members to our new initiative called AGA Giving Day, we can provide researchers with a secure source of funding that helps understand the causes of known health disparities, understand why the disparity exists, and develop interventions to reduce and eliminate health disparities.
The AGA Research Foundation invites you to support AGA Giving Day today through Dec. 3. Contributors will be recognized as supporters of our fight to achieve equity and eradicate disparities in digestive diseases.
Learn more at gastro.org/agagivingday.
ginews@gastro.org
Our patients face racial health disparities daily, leading to inequalities in care and poorer health outcomes.
At this important moment in history, the AGA Research Foundation is uniquely qualified to push forward innovative research in health disparities in gastroenterology. With donations from AGA members to our new initiative called AGA Giving Day, we can provide researchers with a secure source of funding that helps understand the causes of known health disparities, understand why the disparity exists, and develop interventions to reduce and eliminate health disparities.
The AGA Research Foundation invites you to support AGA Giving Day today through Dec. 3. Contributors will be recognized as supporters of our fight to achieve equity and eradicate disparities in digestive diseases.
Learn more at gastro.org/agagivingday.
ginews@gastro.org
AGA releases largest real-world report on safety and effectiveness of fecal microbiota transplantation
Ninety percent of patients tracked in the AGA FMT National Registry were cured of Clostridioides difficile infection with few serious side effects.
AGA has released the first results from the NIH-funded AGA Fecal Microbiota Transplantation (FMT) National Registry, the largest real-world study on the safety and effectiveness of FMT. Few serious side effects were reported.
“While the value of fecal microbiota transplantation for treating recurrent C. difficile infection is clear from research studies, the potential long-term consequences of altering a patient’s gut microbiota are not fully known,” says Colleen R. Kelly, MD, AGAF, associate professor of medicine at Brown University in Providence, R.I. and co-principal investigator of the AGA FMT National Registry. “Releasing the initial results of the AGA FMT National Registry is an important step toward understanding the true risks and benefits of microbiota therapeutics in a real-world setting.”
This new report details effectiveness and safety outcomes from the first 259 patients enrolled in the registry between December 2017 and September 2019. Almost all participants received FMT using an unknown donor from stool banks. The most common method of FMT delivery was colonoscopy followed by upper endoscopy. Of the 222 participants who returned for the one-month follow-up, 200 participants (90%) had their C. difficile infection cured with 197 of those requiring only a single FMT. Infections were reported in 11 participants, but only 2 were thought to be possibly related to the procedure. FMT response was deemed durable, with recurrence of C. difficile infection in the 6 months after successful FMT occurring in only 4% of participants. This data includes patients with comorbidities, such as inflammatory bowel disease and immunocompromised status, who are typically excluded from FMT clinical trials.
“These initial results show a high success rate of FMT in the real-world setting. We’ll continue to track these patients for 10 years to assess long-term safety, which will be critical to determining the full safety profile of FMT,” added Dr. Kelly.
Ninety percent of patients tracked in the AGA FMT National Registry were cured of Clostridioides difficile infection with few serious side effects.
AGA has released the first results from the NIH-funded AGA Fecal Microbiota Transplantation (FMT) National Registry, the largest real-world study on the safety and effectiveness of FMT. Few serious side effects were reported.
“While the value of fecal microbiota transplantation for treating recurrent C. difficile infection is clear from research studies, the potential long-term consequences of altering a patient’s gut microbiota are not fully known,” says Colleen R. Kelly, MD, AGAF, associate professor of medicine at Brown University in Providence, R.I. and co-principal investigator of the AGA FMT National Registry. “Releasing the initial results of the AGA FMT National Registry is an important step toward understanding the true risks and benefits of microbiota therapeutics in a real-world setting.”
This new report details effectiveness and safety outcomes from the first 259 patients enrolled in the registry between December 2017 and September 2019. Almost all participants received FMT using an unknown donor from stool banks. The most common method of FMT delivery was colonoscopy followed by upper endoscopy. Of the 222 participants who returned for the one-month follow-up, 200 participants (90%) had their C. difficile infection cured with 197 of those requiring only a single FMT. Infections were reported in 11 participants, but only 2 were thought to be possibly related to the procedure. FMT response was deemed durable, with recurrence of C. difficile infection in the 6 months after successful FMT occurring in only 4% of participants. This data includes patients with comorbidities, such as inflammatory bowel disease and immunocompromised status, who are typically excluded from FMT clinical trials.
“These initial results show a high success rate of FMT in the real-world setting. We’ll continue to track these patients for 10 years to assess long-term safety, which will be critical to determining the full safety profile of FMT,” added Dr. Kelly.
Ninety percent of patients tracked in the AGA FMT National Registry were cured of Clostridioides difficile infection with few serious side effects.
AGA has released the first results from the NIH-funded AGA Fecal Microbiota Transplantation (FMT) National Registry, the largest real-world study on the safety and effectiveness of FMT. Few serious side effects were reported.
“While the value of fecal microbiota transplantation for treating recurrent C. difficile infection is clear from research studies, the potential long-term consequences of altering a patient’s gut microbiota are not fully known,” says Colleen R. Kelly, MD, AGAF, associate professor of medicine at Brown University in Providence, R.I. and co-principal investigator of the AGA FMT National Registry. “Releasing the initial results of the AGA FMT National Registry is an important step toward understanding the true risks and benefits of microbiota therapeutics in a real-world setting.”
This new report details effectiveness and safety outcomes from the first 259 patients enrolled in the registry between December 2017 and September 2019. Almost all participants received FMT using an unknown donor from stool banks. The most common method of FMT delivery was colonoscopy followed by upper endoscopy. Of the 222 participants who returned for the one-month follow-up, 200 participants (90%) had their C. difficile infection cured with 197 of those requiring only a single FMT. Infections were reported in 11 participants, but only 2 were thought to be possibly related to the procedure. FMT response was deemed durable, with recurrence of C. difficile infection in the 6 months after successful FMT occurring in only 4% of participants. This data includes patients with comorbidities, such as inflammatory bowel disease and immunocompromised status, who are typically excluded from FMT clinical trials.
“These initial results show a high success rate of FMT in the real-world setting. We’ll continue to track these patients for 10 years to assess long-term safety, which will be critical to determining the full safety profile of FMT,” added Dr. Kelly.
Engage rather than react: A call for hepatologists
In a new practice management commentary, Dr. Meena B. Bansal challenges hepatologists to champion value-based care.
In the September issue of Clinical Gastroenterology and Hepatology, Meena B. Bansal, MD, FAASLD, from Icahn School of Medicine at Mount Sinai, New York, provides clinicians with practical guidance on their essential role in value-based health care. Read the article, which appears in CGH’s Practice Management: The Road Ahead column: How Hepatologists Can Contribute to Value-Based Care.
Since hepatologists care for some of the sickest patients in the system, their role in documenting and managing chronic conditions is paramount to a system’s success in value-based care. Hepatologists can expand their reach by:
- Advocating for improvement of coding specificity.
- Participating in quality improvement work.
- Supporting efforts to create a shift in the cost curve for their high-risk patients.
By highlighting how they can shift the cost curve while improving outcomes, they can advocate for the additional resources needed to care for this high-risk population and can have the opportunity to show the return on investment. With this outlook, hepatologists who “engage” rather than “react” can make a real impact on system leadership and play a key role in this dynamic health care landscape.
Read the full article in the September issue of Clinical Gastroenterology and Hepatology.
In a new practice management commentary, Dr. Meena B. Bansal challenges hepatologists to champion value-based care.
In the September issue of Clinical Gastroenterology and Hepatology, Meena B. Bansal, MD, FAASLD, from Icahn School of Medicine at Mount Sinai, New York, provides clinicians with practical guidance on their essential role in value-based health care. Read the article, which appears in CGH’s Practice Management: The Road Ahead column: How Hepatologists Can Contribute to Value-Based Care.
Since hepatologists care for some of the sickest patients in the system, their role in documenting and managing chronic conditions is paramount to a system’s success in value-based care. Hepatologists can expand their reach by:
- Advocating for improvement of coding specificity.
- Participating in quality improvement work.
- Supporting efforts to create a shift in the cost curve for their high-risk patients.
By highlighting how they can shift the cost curve while improving outcomes, they can advocate for the additional resources needed to care for this high-risk population and can have the opportunity to show the return on investment. With this outlook, hepatologists who “engage” rather than “react” can make a real impact on system leadership and play a key role in this dynamic health care landscape.
Read the full article in the September issue of Clinical Gastroenterology and Hepatology.
In a new practice management commentary, Dr. Meena B. Bansal challenges hepatologists to champion value-based care.
In the September issue of Clinical Gastroenterology and Hepatology, Meena B. Bansal, MD, FAASLD, from Icahn School of Medicine at Mount Sinai, New York, provides clinicians with practical guidance on their essential role in value-based health care. Read the article, which appears in CGH’s Practice Management: The Road Ahead column: How Hepatologists Can Contribute to Value-Based Care.
Since hepatologists care for some of the sickest patients in the system, their role in documenting and managing chronic conditions is paramount to a system’s success in value-based care. Hepatologists can expand their reach by:
- Advocating for improvement of coding specificity.
- Participating in quality improvement work.
- Supporting efforts to create a shift in the cost curve for their high-risk patients.
By highlighting how they can shift the cost curve while improving outcomes, they can advocate for the additional resources needed to care for this high-risk population and can have the opportunity to show the return on investment. With this outlook, hepatologists who “engage” rather than “react” can make a real impact on system leadership and play a key role in this dynamic health care landscape.
Read the full article in the September issue of Clinical Gastroenterology and Hepatology.
IBD can be treated with diet alone
Dear colleagues and friends,
Thank you for your continued interest and support of the Perspectives debates. In this edition, Dr. Ashwin Ananthakrishnan and Dr. Laura Raffals explore the controversial topic of diet-based therapy in inflammatory bowel disease, highlights of the rationales for and against, and the current state of the evidence. All gastroenterologists frequently face questions pertaining to diet and its purported effects on digestive health. I found the discussion relevant to my own general practice, and I hope you will enjoy reading it as much as I did. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org.
