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FDA panel calls for changes to breast implant rupture screening
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
AT AN FDA ADVISORY PANEL MEETING
FDA panel leans toward more robust breast implant surveillance
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
Industry-funded rheumatology RCTs are higher quality
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
REPORTING FROM RWCS 2019
Sjögren’s syndrome risk increases with infections
Patients with a history of infection have nearly double the risk of developing Sjögren’s syndrome when compared with the general population (odds ratio, 1.9; 95% confidence interval, 1.6-2.3), according to new findings reported online March 20 in the Journal of Internal Medicine (doi: 10.1111/joim.12888).
The risk is almost three times higher among patients with a history of infection plus Ro/SSA and La/SSB antibodies (OR, 2.7; 95% CI, 2.0-3.5). The study included 945 Swedish patients with primary Sjögren’s syndrome and compared their data with those from 9,048 matched controls from the general population.
We previously covered results from this study when they were presented at the International Symposium on Sjögren’s Syndrome in Washington. Read our previous story at the link above.
Patients with a history of infection have nearly double the risk of developing Sjögren’s syndrome when compared with the general population (odds ratio, 1.9; 95% confidence interval, 1.6-2.3), according to new findings reported online March 20 in the Journal of Internal Medicine (doi: 10.1111/joim.12888).
The risk is almost three times higher among patients with a history of infection plus Ro/SSA and La/SSB antibodies (OR, 2.7; 95% CI, 2.0-3.5). The study included 945 Swedish patients with primary Sjögren’s syndrome and compared their data with those from 9,048 matched controls from the general population.
We previously covered results from this study when they were presented at the International Symposium on Sjögren’s Syndrome in Washington. Read our previous story at the link above.
Patients with a history of infection have nearly double the risk of developing Sjögren’s syndrome when compared with the general population (odds ratio, 1.9; 95% confidence interval, 1.6-2.3), according to new findings reported online March 20 in the Journal of Internal Medicine (doi: 10.1111/joim.12888).
The risk is almost three times higher among patients with a history of infection plus Ro/SSA and La/SSB antibodies (OR, 2.7; 95% CI, 2.0-3.5). The study included 945 Swedish patients with primary Sjögren’s syndrome and compared their data with those from 9,048 matched controls from the general population.
We previously covered results from this study when they were presented at the International Symposium on Sjögren’s Syndrome in Washington. Read our previous story at the link above.
FROM THE JOURNAL OF INTERNAL MEDICINE
Socioeconomic status affects scleroderma severity in African Americans
according to findings from an analysis of single-center cohort data over a 10-year period.
Indeed, among patients in the cohort of 402 scleroderma patients at MedStar Georgetown University Hospital in Washington, lower household income was predictive of higher mortality during follow-up, independent of race, according to first author Duncan F. Moore, MD, and his colleagues at the hospital.
Previous studies have demonstrated increased risk for scleroderma in African American patients, who also are more likely than non–African Americans to be diagnosed at a younger age and to have conditions including more diffuse cutaneous disease, more severe restrictive lung disease, more cardiac and renal involvement, and increased mortality, the authors wrote in Arthritis Care & Research.
“We did clearly show that African Americans have worse outcomes and severe pulmonary involvement, but I was surprised that there still was a major contribution of socioeconomic status affecting outcomes for all patients, even though only 10% of our patients were indigent and on medical assistance,” Virginia Steen, MD, senior author of the study and professor of rheumatology at Georgetown University, said in an interview. “I still feel strongly that there are likely genetic issues as to why African Americans have such severe disease. We are eager to learn more from the GRASP [Genome Research in African American Scleroderma Patients] study, which is specifically looking at the genetic issues in African American scleroderma patients,” she said.
Of the 402 scleroderma patients at MedStar Georgetown who were seen during 2006-2016, 202 were African American. A total of 186 African American and 184 non–African American patients in the study met the 2013 American College of Rheumatology/European League Against Rheumatism criteria for systemic sclerosis (SSc). Demographics including gender (87% female) and age (mean of 48 years) were similar between the groups.
Overall, the African American patients showed more severe lung disease, more pulmonary hypertension, and more severe cardiac involvement than did non–African American patients, and autoantibodies were significantly different between the groups.
During follow-up, mortality proved much higher among African Americans at 21%, compared with 11% in non–African Americans (P = .005). However, the unadjusted hazard ratio for death declined from 2.061 (P = .006) to a nonsignificant 1.256 after adjustment for socioeconomic variables.
All socioeconomic measures showed significant differences between the groups. African Americans were more likely to be single and disabled at the initial study visit and to have Medicaid, but they were less likely to be a homemaker, have private insurance, or have a college degree. African Americans’ $74,000 median household income (based on ZIP code) was also a statistically significant $23,000 less than non–African American patients. But the researchers noted that “for every additional $10,000 of household income, independent of race, the hazard of death during follow-up declined by 15.5%.”
Notable differences in antibodies appeared between the groups, with more African American patients having isolated nucleolar ANA, anti-U1RNP antibody, or other positive antinuclear antibodies without SSc-specific antibodies. African American patients also were less likely to have anticentromere or anti-RNA polymerase III antibodies.
The study findings were limited by several factors, including possible bias in the matching process and the use of only index values for socioeconomic variables, the researchers noted.
Regardless of relative socioeconomic and genetic influences, “it is clear that African Americans with scleroderma merit more intensive efforts to facilitate timely diagnosis and access to continued evaluation and suppressive treatment, particularly with respect to cardiopulmonary involvement,” they wrote.
Next steps for research, according to Dr. Steen, include studying clinical subsets of African American patients to try to identify factors to predict outcomes, including the nucleolar pattern ANA, overlap with lupus, history of hypertension, and the relationship with renal crisis.
“We are also looking at whether the African American patients are less responsive to mycophenolate than the non–African American patients. We definitely need to find ways to be more aggressive at identifying and treating African American patients early in their disease,” she added.
The researchers had no financial conflicts to disclose. Dr. Steen serves on the MDedge Rheumatology Editorial Advisory Board.
SOURCE: Moore DF et al. Arthritis Care Res. 2019 March 1. doi: 10.1002/acr.23861.
“Not only do patients who manifest the diffuse cutaneous subset of disease experience a more severe course, but so do affected persons of African American race,” Nadia D. Morgan, MBBS, and Allan C. Gelber, MD, wrote in an accompanying editorial. The effects of socioeconomic status should not be overlooked based on the current study, in which the inclusion of socioeconomic factors eliminated the significance of association between race and mortality among scleroderma patients, they wrote.
“Overall, and in the context of these published reports which underscore the disproportionate and adverse impact of scleroderma among African Americans, and in light of the ongoing efforts of the GRASP study, the current paper by Moore et al. emphasizes the importance of socioeconomic status, and of socioeconomic determinants of health, to account for differences in clinically relevant outcomes,” they wrote.
Dr. Gelber is affiliated with the division of rheumatology at Johns Hopkins University, Baltimore. Dr. Morgan, who was also with Johns Hopkins, died before publication of the editorial. They made no conflict of interest disclosures.
“Not only do patients who manifest the diffuse cutaneous subset of disease experience a more severe course, but so do affected persons of African American race,” Nadia D. Morgan, MBBS, and Allan C. Gelber, MD, wrote in an accompanying editorial. The effects of socioeconomic status should not be overlooked based on the current study, in which the inclusion of socioeconomic factors eliminated the significance of association between race and mortality among scleroderma patients, they wrote.
“Overall, and in the context of these published reports which underscore the disproportionate and adverse impact of scleroderma among African Americans, and in light of the ongoing efforts of the GRASP study, the current paper by Moore et al. emphasizes the importance of socioeconomic status, and of socioeconomic determinants of health, to account for differences in clinically relevant outcomes,” they wrote.
Dr. Gelber is affiliated with the division of rheumatology at Johns Hopkins University, Baltimore. Dr. Morgan, who was also with Johns Hopkins, died before publication of the editorial. They made no conflict of interest disclosures.
“Not only do patients who manifest the diffuse cutaneous subset of disease experience a more severe course, but so do affected persons of African American race,” Nadia D. Morgan, MBBS, and Allan C. Gelber, MD, wrote in an accompanying editorial. The effects of socioeconomic status should not be overlooked based on the current study, in which the inclusion of socioeconomic factors eliminated the significance of association between race and mortality among scleroderma patients, they wrote.
“Overall, and in the context of these published reports which underscore the disproportionate and adverse impact of scleroderma among African Americans, and in light of the ongoing efforts of the GRASP study, the current paper by Moore et al. emphasizes the importance of socioeconomic status, and of socioeconomic determinants of health, to account for differences in clinically relevant outcomes,” they wrote.
Dr. Gelber is affiliated with the division of rheumatology at Johns Hopkins University, Baltimore. Dr. Morgan, who was also with Johns Hopkins, died before publication of the editorial. They made no conflict of interest disclosures.
according to findings from an analysis of single-center cohort data over a 10-year period.
Indeed, among patients in the cohort of 402 scleroderma patients at MedStar Georgetown University Hospital in Washington, lower household income was predictive of higher mortality during follow-up, independent of race, according to first author Duncan F. Moore, MD, and his colleagues at the hospital.
Previous studies have demonstrated increased risk for scleroderma in African American patients, who also are more likely than non–African Americans to be diagnosed at a younger age and to have conditions including more diffuse cutaneous disease, more severe restrictive lung disease, more cardiac and renal involvement, and increased mortality, the authors wrote in Arthritis Care & Research.
“We did clearly show that African Americans have worse outcomes and severe pulmonary involvement, but I was surprised that there still was a major contribution of socioeconomic status affecting outcomes for all patients, even though only 10% of our patients were indigent and on medical assistance,” Virginia Steen, MD, senior author of the study and professor of rheumatology at Georgetown University, said in an interview. “I still feel strongly that there are likely genetic issues as to why African Americans have such severe disease. We are eager to learn more from the GRASP [Genome Research in African American Scleroderma Patients] study, which is specifically looking at the genetic issues in African American scleroderma patients,” she said.
Of the 402 scleroderma patients at MedStar Georgetown who were seen during 2006-2016, 202 were African American. A total of 186 African American and 184 non–African American patients in the study met the 2013 American College of Rheumatology/European League Against Rheumatism criteria for systemic sclerosis (SSc). Demographics including gender (87% female) and age (mean of 48 years) were similar between the groups.
Overall, the African American patients showed more severe lung disease, more pulmonary hypertension, and more severe cardiac involvement than did non–African American patients, and autoantibodies were significantly different between the groups.
During follow-up, mortality proved much higher among African Americans at 21%, compared with 11% in non–African Americans (P = .005). However, the unadjusted hazard ratio for death declined from 2.061 (P = .006) to a nonsignificant 1.256 after adjustment for socioeconomic variables.
All socioeconomic measures showed significant differences between the groups. African Americans were more likely to be single and disabled at the initial study visit and to have Medicaid, but they were less likely to be a homemaker, have private insurance, or have a college degree. African Americans’ $74,000 median household income (based on ZIP code) was also a statistically significant $23,000 less than non–African American patients. But the researchers noted that “for every additional $10,000 of household income, independent of race, the hazard of death during follow-up declined by 15.5%.”
