User login
Global Quest to Cut CAR T Costs
In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.
At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.
“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”
However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.
A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.
“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.
Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
Harnessing the Power of T-Cells
Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.
Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.
These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”
As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”
In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”
The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
Treatment: Individual, Complex, and Costly
Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.
“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”
Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”
Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”
Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
Taking Gene Therapy In-House
As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.
“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”
The device is experimental and not yet FDA approved, Dr. Grupp noted, so that patients are all in clinical trials. Children’s Hospital of Philadelphia has treated more than a dozen patients with the device, he said.
Another member of Children’s Hospital of Philadelphia’s CAR T-cell team told WHYY-FM that a single patient’s treatment would run about $30,000 for labor and testing, but not other expenses such as facility costs.
Dr. Grupp estimated that about half a dozen of these devices are in use in the United States, and many more worldwide. “They’re all just like we are — at the absolute beginning. We’ve only been doing this for about a year.”
In the big picture, Dr. Grupp said, “this is where cell therapy is going. Whether it’s point of care or not, automated cell manufacturing is the obvious next step.”
India: Big Hopes for Homegrown Technology
In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.
Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.
In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.
Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.
According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
A US-Brazil Partnership Holds Promise
Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.
“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”
According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.
The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.
Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.
In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.
At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.
“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”
However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.
A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.
“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.
Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
Harnessing the Power of T-Cells
Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.
Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.
These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”
As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”
In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”
The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
Treatment: Individual, Complex, and Costly
Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.
“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”
Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”
Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”
Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
Taking Gene Therapy In-House
As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.
“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”
The device is experimental and not yet FDA approved, Dr. Grupp noted, so that patients are all in clinical trials. Children’s Hospital of Philadelphia has treated more than a dozen patients with the device, he said.
Another member of Children’s Hospital of Philadelphia’s CAR T-cell team told WHYY-FM that a single patient’s treatment would run about $30,000 for labor and testing, but not other expenses such as facility costs.
Dr. Grupp estimated that about half a dozen of these devices are in use in the United States, and many more worldwide. “They’re all just like we are — at the absolute beginning. We’ve only been doing this for about a year.”
In the big picture, Dr. Grupp said, “this is where cell therapy is going. Whether it’s point of care or not, automated cell manufacturing is the obvious next step.”
India: Big Hopes for Homegrown Technology
In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.
Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.
In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.
Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.
According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
A US-Brazil Partnership Holds Promise
Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.
“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”
According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.
The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.
Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.
In the United States, a stand-alone device could greatly reduce the expense of producing modified immune cells. In India, researchers hope homegrown technology is the key to getting costs under control. In Latin America, a partnership between the Brazilian government and a US nonprofit may be just the ticket.
At stake is expanded access to CAR T-cell therapy, a form of immunotherapy that in just the past few years has revolutionized the care of hematologic cancers.
“Among patients with lymphoma, leukemia, and myeloma, anywhere between 30% to 50% reach long-term remission after one CAR T-cell infusion,” Mayo Clinic–Rochester hematologist/oncologist Saad J. Kenderian, MB, ChB, said in an interview. “It’s such an important therapy.”
However, only a small percentage of eligible patients in the United States — perhaps 20% or fewer — are receiving the treatment, he added.
A 2024 report suggested that many patients in the United States who may benefit aren’t being treated because of a range of possible reasons, including high prices, manufacturing logistics, and far distance from the limited number of institutions offering the therapy.
“Taken together, the real-world cost of CAR T-cell therapy can range from $700,000 to $1 million, which may make the treatment unaffordable to those patients without robust financial and/or social support,” the report authors noted.
Outside Western countries, access to the therapy is even more limited, because of its exorbitant price. The 2024 report noted that “there is a wide use of CAR T-cell therapy in Europe and China, but access is limited in developing countries in Southeast Asia, Africa, and Latin America.”
Harnessing the Power of T-Cells
Several types of CAR T-cell therapy have been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory blood cancers such as follicular lymphoma, large B-cell lymphoma, multiple myeloma, and B-cell precursor acute lymphoblastic leukemia. A 2023 review analyzed clinical trials and reported that complete response rates were 40%-54% in aggressive B-cell lymphoma, 67% in mantle cell lymphoma, and 69%-74% in indolent B-cell lymphoma.