Charles Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.
IBD can be treated with diet alone
Inflammatory bowel diseases (IBD), comprising Crohn’s disease and ulcerative colitis, have emerged as global diseases. The past 3 decades have seen a rising incidence of these diseases not just in the Western hemisphere, where their prevalence has been well recognized, but also in regions of the world such as Asia and South America where they were previously rare. Whereas several possible factors have been proposed to explain this rising incidence and globalization of disease with varying degrees of supportive evidence, one of the most likely factors is a changing diet. Over the same period that the disease incidence and prevalence have risen, diets worldwide have converged with several common trends observed across countries and continents. These include reductions in dietary fiber, fruits, and vegetables, and increased intake of processed food, animal protein, fats, and sugary drinks, all of which have been linked epidemiologically to Crohn’s disease.
Treatment of Crohn’s disease and ulcerative colitis over the past 2 decades has focused on the immunologic dysfunction observed in these patients. Successful treatment has relied on suppressing immune responses either broadly or through targeted suppression of specific immunologic pathways. By and large, whereas these approaches have enabled us to make significant progress in reducing disease-related morbidity, success has been moderate at best, with fewer than half of patients in any clinical trial achieving remission at the end of a year. Thus, this approach alone may not be sufficient for most patients with IBD.
Treatment of IBD with diet was long considered out of the mainstream and confined to the realm of anecdotes and message boards. Despite most patients believing that diet played a role in development of IBD and onset of flares and that dietary modification was helpful in relieving symptoms, physicians – who for the most part were not trained in these approaches – were not believers, and probably rightly so in the absence of any supporting data.1 However, the parallel emergence of three bodies of literature has now brought diet back into the mainstream of IBD care (such that not a single IBD conference goes by without at least a session or two on diet). First, large prospective cohorts from Europe and North America provided robust evidence linking long-term adult dietary patterns to disease incidence in adult-onset IBD, which supports many important case-control observations made over the past 2 decades.2 Second, and perhaps most important, we began understanding the role of the microbiome in the development of these diseases and recognizing its centrality to bowel inflammation. One of the key determinants of the microbiome is diet, exerting both short-term and long-term influences on the microbial structure. While microbial changes are by no means the only mechanism through which diet can influence intestinal inflammation, they are among the most important, with broad effects across many dietary components. These findings provided a robust scientific basis for investigating the role of diet. Third, while still far from the high-quality (and expensive) set-up of investigational trials of pharmacologic therapies, dietary therapy studies have also evolved to randomized controlled trial designs and investigation of mechanism-driven dietary combinations. Together, I think these three recent advances, in addition to the wealth of existing literature and anecdotal experience, have been important in moving diet (back) into the IBD mainstream.
So what evidence is there that diet is effective in the treatment of IBD? Randomized controlled trials published more than a decade ago demonstrated that exclusive enteral nutrition, wherein all table foods are eliminated from a diet and the patient relies on an elemental diet alone for nutrition, was effective in not just inducing clinical remission but also improving inflammatory biomarkers.3 With results replicated in several trials, exclusive enteral nutrition is, in many parts of the world, one of the first-line treatments for pediatric Crohn’s disease. That this has not been translated to longer-term maintenance therapy is not necessarily an indicator of lack of durable efficacy, but reflects the challenges of maintaining such a restrictive diet long term while living an active, normal life. However, more recent rigorous studies have demonstrated that the effects of exclusive enteral nutrition can be mimicked either by a selected, less-restrictive diet (such as CD-TREAT4), which is more sustainable, or by combining partial enteral nutrition with an elimination diet that is quite diverse (such as CDED5). The latter two are considerably more promising as longer-term dietary treatments for Crohn’s disease with durable efficacy in open-label studies and randomized trials.
What are my final arguments for diet being used as a treatment for IBD? With the exception of very restrictive ones, diets are generally safe. Of course, patients on restricted diets need monitoring for nutritional deficiencies, but this monitoring is likely less intense than that needed for many of our immunosuppressive therapies. Dietary therapies are not associated with an increase in risk of infections or malignancy (unlike our traditional immunosuppressive therapies), and consequently are much more likely to be accepted by our patients than what we are currently offering. In addition, the existing treatments are expensive and consequently difficult to sustain globally with the increasing burden of these diseases. On the other hand, as eating and dietary choices are a routine part of day-to-day life, dietary therapies are not likely to be associated with any excess costs.
Therefore, treating IBD with diet alone is supported by epidemiologic, mechanistic, and clinical evidence and is a safe, effective, and inexpensive alternative for our patients.
References
1. Zallot C et al. Inflamm Bowel Dis. 2013 Jan;19(1):66-72.
2. Sasson AN et al. Clin Gastroenterol Hepatol. 2019 Dec 5;S1542-3565(19)31394-1.
3. Wall CL et al. World J Gastroenterol. 2013;19:7652-60.
4. Svolos V et al. Gastroenterology. 2019;156:1354-67.e6.
5. Levine A et al. Gastroenterology. 2019;157:440-50.e8.
Dr. Ananthakrishnan is a gastroenterologist in the division of gastroenterology, Crohn’s and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston. He is supported by funding from the Crohn’s and Colitis Foundation and the Chleck Family Foundation.
IBD can be treated with diet alone – No, it cannot!
The cause of IBD is not completely understood, but we believe something in our environment triggers a dysregulated immune response in individuals with a genetic predisposition to IBD. Among the environmental triggers commonly recognized, diet is considered an important trigger through its ability to affect the composition and health of the gut microbiome and host barrier function. Epidemiologic data support this assumption. Westernization of diet has been associated with the increasing incidence of IBD across the globe and in immigrants who move from developing countries to an industrialized country. Observational studies have shown diets higher in meat and polyunsaturated fatty acids and omega-6 fatty acids are associated with a higher risk for IBD, whereas diets high in fruits, vegetables, and other sources of dietary fiber have a lower risk of IBD.
A growing body of evidence supports the impact food can have on gut health, specifically in mouse IBD models, but it is challenging to translate findings from animal studies into dietary interventions for IBD patients. Mouse studies help us understand the mechanistic basis of how diet may affect IBD, but randomized clinical trials establishing their role in IBD are lacking. This is not surprising as dietary studies are challenging, particularly if done in a robust manner, given the difficulties of ensuring and measuring dietary compliance.
Exclusive enteral nutrition (EEN) has been studied the most rigorously of all diets in IBD and has demonstrated the greatest benefit, compared with other diet studies in IBD. EEN requires the intake of elemental, semi-elemental, or polymeric formulas to meet all nutritional requirements without additional intake of food for 6-8 weeks. Studies have been performed mostly in pediatric populations and have shown effectiveness in induction of remission with reduction in inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin, and even mucosal healing. EEN has not worked out as well for adult populations, because of the poor tolerability of exclusive intake of enteral formulas. Because of this limitation, studies of partial enteral nutrition have been performed that generally allow some food intake in addition to the enteral nutrition. When compared with EEN or anti–tumor necrosis factor–alpha therapy, partial enteral nutrition is a less-effective treatment of Crohn’s disease; however, partial enteral nutrition does appear to improve clinical symptoms.
Beyond EEN, there are many diets that have been considered for the treatment of IBD, including the specific carbohydrate diet (SCD), Crohn’s disease exclusion diet, autoimmune diet, low FODMAP (fermentable oligo-, di-, mono-saccharides and polyols), Paleolithic diet, Mediterranean diet, and the semi-vegetarian diet, to name a few. Of these, only the SCD and Crohn’s disease exclusion diets have shown improvement in clinical remission and reduction in inflammatory markers.
The SCD diet is based on the theory that malabsorption of disaccharide and polysaccharide carbohydrates leads to bacterial overgrowth and host barrier dysfunction. This diet eliminates grains, dairy, processed meats, and certain vegetables such as potatoes, yams, and legumes. Small uncontrolled studies have shown improvement in symptoms and endoscopy findings. However, this restrictive diet is nearly impossible to follow long term. The Crohn’s disease exclusion diet is a whole foods diet avoiding all processed foods, animal fats, dairy, and gluten. Small studies of this diet have also shown improvement in clinical symptoms and inflammatory markers.
The plethora of studies and reports of the therapeutic effect of diet on IBD provide some promise of the benefit dietary modifications can bring to our IBD patients. However, most dietary studies are underpowered, lack a control arm, and do not include endoscopic endpoints. The current body of evidence remains insufficient to support the use of diet alone for the treatment of IBD. We need randomized clinical controlled trials that are held to the same rigor as those of our approved medical treatments for IBD. Although such trials are challenging, we’ve seen groups rise to the task to carry out more robust dietary studies in the IBD population, and we await the results of several ongoing trials.
IBD is a challenging disease to live with and often leaves our patients feeling out of control. Dietary choices provide an avenue for patients to have some control of their health. However, current evidence does not support the prescription of dietary interventions alone to treat IBD, particularly when we have known, effective therapies. While I am not ready to prescribe diet as a stand-alone treatment for IBD, I make a point to discuss the role diet may play in helping our patients achieve optimal health. As health care providers, it is our responsibility to provide holistic care to our patients, which includes promotion of a healthy diet, absent processed foods and added sugars. Healthy lifestyle choices combined with effective medical and surgical treatments offer our patients the best shot at sustained disease control.
References
1. Hou JK et al. Am J Gastroenterol. 2011;106(4):563-73.
2. Zachos M et al. Cochrane Database Syst Rev. 2007(1):CD000542.
3. Lee D et al. Inflamm Bowel Dis. 2015;21(8):1786-93.
4. Obih C et al. Nutrition. 2016;32(4):418-25.
5. Sigall Boneh R et al. J Crohns Colitis. 2017;11(10):1205-12.
Dr. Raffals is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. She has no financial conflicts of interest relevant to this paper.