Notable differences in antibodies appeared between the groups, with more African American patients having isolated nucleolar ANA, anti-U1RNP antibody, or other positive antinuclear antibodies without SSc-specific antibodies. African American patients also were less likely to have anticentromere or anti-RNA polymerase III antibodies.
The study findings were limited by several factors, including possible bias in the matching process and the use of only index values for socioeconomic variables, the researchers noted.
Regardless of relative socioeconomic and genetic influences, “it is clear that African Americans with scleroderma merit more intensive efforts to facilitate timely diagnosis and access to continued evaluation and suppressive treatment, particularly with respect to cardiopulmonary involvement,” they wrote.
Next steps for research, according to Dr. Steen, include studying clinical subsets of African American patients to try to identify factors to predict outcomes, including the nucleolar pattern ANA, overlap with lupus, history of hypertension, and the relationship with renal crisis.
“We are also looking at whether the African American patients are less responsive to mycophenolate than the non–African American patients. We definitely need to find ways to be more aggressive at identifying and treating African American patients early in their disease,” she added.
The researchers had no financial conflicts to disclose. Dr. Steen serves on the MDedge Rheumatology Editorial Advisory Board.
SOURCE: Moore DF et al. Arthritis Care Res. 2019 March 1. doi: 10.1002/acr.23861.
according to findings from an analysis of single-center cohort data over a 10-year period.
Indeed, among patients in the cohort of 402 scleroderma patients at MedStar Georgetown University Hospital in Washington, lower household income was predictive of higher mortality during follow-up, independent of race, according to first author Duncan F. Moore, MD, and his colleagues at the hospital.
Previous studies have demonstrated increased risk for scleroderma in African American patients, who also are more likely than non–African Americans to be diagnosed at a younger age and to have conditions including more diffuse cutaneous disease, more severe restrictive lung disease, more cardiac and renal involvement, and increased mortality, the authors wrote in Arthritis Care & Research.
“We did clearly show that African Americans have worse outcomes and severe pulmonary involvement, but I was surprised that there still was a major contribution of socioeconomic status affecting outcomes for all patients, even though only 10% of our patients were indigent and on medical assistance,” Virginia Steen, MD, senior author of the study and professor of rheumatology at Georgetown University, said in an interview. “I still feel strongly that there are likely genetic issues as to why African Americans have such severe disease. We are eager to learn more from the GRASP [Genome Research in African American Scleroderma Patients] study, which is specifically looking at the genetic issues in African American scleroderma patients,” she said.
Of the 402 scleroderma patients at MedStar Georgetown who were seen during 2006-2016, 202 were African American. A total of 186 African American and 184 non–African American patients in the study met the 2013 American College of Rheumatology/European League Against Rheumatism criteria for systemic sclerosis (SSc). Demographics including gender (87% female) and age (mean of 48 years) were similar between the groups.
Overall, the African American patients showed more severe lung disease, more pulmonary hypertension, and more severe cardiac involvement than did non–African American patients, and autoantibodies were significantly different between the groups.
During follow-up, mortality proved much higher among African Americans at 21%, compared with 11% in non–African Americans (P = .005). However, the unadjusted hazard ratio for death declined from 2.061 (P = .006) to a nonsignificant 1.256 after adjustment for socioeconomic variables.
All socioeconomic measures showed significant differences between the groups. African Americans were more likely to be single and disabled at the initial study visit and to have Medicaid, but they were less likely to be a homemaker, have private insurance, or have a college degree. African Americans’ $74,000 median household income (based on ZIP code) was also a statistically significant $23,000 less than non–African American patients. But the researchers noted that “for every additional $10,000 of household income, independent of race, the hazard of death during follow-up declined by 15.5%.”
Notable differences in antibodies appeared between the groups, with more African American patients having isolated nucleolar ANA, anti-U1RNP antibody, or other positive antinuclear antibodies without SSc-specific antibodies. African American patients also were less likely to have anticentromere or anti-RNA polymerase III antibodies.
The study findings were limited by several factors, including possible bias in the matching process and the use of only index values for socioeconomic variables, the researchers noted.
Regardless of relative socioeconomic and genetic influences, “it is clear that African Americans with scleroderma merit more intensive efforts to facilitate timely diagnosis and access to continued evaluation and suppressive treatment, particularly with respect to cardiopulmonary involvement,” they wrote.
Next steps for research, according to Dr. Steen, include studying clinical subsets of African American patients to try to identify factors to predict outcomes, including the nucleolar pattern ANA, overlap with lupus, history of hypertension, and the relationship with renal crisis.
“We are also looking at whether the African American patients are less responsive to mycophenolate than the non–African American patients. We definitely need to find ways to be more aggressive at identifying and treating African American patients early in their disease,” she added.
The researchers had no financial conflicts to disclose. Dr. Steen serves on the MDedge Rheumatology Editorial Advisory Board.
SOURCE: Moore DF et al. Arthritis Care Res. 2019 March 1. doi: 10.1002/acr.23861.
FROM ARTHRITIS CARE & RESEARCH
Resistant hypertension hits SLE patients hard
at a tertiary care center.
A patient with resistant hypertension either has blood pressure remaining above 140/90 mm Hg while taking three antihypertensive medications or requires the use of four or more antihypertensives to attain blood pressure control. Resistant hypertension, which was more likely to occur among blacks and patients with lower renal function, hypercholesterolemia, and increased inflammatory markers, increased the risk of death nearly threefold (hazard ratio, 2.91; P = .0005) when compared with those who didn’t have this condition.
The results of this analysis were published March 15 in Arthritis Care & Research (doi: 10.1002/acr.23880). We covered this study at the 2018 annual meeting of the American College of Rheumatology in Chicago before it was published in the journal. Read our previous story at the link above.
at a tertiary care center.
A patient with resistant hypertension either has blood pressure remaining above 140/90 mm Hg while taking three antihypertensive medications or requires the use of four or more antihypertensives to attain blood pressure control. Resistant hypertension, which was more likely to occur among blacks and patients with lower renal function, hypercholesterolemia, and increased inflammatory markers, increased the risk of death nearly threefold (hazard ratio, 2.91; P = .0005) when compared with those who didn’t have this condition.
The results of this analysis were published March 15 in Arthritis Care & Research (doi: 10.1002/acr.23880). We covered this study at the 2018 annual meeting of the American College of Rheumatology in Chicago before it was published in the journal. Read our previous story at the link above.
at a tertiary care center.
A patient with resistant hypertension either has blood pressure remaining above 140/90 mm Hg while taking three antihypertensive medications or requires the use of four or more antihypertensives to attain blood pressure control. Resistant hypertension, which was more likely to occur among blacks and patients with lower renal function, hypercholesterolemia, and increased inflammatory markers, increased the risk of death nearly threefold (hazard ratio, 2.91; P = .0005) when compared with those who didn’t have this condition.
The results of this analysis were published March 15 in Arthritis Care & Research (doi: 10.1002/acr.23880). We covered this study at the 2018 annual meeting of the American College of Rheumatology in Chicago before it was published in the journal. Read our previous story at the link above.
FROM ARTHRITIS CARE & RESEARCH
BTK inhibitor calms pemphigus vulgaris with low-dose steroids
WASHINGTON – An investigational molecule that blocks the downstream proinflammatory effects of B cells controlled disease activity and induced clinical remission in patients with pemphigus by 12 weeks.
At the end of a 24-week, open-label trial, a key driver of the sometimes-fatal blistering disease, Deedee Murrell, MD, said at the annual meeting of the American Academy of Dermatology.
The clinical efficacy plus a favorable safety profile supports the further development of the molecule, designed and manufactured by Principia Biopharma in San Francisco. The company is currently recruiting for a pivotal phase 3 trial of PRN1008 in 120 patients with moderate to severe pemphigus vulgaris.
Despite the recent approval of rituximab (Rituxan) for moderate to severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment, said Dr. Murrell, professor and head of the department of dermatology at the University of New South Wales, Sydney.
“We need something to use instead of high-dose steroids while we are waiting for rituximab to kick in, which can take 3 months,” and rituximab, which depletes B cells, puts patients at risk for infection, she said. “We need something that has rapid onset, is steroid sparing, safe for chronic administration, avoids B-cell depletion, and is convenient.”
Blocking the BTK receptor on B cells puts the brakes on the B-cell mediated inflammatory pathway, preventing activation of monocytes, macrophages, mast cells, basophils, and neutrophils. At the same time, however, it does not deplete the B-cell population, said Dr. Murrell, the lead investigator.
The BELIEVE study comprised 27 patients with mild to severe pemphigus of an average 6 years’ duration. Most (18) had relapsing disease; the remainder had newly diagnosed pemphigus. A majority (16) had severe disease, as measured by a score of 15 or more on the Pemphigus Disease Activity Index (PDAI). Almost all (23) were positive for antidesmoglein antibodies. Only one patient was negative for antibodies.
The mean corticosteroid dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day.
The study consisted of a 12-week treatment phase and a 12-week follow-up phase. During treatment, patients could take no more than 0.5 mg/kg of prednisone daily, although with 400 mg PRN1008 twice a day. They were allowed to undertake rescue immunosuppression if they experienced a disease flare.
The primary endpoint was disease control by day 29 as evidenced by no new lesions. Secondary endpoints were complete remission, minimization of prednisone, quality of life, antibody levels, and clinician measures including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.
By the end of week 4, 54% of patients had achieved the primary endpoint. The benefit continued to expand, with 73% reaching that response by the end of week 12. During this period, the mean prednisone dose was 12 mg/day.
Among the 24 patients who completed the study, complete remission occurred in 17% by week 12. However, patients continued to respond through the follow-up period, even after the study medication was stopped. By week 24, 25% of these patients experienced a complete remission. At the point of remission, the mean steroid dose was 8 mg/day. The median duration of remission was 2 months after stopping PRN1008.
The PDAI fell by a median of 70% by week 12 and was maintained at that level by the end of week 24. The median level of antidesmoglein autoantibodies fell by up to 65%. Again, the improvement continued throughout the off-drug follow-up period. In subgroup analyses, PRN1008 was more effective in patients with moderate to severe disease than those with mild disease (80% response vs. 64%). It was equally effective in those with newly diagnosed disease (75% vs. 72%) and regardless of antibody level at baseline.
The adverse event profile was relatively benign. Most side effects were mild and transient, and included upper abdominal pain, headache, and nausea. There were two mild infections and one serious infection, which presented in a patient with a long-standing localized cellulitis that activated and was associated a high fever. It was culture negative and PRN1008 was restarted without issue.
There was also one serious adverse event and one death, both unrelated to the study drug. One patient developed a pancreatic cyst that was discovered on day 29. The patient dropped out of the study to have elective surgery. The death occurred in a patient who developed acute respiratory failure on day 8 of treatment, caused by an undiagnosed congenital pulmonary sequestration. The patient died of a brain embolism shortly after lung surgery.