Pediatric hematologist/oncologist Kirsten Williams, MD, who specializes in pediatric blood and marrow transplant and cellular therapy at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, described CAR T-cell therapy as “a very unique form of immunotherapy” that harnesses the power of the immune system’s T-cells.
These cells are effective tumor killers, but they typically aren’t assigned to control cancer, she said in an interview. “We have very few of them, and most of our T cells are focused on killing various viruses,” she said. The therapy “allows us to take the T cell that would have killed the flu or mono and instead target leukemia, B-cell leukemia, or lymphoma.”
As she explained, “T cells are collected by a machine that reserves white blood cells and gives back the rest of the blood to the patient. We insert a gene into the T cells that encodes for a B-cell receptor. This receptor acts as a GPS signal, pulling T cells to the cancer so that they can kill it.”
In addition, “with this genetic change, we also add some things that allow the T cell to be stronger, to have a higher signal to kill the cancer cell once it locks on.”
The therapy is unique for each patient, Dr. Williams said. “We have collected and modified your specific T cells, and they can now only be infused into you. If we try to give your product to someone else, those cells would either cause harm by attacking the patient or would be immediately killed by that patient’s own immune system. This is very different than all the other kinds of therapies. When you take other medicines, it doesn’t matter who receives that pill.”
Treatment: Individual, Complex, and Costly
Why is CAR T-cell therapy so expensive? While only a single treatment is needed, the T cells have to go through an “individualized, bespoke manufacturing” process that’s “highly technical,” pediatric oncologist Stephan A. Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia, said in an interview. As he explained, the cells for a single patient have to go through the same testing as with a drug that might be given to 1,000 people.
“The first thing we need to do is collect the cells from a patient,” said Dr. Williams. “For adults, that process involves putting in two big IVs — one in each arm — and then pulling the blood through a machine. This typically involves an 8-hour collection in the hospital and very highly specialized people to oversee the collection process.”
Secondly, at some institutions, “the cells get sent to a company where they undergo the process where the gene is inserted,” she said. “This process needs to be done in a very sterile environment so there’s no infections, and it needs to have a lot of oversight.”
Finally, “after the cells are generated, they are typically frozen and shipped back to the site where the patient is at the hospital,” she said. “Then we give chemotherapy to the patient, which prepares the patient’s blood system. It removes some of the T-cells that are there, allowing for the T cells that we’re about to infuse to quickly be activated, find the cancer, and kill it.”
Side effects can boost costs even more. “Unfortunately, some significant toxicities can occur after we infuse these cells,” Dr. Williams noted. “Patients can have trouble breathing and sometimes need ventilatory support. They can have trouble maintaining their blood pressure and become swollen as fluid seeps into tissues. Or they can have high fevers and organ dysfunction. Many of those patients go to the intensive care unit, which is obviously expensive as well.”
Taking Gene Therapy In-House
As Dr. Williams explained, one way to reduce costs is to “perform the genetic manipulation and expansion of the cells outside of a company.” Several academic institutions in the United States are embracing this approach, including Children’s Hospital of Philadelphia, which is experimenting with an automated device developed by the German company Miltenyi Biotec and known as the CliniMACS Prodigy machine.
“The current manufacturing process is very manual and requires a lot of interaction with the product and highly trained personnel,” Dr. Grupp said. “If you have an automated device, you have those cells in the device over the 7 to 12 days that you actually need to grow the cells. There’s much less interaction, so you need fewer trained personnel.”
The device is experimental and not yet FDA approved, Dr. Grupp noted, so that patients are all in clinical trials. Children’s Hospital of Philadelphia has treated more than a dozen patients with the device, he said.
Another member of Children’s Hospital of Philadelphia’s CAR T-cell team told WHYY-FM that a single patient’s treatment would run about $30,000 for labor and testing, but not other expenses such as facility costs.