Dear colleagues and friends,
Thank you for your continued interest and support of the Perspectives debates. In this edition, Dr. Ashwin Ananthakrishnan and Dr. Laura Raffals explore the controversial topic of diet-based therapy in inflammatory bowel disease, highlights of the rationales for and against, and the current state of the evidence. All gastroenterologists frequently face questions pertaining to diet and its purported effects on digestive health. I found the discussion relevant to my own general practice, and I hope you will enjoy reading it as much as I did. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org.
Charles Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.
IBD can be treated with diet alone
Inflammatory bowel diseases (IBD), comprising Crohn’s disease and ulcerative colitis, have emerged as global diseases. The past 3 decades have seen a rising incidence of these diseases not just in the Western hemisphere, where their prevalence has been well recognized, but also in regions of the world such as Asia and South America where they were previously rare. Whereas several possible factors have been proposed to explain this rising incidence and globalization of disease with varying degrees of supportive evidence, one of the most likely factors is a changing diet. Over the same period that the disease incidence and prevalence have risen, diets worldwide have converged with several common trends observed across countries and continents. These include reductions in dietary fiber, fruits, and vegetables, and increased intake of processed food, animal protein, fats, and sugary drinks, all of which have been linked epidemiologically to Crohn’s disease.
Treatment of Crohn’s disease and ulcerative colitis over the past 2 decades has focused on the immunologic dysfunction observed in these patients. Successful treatment has relied on suppressing immune responses either broadly or through targeted suppression of specific immunologic pathways. By and large, whereas these approaches have enabled us to make significant progress in reducing disease-related morbidity, success has been moderate at best, with fewer than half of patients in any clinical trial achieving remission at the end of a year. Thus, this approach alone may not be sufficient for most patients with IBD.
Treatment of IBD with diet was long considered out of the mainstream and confined to the realm of anecdotes and message boards. Despite most patients believing that diet played a role in development of IBD and onset of flares and that dietary modification was helpful in relieving symptoms, physicians – who for the most part were not trained in these approaches – were not believers, and probably rightly so in the absence of any supporting data.1 However, the parallel emergence of three bodies of literature has now brought diet back into the mainstream of IBD care (such that not a single IBD conference goes by without at least a session or two on diet). First, large prospective cohorts from Europe and North America provided robust evidence linking long-term adult dietary patterns to disease incidence in adult-onset IBD, which supports many important case-control observations made over the past 2 decades.2 Second, and perhaps most important, we began understanding the role of the microbiome in the development of these diseases and recognizing its centrality to bowel inflammation. One of the key determinants of the microbiome is diet, exerting both short-term and long-term influences on the microbial structure. While microbial changes are by no means the only mechanism through which diet can influence intestinal inflammation, they are among the most important, with broad effects across many dietary components. These findings provided a robust scientific basis for investigating the role of diet. Third, while still far from the high-quality (and expensive) set-up of investigational trials of pharmacologic therapies, dietary therapy studies have also evolved to randomized controlled trial designs and investigation of mechanism-driven dietary combinations. Together, I think these three recent advances, in addition to the wealth of existing literature and anecdotal experience, have been important in moving diet (back) into the IBD mainstream.
So what evidence is there that diet is effective in the treatment of IBD? Randomized controlled trials published more than a decade ago demonstrated that exclusive enteral nutrition, wherein all table foods are eliminated from a diet and the patient relies on an elemental diet alone for nutrition, was effective in not just inducing clinical remission but also improving inflammatory biomarkers.3 With results replicated in several trials, exclusive enteral nutrition is, in many parts of the world, one of the first-line treatments for pediatric Crohn’s disease. That this has not been translated to longer-term maintenance therapy is not necessarily an indicator of lack of durable efficacy, but reflects the challenges of maintaining such a restrictive diet long term while living an active, normal life. However, more recent rigorous studies have demonstrated that the effects of exclusive enteral nutrition can be mimicked either by a selected, less-restrictive diet (such as CD-TREAT4), which is more sustainable, or by combining partial enteral nutrition with an elimination diet that is quite diverse (such as CDED5). The latter two are considerably more promising as longer-term dietary treatments for Crohn’s disease with durable efficacy in open-label studies and randomized trials.
What are my final arguments for diet being used as a treatment for IBD? With the exception of very restrictive ones, diets are generally safe. Of course, patients on restricted diets need monitoring for nutritional deficiencies, but this monitoring is likely less intense than that needed for many of our immunosuppressive therapies. Dietary therapies are not associated with an increase in risk of infections or malignancy (unlike our traditional immunosuppressive therapies), and consequently are much more likely to be accepted by our patients than what we are currently offering. In addition, the existing treatments are expensive and consequently difficult to sustain globally with the increasing burden of these diseases. On the other hand, as eating and dietary choices are a routine part of day-to-day life, dietary therapies are not likely to be associated with any excess costs.
Therefore, treating IBD with diet alone is supported by epidemiologic, mechanistic, and clinical evidence and is a safe, effective, and inexpensive alternative for our patients.
References
1. Zallot C et al. Inflamm Bowel Dis. 2013 Jan;19(1):66-72.
2. Sasson AN et al. Clin Gastroenterol Hepatol. 2019 Dec 5;S1542-3565(19)31394-1.
3. Wall CL et al. World J Gastroenterol. 2013;19:7652-60.
4. Svolos V et al. Gastroenterology. 2019;156:1354-67.e6.
5. Levine A et al. Gastroenterology. 2019;157:440-50.e8.
Dr. Ananthakrishnan is a gastroenterologist in the division of gastroenterology, Crohn’s and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston. He is supported by funding from the Crohn’s and Colitis Foundation and the Chleck Family Foundation.
IBD can be treated with diet alone – No, it cannot!
The cause of IBD is not completely understood, but we believe something in our environment triggers a dysregulated immune response in individuals with a genetic predisposition to IBD. Among the environmental triggers commonly recognized, diet is considered an important trigger through its ability to affect the composition and health of the gut microbiome and host barrier function. Epidemiologic data support this assumption. Westernization of diet has been associated with the increasing incidence of IBD across the globe and in immigrants who move from developing countries to an industrialized country. Observational studies have shown diets higher in meat and polyunsaturated fatty acids and omega-6 fatty acids are associated with a higher risk for IBD, whereas diets high in fruits, vegetables, and other sources of dietary fiber have a lower risk of IBD.
A growing body of evidence supports the impact food can have on gut health, specifically in mouse IBD models, but it is challenging to translate findings from animal studies into dietary interventions for IBD patients. Mouse studies help us understand the mechanistic basis of how diet may affect IBD, but randomized clinical trials establishing their role in IBD are lacking. This is not surprising as dietary studies are challenging, particularly if done in a robust manner, given the difficulties of ensuring and measuring dietary compliance.
Exclusive enteral nutrition (EEN) has been studied the most rigorously of all diets in IBD and has demonstrated the greatest benefit, compared with other diet studies in IBD. EEN requires the intake of elemental, semi-elemental, or polymeric formulas to meet all nutritional requirements without additional intake of food for 6-8 weeks. Studies have been performed mostly in pediatric populations and have shown effectiveness in induction of remission with reduction in inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin, and even mucosal healing. EEN has not worked out as well for adult populations, because of the poor tolerability of exclusive intake of enteral formulas. Because of this limitation, studies of partial enteral nutrition have been performed that generally allow some food intake in addition to the enteral nutrition. When compared with EEN or anti–tumor necrosis factor–alpha therapy, partial enteral nutrition is a less-effective treatment of Crohn’s disease; however, partial enteral nutrition does appear to improve clinical symptoms.
Beyond EEN, there are many diets that have been considered for the treatment of IBD, including the specific carbohydrate diet (SCD), Crohn’s disease exclusion diet, autoimmune diet, low FODMAP (fermentable oligo-, di-, mono-saccharides and polyols), Paleolithic diet, Mediterranean diet, and the semi-vegetarian diet, to name a few. Of these, only the SCD and Crohn’s disease exclusion diets have shown improvement in clinical remission and reduction in inflammatory markers.
The SCD diet is based on the theory that malabsorption of disaccharide and polysaccharide carbohydrates leads to bacterial overgrowth and host barrier dysfunction. This diet eliminates grains, dairy, processed meats, and certain vegetables such as potatoes, yams, and legumes. Small uncontrolled studies have shown improvement in symptoms and endoscopy findings. However, this restrictive diet is nearly impossible to follow long term. The Crohn’s disease exclusion diet is a whole foods diet avoiding all processed foods, animal fats, dairy, and gluten. Small studies of this diet have also shown improvement in clinical symptoms and inflammatory markers.
The plethora of studies and reports of the therapeutic effect of diet on IBD provide some promise of the benefit dietary modifications can bring to our IBD patients. However, most dietary studies are underpowered, lack a control arm, and do not include endoscopic endpoints. The current body of evidence remains insufficient to support the use of diet alone for the treatment of IBD. We need randomized clinical controlled trials that are held to the same rigor as those of our approved medical treatments for IBD. Although such trials are challenging, we’ve seen groups rise to the task to carry out more robust dietary studies in the IBD population, and we await the results of several ongoing trials.
IBD is a challenging disease to live with and often leaves our patients feeling out of control. Dietary choices provide an avenue for patients to have some control of their health. However, current evidence does not support the prescription of dietary interventions alone to treat IBD, particularly when we have known, effective therapies. While I am not ready to prescribe diet as a stand-alone treatment for IBD, I make a point to discuss the role diet may play in helping our patients achieve optimal health. As health care providers, it is our responsibility to provide holistic care to our patients, which includes promotion of a healthy diet, absent processed foods and added sugars. Healthy lifestyle choices combined with effective medical and surgical treatments offer our patients the best shot at sustained disease control.