Dr. Murrell designed the study and was an investigator. She reported a financial relationship with Principia, as well as with numerous other pharmaceutical companies.
SOURCE: Murrell D et al. AAD 2019, Session S034.
WASHINGTON – An investigational molecule that blocks the downstream proinflammatory effects of B cells controlled disease activity and induced clinical remission in patients with pemphigus by 12 weeks.
At the end of a 24-week, open-label trial, a key driver of the sometimes-fatal blistering disease, Deedee Murrell, MD, said at the annual meeting of the American Academy of Dermatology.
The clinical efficacy plus a favorable safety profile supports the further development of the molecule, designed and manufactured by Principia Biopharma in San Francisco. The company is currently recruiting for a pivotal phase 3 trial of PRN1008 in 120 patients with moderate to severe pemphigus vulgaris.
Despite the recent approval of rituximab (Rituxan) for moderate to severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment, said Dr. Murrell, professor and head of the department of dermatology at the University of New South Wales, Sydney.
“We need something to use instead of high-dose steroids while we are waiting for rituximab to kick in, which can take 3 months,” and rituximab, which depletes B cells, puts patients at risk for infection, she said. “We need something that has rapid onset, is steroid sparing, safe for chronic administration, avoids B-cell depletion, and is convenient.”
Blocking the BTK receptor on B cells puts the brakes on the B-cell mediated inflammatory pathway, preventing activation of monocytes, macrophages, mast cells, basophils, and neutrophils. At the same time, however, it does not deplete the B-cell population, said Dr. Murrell, the lead investigator.
The BELIEVE study comprised 27 patients with mild to severe pemphigus of an average 6 years’ duration. Most (18) had relapsing disease; the remainder had newly diagnosed pemphigus. A majority (16) had severe disease, as measured by a score of 15 or more on the Pemphigus Disease Activity Index (PDAI). Almost all (23) were positive for antidesmoglein antibodies. Only one patient was negative for antibodies.
The mean corticosteroid dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day.
The study consisted of a 12-week treatment phase and a 12-week follow-up phase. During treatment, patients could take no more than 0.5 mg/kg of prednisone daily, although with 400 mg PRN1008 twice a day. They were allowed to undertake rescue immunosuppression if they experienced a disease flare.
The primary endpoint was disease control by day 29 as evidenced by no new lesions. Secondary endpoints were complete remission, minimization of prednisone, quality of life, antibody levels, and clinician measures including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.
By the end of week 4, 54% of patients had achieved the primary endpoint. The benefit continued to expand, with 73% reaching that response by the end of week 12. During this period, the mean prednisone dose was 12 mg/day.
Among the 24 patients who completed the study, complete remission occurred in 17% by week 12. However, patients continued to respond through the follow-up period, even after the study medication was stopped. By week 24, 25% of these patients experienced a complete remission. At the point of remission, the mean steroid dose was 8 mg/day. The median duration of remission was 2 months after stopping PRN1008.
The PDAI fell by a median of 70% by week 12 and was maintained at that level by the end of week 24. The median level of antidesmoglein autoantibodies fell by up to 65%. Again, the improvement continued throughout the off-drug follow-up period. In subgroup analyses, PRN1008 was more effective in patients with moderate to severe disease than those with mild disease (80% response vs. 64%). It was equally effective in those with newly diagnosed disease (75% vs. 72%) and regardless of antibody level at baseline.
The adverse event profile was relatively benign. Most side effects were mild and transient, and included upper abdominal pain, headache, and nausea. There were two mild infections and one serious infection, which presented in a patient with a long-standing localized cellulitis that activated and was associated a high fever. It was culture negative and PRN1008 was restarted without issue.
There was also one serious adverse event and one death, both unrelated to the study drug. One patient developed a pancreatic cyst that was discovered on day 29. The patient dropped out of the study to have elective surgery. The death occurred in a patient who developed acute respiratory failure on day 8 of treatment, caused by an undiagnosed congenital pulmonary sequestration. The patient died of a brain embolism shortly after lung surgery.
Dr. Murrell designed the study and was an investigator. She reported a financial relationship with Principia, as well as with numerous other pharmaceutical companies.
SOURCE: Murrell D et al. AAD 2019, Session S034.
WASHINGTON – An investigational molecule that blocks the downstream proinflammatory effects of B cells controlled disease activity and induced clinical remission in patients with pemphigus by 12 weeks.
At the end of a 24-week, open-label trial, a key driver of the sometimes-fatal blistering disease, Deedee Murrell, MD, said at the annual meeting of the American Academy of Dermatology.
The clinical efficacy plus a favorable safety profile supports the further development of the molecule, designed and manufactured by Principia Biopharma in San Francisco. The company is currently recruiting for a pivotal phase 3 trial of PRN1008 in 120 patients with moderate to severe pemphigus vulgaris.
Despite the recent approval of rituximab (Rituxan) for moderate to severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment, said Dr. Murrell, professor and head of the department of dermatology at the University of New South Wales, Sydney.
“We need something to use instead of high-dose steroids while we are waiting for rituximab to kick in, which can take 3 months,” and rituximab, which depletes B cells, puts patients at risk for infection, she said. “We need something that has rapid onset, is steroid sparing, safe for chronic administration, avoids B-cell depletion, and is convenient.”
Blocking the BTK receptor on B cells puts the brakes on the B-cell mediated inflammatory pathway, preventing activation of monocytes, macrophages, mast cells, basophils, and neutrophils. At the same time, however, it does not deplete the B-cell population, said Dr. Murrell, the lead investigator.
The BELIEVE study comprised 27 patients with mild to severe pemphigus of an average 6 years’ duration. Most (18) had relapsing disease; the remainder had newly diagnosed pemphigus. A majority (16) had severe disease, as measured by a score of 15 or more on the Pemphigus Disease Activity Index (PDAI). Almost all (23) were positive for antidesmoglein antibodies. Only one patient was negative for antibodies.
The mean corticosteroid dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day.
The study consisted of a 12-week treatment phase and a 12-week follow-up phase. During treatment, patients could take no more than 0.5 mg/kg of prednisone daily, although with 400 mg PRN1008 twice a day. They were allowed to undertake rescue immunosuppression if they experienced a disease flare.
The primary endpoint was disease control by day 29 as evidenced by no new lesions. Secondary endpoints were complete remission, minimization of prednisone, quality of life, antibody levels, and clinician measures including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.
By the end of week 4, 54% of patients had achieved the primary endpoint. The benefit continued to expand, with 73% reaching that response by the end of week 12. During this period, the mean prednisone dose was 12 mg/day.
Among the 24 patients who completed the study, complete remission occurred in 17% by week 12. However, patients continued to respond through the follow-up period, even after the study medication was stopped. By week 24, 25% of these patients experienced a complete remission. At the point of remission, the mean steroid dose was 8 mg/day. The median duration of remission was 2 months after stopping PRN1008.
The PDAI fell by a median of 70% by week 12 and was maintained at that level by the end of week 24. The median level of antidesmoglein autoantibodies fell by up to 65%. Again, the improvement continued throughout the off-drug follow-up period. In subgroup analyses, PRN1008 was more effective in patients with moderate to severe disease than those with mild disease (80% response vs. 64%). It was equally effective in those with newly diagnosed disease (75% vs. 72%) and regardless of antibody level at baseline.
The adverse event profile was relatively benign. Most side effects were mild and transient, and included upper abdominal pain, headache, and nausea. There were two mild infections and one serious infection, which presented in a patient with a long-standing localized cellulitis that activated and was associated a high fever. It was culture negative and PRN1008 was restarted without issue.
There was also one serious adverse event and one death, both unrelated to the study drug. One patient developed a pancreatic cyst that was discovered on day 29. The patient dropped out of the study to have elective surgery. The death occurred in a patient who developed acute respiratory failure on day 8 of treatment, caused by an undiagnosed congenital pulmonary sequestration. The patient died of a brain embolism shortly after lung surgery.
Dr. Murrell designed the study and was an investigator. She reported a financial relationship with Principia, as well as with numerous other pharmaceutical companies.
SOURCE: Murrell D et al. AAD 2019, Session S034.
REPORTING FROM AAD 2019
Vagus nerve stimulation for rheumatology? Maybe
The work is being led by SetPoint Medical, a small company in Valencia, Calif., just north of Los Angeles. Its vagus nerve stimulation (VNS) device, dubbed the microregulator, has been implanted in 14 patients with refractory rheumatoid arthritis (RA) in the company’s initial safety study.
The microregulator is a small lithium ion battery encased in an inert silastic pod; it’s surgically implanted to sit atop the vagus nerve in the left side of the neck, and delivers an electrical pulse at set intervals. Data from the 12-week, sham-controlled safety study is set to be unblinded in coming weeks. A pivotal trial also is in the works, perhaps to start in late 2019, according to rheumatologist and SetPoint’s Chief Medical Officer David Chernoff, MD.
Although SetPoint is ahead of the pack, it’s not alone. ElectroCore, a biotech company in Basking Ridge, N.J., has expressed interest in pursuing rheumatoid arthritis and Sjögren’s syndrome indications for its gammaCore device, a vagus nerve stimulator patients apply to the neck. It’s already on the market for migraines and cluster headaches.
Researchers recently reported a small decrease in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) results after 16 RA patients with flares used the device for 4 days (Ann Rheum Dis. 2018;77:1401. Abstract AB0481). In another recent open-label study, 15 women with Sjögren’s reported less fatigue while using the device for a month (Arthritis Rheumatol. 2017;69[suppl 10]: Abstract 563).
Meanwhile, The Feinstein Institute for Medical Research, based in Manhasset, N.Y., on Long Island, recently reported positive outcomes in 18 patients with systemic lupus erythematosus, using its own novel device, which stimulates the vagus nerve through the ear lobe. VNS was delivered for 5 minutes per day for 4 days (Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2652).
On day 5, patients who received VNS, versus sham patients in whom the device was not turned on, had a significant decrease in pain, fatigue, and joint scores. The investigators concluded that “additional studies evaluating this promising intervention and its potential mechanisms are warranted.”
“We are clearly ahead of everybody because we’ve already implanted people, but I think it’s good for the field if more people are chasing this. The more resources that are put into it, the more we can show that this approach actually works,” said SetPoint’s Dr. Chernoff.
The hope
In general, interest in VNS for rheumatology is being driven by the possibility that it may reduce proinflammatory cytokines, which opens the door for VNS as an alternative to biologics. The hope is that instead of going after tumor necrosis factor and other cytokines one at a time, VNS could be used to target a range of cytokines all at once, without the cost and side effects of biologics.
“It seems so dramatically different” from what rheumatologists have done in the past, “that our first instinct is to say ‘oh, that’s ridiculous,’ but the science behind it is actually not bad. There may indeed be something to this,” said rheumatologist Joel Kremer, MD, Pfaff Family Professor of Medicine at Albany (N.Y.) Medical College.
Dr. Kremer reviewed SetPoint’s early scientific data after being asked by the company to participate in the safety study; he declined for logistical reasons.