Dr. Grupp estimated that about half a dozen of these devices are in use in the United States, and many more worldwide. “They’re all just like we are — at the absolute beginning. We’ve only been doing this for about a year.”
In the big picture, Dr. Grupp said, “this is where cell therapy is going. Whether it’s point of care or not, automated cell manufacturing is the obvious next step.”
India: Big Hopes for Homegrown Technology
In India, researchers are hoping that their homegrown approach to CAR T-cell therapy will expand access by greatly lowering treatment prices.
Last fall, India’s equivalent of the FDA-granted approval for actalycabtagene autoleucel (NexCAR19), which was developed by Indian scientists who worked closely with the US National Institutes of Health (NIH). The therapy’s developer is a company called ImmunoACT.
In an interview, ImmunoACT founder Rahul Purwar, PhD, MSc, associate professor at Indian Institute of Technology Bombay, said the treatment costs about $40,000. The price is much lower than in the United States because staffing, facility construction, and maintenance are less expensive in India, he said.
Results of small early clinical trials have been promising, with complete responses in 68% of 38 lymphoma patients and 72% of 15 leukemia patients. Updated data will be presented at the annual American Society of Hematology meeting in December 2024, Dr. Purwar said.
According to the NIH, at first ImmunoACT hopes to treat about 1,200 patients a year. The immediate goal is to “focus and stabilize our operation in India,” Dr. Purwar said. “Then, if opportunities come, we will try to bring CAR T to all who might benefit from these technologies. A majority of countries don’t have access to these technologies.”
A US-Brazil Partnership Holds Promise
Meanwhile, a US nonprofit known as Caring Cross announced this year that it has partnered with Fundação Oswaldo Cruz (Fiocruz), a Brazilian government foundation, to manufacture CAR T cells at point-of-care in South America.
“Our model is different than traditional biotech/pharma,” Boro Dropulic, PhD, MBA, cofounder and executive director of Caring Cross, said in an interview. “Our goal is to develop technologies and transfer them to organizations like Fiocruz to enable them to manufacture these transformative therapies for patients in their regions. We believe this model is an important solution for therapies that are priced so high that they are not accessible to many patients that need them, particularly underserved populations and those in low- and middle-income countries.”
According to Dr. Dropulic: “We have developed a production process where the material cost is about $20,000 per dose.” When labor and infrastructure costs are added, the total expense won’t be more than $37,000-$47,500, he said.
The research process for the CAR T-cell technology is at an earlier stage than in India. Scientists plan to start clinical trials of the technology in the United States by the end of 2024 and then begin them in Brazil in 2025, after safety and efficacy have been demonstrated. The first trial, a phase I/II study, will enroll about 20 patients, Dr. Dropulic said.
Dr. Kenderian reported ties with Novartis, Capstan Bio, Kite/Gilead, Juno/BMS, Humanigen, Tolero, Leah Labs, Lentigen, Luminary, Sunesis/Viracta, Morphosys, Troque, Carisma, Sendero, and LifEngine. Dr. Williams disclosed grants from National Institutes of Health and philanthropic organizations. Dr. Grupp reported relationships with Novartis, Kite, Vertex and Servier, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, Jazz, Adaptimmune, TCR2, Cellectis, Juno, Allogene, and Cabaletta. Dr. Purwar is the founder of ImmunoACT. Dr. Dropulic serves as executive director of Caring Cross and CEO of Vector BioMed, which provides vectors for gene therapy.
More Cases of Acute Diverticulitis Treated Outside Hospital
BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.
Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.
CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.
Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition.
“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.
An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said.
A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.
The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.
The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis.
“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said.
Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees
“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said.
Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence.
Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears.
Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.
“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.”
The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided.
Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said.
Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.
Dr. Sharzehi reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.
Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.
CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.
Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition.
“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.
An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said.
A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.
The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.
The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis.
“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said.
Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees
“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said.
Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence.
Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears.
Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.
“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.”
The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided.
Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said.
Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.
Dr. Sharzehi reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
BOSTON — Patients with acute colonic diverticulitis are more likely to be seen by primary care providers than by emergency physicians, representing a shift in the way clinicians detect and treat the condition.