References
1. Hou JK et al. Am J Gastroenterol. 2011;106(4):563-73.
2. Zachos M et al. Cochrane Database Syst Rev. 2007(1):CD000542.
3. Lee D et al. Inflamm Bowel Dis. 2015;21(8):1786-93.
4. Obih C et al. Nutrition. 2016;32(4):418-25.
5. Sigall Boneh R et al. J Crohns Colitis. 2017;11(10):1205-12.
Dr. Raffals is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. She has no financial conflicts of interest relevant to this paper.
Dear colleagues and friends,
Thank you for your continued interest and support of the Perspectives debates. In this edition, Dr. Ashwin Ananthakrishnan and Dr. Laura Raffals explore the controversial topic of diet-based therapy in inflammatory bowel disease, highlights of the rationales for and against, and the current state of the evidence. All gastroenterologists frequently face questions pertaining to diet and its purported effects on digestive health. I found the discussion relevant to my own general practice, and I hope you will enjoy reading it as much as I did. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org.
Charles Kahi, MD, MS, AGAF, professor of medicine, Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.
IBD can be treated with diet alone
Inflammatory bowel diseases (IBD), comprising Crohn’s disease and ulcerative colitis, have emerged as global diseases. The past 3 decades have seen a rising incidence of these diseases not just in the Western hemisphere, where their prevalence has been well recognized, but also in regions of the world such as Asia and South America where they were previously rare. Whereas several possible factors have been proposed to explain this rising incidence and globalization of disease with varying degrees of supportive evidence, one of the most likely factors is a changing diet. Over the same period that the disease incidence and prevalence have risen, diets worldwide have converged with several common trends observed across countries and continents. These include reductions in dietary fiber, fruits, and vegetables, and increased intake of processed food, animal protein, fats, and sugary drinks, all of which have been linked epidemiologically to Crohn’s disease.
Treatment of Crohn’s disease and ulcerative colitis over the past 2 decades has focused on the immunologic dysfunction observed in these patients. Successful treatment has relied on suppressing immune responses either broadly or through targeted suppression of specific immunologic pathways. By and large, whereas these approaches have enabled us to make significant progress in reducing disease-related morbidity, success has been moderate at best, with fewer than half of patients in any clinical trial achieving remission at the end of a year. Thus, this approach alone may not be sufficient for most patients with IBD.
Treatment of IBD with diet was long considered out of the mainstream and confined to the realm of anecdotes and message boards. Despite most patients believing that diet played a role in development of IBD and onset of flares and that dietary modification was helpful in relieving symptoms, physicians – who for the most part were not trained in these approaches – were not believers, and probably rightly so in the absence of any supporting data.1 However, the parallel emergence of three bodies of literature has now brought diet back into the mainstream of IBD care (such that not a single IBD conference goes by without at least a session or two on diet). First, large prospective cohorts from Europe and North America provided robust evidence linking long-term adult dietary patterns to disease incidence in adult-onset IBD, which supports many important case-control observations made over the past 2 decades.2 Second, and perhaps most important, we began understanding the role of the microbiome in the development of these diseases and recognizing its centrality to bowel inflammation. One of the key determinants of the microbiome is diet, exerting both short-term and long-term influences on the microbial structure. While microbial changes are by no means the only mechanism through which diet can influence intestinal inflammation, they are among the most important, with broad effects across many dietary components. These findings provided a robust scientific basis for investigating the role of diet. Third, while still far from the high-quality (and expensive) set-up of investigational trials of pharmacologic therapies, dietary therapy studies have also evolved to randomized controlled trial designs and investigation of mechanism-driven dietary combinations. Together, I think these three recent advances, in addition to the wealth of existing literature and anecdotal experience, have been important in moving diet (back) into the IBD mainstream.
So what evidence is there that diet is effective in the treatment of IBD? Randomized controlled trials published more than a decade ago demonstrated that exclusive enteral nutrition, wherein all table foods are eliminated from a diet and the patient relies on an elemental diet alone for nutrition, was effective in not just inducing clinical remission but also improving inflammatory biomarkers.3 With results replicated in several trials, exclusive enteral nutrition is, in many parts of the world, one of the first-line treatments for pediatric Crohn’s disease. That this has not been translated to longer-term maintenance therapy is not necessarily an indicator of lack of durable efficacy, but reflects the challenges of maintaining such a restrictive diet long term while living an active, normal life. However, more recent rigorous studies have demonstrated that the effects of exclusive enteral nutrition can be mimicked either by a selected, less-restrictive diet (such as CD-TREAT4), which is more sustainable, or by combining partial enteral nutrition with an elimination diet that is quite diverse (such as CDED5). The latter two are considerably more promising as longer-term dietary treatments for Crohn’s disease with durable efficacy in open-label studies and randomized trials.
What are my final arguments for diet being used as a treatment for IBD? With the exception of very restrictive ones, diets are generally safe. Of course, patients on restricted diets need monitoring for nutritional deficiencies, but this monitoring is likely less intense than that needed for many of our immunosuppressive therapies. Dietary therapies are not associated with an increase in risk of infections or malignancy (unlike our traditional immunosuppressive therapies), and consequently are much more likely to be accepted by our patients than what we are currently offering. In addition, the existing treatments are expensive and consequently difficult to sustain globally with the increasing burden of these diseases. On the other hand, as eating and dietary choices are a routine part of day-to-day life, dietary therapies are not likely to be associated with any excess costs.
Therefore, treating IBD with diet alone is supported by epidemiologic, mechanistic, and clinical evidence and is a safe, effective, and inexpensive alternative for our patients.
References
1. Zallot C et al. Inflamm Bowel Dis. 2013 Jan;19(1):66-72.
2. Sasson AN et al. Clin Gastroenterol Hepatol. 2019 Dec 5;S1542-3565(19)31394-1.
3. Wall CL et al. World J Gastroenterol. 2013;19:7652-60.
4. Svolos V et al. Gastroenterology. 2019;156:1354-67.e6.
5. Levine A et al. Gastroenterology. 2019;157:440-50.e8.
Dr. Ananthakrishnan is a gastroenterologist in the division of gastroenterology, Crohn’s and Colitis Center, Massachusetts General Hospital and Harvard Medical School, Boston. He is supported by funding from the Crohn’s and Colitis Foundation and the Chleck Family Foundation.
IBD can be treated with diet alone – No, it cannot!
The cause of IBD is not completely understood, but we believe something in our environment triggers a dysregulated immune response in individuals with a genetic predisposition to IBD. Among the environmental triggers commonly recognized, diet is considered an important trigger through its ability to affect the composition and health of the gut microbiome and host barrier function. Epidemiologic data support this assumption. Westernization of diet has been associated with the increasing incidence of IBD across the globe and in immigrants who move from developing countries to an industrialized country. Observational studies have shown diets higher in meat and polyunsaturated fatty acids and omega-6 fatty acids are associated with a higher risk for IBD, whereas diets high in fruits, vegetables, and other sources of dietary fiber have a lower risk of IBD.
A growing body of evidence supports the impact food can have on gut health, specifically in mouse IBD models, but it is challenging to translate findings from animal studies into dietary interventions for IBD patients. Mouse studies help us understand the mechanistic basis of how diet may affect IBD, but randomized clinical trials establishing their role in IBD are lacking. This is not surprising as dietary studies are challenging, particularly if done in a robust manner, given the difficulties of ensuring and measuring dietary compliance.
Exclusive enteral nutrition (EEN) has been studied the most rigorously of all diets in IBD and has demonstrated the greatest benefit, compared with other diet studies in IBD. EEN requires the intake of elemental, semi-elemental, or polymeric formulas to meet all nutritional requirements without additional intake of food for 6-8 weeks. Studies have been performed mostly in pediatric populations and have shown effectiveness in induction of remission with reduction in inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin, and even mucosal healing. EEN has not worked out as well for adult populations, because of the poor tolerability of exclusive intake of enteral formulas. Because of this limitation, studies of partial enteral nutrition have been performed that generally allow some food intake in addition to the enteral nutrition. When compared with EEN or anti–tumor necrosis factor–alpha therapy, partial enteral nutrition is a less-effective treatment of Crohn’s disease; however, partial enteral nutrition does appear to improve clinical symptoms.
Beyond EEN, there are many diets that have been considered for the treatment of IBD, including the specific carbohydrate diet (SCD), Crohn’s disease exclusion diet, autoimmune diet, low FODMAP (fermentable oligo-, di-, mono-saccharides and polyols), Paleolithic diet, Mediterranean diet, and the semi-vegetarian diet, to name a few. Of these, only the SCD and Crohn’s disease exclusion diets have shown improvement in clinical remission and reduction in inflammatory markers.
The SCD diet is based on the theory that malabsorption of disaccharide and polysaccharide carbohydrates leads to bacterial overgrowth and host barrier dysfunction. This diet eliminates grains, dairy, processed meats, and certain vegetables such as potatoes, yams, and legumes. Small uncontrolled studies have shown improvement in symptoms and endoscopy findings. However, this restrictive diet is nearly impossible to follow long term. The Crohn’s disease exclusion diet is a whole foods diet avoiding all processed foods, animal fats, dairy, and gluten. Small studies of this diet have also shown improvement in clinical symptoms and inflammatory markers.
The plethora of studies and reports of the therapeutic effect of diet on IBD provide some promise of the benefit dietary modifications can bring to our IBD patients. However, most dietary studies are underpowered, lack a control arm, and do not include endoscopic endpoints. The current body of evidence remains insufficient to support the use of diet alone for the treatment of IBD. We need randomized clinical controlled trials that are held to the same rigor as those of our approved medical treatments for IBD. Although such trials are challenging, we’ve seen groups rise to the task to carry out more robust dietary studies in the IBD population, and we await the results of several ongoing trials.
IBD is a challenging disease to live with and often leaves our patients feeling out of control. Dietary choices provide an avenue for patients to have some control of their health. However, current evidence does not support the prescription of dietary interventions alone to treat IBD, particularly when we have known, effective therapies. While I am not ready to prescribe diet as a stand-alone treatment for IBD, I make a point to discuss the role diet may play in helping our patients achieve optimal health. As health care providers, it is our responsibility to provide holistic care to our patients, which includes promotion of a healthy diet, absent processed foods and added sugars. Healthy lifestyle choices combined with effective medical and surgical treatments offer our patients the best shot at sustained disease control.