He noted that “there are some strange interactions between the CNS and inflammatory disease.” When RA patients have a stroke, for instance, RA goes into remission on the side of their body affected by the stroke. “That’s been known for decades, but we really don’t understand what’s going on there,” Dr. Kremer said.
The evidence
Perhaps the strongest evidence to date for VNS as a cytokine blocker in rheumatology comes from an open-label, 12-week study, also conducted by SetPoint, in 17 patients with active RA despite methotrexate treatment; some had failed biologics (Proc Natl Acad Sci U S A. 2016 Jul 19;113[29]:8284-9. doi: 10.1073/pnas.160563511).
The microregulator wasn’t ready yet, so investigators implanted a VNS system commercially available for epilepsy and reprogrammed it to deliver a 60-second pulse once a day to the left cervical vagus nerve, which was increased after a month to four 60-second stimulations a day in nonresponders.
The investigators “observed that TNF production in cultured peripheral blood obtained ... on day 42 was significantly reduced from” 21 days before the study was started (TNF 2,900 pg/mL on day –21, versus 1,776 pg/mL on day 42; P less than .05).
When VNS was shut off, TNF production increased; when it was turned back on, it dropped. Interleukin 6 also fell significantly among responders. Overall, DAS28-CRP scores fell about 1.5 points on the 10-point scale from baseline to week 12.
Two-year outcomes were recently reported (Ann Rheum Dis. 2018;77:981-2. Abstract SAT0240). All 17 patients elected to continue treatment after the initial 12 weeks. Biologics were added in nine subjects (53%), because of no or limited response to VNS. Investigators were free to change the VNS dosing regimen, which varied during the study extension up to eight 60-second bursts a day. The roughly 1.5-point improvement in DAS28-CRP was maintained at 2 years.
“These long-term data suggest that bioelectronic therapy may be used as an alternative to, or in combination with, biological[s],” concluded Dr. Chernoff and other study team members.
Awaiting more data
When asked for comment, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, said “there certainly are neurotropic factors” at play in rheumatology, “so there’s sort of a potential reason why” VNS might work, “but we need to understand far more about its mechanism, and [remember] that open-label studies are not to be believed until” large, randomized, blinded, placebo-controlled studies are done.
Dr. Furst also is an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). He is in part-time practice in Los Angeles and Seattle.
If everything works out, however, “the vagus nerve may give us a much wider opportunity to block a host of cytokines; it may change the whole paradigm of how we manage rheumatoid arthritis. I think this is possibly a groundbreaking new therapeutic area, much in the way the biologics were” 20 years ago, said rheumatologist Norman B. Gaylis, MD.
Several of the 14 patients in SetPoint’s safety study were enrolled at Dr. Gaylis’s practice in Aventura, Fla., just north of Miami; he said he is eagerly awaiting for the results to be unblinded. If clinical response in that study and others correlates with a cytokine response, “that’s going to be big, and very significant” in the rheumatology community, he said.
SetPoint’s microregulator is charged wirelessly through a collar patients wear for a few minutes once a week. Dosing can also be adjusted through the collar with the help of a computer application.
The device wasn’t turned on in 4 of the 14 patients in the safety study, as a sham control, but shamming was problematic because patients can potentially feel VNS as a buzz or a change in their voice. To get around that potential confounder, both sham and treated patients were told they might or might not feel something during the study.
Implantation takes about an hour, and is much less complex than implanting currently available epilepsy VNS systems, which require implantation of both a power source on the chest wall and wire coils on the vagus nerve.
Cardiac concerns are the main safety issue with VNS, beyond the surgery itself. Cardiac monitoring was done in the safety study to “ensure that we did not cause things like bradycardia, heart block, syncope, etc.” Dr. Chernoff said. So far, they haven’t turned out to be a problem.
Dr. Furst and Dr. Kremer had no relevant disclosures. Dr. Gaylis was compensated by SetPoint for participating in the safety study; he is a consultant and investigator for Electrocore. Dr. Furst and Dr. Gaylis are members of the editorial advisory board for MDedge Rheumatology/Rheumatology News.
The work is being led by SetPoint Medical, a small company in Valencia, Calif., just north of Los Angeles. Its vagus nerve stimulation (VNS) device, dubbed the microregulator, has been implanted in 14 patients with refractory rheumatoid arthritis (RA) in the company’s initial safety study.
The microregulator is a small lithium ion battery encased in an inert silastic pod; it’s surgically implanted to sit atop the vagus nerve in the left side of the neck, and delivers an electrical pulse at set intervals. Data from the 12-week, sham-controlled safety study is set to be unblinded in coming weeks. A pivotal trial also is in the works, perhaps to start in late 2019, according to rheumatologist and SetPoint’s Chief Medical Officer David Chernoff, MD.
Although SetPoint is ahead of the pack, it’s not alone. ElectroCore, a biotech company in Basking Ridge, N.J., has expressed interest in pursuing rheumatoid arthritis and Sjögren’s syndrome indications for its gammaCore device, a vagus nerve stimulator patients apply to the neck. It’s already on the market for migraines and cluster headaches.
Researchers recently reported a small decrease in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) results after 16 RA patients with flares used the device for 4 days (Ann Rheum Dis. 2018;77:1401. Abstract AB0481). In another recent open-label study, 15 women with Sjögren’s reported less fatigue while using the device for a month (Arthritis Rheumatol. 2017;69[suppl 10]: Abstract 563).
Meanwhile, The Feinstein Institute for Medical Research, based in Manhasset, N.Y., on Long Island, recently reported positive outcomes in 18 patients with systemic lupus erythematosus, using its own novel device, which stimulates the vagus nerve through the ear lobe. VNS was delivered for 5 minutes per day for 4 days (Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2652).
On day 5, patients who received VNS, versus sham patients in whom the device was not turned on, had a significant decrease in pain, fatigue, and joint scores. The investigators concluded that “additional studies evaluating this promising intervention and its potential mechanisms are warranted.”
“We are clearly ahead of everybody because we’ve already implanted people, but I think it’s good for the field if more people are chasing this. The more resources that are put into it, the more we can show that this approach actually works,” said SetPoint’s Dr. Chernoff.
The hope
In general, interest in VNS for rheumatology is being driven by the possibility that it may reduce proinflammatory cytokines, which opens the door for VNS as an alternative to biologics. The hope is that instead of going after tumor necrosis factor and other cytokines one at a time, VNS could be used to target a range of cytokines all at once, without the cost and side effects of biologics.
“It seems so dramatically different” from what rheumatologists have done in the past, “that our first instinct is to say ‘oh, that’s ridiculous,’ but the science behind it is actually not bad. There may indeed be something to this,” said rheumatologist Joel Kremer, MD, Pfaff Family Professor of Medicine at Albany (N.Y.) Medical College.
Dr. Kremer reviewed SetPoint’s early scientific data after being asked by the company to participate in the safety study; he declined for logistical reasons.
He noted that “there are some strange interactions between the CNS and inflammatory disease.” When RA patients have a stroke, for instance, RA goes into remission on the side of their body affected by the stroke. “That’s been known for decades, but we really don’t understand what’s going on there,” Dr. Kremer said.
The evidence
Perhaps the strongest evidence to date for VNS as a cytokine blocker in rheumatology comes from an open-label, 12-week study, also conducted by SetPoint, in 17 patients with active RA despite methotrexate treatment; some had failed biologics (Proc Natl Acad Sci U S A. 2016 Jul 19;113[29]:8284-9. doi: 10.1073/pnas.160563511).
The microregulator wasn’t ready yet, so investigators implanted a VNS system commercially available for epilepsy and reprogrammed it to deliver a 60-second pulse once a day to the left cervical vagus nerve, which was increased after a month to four 60-second stimulations a day in nonresponders.
The investigators “observed that TNF production in cultured peripheral blood obtained ... on day 42 was significantly reduced from” 21 days before the study was started (TNF 2,900 pg/mL on day –21, versus 1,776 pg/mL on day 42; P less than .05).
When VNS was shut off, TNF production increased; when it was turned back on, it dropped. Interleukin 6 also fell significantly among responders. Overall, DAS28-CRP scores fell about 1.5 points on the 10-point scale from baseline to week 12.
Two-year outcomes were recently reported (Ann Rheum Dis. 2018;77:981-2. Abstract SAT0240). All 17 patients elected to continue treatment after the initial 12 weeks. Biologics were added in nine subjects (53%), because of no or limited response to VNS. Investigators were free to change the VNS dosing regimen, which varied during the study extension up to eight 60-second bursts a day. The roughly 1.5-point improvement in DAS28-CRP was maintained at 2 years.
“These long-term data suggest that bioelectronic therapy may be used as an alternative to, or in combination with, biological[s],” concluded Dr. Chernoff and other study team members.
Awaiting more data
When asked for comment, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, said “there certainly are neurotropic factors” at play in rheumatology, “so there’s sort of a potential reason why” VNS might work, “but we need to understand far more about its mechanism, and [remember] that open-label studies are not to be believed until” large, randomized, blinded, placebo-controlled studies are done.
Dr. Furst also is an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). He is in part-time practice in Los Angeles and Seattle.
If everything works out, however, “the vagus nerve may give us a much wider opportunity to block a host of cytokines; it may change the whole paradigm of how we manage rheumatoid arthritis. I think this is possibly a groundbreaking new therapeutic area, much in the way the biologics were” 20 years ago, said rheumatologist Norman B. Gaylis, MD.
Several of the 14 patients in SetPoint’s safety study were enrolled at Dr. Gaylis’s practice in Aventura, Fla., just north of Miami; he said he is eagerly awaiting for the results to be unblinded. If clinical response in that study and others correlates with a cytokine response, “that’s going to be big, and very significant” in the rheumatology community, he said.
SetPoint’s microregulator is charged wirelessly through a collar patients wear for a few minutes once a week. Dosing can also be adjusted through the collar with the help of a computer application.
The device wasn’t turned on in 4 of the 14 patients in the safety study, as a sham control, but shamming was problematic because patients can potentially feel VNS as a buzz or a change in their voice. To get around that potential confounder, both sham and treated patients were told they might or might not feel something during the study.
Implantation takes about an hour, and is much less complex than implanting currently available epilepsy VNS systems, which require implantation of both a power source on the chest wall and wire coils on the vagus nerve.
Cardiac concerns are the main safety issue with VNS, beyond the surgery itself. Cardiac monitoring was done in the safety study to “ensure that we did not cause things like bradycardia, heart block, syncope, etc.” Dr. Chernoff said. So far, they haven’t turned out to be a problem.
Dr. Furst and Dr. Kremer had no relevant disclosures. Dr. Gaylis was compensated by SetPoint for participating in the safety study; he is a consultant and investigator for Electrocore. Dr. Furst and Dr. Gaylis are members of the editorial advisory board for MDedge Rheumatology/Rheumatology News.
The work is being led by SetPoint Medical, a small company in Valencia, Calif., just north of Los Angeles. Its vagus nerve stimulation (VNS) device, dubbed the microregulator, has been implanted in 14 patients with refractory rheumatoid arthritis (RA) in the company’s initial safety study.