Acute colonic diverticulitis affects roughly 180 per 100,000 people per year in the United States.
CT of the abdomen and pelvis may not be a first-line method to detect diverticulitis in the primary care setting as it has been in emergent care, according to Kaveh Sharzehi, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at Oregon Health & Science University in Portland.
Indeed, clinical guidelines by multiple physician groups recommend that providers use a more individualized approach to detecting and treating the condition.
“There is still great value in proper and thorough physical history and some adjunct testing,” Dr. Sharzehi told attendees during a presentation on April 20 at the American College of Physicians Internal Medicine Meeting 2024. These two methods can detect the disease up to 65% of the time, Dr. Sharzehi added.
An initial evaluation of a patient with suspected acute diverticulitis should first assess the patient’s history of abdominal pain, fever, and leukocytosis, Dr. Sharzehi said.
A C-reactive protein level > 50 mg/L “almost doubles the odds of having diverticulitis,” Dr. Sharzehi said. Studies also suggest increased levels of procalcitonin and fecal calprotectin can indicate the presence of the condition.
The American Gastroenterological Association (AGA) and the American College of Physicians recommend abdominal CT if clinicians are uncertain of the diagnosis, and to evaluate potential complications in severe cases. Ultrasound and MRI can be useful alternatives, according to guidelines from the American Society of Colon and Rectal Surgeons.
The chances of developing diverticulitis increase with age. More than 60% of Americans aged 60 years or older have diverticulosis, a condition characterized by small pouches in the colon lining that can weaken the colon wall. Less than 5% of people with diverticulosis go on to develop diverticulitis.
“Aspirin and opioid use are also risk factors, likely from their effect on the colonic transit time and causing constipation that might contribute to diverticulitis, but that›s not very well understood,” Dr. Sharzehi said.
Medical management has shifted from predominantly inpatient to predominantly outpatient care, Dr. Sharzehi told attendees
“Unfortunately, there are not that many supportive guidelines for what diet a patient should have in the acute setting of diverticulitis,” he said.
Patients with a mild case may benefit from a clear liquid diet; for some patients, high-fiber diets, regular physical activity, and statins may protect against recurrence.
Current guidelines recommend against prescribing antibiotics for most cases because evidence suggests that diverticulitis is primarily an inflammatory process that can result in small tears in the diverticulum, rather than the disease being a complication of existing tears.
Patients should also not be treated with probiotics or 5-aminosalicylic acid agents, Dr. Sharzehi said.
“My practice is in the Pacific Northwest, where there’s a lot of belief in naturopathic remedies, so we get a lot of questions about supplements and probiotics in preventing diverticulitis,” he said. “We don’t think it does help, and this is unanimous among all the main [physician] societies.”
The AGA recommends referring patients for a colonoscopy within a year after diverticulitis symptoms have resided.
Severe or unresolved cases could require inpatient procedures such as percutaneous drainage or surgery. An estimated 15%-30% of patients admitted to hospital with acute diverticulitis require surgery, Dr. Sharzehi said.
Surgery may become an option for patients who have recurrent cases of the disease, even if not severe, Dr. Sharzehi said.
Dr. Sharzehi reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Asthma, COPD inhaler price caps set for summer
In addition to warmer weather, June will usher in changes in asthma and COPD inhaler costs for many patients, potentially reducing barriers to those seeing high prescription prices. Price ceilings have been set by some companies, likely following action earlier this year by a Senate Committee which pointed to higher costs of US inhalers compared with other countries.
Senator Sanders stated: “In my view, Americans who have asthma and COPD should not be forced to pay, in many cases, 10-70 times more for the same exact inhalers as patients in Europe and other parts of the world.”