References
1. Hou JK et al. Am J Gastroenterol. 2011;106(4):563-73.
2. Zachos M et al. Cochrane Database Syst Rev. 2007(1):CD000542.
3. Lee D et al. Inflamm Bowel Dis. 2015;21(8):1786-93.
4. Obih C et al. Nutrition. 2016;32(4):418-25.
5. Sigall Boneh R et al. J Crohns Colitis. 2017;11(10):1205-12.
Dr. Raffals is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. She has no financial conflicts of interest relevant to this paper.
JIA arthritis and uveitis flares ‘often run parallel’
Children with juvenile idiopathic arthritis–associated uveitis (JIA-U) are significantly more likely to experience a flare in their eye disease if their arthritis is also worsening, a team of U.S.-based researchers has found.
In a longitudinal cohort study, children with active arthritis at the time of a routine rheumatology assessment had an almost 2.5-fold increased risk of also having active uveitis 45 days before or after the assessment than did children whose arthritis was not flaring at the rheumatology assessment.
“We demonstrate that the two diseases often run parallel courses,” corresponding author Emily J. Liebling, MD, of the Children’s Hospital of Philadelphia and associates state in Arthritis Care & Research, noting that the magnitude of the association is striking.
“Although there are known risk factors associated with uveitis development in children with JIA, less data are available about factors associated with uveitis flare or activity,” said Sheila T. Angeles-Han, MD, MSc, of the departments of pediatrics and ophthalmology at Cincinnati Children’s Hospital Medical Center who commented on the study in an interview.
“If proven, this knowledge has the potential to impact practice patterns and current guidelines wherein a pediatric rheumatologist who evaluates a child with JIA-associated uveitis and finds active arthritis would request an expedited ophthalmic examination,” Dr. Angeles-Han suggested.
Dr. Angeles-Han led the development of the first American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of JIA-Associated Uveitis, which recommends regular screening for uveitis in all children with JIA. Children found to have uveitis should then be screened at least every 3 months, and more frequently if they are taking glucocorticoids and treatment is being tapered.
JIA-associated uveitis accounts for around 20%-40% of all cases of noninfectious childhood eye inflammation, and it can run an insidious and chronic course.
“Children with acute anterior uveitis are symptomatic and tend to have a painful red eye, thus prompting an ophthalmic evaluation,” Dr. Angeles-Han explained. “This is different from children with chronic anterior uveitis who tend not to have any symptoms, thus a screening examination is critical to detect ocular inflammation.”
While the ACR/AF guideline distinguishes between acute and chronic uveitis, Dr. Liebling and colleagues explain that they did not because their experience shows that “even patients with chronic anterior uveitis, typically thought to have silent disease, may exhibit symptoms of eye pain, redness, vision changes, and photophobia.”
Conversely, they say “the JIA subtypes usually associated with acute anterior uveitis may instead manifest as asymptomatic eye disease.”
For their study, Dr. Liebling and coinvestigators examined the records of children seen at the Children’s Hospital of Philadelphia over a 6.5-year period. For inclusion, children had to have a physician diagnosis of JIA of any subtype and a history of uveitis.
A total of 98 children were included in the retrospective evaluation; the median age at diagnosis of JIA was 3.3 years, and the median age at first uveitis diagnosis was 5.1 years. The majority (82%) were female, 69% were antinuclear antibody (ANA) positive, and 60% had oligoarthritis – all of which have been associated with having a higher risk for developing uveitis.
However, independent of these and several other factors, the probability of having active uveitis within 45 days of a rheumatology assessment was 65% in those with active arthritis versus 42% for those with no active joints.
Their data are based on 1,229 rheumatology visits that occurred between 2013 and 2019, with a median of 13 visits per patient. Overall, arthritis was defined as being active in 17% of visits, and active uveitis was observed in 18% of rheumatology visits.
Concordance between arthritis and uveitis activity was observed 73% of the time, the researchers reported. A sensitivity analysis that excluded children with the enthesitis-related arthritis subtype of JIA, who may not undergo frequent eye exams, did not change their findings.
Decreased odds of active uveitis at any time point were seen with the use of combination biologic and nonbiologic disease-modifying antirheumatic drugs. Years from uveitis diagnosis was also associated with lower odds of active uveitis over time.
Other factors associated with lower odds of uveitis were female sex, HLA-B27 positivity, and having any subtype of JIA other than the oligoarticular subtype.
Dr. Liebling and coinvestigators concluded that, contrary to the historical dogma, arthritis and uveitis do not run distinct and unrelated courses: “In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity.”
The study was sponsored by the Children’s Hospital of Philadelphia Rheumatology Research Fund. The investigators for the study had no financial support from commercial sources or any other potential conflicts of interest. Dr. Angeles-Han had no conflicts of interest to disclose.
SOURCE: Liebling EJ et al. Arthritis Care Res. 2020 Oct 12. doi: 10.1002/acr.24483.
Children with juvenile idiopathic arthritis–associated uveitis (JIA-U) are significantly more likely to experience a flare in their eye disease if their arthritis is also worsening, a team of U.S.-based researchers has found.
In a longitudinal cohort study, children with active arthritis at the time of a routine rheumatology assessment had an almost 2.5-fold increased risk of also having active uveitis 45 days before or after the assessment than did children whose arthritis was not flaring at the rheumatology assessment.
“We demonstrate that the two diseases often run parallel courses,” corresponding author Emily J. Liebling, MD, of the Children’s Hospital of Philadelphia and associates state in Arthritis Care & Research, noting that the magnitude of the association is striking.
“Although there are known risk factors associated with uveitis development in children with JIA, less data are available about factors associated with uveitis flare or activity,” said Sheila T. Angeles-Han, MD, MSc, of the departments of pediatrics and ophthalmology at Cincinnati Children’s Hospital Medical Center who commented on the study in an interview.
“If proven, this knowledge has the potential to impact practice patterns and current guidelines wherein a pediatric rheumatologist who evaluates a child with JIA-associated uveitis and finds active arthritis would request an expedited ophthalmic examination,” Dr. Angeles-Han suggested.
Dr. Angeles-Han led the development of the first American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of JIA-Associated Uveitis, which recommends regular screening for uveitis in all children with JIA. Children found to have uveitis should then be screened at least every 3 months, and more frequently if they are taking glucocorticoids and treatment is being tapered.
JIA-associated uveitis accounts for around 20%-40% of all cases of noninfectious childhood eye inflammation, and it can run an insidious and chronic course.
“Children with acute anterior uveitis are symptomatic and tend to have a painful red eye, thus prompting an ophthalmic evaluation,” Dr. Angeles-Han explained. “This is different from children with chronic anterior uveitis who tend not to have any symptoms, thus a screening examination is critical to detect ocular inflammation.”
While the ACR/AF guideline distinguishes between acute and chronic uveitis, Dr. Liebling and colleagues explain that they did not because their experience shows that “even patients with chronic anterior uveitis, typically thought to have silent disease, may exhibit symptoms of eye pain, redness, vision changes, and photophobia.”
Conversely, they say “the JIA subtypes usually associated with acute anterior uveitis may instead manifest as asymptomatic eye disease.”
For their study, Dr. Liebling and coinvestigators examined the records of children seen at the Children’s Hospital of Philadelphia over a 6.5-year period. For inclusion, children had to have a physician diagnosis of JIA of any subtype and a history of uveitis.
A total of 98 children were included in the retrospective evaluation; the median age at diagnosis of JIA was 3.3 years, and the median age at first uveitis diagnosis was 5.1 years. The majority (82%) were female, 69% were antinuclear antibody (ANA) positive, and 60% had oligoarthritis – all of which have been associated with having a higher risk for developing uveitis.
However, independent of these and several other factors, the probability of having active uveitis within 45 days of a rheumatology assessment was 65% in those with active arthritis versus 42% for those with no active joints.
Their data are based on 1,229 rheumatology visits that occurred between 2013 and 2019, with a median of 13 visits per patient. Overall, arthritis was defined as being active in 17% of visits, and active uveitis was observed in 18% of rheumatology visits.
Concordance between arthritis and uveitis activity was observed 73% of the time, the researchers reported. A sensitivity analysis that excluded children with the enthesitis-related arthritis subtype of JIA, who may not undergo frequent eye exams, did not change their findings.
Decreased odds of active uveitis at any time point were seen with the use of combination biologic and nonbiologic disease-modifying antirheumatic drugs. Years from uveitis diagnosis was also associated with lower odds of active uveitis over time.
Other factors associated with lower odds of uveitis were female sex, HLA-B27 positivity, and having any subtype of JIA other than the oligoarticular subtype.
Dr. Liebling and coinvestigators concluded that, contrary to the historical dogma, arthritis and uveitis do not run distinct and unrelated courses: “In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity.”
The study was sponsored by the Children’s Hospital of Philadelphia Rheumatology Research Fund. The investigators for the study had no financial support from commercial sources or any other potential conflicts of interest. Dr. Angeles-Han had no conflicts of interest to disclose.
SOURCE: Liebling EJ et al. Arthritis Care Res. 2020 Oct 12. doi: 10.1002/acr.24483.
Children with juvenile idiopathic arthritis–associated uveitis (JIA-U) are significantly more likely to experience a flare in their eye disease if their arthritis is also worsening, a team of U.S.-based researchers has found.
In a longitudinal cohort study, children with active arthritis at the time of a routine rheumatology assessment had an almost 2.5-fold increased risk of also having active uveitis 45 days before or after the assessment than did children whose arthritis was not flaring at the rheumatology assessment.
“We demonstrate that the two diseases often run parallel courses,” corresponding author Emily J. Liebling, MD, of the Children’s Hospital of Philadelphia and associates state in Arthritis Care & Research, noting that the magnitude of the association is striking.