The microregulator is a small lithium ion battery encased in an inert silastic pod; it’s surgically implanted to sit atop the vagus nerve in the left side of the neck, and delivers an electrical pulse at set intervals. Data from the 12-week, sham-controlled safety study is set to be unblinded in coming weeks. A pivotal trial also is in the works, perhaps to start in late 2019, according to rheumatologist and SetPoint’s Chief Medical Officer David Chernoff, MD.
Although SetPoint is ahead of the pack, it’s not alone. ElectroCore, a biotech company in Basking Ridge, N.J., has expressed interest in pursuing rheumatoid arthritis and Sjögren’s syndrome indications for its gammaCore device, a vagus nerve stimulator patients apply to the neck. It’s already on the market for migraines and cluster headaches.
Researchers recently reported a small decrease in 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) results after 16 RA patients with flares used the device for 4 days (Ann Rheum Dis. 2018;77:1401. Abstract AB0481). In another recent open-label study, 15 women with Sjögren’s reported less fatigue while using the device for a month (Arthritis Rheumatol. 2017;69[suppl 10]: Abstract 563).
Meanwhile, The Feinstein Institute for Medical Research, based in Manhasset, N.Y., on Long Island, recently reported positive outcomes in 18 patients with systemic lupus erythematosus, using its own novel device, which stimulates the vagus nerve through the ear lobe. VNS was delivered for 5 minutes per day for 4 days (Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2652).
On day 5, patients who received VNS, versus sham patients in whom the device was not turned on, had a significant decrease in pain, fatigue, and joint scores. The investigators concluded that “additional studies evaluating this promising intervention and its potential mechanisms are warranted.”
“We are clearly ahead of everybody because we’ve already implanted people, but I think it’s good for the field if more people are chasing this. The more resources that are put into it, the more we can show that this approach actually works,” said SetPoint’s Dr. Chernoff.
The hope
In general, interest in VNS for rheumatology is being driven by the possibility that it may reduce proinflammatory cytokines, which opens the door for VNS as an alternative to biologics. The hope is that instead of going after tumor necrosis factor and other cytokines one at a time, VNS could be used to target a range of cytokines all at once, without the cost and side effects of biologics.
“It seems so dramatically different” from what rheumatologists have done in the past, “that our first instinct is to say ‘oh, that’s ridiculous,’ but the science behind it is actually not bad. There may indeed be something to this,” said rheumatologist Joel Kremer, MD, Pfaff Family Professor of Medicine at Albany (N.Y.) Medical College.
Dr. Kremer reviewed SetPoint’s early scientific data after being asked by the company to participate in the safety study; he declined for logistical reasons.
He noted that “there are some strange interactions between the CNS and inflammatory disease.” When RA patients have a stroke, for instance, RA goes into remission on the side of their body affected by the stroke. “That’s been known for decades, but we really don’t understand what’s going on there,” Dr. Kremer said.
The evidence
Perhaps the strongest evidence to date for VNS as a cytokine blocker in rheumatology comes from an open-label, 12-week study, also conducted by SetPoint, in 17 patients with active RA despite methotrexate treatment; some had failed biologics (Proc Natl Acad Sci U S A. 2016 Jul 19;113[29]:8284-9. doi: 10.1073/pnas.160563511).
The microregulator wasn’t ready yet, so investigators implanted a VNS system commercially available for epilepsy and reprogrammed it to deliver a 60-second pulse once a day to the left cervical vagus nerve, which was increased after a month to four 60-second stimulations a day in nonresponders.
The investigators “observed that TNF production in cultured peripheral blood obtained ... on day 42 was significantly reduced from” 21 days before the study was started (TNF 2,900 pg/mL on day –21, versus 1,776 pg/mL on day 42; P less than .05).
When VNS was shut off, TNF production increased; when it was turned back on, it dropped. Interleukin 6 also fell significantly among responders. Overall, DAS28-CRP scores fell about 1.5 points on the 10-point scale from baseline to week 12.
Two-year outcomes were recently reported (Ann Rheum Dis. 2018;77:981-2. Abstract SAT0240). All 17 patients elected to continue treatment after the initial 12 weeks. Biologics were added in nine subjects (53%), because of no or limited response to VNS. Investigators were free to change the VNS dosing regimen, which varied during the study extension up to eight 60-second bursts a day. The roughly 1.5-point improvement in DAS28-CRP was maintained at 2 years.
“These long-term data suggest that bioelectronic therapy may be used as an alternative to, or in combination with, biological[s],” concluded Dr. Chernoff and other study team members.
Awaiting more data
When asked for comment, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, said “there certainly are neurotropic factors” at play in rheumatology, “so there’s sort of a potential reason why” VNS might work, “but we need to understand far more about its mechanism, and [remember] that open-label studies are not to be believed until” large, randomized, blinded, placebo-controlled studies are done.
Dr. Furst also is an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). He is in part-time practice in Los Angeles and Seattle.
If everything works out, however, “the vagus nerve may give us a much wider opportunity to block a host of cytokines; it may change the whole paradigm of how we manage rheumatoid arthritis. I think this is possibly a groundbreaking new therapeutic area, much in the way the biologics were” 20 years ago, said rheumatologist Norman B. Gaylis, MD.
Several of the 14 patients in SetPoint’s safety study were enrolled at Dr. Gaylis’s practice in Aventura, Fla., just north of Miami; he said he is eagerly awaiting for the results to be unblinded. If clinical response in that study and others correlates with a cytokine response, “that’s going to be big, and very significant” in the rheumatology community, he said.
SetPoint’s microregulator is charged wirelessly through a collar patients wear for a few minutes once a week. Dosing can also be adjusted through the collar with the help of a computer application.
The device wasn’t turned on in 4 of the 14 patients in the safety study, as a sham control, but shamming was problematic because patients can potentially feel VNS as a buzz or a change in their voice. To get around that potential confounder, both sham and treated patients were told they might or might not feel something during the study.
Implantation takes about an hour, and is much less complex than implanting currently available epilepsy VNS systems, which require implantation of both a power source on the chest wall and wire coils on the vagus nerve.
Cardiac concerns are the main safety issue with VNS, beyond the surgery itself. Cardiac monitoring was done in the safety study to “ensure that we did not cause things like bradycardia, heart block, syncope, etc.” Dr. Chernoff said. So far, they haven’t turned out to be a problem.
Dr. Furst and Dr. Kremer had no relevant disclosures. Dr. Gaylis was compensated by SetPoint for participating in the safety study; he is a consultant and investigator for Electrocore. Dr. Furst and Dr. Gaylis are members of the editorial advisory board for MDedge Rheumatology/Rheumatology News.
Belimumab data out to 13 years show continued safety, efficacy
New data from the longest continuous belimumab treatment in a clinical trial of patients with systemic lupus erythematosus (SLE) indicate similar or lower adverse events each year and maintenance of efficacy for up to 13 years in those who initially respond to and stay on treatment.
First author Daniel J. Wallace, MD, and his colleagues reported in Arthritis & Rheumatology on 298 patients who continued from a phase 2 trial of 476 patients and its extension phase to a continuation study with belimumab (Benlysta) plus standard of care. These patients entered the continuation study having gone from placebo to 10 mg/kg belimumab or continued on 1, 4, or 10 mg/kg belimumab or escalated treatment up to 10 mg/kg. They needed to have an improvement in Physician’s Global Assessment (PGA) score, compared with baseline, and had no severe flare in the last 30 days of the extension study.
At year 5, 70% of patients were still in the study, and this declined to 44% at year 10 and 32% (96 patients) at the end of the study. There were stable or declining rates of the most common adverse events from year 1 to year 11 or later, and serious infections and infestations occurred at a stable rate, from 3.7 per 100 patient-years in year 1 to 6.7 per 100 patients-years through year 11, despite a reduction in immunoglobulin G levels during the study. A total of 15% of patients overall withdrew because of adverse events.
The overall SLE Responder Index response rate rose as the number of participants declined, going from 33% at 1 year and 16 weeks to 76% at 12 years and 32 weeks.
In addition to consistently low flare rates starting at year 5, “those patients remaining had reduced requirements for corticosteroids, and the percentage achieving low disease activity increased. Furthermore, patients continued to have serological improvements. ” Dr. Wallace and his coauthors wrote.
“Patients who remained in the study were likely to be those who responded better or tolerated belimumab better than patients who withdrew; hence, the findings may not be representative of all patients with SLE,” they said.
GlaxoSmithKline and Human Genome Sciences funded the study. Most of the investigators received grants, research support, or consulting fees; held shares in; or were employees of GlaxoSmithKline.
New data from the longest continuous belimumab treatment in a clinical trial of patients with systemic lupus erythematosus (SLE) indicate similar or lower adverse events each year and maintenance of efficacy for up to 13 years in those who initially respond to and stay on treatment.
First author Daniel J. Wallace, MD, and his colleagues reported in Arthritis & Rheumatology on 298 patients who continued from a phase 2 trial of 476 patients and its extension phase to a continuation study with belimumab (Benlysta) plus standard of care. These patients entered the continuation study having gone from placebo to 10 mg/kg belimumab or continued on 1, 4, or 10 mg/kg belimumab or escalated treatment up to 10 mg/kg. They needed to have an improvement in Physician’s Global Assessment (PGA) score, compared with baseline, and had no severe flare in the last 30 days of the extension study.
At year 5, 70% of patients were still in the study, and this declined to 44% at year 10 and 32% (96 patients) at the end of the study. There were stable or declining rates of the most common adverse events from year 1 to year 11 or later, and serious infections and infestations occurred at a stable rate, from 3.7 per 100 patient-years in year 1 to 6.7 per 100 patients-years through year 11, despite a reduction in immunoglobulin G levels during the study. A total of 15% of patients overall withdrew because of adverse events.
The overall SLE Responder Index response rate rose as the number of participants declined, going from 33% at 1 year and 16 weeks to 76% at 12 years and 32 weeks.
In addition to consistently low flare rates starting at year 5, “those patients remaining had reduced requirements for corticosteroids, and the percentage achieving low disease activity increased. Furthermore, patients continued to have serological improvements. ” Dr. Wallace and his coauthors wrote.
“Patients who remained in the study were likely to be those who responded better or tolerated belimumab better than patients who withdrew; hence, the findings may not be representative of all patients with SLE,” they said.
GlaxoSmithKline and Human Genome Sciences funded the study. Most of the investigators received grants, research support, or consulting fees; held shares in; or were employees of GlaxoSmithKline.
New data from the longest continuous belimumab treatment in a clinical trial of patients with systemic lupus erythematosus (SLE) indicate similar or lower adverse events each year and maintenance of efficacy for up to 13 years in those who initially respond to and stay on treatment.