Starting June 1, Boehringer Ingelheim will cap out-of-pocket costs for the company’s inhaler products for chronic lung disease and asthma at $35 per month, according to a March 7, 2024, press release from the German drugmaker’s US headquarters in Ridgefield, Conn. The reductions cover the full range of the company’s inhaler products for asthma and chronic obstructive pulmonary disease (COPD) including Atrovent, Combivent Respimat and Spiriva HandiHaler and Respimat, Stiolto Respimat and Striverdi Respimat. In the release, Boehringer Ingelheim USA Corporation’s President and CEO Jean-Michel Boers stated, “The US health care system is complex and often doesn’t work for patients, especially the most vulnerable. While we can’t fix the entire system alone, we are bringing forward a solution to make it fairer. We want to do our part to help patients living with COPD or asthma who struggle to pay for their medications.”
Similar announcements were made by AstraZeneca and GSK. GSK’s cap will go into effect on January 1, 2025, and includes Advair Diskus, Advair HFA, Anoro Ellipta, Arnuity Ellipta, Breo Ellipta, Incruse Ellipta, Serevent Diskus, Trelegy Ellipta, and Ventolin HFA. The AstraZeneca cap, which covers Airsupra, Bevespi Aerosphere, Breztri Aeroshpere, and Symbicort, goes into effect on June 1, 2024.
Senate statement on pricing
These companies plus Teva had received letters sent on January 8, 2024, by the members of the Senate Committee on Health, Education, Labor, and Pensions: senators Sanders, Baldwin, Luján and Markey. The letters cited enormous inhaler price discrepancies, for example $489 for Combivent Respimat in the United States but just $7 in France, and announced the conduct of an investigation into efforts by these companies to artificially inflate and manipulate prices of asthma inhalers that have been on the market for decades. A statement from Sen. Sanders’ office noted that AstraZeneca, GSK, and Teva made more than $25 billion in revenue from inhalers alone in the past 5 years (Boehringer Ingelheim does not provide public US inhaler revenue information).
Suit claims generic delay
A federal lawsuit filed in Boston on March 6, according to a Reuters brief from March 7, cited Boehringer for improperly submitting patents to the US Food and Drug Administration (FDA). The purpose of those patents, the suit charges, was to delay generic competition and inflate Combivent Respimat and Spiriva Respimat inhaler prices.
Inhaler prices soared in the United States, according to a March 10 U.S. News & World Report commentary by The Conversation, a nonprofit news organization, after the 2008 FDA ban on chlorofluorocarbon (CFC)-propellants led to the phase-out of CFC-containing inhalers and their replacement with hydrofluoroalkane-propellant inhalers. For the insured that meant an average out-of-pocket inhaler cost increase from $13.60 per prescription in 2004 to $25 in 2015. The current rate for the now nongeneric HFA-propelled but otherwise identical albuterol inhaler is $98. Competition from a more recently FDA-approved (2020) generic version has not been robust enough to effect meaningful price reductions, the report stated. While good insurance generally covers most of inhaler costs, the more than 25 million uninsured in 2023 faced steep market prices that put strain even on some insured, the CDC found, driving many in the United States to purchase from Mexican, Canadian, or other foreign pharmacies. The Teva QVAR REdiHaler corticosteroid inhaler, costing $9 in Germany, costs $286 in the US. Dosages, however, may not be identical. A first FDA-authorization of drug importing this past January applied only to agents for a limited number of disease states and pertained only to Florida, but may serve as a model for other states, according to the commentary.
“The announced price cap from Boehringer Ingelheim,” stated Kenneth Mendez, president and CEO of the Asthma and Allergy Foundation of America (AAFA) in a press release, “is a step toward improving access to essential asthma medicine and demonstrates that the voice of the asthma patient community is being heard.” The AAFA release noted further that asthma death rates, while declining overall, are triple in Blacks compared with Whites. Death rates, asthma rates, and rates of being uninsured or underinsured are much higher in Black and Puerto Rican populations than in Whites. The complex layers of the current US system, composed of pharmaceutical manufacturers, pharmacy benefit managers, insurance companies, employers, and federal policies often conspire against those people who need asthma drugs the most. AAFA research has shown that when drug prices become a barrier to treatment, people with asthma ration or simply discontinue their essential asthma medications. Beyond saved lives, access to asthma medications can reduce hospitalizations and lower the more than $82 billion in annual asthma costs to the US economy.