“Although there are known risk factors associated with uveitis development in children with JIA, less data are available about factors associated with uveitis flare or activity,” said Sheila T. Angeles-Han, MD, MSc, of the departments of pediatrics and ophthalmology at Cincinnati Children’s Hospital Medical Center who commented on the study in an interview.
“If proven, this knowledge has the potential to impact practice patterns and current guidelines wherein a pediatric rheumatologist who evaluates a child with JIA-associated uveitis and finds active arthritis would request an expedited ophthalmic examination,” Dr. Angeles-Han suggested.
Dr. Angeles-Han led the development of the first American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of JIA-Associated Uveitis, which recommends regular screening for uveitis in all children with JIA. Children found to have uveitis should then be screened at least every 3 months, and more frequently if they are taking glucocorticoids and treatment is being tapered.
JIA-associated uveitis accounts for around 20%-40% of all cases of noninfectious childhood eye inflammation, and it can run an insidious and chronic course.
“Children with acute anterior uveitis are symptomatic and tend to have a painful red eye, thus prompting an ophthalmic evaluation,” Dr. Angeles-Han explained. “This is different from children with chronic anterior uveitis who tend not to have any symptoms, thus a screening examination is critical to detect ocular inflammation.”
While the ACR/AF guideline distinguishes between acute and chronic uveitis, Dr. Liebling and colleagues explain that they did not because their experience shows that “even patients with chronic anterior uveitis, typically thought to have silent disease, may exhibit symptoms of eye pain, redness, vision changes, and photophobia.”
Conversely, they say “the JIA subtypes usually associated with acute anterior uveitis may instead manifest as asymptomatic eye disease.”
For their study, Dr. Liebling and coinvestigators examined the records of children seen at the Children’s Hospital of Philadelphia over a 6.5-year period. For inclusion, children had to have a physician diagnosis of JIA of any subtype and a history of uveitis.
A total of 98 children were included in the retrospective evaluation; the median age at diagnosis of JIA was 3.3 years, and the median age at first uveitis diagnosis was 5.1 years. The majority (82%) were female, 69% were antinuclear antibody (ANA) positive, and 60% had oligoarthritis – all of which have been associated with having a higher risk for developing uveitis.
However, independent of these and several other factors, the probability of having active uveitis within 45 days of a rheumatology assessment was 65% in those with active arthritis versus 42% for those with no active joints.
Their data are based on 1,229 rheumatology visits that occurred between 2013 and 2019, with a median of 13 visits per patient. Overall, arthritis was defined as being active in 17% of visits, and active uveitis was observed in 18% of rheumatology visits.
Concordance between arthritis and uveitis activity was observed 73% of the time, the researchers reported. A sensitivity analysis that excluded children with the enthesitis-related arthritis subtype of JIA, who may not undergo frequent eye exams, did not change their findings.
Decreased odds of active uveitis at any time point were seen with the use of combination biologic and nonbiologic disease-modifying antirheumatic drugs. Years from uveitis diagnosis was also associated with lower odds of active uveitis over time.
Other factors associated with lower odds of uveitis were female sex, HLA-B27 positivity, and having any subtype of JIA other than the oligoarticular subtype.
Dr. Liebling and coinvestigators concluded that, contrary to the historical dogma, arthritis and uveitis do not run distinct and unrelated courses: “In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity.”
The study was sponsored by the Children’s Hospital of Philadelphia Rheumatology Research Fund. The investigators for the study had no financial support from commercial sources or any other potential conflicts of interest. Dr. Angeles-Han had no conflicts of interest to disclose.
SOURCE: Liebling EJ et al. Arthritis Care Res. 2020 Oct 12. doi: 10.1002/acr.24483.
FROM ARTHRITIS CARE & RESEARCH
Sleep-disordered breathing in neuromuscular disease
Sleep-disordered breathing (SDB) is a common sleep disturbance in neuromuscular disease (NMD) affecting 36% to 53% of diagnosed adults (Arens R, et al. Paediatr Respir Rev. 2010;11[1]:24). Disturbances in sleep may serve as the earliest sign of muscle weakness in these patients, at times being detected before their underlying neuromuscular disease is diagnosed. This is of paramount importance to sleep medicine and pulmonary physicians who may be among the first specialists to evaluate these patients and can play a vital role in the recognition and diagnosis of neuromuscular disease. Herein, we will provide a guide to aid the reader in recognizing the early signs and symptoms of NMD as it pertains to sleep, as earlier diagnosis may lead to improved quality of life or possibly even survival, in some cases.
Pathophysiology
To begin, it is important to understand the pathophysiology of NMD and how it is altered during the sleep state. Sleep-related physiologic changes in healthy humans include reduction in upper airway muscle tone, blunting of chemoreceptors associated with pharyngeal dilator augmentation, and sleep stage-specific changes in skeletal muscle tone. In patients with NMD, these changes may not be adequately compensated for, leading to sleep-disordered breathing that can present as sleep apnea, hypoventilation, or hypoxia (Govindarajan R, et al. Sleep Issues in Neuromuscular Disorders: A Clinical Guide. Springer International Publishing AG, Springer Nature 2018).
Central respiratory control
The respiratory centers in the pons and medulla are generally spared from the primary effects of most NMD; however, over time, they may be affected secondarily. Similar to obesity hypoventilation syndrome (OHS), untreated chronic sleep-related hypoventilation from NMD can impair the sensitivity of respiratory chemoreceptors leading to worsening hypoventilation.
Upper airway resistance
Pharyngeal muscle tone is key to maintaining a patent airway during sleep. In some NMD, bulbar muscle weakness with pharyngeal dilator muscle hypotonia leads to increased upper airway resistance, especially during REM sleep, which can result in obstructive sleep apnea (OSA). In addition to weakness affecting the upper airway musculature, anatomical changes may also contribute to sleep-disordered breathing. In Pompe disease, for example, macroglossia and fibro-fatty replacement of tongue muscles may occur, leading to the development of OSA.
Diaphragm weakness
In NMD that affects the diaphragm, there is an increased reliance on the skeletal muscles of respiration to maintain adequate ventilation as the underlying disease progresses. Generally, weakness of the diaphragm will cause disturbances in REM sleep first as, during REM, ventilation predominately depends on the diaphragm and patients lose the assistance of their skeletal muscles. However, over time, the progressive weakening of the diaphragm will progress to involve NREM sleep as well, clinically manifesting with frank sleep apnea, hypoventilation, and, ultimately, chronic hypercapnic respiratory failure.
Inspiratory muscle weakness
As noted above, there are many other muscles used in inspiration in addition to the diaphragm. Other primary muscles include the intercostal and scalene muscles, and accessory muscles include the sternocleidomastoid, pectoralis, latissimus dorsi, erector spinae, and trapezius muscles. While sleep and breathing problems may begin early in the course of a neuromuscular disease, the complex restrictive lung disease pattern that we see in these patients may not develop until the respiratory muscles of the chest wall are involved. This restriction, which corresponds to lower lung volumes, leads to a fall in the caudal traction force of the airways which can lead to reduction in the pharyngeal airway cross section. Because these issues are worsened in the supine position, their pathophysiologic effects on respiration are most notable during sleep, putting patients at higher risk of OSA.
Cardiac abnormalities
Lastly, it should be noted that diseases such as the muscular dystrophies, myotonic dystrophy, mitochondriopathies, and nemaline myopathy can be associated with a cardiomyopathy ,which can lead to central sleep apnea in the form of Cheyne-Stokes breathing.
Sleep-disordered breathing in specific NMDs
In amyotrophic lateral sclerosis (ALS), up to 75% of patients may have SDB, the majority of which is central sleep apnea (CSA) and hypoventilation although they still have a higher prevalence of obstructive sleep apnea (OSA) than the general population. Whether the diaphragm or the pharyngeal muscles are predominantly affected may have something to do with the type of apnea a patient experiences; however, studies have shown that even in bulbar ALS, CSA is most common. It should be noted, that this is not Cheyne-Stokes CSA, but rather lack of chest wall and abdominal movement due to weakness. (David WS, et al. J Neurol Sci. 1997;152[suppl 1]:S29-35).
In myasthenia gravis (MG), about 40% to 60% of patients have SDB, and about 30% develop overt respiratory weakness, generally late in the course of their disease. Many of these patients report excessive daytime sleepiness, often attributed to myasthenic fatigue requiring treatment with corticosteroids. It is important to evaluate for sleep apnea, given that if diagnosed and treated, their generalized fatigue may improve and the need for steroids may be reduced or eliminated altogether. It is also important to note that the respiratory and sleep issues MG patients face may not correlate with the severity of their overall disease, such that patients well-controlled on medications from a generalized weakness standpoint may still require home noninvasive ventilation (NIV) for chronic respiratory failure due to weakness of the respiratory system muscles.
Duchenne muscular dystrophy (DMD), an X-linked disease associated with dysfunction of dystrophin synthesis, is often diagnosed in early childhood and gradually progresses over years. Their initial sleep and respiratory symptoms can be subtle and may start with increased nighttime awakenings and daytime somnolence. Generally, these patients will develop OSA in the first decade of life and progress to hypoventilation in their second decade and beyond. These patients are especially important to recognize, as studies have shown appropriate NIV therapy may significantly prolong their life (Finder JD, et al; American Thoracic Society. Am J Respir Crit Care Med. 2004(Aug 15);170[4]:456-465).
In addition to the well-known motor neuron and neuromuscular diseases mentioned above, neuropathic diseases can lead to sleep disturbances, as well. In Charcot-Marie-Tooth (CMT), pharyngeal and laryngeal neuropathy, as well as hypoglossal nerve dysfunction, lead to OSA. Similar to ALS and MG, there is a significant amount of CSA and hypoventilation, likely related to phrenic neuropathy. In contrast to MG, in CMT, the severity of neuropathic disease does correlate to the severity of sleep apnea.