First author Daniel J. Wallace, MD, and his colleagues reported in Arthritis & Rheumatology on 298 patients who continued from a phase 2 trial of 476 patients and its extension phase to a continuation study with belimumab (Benlysta) plus standard of care. These patients entered the continuation study having gone from placebo to 10 mg/kg belimumab or continued on 1, 4, or 10 mg/kg belimumab or escalated treatment up to 10 mg/kg. They needed to have an improvement in Physician’s Global Assessment (PGA) score, compared with baseline, and had no severe flare in the last 30 days of the extension study.
At year 5, 70% of patients were still in the study, and this declined to 44% at year 10 and 32% (96 patients) at the end of the study. There were stable or declining rates of the most common adverse events from year 1 to year 11 or later, and serious infections and infestations occurred at a stable rate, from 3.7 per 100 patient-years in year 1 to 6.7 per 100 patients-years through year 11, despite a reduction in immunoglobulin G levels during the study. A total of 15% of patients overall withdrew because of adverse events.
The overall SLE Responder Index response rate rose as the number of participants declined, going from 33% at 1 year and 16 weeks to 76% at 12 years and 32 weeks.
In addition to consistently low flare rates starting at year 5, “those patients remaining had reduced requirements for corticosteroids, and the percentage achieving low disease activity increased. Furthermore, patients continued to have serological improvements. ” Dr. Wallace and his coauthors wrote.
“Patients who remained in the study were likely to be those who responded better or tolerated belimumab better than patients who withdrew; hence, the findings may not be representative of all patients with SLE,” they said.
GlaxoSmithKline and Human Genome Sciences funded the study. Most of the investigators received grants, research support, or consulting fees; held shares in; or were employees of GlaxoSmithKline.
FROM ARTHRITIS & RHEUMATOLOGY
Rheumatologist involvement often reclassifies interstitial lung disease
MAUI, HAWAII – The latest practice guidelines on the diagnosis of interstitial lung disease issued by the American Thoracic Society and allied organizations recommend as the standard of care a review of all cases by a multidisciplinary team consisting of a pulmonologist, radiologist, and pathologist to ensure accurate diagnosis and classification.
That’s not good enough. A rheumatologist needs to routinely be involved in those multidisciplinary discussions as well, Aryeh Fischer, MD, asserted at the 2019 Rheumatology Winter Clinical Symposium.
Why? Because a rheumatologist’s input often leads to a change in diagnosis. And that change can have important prognostic and therapeutic implications.
“We want to distinguish the IPF [idiopathic pulmonary fibrosis] patients from everybody else. The most important thing with regards to therapy is to identify the IPF patient. The IPF patients are the only ones who are able to be treated with antifibrotic agents: pirfenidone or nintedanib. And we know that immunosuppression can make patients with IPF worse; their risks of hospitalization and mortality are higher on immunosuppression. But everybody else, including anyone with any of the autoimmune diseases along with ILD [interstitial lung disease] or any other causes of ILD, gets treated with immunosuppression,” explained Dr. Fischer, a rheumatologist with a special interest in autoimmune lung disease at the University of Colorado, Denver.
He cited a recent prospective blinded study in which 60 newly diagnosed ILD patients were evaluated separately by a multidisciplinary team comprising a pulmonologist, radiologist, and pathologist and once again with the involvement of a rheumatologist. The rheumatologic assessment reclassified 21% of patients from IPF – that is, lung disease unrelated to connective tissue disease (CTD) or exposure to asbestos, bird droppings, or other triggers – to ILD with connective tissue disease (CTD-ILD). And the number of patients classified as having ILD with autoimmune features without meeting full diagnostic criteria for a major CTD, a category that includes antisynthetase syndrome and IgG4-related ILD, jumped by 77%. Also, the investigators determined that adding a rheumatologist to the multidisciplinary team would have resulted in seven fewer bronchoscopies and one less surgical biopsy among this 60-patient cohort (J Rheumatol. 2018 Nov;45[11]:1509-14).
It’s not at all uncommon to identify a new occult CTD in patients presenting with ILD. Dr. Fischer noted that in a series of 114 consecutive patients evaluated at the interdisciplinary ILD program at Johns Hopkins University, Baltimore, 30% of them had a well-defined CTD, half of whom, or 15% of the total, were newly diagnosed with CTD by virtue of their ILD evaluation (Respir Med. 2009 Aug;103[8]:1152-8).
A CTD-ILD diagnosis has prognostic implications: Survival is significantly better than with IPF, with the exception of ILD with rheumatoid arthritis (RA-ILD), where the prognosis seems to be worse than for other forms of CTD-ILD and is more akin to that of IPF. Indeed, the risk of death is threefold higher in patients with RA-ILD than in those with RA without ILD. While the predominant pattern of lung injury in RA-ILD is usual interstitial pneumonia, marked by fibrosis and honeycombing, the predominant pattern in all other forms of CTD-ILD is nonspecific interstitial pneumonia.
A French study of 778 consecutive patients with ILD highlighted how common autoimmune disease is in the ILD population. Nearly one-third of the ILD patients had autoimmune disease: 22% had CTD-ILD and another 7% had interstitial pneumonia with autoimmune features, or IPAF (Respir Med. 2017 Feb;123:56-62).
Dr. Fischer was lead author of a report by a European Respiratory Society/American Thoracic Society task force that first put forth the term IPAF to describe ILD patients with subtle serologic, clinical, and/or morphologic findings that don’t rise to the level required for formal diagnosis of a defined CTD (Eur Respir J. 2015 Oct;46[4]:976-87).
IPAF is a research construct. Patients who fall into this category are the focus of ongoing prospective studies aimed at better understanding their prognosis and appropriate treatment.
The big three autoimmune diseases comorbid with ILD as reported by Dr. Fischer and coinvestigators in a study of 237 patients with an autoimmune phenotype in a Denver ILD clinic were scleroderma, present in 37%; rheumatoid arthritis, present in 18%; and myositis, with a prevalence of 11%. Another 24% had IPAF.
“There was surprisingly little SLE [3%], and not much Sjögren’s [6%],” he observed.
When pulmonologists come knocking on Dr. Fischer’s door asking if their patients with ILD have occult CTD, he finds it helpful to look for quantifiable specific extrathoracic features suggestive of rheumatologic disease, such as Raynaud’s, sclerodactyly, mechanic hands, and Gottron’s papules.
The ILD practice guidelines recently issued jointly by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society recommend that serologic evaluation for a long list of autoantibodies “should be performed even in the absence of signs or symptoms of connective tissue disease” (Am J Respir Crit Care Med. 2018 Sep 1;198[5]:e44-e68). Dr. Fischer indicated he has a problem with that recommendation since nonrheumatologists aren’t typically adept in interpreting the significance of autoantibodies.
“I will just tell you, I see a lot of patients for ILD evaluation, and autoimmune serologies often lead to more questions than answers. They always need to be considered within the clinical context,” the rheumatologist said.
High-resolution CT (HRCT) is the imaging method of choice for detecting ILD and classifying its severity. HRCT also holds clues for detection of CTD-ILD.
“There are no upper lung–predominant ILDs that really make you think CTD. Our diseases like the lower lung zones. We like to see multicompartment involvement. When you hear ‘airways and parenchymal,’ ‘pleural,’ ‘pericardial thickening,’ that sounds a lot like autoimmune disease,” according to Dr. Fischer.
Also, the presence of a dilated esophagus on HRCT is strongly suggestive of scleroderma, he added.
In the event a pathology report is available, it’s important to read the fine print. Secondary histopathologic features of CTD-ILD include extensive pleuritis, lymphoid aggregates with germinal center formation, dense perivascular collagen, and/or prominent plasmacytic infiltration.
While ILD can be the first manifestation of an underlying occult CTD, it’s also common for a patient with an established CTD to subsequently develop ILD.
Rheumatologists are no strangers to ambiguity, so it should come as no surprise that while audible bibasilar crackles on physical examination are strongly predictive of ILD, their absence doesn’t indicate absence of ILD. Similarly, dyspnea in a patient with established CTD can be tough to interpret, and absence of dyspnea doesn’t imply absence of ILD. If a patient with CTD is on immunosuppressive therapy, bronchoalveolar lavage is of value in ruling out infection.
When to order a surgical lung biopsy
“If you’re pretty sure your patient had a CTD and then you get a characteristic HRCT and there are no exposures to account for the imaging findings – if we have a scenario where it all fits – we often don’t biopsy. Biopsy usually means a 2-night hospital stay, and it’s reportedly associated with about a 1% mortality risk. And the clinical reality is the biopsy may not impact treatment. They’re going to give you azathioprine, mycophenolate, cyclophosphamide, or prednisone for the ILD and the extrathoracic disease irrespective of the ILD pattern,” the rheumatologist said.
He reserves surgical biopsy for patients with an atypical HRCT, those with known CTD and a possible alternative etiology for the ILD, such as exposure to asbestos or owning pet birds, and patients where he’s just not sure a CTD is actually present.
Treatment of CTD-ILD
“The available controlled efficacy data are limited to scleroderma-ILD, where cyclophosphamide and mycophenolate work a little bit. And that’s it. We don’t have good data to guide us on which agent for which CTD or ILD pattern, for how long, or what dose,” Dr. Fischer said. “We have good drugs for the joints, nothing for the lungs. Treatment is not evidence based. We initiate with high-dose steroids, switch to a steroid-sparing agent, we evaluate the response to treatment with surveillance every 3-6 months by 6-minute walking, lung function tests, and sometimes imaging, and we treat for a long time. Oftentimes stability equals success.”
That being said, it must be emphasized that not all CTD-ILD warrants treatment of the pulmonary disease. If the patient’s ILD is mild and indolent, clinical surveillance is often appropriate, he continued.
More important than the pharmacotherapy available at present are adjunctive nonpharmacologic approaches: supplemental oxygen, pulmonary rehabilitation, treatment of comorbid GERD, immunizations, and addressing mental health issues related to these devastating diseases.
“We really don’t do these things well,” Dr. Fischer said.
On the horizon
An investigator-driven phase 2 clinical trial of the antifibrotic drug pirfenidone (Esbriet), now approved for IPF, is underway in patients with RA-ILD. Results of a trial of antifibrotic therapy in patients with scleroderma-ILD are due to be presented this year at EULAR. And a small study of antifibrotic therapy in patients with myositis-ILD is ongoing.
As for the biologics, there is a signal in the literature that tumor necrosis factor inhibitors may be associated with increased risk of rapidly progressive lung disease in patients with RA-ILD. An influential report from the British Society for Rheumatology Biologics Register on 299 patients with preexisting RA-ILD treated with anti-TNF therapy and 68 who received traditional disease-modifying antirrheumatic drugs showed that while mortality during follow-up was similar in the two groups, the proportion of deaths attributed to RA-ILD was 21% in the group on anti-TNF therapy, compared with only 7% in those on traditional DMARDs (Ann Rheum Dis. 2010 Jun;69[6]:1086-91).
Paul Emery, MD, rose from the audience at Dr. Fischer’s request to share his extensive experience with anti-TNF therapy and rituximab (Rituxan) in the setting of RA-ILD. When he was involved in several of the pivotal clinical trials of anti-TNF agents for RA he encountered a couple of cases of rapidly progressive ILD in patients on treatment.