Testing
Testing can range from overnight oximetry to polysomnogram (PSG) with CO2 monitoring. Generally, all patients with a rapidly progressive neuromuscular disease should get pulmonary function testing (PFT) (upright and supine) to evaluate forced vital capacity (FVC) every 3 to 6 months to monitor for respiratory failure. Laboratory studies that can be helpful in assessing for SDB are the PaCO2 (> 45 mm Hg) measured on an arterial blood gas and serum bicarbonate levels (>27 mmol/L or a base excess >4 mmol/L). Patients can qualify for NIV with an overnight SaO2 less than or equal to 88% for greater than or equal to 5 minutes in a 2-hour recording period, PaCO2 greater than or equal to 45 mm Hg, forced vital capacity (FVC) < 50% of predicted, or maximal inspiratory pressure (MIP) <60 cm H2O. For ALS specifically, sniff nasal pressure < 40 cm H2O and orthopnea are additional criteria that can be used. It is worth noting that a PSG is not required for NIV qualification in neuromuscular respiratory insufficiency. However, PSG is beneficial in patients with preserved PFTs but suspected of having early nocturnal respiratory impairment.
Therapy
NIV is the mainstay of therapy for SDB in patients with NMD and has been associated with a slower decline in FVC and improved survival in some cases, as demonstrated in studies of patients with DMD or ALS. Generally, a bi-level PAP mode is preferred; the expiratory positive airway pressure prevents micro-atelectasis and improves V/Q matching and the inspiratory positive airway pressure reduces inspiratory muscle load and optimizes ventilation. As weakness progresses, patients may have difficulty creating enough negative force to initiate a spontaneous breath, thus a mode with a set respiratory rate is preferred that can be implemented in bi-level PAP or more advanced modes such as volume-assured pressure support (VAPS) modality. For patients who are unable to tolerate NIV, particularly those with severe bulbar disease and difficult to manage respiratory secretions, tracheostomy with mechanical ventilation may ultimately be needed. This decision should be made as part of a multidisciplinary shared decision-making conversation with the patient, their family, and their team of providers.
Summary
Sleep is a particularly vulnerable state for patients with NMD, and in many patients, disturbances in sleep may be the first clue to their ultimate diagnosis. It is important that sleep medicine and pulmonary specialists understand the pathophysiology and management of NMD as they can play a vital role in the interdisciplinary care of these patients.
Dr. Greer is a Sleep Medicine Fellow, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine; Dr. Collop is Professor of Medicine and Neurology, Director, Emory Sleep Center; Emory University, Atlanta, Georgia.
Sleep-disordered breathing (SDB) is a common sleep disturbance in neuromuscular disease (NMD) affecting 36% to 53% of diagnosed adults (Arens R, et al. Paediatr Respir Rev. 2010;11[1]:24). Disturbances in sleep may serve as the earliest sign of muscle weakness in these patients, at times being detected before their underlying neuromuscular disease is diagnosed. This is of paramount importance to sleep medicine and pulmonary physicians who may be among the first specialists to evaluate these patients and can play a vital role in the recognition and diagnosis of neuromuscular disease. Herein, we will provide a guide to aid the reader in recognizing the early signs and symptoms of NMD as it pertains to sleep, as earlier diagnosis may lead to improved quality of life or possibly even survival, in some cases.
Pathophysiology
To begin, it is important to understand the pathophysiology of NMD and how it is altered during the sleep state. Sleep-related physiologic changes in healthy humans include reduction in upper airway muscle tone, blunting of chemoreceptors associated with pharyngeal dilator augmentation, and sleep stage-specific changes in skeletal muscle tone. In patients with NMD, these changes may not be adequately compensated for, leading to sleep-disordered breathing that can present as sleep apnea, hypoventilation, or hypoxia (Govindarajan R, et al. Sleep Issues in Neuromuscular Disorders: A Clinical Guide. Springer International Publishing AG, Springer Nature 2018).
Central respiratory control
The respiratory centers in the pons and medulla are generally spared from the primary effects of most NMD; however, over time, they may be affected secondarily. Similar to obesity hypoventilation syndrome (OHS), untreated chronic sleep-related hypoventilation from NMD can impair the sensitivity of respiratory chemoreceptors leading to worsening hypoventilation.
Upper airway resistance
Pharyngeal muscle tone is key to maintaining a patent airway during sleep. In some NMD, bulbar muscle weakness with pharyngeal dilator muscle hypotonia leads to increased upper airway resistance, especially during REM sleep, which can result in obstructive sleep apnea (OSA). In addition to weakness affecting the upper airway musculature, anatomical changes may also contribute to sleep-disordered breathing. In Pompe disease, for example, macroglossia and fibro-fatty replacement of tongue muscles may occur, leading to the development of OSA.
Diaphragm weakness
In NMD that affects the diaphragm, there is an increased reliance on the skeletal muscles of respiration to maintain adequate ventilation as the underlying disease progresses. Generally, weakness of the diaphragm will cause disturbances in REM sleep first as, during REM, ventilation predominately depends on the diaphragm and patients lose the assistance of their skeletal muscles. However, over time, the progressive weakening of the diaphragm will progress to involve NREM sleep as well, clinically manifesting with frank sleep apnea, hypoventilation, and, ultimately, chronic hypercapnic respiratory failure.
Inspiratory muscle weakness
As noted above, there are many other muscles used in inspiration in addition to the diaphragm. Other primary muscles include the intercostal and scalene muscles, and accessory muscles include the sternocleidomastoid, pectoralis, latissimus dorsi, erector spinae, and trapezius muscles. While sleep and breathing problems may begin early in the course of a neuromuscular disease, the complex restrictive lung disease pattern that we see in these patients may not develop until the respiratory muscles of the chest wall are involved. This restriction, which corresponds to lower lung volumes, leads to a fall in the caudal traction force of the airways which can lead to reduction in the pharyngeal airway cross section. Because these issues are worsened in the supine position, their pathophysiologic effects on respiration are most notable during sleep, putting patients at higher risk of OSA.
Cardiac abnormalities
Lastly, it should be noted that diseases such as the muscular dystrophies, myotonic dystrophy, mitochondriopathies, and nemaline myopathy can be associated with a cardiomyopathy ,which can lead to central sleep apnea in the form of Cheyne-Stokes breathing.
Sleep-disordered breathing in specific NMDs
In amyotrophic lateral sclerosis (ALS), up to 75% of patients may have SDB, the majority of which is central sleep apnea (CSA) and hypoventilation although they still have a higher prevalence of obstructive sleep apnea (OSA) than the general population. Whether the diaphragm or the pharyngeal muscles are predominantly affected may have something to do with the type of apnea a patient experiences; however, studies have shown that even in bulbar ALS, CSA is most common. It should be noted, that this is not Cheyne-Stokes CSA, but rather lack of chest wall and abdominal movement due to weakness. (David WS, et al. J Neurol Sci. 1997;152[suppl 1]:S29-35).
In myasthenia gravis (MG), about 40% to 60% of patients have SDB, and about 30% develop overt respiratory weakness, generally late in the course of their disease. Many of these patients report excessive daytime sleepiness, often attributed to myasthenic fatigue requiring treatment with corticosteroids. It is important to evaluate for sleep apnea, given that if diagnosed and treated, their generalized fatigue may improve and the need for steroids may be reduced or eliminated altogether. It is also important to note that the respiratory and sleep issues MG patients face may not correlate with the severity of their overall disease, such that patients well-controlled on medications from a generalized weakness standpoint may still require home noninvasive ventilation (NIV) for chronic respiratory failure due to weakness of the respiratory system muscles.
Duchenne muscular dystrophy (DMD), an X-linked disease associated with dysfunction of dystrophin synthesis, is often diagnosed in early childhood and gradually progresses over years. Their initial sleep and respiratory symptoms can be subtle and may start with increased nighttime awakenings and daytime somnolence. Generally, these patients will develop OSA in the first decade of life and progress to hypoventilation in their second decade and beyond. These patients are especially important to recognize, as studies have shown appropriate NIV therapy may significantly prolong their life (Finder JD, et al; American Thoracic Society. Am J Respir Crit Care Med. 2004(Aug 15);170[4]:456-465).
In addition to the well-known motor neuron and neuromuscular diseases mentioned above, neuropathic diseases can lead to sleep disturbances, as well. In Charcot-Marie-Tooth (CMT), pharyngeal and laryngeal neuropathy, as well as hypoglossal nerve dysfunction, lead to OSA. Similar to ALS and MG, there is a significant amount of CSA and hypoventilation, likely related to phrenic neuropathy. In contrast to MG, in CMT, the severity of neuropathic disease does correlate to the severity of sleep apnea.
Testing
Testing can range from overnight oximetry to polysomnogram (PSG) with CO2 monitoring. Generally, all patients with a rapidly progressive neuromuscular disease should get pulmonary function testing (PFT) (upright and supine) to evaluate forced vital capacity (FVC) every 3 to 6 months to monitor for respiratory failure. Laboratory studies that can be helpful in assessing for SDB are the PaCO2 (> 45 mm Hg) measured on an arterial blood gas and serum bicarbonate levels (>27 mmol/L or a base excess >4 mmol/L). Patients can qualify for NIV with an overnight SaO2 less than or equal to 88% for greater than or equal to 5 minutes in a 2-hour recording period, PaCO2 greater than or equal to 45 mm Hg, forced vital capacity (FVC) < 50% of predicted, or maximal inspiratory pressure (MIP) <60 cm H2O. For ALS specifically, sniff nasal pressure < 40 cm H2O and orthopnea are additional criteria that can be used. It is worth noting that a PSG is not required for NIV qualification in neuromuscular respiratory insufficiency. However, PSG is beneficial in patients with preserved PFTs but suspected of having early nocturnal respiratory impairment.