“We had never before seen rapidly progressive ILD that didn’t respond to cyclophosphamide. Both patients died,” recalled Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
“Our experience is if you’ve got mild ILD – and if you look hard enough you can find it in many rheumatoids – TNF inhibitor therapy doesn’t affect it. But if there’s any hint of deterioration we move away from anti-TNF therapy. Our preference has been for rituximab,” he said.
Dr. Emery was senior author of the largest study to date of rituximab in patients with RA-ILD (Rheumatology [Oxford]. 2017 Aug 1;56[8]:1348-57). While he and his coinvestigators concluded that rituximab “appears to be an acceptable therapeutic choice for patients with RA-ILD,” Dr. Fischer didn’t find persuasive evidence from this relatively small retrospective observational study in which only 44 patients had lung data available.
“My own conclusion is evidence is lacking to support a role of rituximab for treating ILD in RA,” Dr. Fischer said.
He reported receiving research grants from Boehringer-Ingelheim and Corbus and serving as a consultant to a handful of other pharmaceutical companies.
MAUI, HAWAII – The latest practice guidelines on the diagnosis of interstitial lung disease issued by the American Thoracic Society and allied organizations recommend as the standard of care a review of all cases by a multidisciplinary team consisting of a pulmonologist, radiologist, and pathologist to ensure accurate diagnosis and classification.
That’s not good enough. A rheumatologist needs to routinely be involved in those multidisciplinary discussions as well, Aryeh Fischer, MD, asserted at the 2019 Rheumatology Winter Clinical Symposium.
Why? Because a rheumatologist’s input often leads to a change in diagnosis. And that change can have important prognostic and therapeutic implications.
“We want to distinguish the IPF [idiopathic pulmonary fibrosis] patients from everybody else. The most important thing with regards to therapy is to identify the IPF patient. The IPF patients are the only ones who are able to be treated with antifibrotic agents: pirfenidone or nintedanib. And we know that immunosuppression can make patients with IPF worse; their risks of hospitalization and mortality are higher on immunosuppression. But everybody else, including anyone with any of the autoimmune diseases along with ILD [interstitial lung disease] or any other causes of ILD, gets treated with immunosuppression,” explained Dr. Fischer, a rheumatologist with a special interest in autoimmune lung disease at the University of Colorado, Denver.
He cited a recent prospective blinded study in which 60 newly diagnosed ILD patients were evaluated separately by a multidisciplinary team comprising a pulmonologist, radiologist, and pathologist and once again with the involvement of a rheumatologist. The rheumatologic assessment reclassified 21% of patients from IPF – that is, lung disease unrelated to connective tissue disease (CTD) or exposure to asbestos, bird droppings, or other triggers – to ILD with connective tissue disease (CTD-ILD). And the number of patients classified as having ILD with autoimmune features without meeting full diagnostic criteria for a major CTD, a category that includes antisynthetase syndrome and IgG4-related ILD, jumped by 77%. Also, the investigators determined that adding a rheumatologist to the multidisciplinary team would have resulted in seven fewer bronchoscopies and one less surgical biopsy among this 60-patient cohort (J Rheumatol. 2018 Nov;45[11]:1509-14).
It’s not at all uncommon to identify a new occult CTD in patients presenting with ILD. Dr. Fischer noted that in a series of 114 consecutive patients evaluated at the interdisciplinary ILD program at Johns Hopkins University, Baltimore, 30% of them had a well-defined CTD, half of whom, or 15% of the total, were newly diagnosed with CTD by virtue of their ILD evaluation (Respir Med. 2009 Aug;103[8]:1152-8).
A CTD-ILD diagnosis has prognostic implications: Survival is significantly better than with IPF, with the exception of ILD with rheumatoid arthritis (RA-ILD), where the prognosis seems to be worse than for other forms of CTD-ILD and is more akin to that of IPF. Indeed, the risk of death is threefold higher in patients with RA-ILD than in those with RA without ILD. While the predominant pattern of lung injury in RA-ILD is usual interstitial pneumonia, marked by fibrosis and honeycombing, the predominant pattern in all other forms of CTD-ILD is nonspecific interstitial pneumonia.
A French study of 778 consecutive patients with ILD highlighted how common autoimmune disease is in the ILD population. Nearly one-third of the ILD patients had autoimmune disease: 22% had CTD-ILD and another 7% had interstitial pneumonia with autoimmune features, or IPAF (Respir Med. 2017 Feb;123:56-62).
Dr. Fischer was lead author of a report by a European Respiratory Society/American Thoracic Society task force that first put forth the term IPAF to describe ILD patients with subtle serologic, clinical, and/or morphologic findings that don’t rise to the level required for formal diagnosis of a defined CTD (Eur Respir J. 2015 Oct;46[4]:976-87).
IPAF is a research construct. Patients who fall into this category are the focus of ongoing prospective studies aimed at better understanding their prognosis and appropriate treatment.
The big three autoimmune diseases comorbid with ILD as reported by Dr. Fischer and coinvestigators in a study of 237 patients with an autoimmune phenotype in a Denver ILD clinic were scleroderma, present in 37%; rheumatoid arthritis, present in 18%; and myositis, with a prevalence of 11%. Another 24% had IPAF.
“There was surprisingly little SLE [3%], and not much Sjögren’s [6%],” he observed.
When pulmonologists come knocking on Dr. Fischer’s door asking if their patients with ILD have occult CTD, he finds it helpful to look for quantifiable specific extrathoracic features suggestive of rheumatologic disease, such as Raynaud’s, sclerodactyly, mechanic hands, and Gottron’s papules.
The ILD practice guidelines recently issued jointly by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society recommend that serologic evaluation for a long list of autoantibodies “should be performed even in the absence of signs or symptoms of connective tissue disease” (Am J Respir Crit Care Med. 2018 Sep 1;198[5]:e44-e68). Dr. Fischer indicated he has a problem with that recommendation since nonrheumatologists aren’t typically adept in interpreting the significance of autoantibodies.
“I will just tell you, I see a lot of patients for ILD evaluation, and autoimmune serologies often lead to more questions than answers. They always need to be considered within the clinical context,” the rheumatologist said.
High-resolution CT (HRCT) is the imaging method of choice for detecting ILD and classifying its severity. HRCT also holds clues for detection of CTD-ILD.
“There are no upper lung–predominant ILDs that really make you think CTD. Our diseases like the lower lung zones. We like to see multicompartment involvement. When you hear ‘airways and parenchymal,’ ‘pleural,’ ‘pericardial thickening,’ that sounds a lot like autoimmune disease,” according to Dr. Fischer.
Also, the presence of a dilated esophagus on HRCT is strongly suggestive of scleroderma, he added.
In the event a pathology report is available, it’s important to read the fine print. Secondary histopathologic features of CTD-ILD include extensive pleuritis, lymphoid aggregates with germinal center formation, dense perivascular collagen, and/or prominent plasmacytic infiltration.
While ILD can be the first manifestation of an underlying occult CTD, it’s also common for a patient with an established CTD to subsequently develop ILD.
Rheumatologists are no strangers to ambiguity, so it should come as no surprise that while audible bibasilar crackles on physical examination are strongly predictive of ILD, their absence doesn’t indicate absence of ILD. Similarly, dyspnea in a patient with established CTD can be tough to interpret, and absence of dyspnea doesn’t imply absence of ILD. If a patient with CTD is on immunosuppressive therapy, bronchoalveolar lavage is of value in ruling out infection.
When to order a surgical lung biopsy
“If you’re pretty sure your patient had a CTD and then you get a characteristic HRCT and there are no exposures to account for the imaging findings – if we have a scenario where it all fits – we often don’t biopsy. Biopsy usually means a 2-night hospital stay, and it’s reportedly associated with about a 1% mortality risk. And the clinical reality is the biopsy may not impact treatment. They’re going to give you azathioprine, mycophenolate, cyclophosphamide, or prednisone for the ILD and the extrathoracic disease irrespective of the ILD pattern,” the rheumatologist said.
He reserves surgical biopsy for patients with an atypical HRCT, those with known CTD and a possible alternative etiology for the ILD, such as exposure to asbestos or owning pet birds, and patients where he’s just not sure a CTD is actually present.
Treatment of CTD-ILD
“The available controlled efficacy data are limited to scleroderma-ILD, where cyclophosphamide and mycophenolate work a little bit. And that’s it. We don’t have good data to guide us on which agent for which CTD or ILD pattern, for how long, or what dose,” Dr. Fischer said. “We have good drugs for the joints, nothing for the lungs. Treatment is not evidence based. We initiate with high-dose steroids, switch to a steroid-sparing agent, we evaluate the response to treatment with surveillance every 3-6 months by 6-minute walking, lung function tests, and sometimes imaging, and we treat for a long time. Oftentimes stability equals success.”
That being said, it must be emphasized that not all CTD-ILD warrants treatment of the pulmonary disease. If the patient’s ILD is mild and indolent, clinical surveillance is often appropriate, he continued.
More important than the pharmacotherapy available at present are adjunctive nonpharmacologic approaches: supplemental oxygen, pulmonary rehabilitation, treatment of comorbid GERD, immunizations, and addressing mental health issues related to these devastating diseases.
“We really don’t do these things well,” Dr. Fischer said.
On the horizon
An investigator-driven phase 2 clinical trial of the antifibrotic drug pirfenidone (Esbriet), now approved for IPF, is underway in patients with RA-ILD. Results of a trial of antifibrotic therapy in patients with scleroderma-ILD are due to be presented this year at EULAR. And a small study of antifibrotic therapy in patients with myositis-ILD is ongoing.
As for the biologics, there is a signal in the literature that tumor necrosis factor inhibitors may be associated with increased risk of rapidly progressive lung disease in patients with RA-ILD. An influential report from the British Society for Rheumatology Biologics Register on 299 patients with preexisting RA-ILD treated with anti-TNF therapy and 68 who received traditional disease-modifying antirrheumatic drugs showed that while mortality during follow-up was similar in the two groups, the proportion of deaths attributed to RA-ILD was 21% in the group on anti-TNF therapy, compared with only 7% in those on traditional DMARDs (Ann Rheum Dis. 2010 Jun;69[6]:1086-91).
Paul Emery, MD, rose from the audience at Dr. Fischer’s request to share his extensive experience with anti-TNF therapy and rituximab (Rituxan) in the setting of RA-ILD. When he was involved in several of the pivotal clinical trials of anti-TNF agents for RA he encountered a couple of cases of rapidly progressive ILD in patients on treatment.
“We had never before seen rapidly progressive ILD that didn’t respond to cyclophosphamide. Both patients died,” recalled Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
“Our experience is if you’ve got mild ILD – and if you look hard enough you can find it in many rheumatoids – TNF inhibitor therapy doesn’t affect it. But if there’s any hint of deterioration we move away from anti-TNF therapy. Our preference has been for rituximab,” he said.
Dr. Emery was senior author of the largest study to date of rituximab in patients with RA-ILD (Rheumatology [Oxford]. 2017 Aug 1;56[8]:1348-57). While he and his coinvestigators concluded that rituximab “appears to be an acceptable therapeutic choice for patients with RA-ILD,” Dr. Fischer didn’t find persuasive evidence from this relatively small retrospective observational study in which only 44 patients had lung data available.
“My own conclusion is evidence is lacking to support a role of rituximab for treating ILD in RA,” Dr. Fischer said.
He reported receiving research grants from Boehringer-Ingelheim and Corbus and serving as a consultant to a handful of other pharmaceutical companies.
MAUI, HAWAII – The latest practice guidelines on the diagnosis of interstitial lung disease issued by the American Thoracic Society and allied organizations recommend as the standard of care a review of all cases by a multidisciplinary team consisting of a pulmonologist, radiologist, and pathologist to ensure accurate diagnosis and classification.
That’s not good enough. A rheumatologist needs to routinely be involved in those multidisciplinary discussions as well, Aryeh Fischer, MD, asserted at the 2019 Rheumatology Winter Clinical Symposium.
Why? Because a rheumatologist’s input often leads to a change in diagnosis. And that change can have important prognostic and therapeutic implications.
“We want to distinguish the IPF [idiopathic pulmonary fibrosis] patients from everybody else. The most important thing with regards to therapy is to identify the IPF patient. The IPF patients are the only ones who are able to be treated with antifibrotic agents: pirfenidone or nintedanib. And we know that immunosuppression can make patients with IPF worse; their risks of hospitalization and mortality are higher on immunosuppression. But everybody else, including anyone with any of the autoimmune diseases along with ILD [interstitial lung disease] or any other causes of ILD, gets treated with immunosuppression,” explained Dr. Fischer, a rheumatologist with a special interest in autoimmune lung disease at the University of Colorado, Denver.
He cited a recent prospective blinded study in which 60 newly diagnosed ILD patients were evaluated separately by a multidisciplinary team comprising a pulmonologist, radiologist, and pathologist and once again with the involvement of a rheumatologist. The rheumatologic assessment reclassified 21% of patients from IPF – that is, lung disease unrelated to connective tissue disease (CTD) or exposure to asbestos, bird droppings, or other triggers – to ILD with connective tissue disease (CTD-ILD). And the number of patients classified as having ILD with autoimmune features without meeting full diagnostic criteria for a major CTD, a category that includes antisynthetase syndrome and IgG4-related ILD, jumped by 77%. Also, the investigators determined that adding a rheumatologist to the multidisciplinary team would have resulted in seven fewer bronchoscopies and one less surgical biopsy among this 60-patient cohort (J Rheumatol. 2018 Nov;45[11]:1509-14).
It’s not at all uncommon to identify a new occult CTD in patients presenting with ILD. Dr. Fischer noted that in a series of 114 consecutive patients evaluated at the interdisciplinary ILD program at Johns Hopkins University, Baltimore, 30% of them had a well-defined CTD, half of whom, or 15% of the total, were newly diagnosed with CTD by virtue of their ILD evaluation (Respir Med. 2009 Aug;103[8]:1152-8).
A CTD-ILD diagnosis has prognostic implications: Survival is significantly better than with IPF, with the exception of ILD with rheumatoid arthritis (RA-ILD), where the prognosis seems to be worse than for other forms of CTD-ILD and is more akin to that of IPF. Indeed, the risk of death is threefold higher in patients with RA-ILD than in those with RA without ILD. While the predominant pattern of lung injury in RA-ILD is usual interstitial pneumonia, marked by fibrosis and honeycombing, the predominant pattern in all other forms of CTD-ILD is nonspecific interstitial pneumonia.
A French study of 778 consecutive patients with ILD highlighted how common autoimmune disease is in the ILD population. Nearly one-third of the ILD patients had autoimmune disease: 22% had CTD-ILD and another 7% had interstitial pneumonia with autoimmune features, or IPAF (Respir Med. 2017 Feb;123:56-62).
Dr. Fischer was lead author of a report by a European Respiratory Society/American Thoracic Society task force that first put forth the term IPAF to describe ILD patients with subtle serologic, clinical, and/or morphologic findings that don’t rise to the level required for formal diagnosis of a defined CTD (Eur Respir J. 2015 Oct;46[4]:976-87).
IPAF is a research construct. Patients who fall into this category are the focus of ongoing prospective studies aimed at better understanding their prognosis and appropriate treatment.
The big three autoimmune diseases comorbid with ILD as reported by Dr. Fischer and coinvestigators in a study of 237 patients with an autoimmune phenotype in a Denver ILD clinic were scleroderma, present in 37%; rheumatoid arthritis, present in 18%; and myositis, with a prevalence of 11%. Another 24% had IPAF.
“There was surprisingly little SLE [3%], and not much Sjögren’s [6%],” he observed.
When pulmonologists come knocking on Dr. Fischer’s door asking if their patients with ILD have occult CTD, he finds it helpful to look for quantifiable specific extrathoracic features suggestive of rheumatologic disease, such as Raynaud’s, sclerodactyly, mechanic hands, and Gottron’s papules.
The ILD practice guidelines recently issued jointly by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society recommend that serologic evaluation for a long list of autoantibodies “should be performed even in the absence of signs or symptoms of connective tissue disease” (Am J Respir Crit Care Med. 2018 Sep 1;198[5]:e44-e68). Dr. Fischer indicated he has a problem with that recommendation since nonrheumatologists aren’t typically adept in interpreting the significance of autoantibodies.
“I will just tell you, I see a lot of patients for ILD evaluation, and autoimmune serologies often lead to more questions than answers. They always need to be considered within the clinical context,” the rheumatologist said.
High-resolution CT (HRCT) is the imaging method of choice for detecting ILD and classifying its severity. HRCT also holds clues for detection of CTD-ILD.
“There are no upper lung–predominant ILDs that really make you think CTD. Our diseases like the lower lung zones. We like to see multicompartment involvement. When you hear ‘airways and parenchymal,’ ‘pleural,’ ‘pericardial thickening,’ that sounds a lot like autoimmune disease,” according to Dr. Fischer.
Also, the presence of a dilated esophagus on HRCT is strongly suggestive of scleroderma, he added.
In the event a pathology report is available, it’s important to read the fine print. Secondary histopathologic features of CTD-ILD include extensive pleuritis, lymphoid aggregates with germinal center formation, dense perivascular collagen, and/or prominent plasmacytic infiltration.
While ILD can be the first manifestation of an underlying occult CTD, it’s also common for a patient with an established CTD to subsequently develop ILD.
Rheumatologists are no strangers to ambiguity, so it should come as no surprise that while audible bibasilar crackles on physical examination are strongly predictive of ILD, their absence doesn’t indicate absence of ILD. Similarly, dyspnea in a patient with established CTD can be tough to interpret, and absence of dyspnea doesn’t imply absence of ILD. If a patient with CTD is on immunosuppressive therapy, bronchoalveolar lavage is of value in ruling out infection.
When to order a surgical lung biopsy
“If you’re pretty sure your patient had a CTD and then you get a characteristic HRCT and there are no exposures to account for the imaging findings – if we have a scenario where it all fits – we often don’t biopsy. Biopsy usually means a 2-night hospital stay, and it’s reportedly associated with about a 1% mortality risk. And the clinical reality is the biopsy may not impact treatment. They’re going to give you azathioprine, mycophenolate, cyclophosphamide, or prednisone for the ILD and the extrathoracic disease irrespective of the ILD pattern,” the rheumatologist said.
He reserves surgical biopsy for patients with an atypical HRCT, those with known CTD and a possible alternative etiology for the ILD, such as exposure to asbestos or owning pet birds, and patients where he’s just not sure a CTD is actually present.
Treatment of CTD-ILD
“The available controlled efficacy data are limited to scleroderma-ILD, where cyclophosphamide and mycophenolate work a little bit. And that’s it. We don’t have good data to guide us on which agent for which CTD or ILD pattern, for how long, or what dose,” Dr. Fischer said. “We have good drugs for the joints, nothing for the lungs. Treatment is not evidence based. We initiate with high-dose steroids, switch to a steroid-sparing agent, we evaluate the response to treatment with surveillance every 3-6 months by 6-minute walking, lung function tests, and sometimes imaging, and we treat for a long time. Oftentimes stability equals success.”
That being said, it must be emphasized that not all CTD-ILD warrants treatment of the pulmonary disease. If the patient’s ILD is mild and indolent, clinical surveillance is often appropriate, he continued.
More important than the pharmacotherapy available at present are adjunctive nonpharmacologic approaches: supplemental oxygen, pulmonary rehabilitation, treatment of comorbid GERD, immunizations, and addressing mental health issues related to these devastating diseases.
“We really don’t do these things well,” Dr. Fischer said.
On the horizon
An investigator-driven phase 2 clinical trial of the antifibrotic drug pirfenidone (Esbriet), now approved for IPF, is underway in patients with RA-ILD. Results of a trial of antifibrotic therapy in patients with scleroderma-ILD are due to be presented this year at EULAR. And a small study of antifibrotic therapy in patients with myositis-ILD is ongoing.
As for the biologics, there is a signal in the literature that tumor necrosis factor inhibitors may be associated with increased risk of rapidly progressive lung disease in patients with RA-ILD. An influential report from the British Society for Rheumatology Biologics Register on 299 patients with preexisting RA-ILD treated with anti-TNF therapy and 68 who received traditional disease-modifying antirrheumatic drugs showed that while mortality during follow-up was similar in the two groups, the proportion of deaths attributed to RA-ILD was 21% in the group on anti-TNF therapy, compared with only 7% in those on traditional DMARDs (Ann Rheum Dis. 2010 Jun;69[6]:1086-91).
Paul Emery, MD, rose from the audience at Dr. Fischer’s request to share his extensive experience with anti-TNF therapy and rituximab (Rituxan) in the setting of RA-ILD. When he was involved in several of the pivotal clinical trials of anti-TNF agents for RA he encountered a couple of cases of rapidly progressive ILD in patients on treatment.
“We had never before seen rapidly progressive ILD that didn’t respond to cyclophosphamide. Both patients died,” recalled Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
“Our experience is if you’ve got mild ILD – and if you look hard enough you can find it in many rheumatoids – TNF inhibitor therapy doesn’t affect it. But if there’s any hint of deterioration we move away from anti-TNF therapy. Our preference has been for rituximab,” he said.
Dr. Emery was senior author of the largest study to date of rituximab in patients with RA-ILD (Rheumatology [Oxford]. 2017 Aug 1;56[8]:1348-57). While he and his coinvestigators concluded that rituximab “appears to be an acceptable therapeutic choice for patients with RA-ILD,” Dr. Fischer didn’t find persuasive evidence from this relatively small retrospective observational study in which only 44 patients had lung data available.
“My own conclusion is evidence is lacking to support a role of rituximab for treating ILD in RA,” Dr. Fischer said.
He reported receiving research grants from Boehringer-Ingelheim and Corbus and serving as a consultant to a handful of other pharmaceutical companies.
REPORTING FROM RWCS 2019