Therapy
NIV is the mainstay of therapy for SDB in patients with NMD and has been associated with a slower decline in FVC and improved survival in some cases, as demonstrated in studies of patients with DMD or ALS. Generally, a bi-level PAP mode is preferred; the expiratory positive airway pressure prevents micro-atelectasis and improves V/Q matching and the inspiratory positive airway pressure reduces inspiratory muscle load and optimizes ventilation. As weakness progresses, patients may have difficulty creating enough negative force to initiate a spontaneous breath, thus a mode with a set respiratory rate is preferred that can be implemented in bi-level PAP or more advanced modes such as volume-assured pressure support (VAPS) modality. For patients who are unable to tolerate NIV, particularly those with severe bulbar disease and difficult to manage respiratory secretions, tracheostomy with mechanical ventilation may ultimately be needed. This decision should be made as part of a multidisciplinary shared decision-making conversation with the patient, their family, and their team of providers.
Summary
Sleep is a particularly vulnerable state for patients with NMD, and in many patients, disturbances in sleep may be the first clue to their ultimate diagnosis. It is important that sleep medicine and pulmonary specialists understand the pathophysiology and management of NMD as they can play a vital role in the interdisciplinary care of these patients.
Dr. Greer is a Sleep Medicine Fellow, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine; Dr. Collop is Professor of Medicine and Neurology, Director, Emory Sleep Center; Emory University, Atlanta, Georgia.
Sleep-disordered breathing (SDB) is a common sleep disturbance in neuromuscular disease (NMD) affecting 36% to 53% of diagnosed adults (Arens R, et al. Paediatr Respir Rev. 2010;11[1]:24). Disturbances in sleep may serve as the earliest sign of muscle weakness in these patients, at times being detected before their underlying neuromuscular disease is diagnosed. This is of paramount importance to sleep medicine and pulmonary physicians who may be among the first specialists to evaluate these patients and can play a vital role in the recognition and diagnosis of neuromuscular disease. Herein, we will provide a guide to aid the reader in recognizing the early signs and symptoms of NMD as it pertains to sleep, as earlier diagnosis may lead to improved quality of life or possibly even survival, in some cases.
Pathophysiology
To begin, it is important to understand the pathophysiology of NMD and how it is altered during the sleep state. Sleep-related physiologic changes in healthy humans include reduction in upper airway muscle tone, blunting of chemoreceptors associated with pharyngeal dilator augmentation, and sleep stage-specific changes in skeletal muscle tone. In patients with NMD, these changes may not be adequately compensated for, leading to sleep-disordered breathing that can present as sleep apnea, hypoventilation, or hypoxia (Govindarajan R, et al. Sleep Issues in Neuromuscular Disorders: A Clinical Guide. Springer International Publishing AG, Springer Nature 2018).
Central respiratory control
The respiratory centers in the pons and medulla are generally spared from the primary effects of most NMD; however, over time, they may be affected secondarily. Similar to obesity hypoventilation syndrome (OHS), untreated chronic sleep-related hypoventilation from NMD can impair the sensitivity of respiratory chemoreceptors leading to worsening hypoventilation.
Upper airway resistance
Pharyngeal muscle tone is key to maintaining a patent airway during sleep. In some NMD, bulbar muscle weakness with pharyngeal dilator muscle hypotonia leads to increased upper airway resistance, especially during REM sleep, which can result in obstructive sleep apnea (OSA). In addition to weakness affecting the upper airway musculature, anatomical changes may also contribute to sleep-disordered breathing. In Pompe disease, for example, macroglossia and fibro-fatty replacement of tongue muscles may occur, leading to the development of OSA.
Diaphragm weakness
In NMD that affects the diaphragm, there is an increased reliance on the skeletal muscles of respiration to maintain adequate ventilation as the underlying disease progresses. Generally, weakness of the diaphragm will cause disturbances in REM sleep first as, during REM, ventilation predominately depends on the diaphragm and patients lose the assistance of their skeletal muscles. However, over time, the progressive weakening of the diaphragm will progress to involve NREM sleep as well, clinically manifesting with frank sleep apnea, hypoventilation, and, ultimately, chronic hypercapnic respiratory failure.
Inspiratory muscle weakness
As noted above, there are many other muscles used in inspiration in addition to the diaphragm. Other primary muscles include the intercostal and scalene muscles, and accessory muscles include the sternocleidomastoid, pectoralis, latissimus dorsi, erector spinae, and trapezius muscles. While sleep and breathing problems may begin early in the course of a neuromuscular disease, the complex restrictive lung disease pattern that we see in these patients may not develop until the respiratory muscles of the chest wall are involved. This restriction, which corresponds to lower lung volumes, leads to a fall in the caudal traction force of the airways which can lead to reduction in the pharyngeal airway cross section. Because these issues are worsened in the supine position, their pathophysiologic effects on respiration are most notable during sleep, putting patients at higher risk of OSA.
Cardiac abnormalities
Lastly, it should be noted that diseases such as the muscular dystrophies, myotonic dystrophy, mitochondriopathies, and nemaline myopathy can be associated with a cardiomyopathy ,which can lead to central sleep apnea in the form of Cheyne-Stokes breathing.
Sleep-disordered breathing in specific NMDs
In amyotrophic lateral sclerosis (ALS), up to 75% of patients may have SDB, the majority of which is central sleep apnea (CSA) and hypoventilation although they still have a higher prevalence of obstructive sleep apnea (OSA) than the general population. Whether the diaphragm or the pharyngeal muscles are predominantly affected may have something to do with the type of apnea a patient experiences; however, studies have shown that even in bulbar ALS, CSA is most common. It should be noted, that this is not Cheyne-Stokes CSA, but rather lack of chest wall and abdominal movement due to weakness. (David WS, et al. J Neurol Sci. 1997;152[suppl 1]:S29-35).
In myasthenia gravis (MG), about 40% to 60% of patients have SDB, and about 30% develop overt respiratory weakness, generally late in the course of their disease. Many of these patients report excessive daytime sleepiness, often attributed to myasthenic fatigue requiring treatment with corticosteroids. It is important to evaluate for sleep apnea, given that if diagnosed and treated, their generalized fatigue may improve and the need for steroids may be reduced or eliminated altogether. It is also important to note that the respiratory and sleep issues MG patients face may not correlate with the severity of their overall disease, such that patients well-controlled on medications from a generalized weakness standpoint may still require home noninvasive ventilation (NIV) for chronic respiratory failure due to weakness of the respiratory system muscles.
Duchenne muscular dystrophy (DMD), an X-linked disease associated with dysfunction of dystrophin synthesis, is often diagnosed in early childhood and gradually progresses over years. Their initial sleep and respiratory symptoms can be subtle and may start with increased nighttime awakenings and daytime somnolence. Generally, these patients will develop OSA in the first decade of life and progress to hypoventilation in their second decade and beyond. These patients are especially important to recognize, as studies have shown appropriate NIV therapy may significantly prolong their life (Finder JD, et al; American Thoracic Society. Am J Respir Crit Care Med. 2004(Aug 15);170[4]:456-465).
In addition to the well-known motor neuron and neuromuscular diseases mentioned above, neuropathic diseases can lead to sleep disturbances, as well. In Charcot-Marie-Tooth (CMT), pharyngeal and laryngeal neuropathy, as well as hypoglossal nerve dysfunction, lead to OSA. Similar to ALS and MG, there is a significant amount of CSA and hypoventilation, likely related to phrenic neuropathy. In contrast to MG, in CMT, the severity of neuropathic disease does correlate to the severity of sleep apnea.
Testing
Testing can range from overnight oximetry to polysomnogram (PSG) with CO2 monitoring. Generally, all patients with a rapidly progressive neuromuscular disease should get pulmonary function testing (PFT) (upright and supine) to evaluate forced vital capacity (FVC) every 3 to 6 months to monitor for respiratory failure. Laboratory studies that can be helpful in assessing for SDB are the PaCO2 (> 45 mm Hg) measured on an arterial blood gas and serum bicarbonate levels (>27 mmol/L or a base excess >4 mmol/L). Patients can qualify for NIV with an overnight SaO2 less than or equal to 88% for greater than or equal to 5 minutes in a 2-hour recording period, PaCO2 greater than or equal to 45 mm Hg, forced vital capacity (FVC) < 50% of predicted, or maximal inspiratory pressure (MIP) <60 cm H2O. For ALS specifically, sniff nasal pressure < 40 cm H2O and orthopnea are additional criteria that can be used. It is worth noting that a PSG is not required for NIV qualification in neuromuscular respiratory insufficiency. However, PSG is beneficial in patients with preserved PFTs but suspected of having early nocturnal respiratory impairment.
Therapy
NIV is the mainstay of therapy for SDB in patients with NMD and has been associated with a slower decline in FVC and improved survival in some cases, as demonstrated in studies of patients with DMD or ALS. Generally, a bi-level PAP mode is preferred; the expiratory positive airway pressure prevents micro-atelectasis and improves V/Q matching and the inspiratory positive airway pressure reduces inspiratory muscle load and optimizes ventilation. As weakness progresses, patients may have difficulty creating enough negative force to initiate a spontaneous breath, thus a mode with a set respiratory rate is preferred that can be implemented in bi-level PAP or more advanced modes such as volume-assured pressure support (VAPS) modality. For patients who are unable to tolerate NIV, particularly those with severe bulbar disease and difficult to manage respiratory secretions, tracheostomy with mechanical ventilation may ultimately be needed. This decision should be made as part of a multidisciplinary shared decision-making conversation with the patient, their family, and their team of providers.
Summary
Sleep is a particularly vulnerable state for patients with NMD, and in many patients, disturbances in sleep may be the first clue to their ultimate diagnosis. It is important that sleep medicine and pulmonary specialists understand the pathophysiology and management of NMD as they can play a vital role in the interdisciplinary care of these patients.
Dr. Greer is a Sleep Medicine Fellow, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine; Dr. Collop is Professor of Medicine and Neurology, Director, Emory Sleep Center; Emory University, Atlanta, Georgia.