Sen. Sanders, on March 20, applauded the GSK announcement: “As Chairman of the Senate Health, Education, Labor, and Pensions Committee, I very much appreciate GlaxoSmithKline’s announcement today that Americans throughout the country with asthma and COPD will pay no more than $35 for the brand name inhalers they manufacture. I look forward to working with GSK to make sure that this decision reaches as many patients as possible.”
“Inhaled medications continue to be an essential part of the therapy for patients with asthma, COPD, and other respiratory conditions,” said Diego J. Maselli, professor and chief, Division of Pulmonary Diseases & Critical Care, UT Health at San Antonio, San Antonio, Texas, in an interview with CHEST Physician. He added, “Unfortunately, with increasing cost of these and other treatments, access has been challenging for many patients. Patients, families, and providers constantly experience frustration with the difficulties of obtaining these lifesaving medications, and cost is the main barrier. Even those with ample insurance coverage face difficult challenges, as the high prices of these medications motivate insurance carriers to constantly adjust what is the ‘preferred’ option among inhalers. Regrettably, noncompliance and nonadherence to inhaled therapies has been linked to poor patient outcomes and increased health care utilization in both asthma and COPD. Because of the high prevalence of these diseases in the US and worldwide, efforts to increase the access of these vital medications has been a priority. With the leveling of the prices of these medications across the world, we hope that there will be both improved access and, as a consequence, better patient outcomes.”
In addition to warmer weather, June will usher in changes in asthma and COPD inhaler costs for many patients, potentially reducing barriers to those seeing high prescription prices. Price ceilings have been set by some companies, likely following action earlier this year by a Senate Committee which pointed to higher costs of US inhalers compared with other countries.
Senator Sanders stated: “In my view, Americans who have asthma and COPD should not be forced to pay, in many cases, 10-70 times more for the same exact inhalers as patients in Europe and other parts of the world.”
Starting June 1, Boehringer Ingelheim will cap out-of-pocket costs for the company’s inhaler products for chronic lung disease and asthma at $35 per month, according to a March 7, 2024, press release from the German drugmaker’s US headquarters in Ridgefield, Conn. The reductions cover the full range of the company’s inhaler products for asthma and chronic obstructive pulmonary disease (COPD) including Atrovent, Combivent Respimat and Spiriva HandiHaler and Respimat, Stiolto Respimat and Striverdi Respimat. In the release, Boehringer Ingelheim USA Corporation’s President and CEO Jean-Michel Boers stated, “The US health care system is complex and often doesn’t work for patients, especially the most vulnerable. While we can’t fix the entire system alone, we are bringing forward a solution to make it fairer. We want to do our part to help patients living with COPD or asthma who struggle to pay for their medications.”
Similar announcements were made by AstraZeneca and GSK. GSK’s cap will go into effect on January 1, 2025, and includes Advair Diskus, Advair HFA, Anoro Ellipta, Arnuity Ellipta, Breo Ellipta, Incruse Ellipta, Serevent Diskus, Trelegy Ellipta, and Ventolin HFA. The AstraZeneca cap, which covers Airsupra, Bevespi Aerosphere, Breztri Aeroshpere, and Symbicort, goes into effect on June 1, 2024.
Senate statement on pricing
These companies plus Teva had received letters sent on January 8, 2024, by the members of the Senate Committee on Health, Education, Labor, and Pensions: senators Sanders, Baldwin, Luján and Markey. The letters cited enormous inhaler price discrepancies, for example $489 for Combivent Respimat in the United States but just $7 in France, and announced the conduct of an investigation into efforts by these companies to artificially inflate and manipulate prices of asthma inhalers that have been on the market for decades. A statement from Sen. Sanders’ office noted that AstraZeneca, GSK, and Teva made more than $25 billion in revenue from inhalers alone in the past 5 years (Boehringer Ingelheim does not provide public US inhaler revenue information).
Suit claims generic delay
A federal lawsuit filed in Boston on March 6, according to a Reuters brief from March 7, cited Boehringer for improperly submitting patents to the US Food and Drug Administration (FDA). The purpose of those patents, the suit charges, was to delay generic competition and inflate Combivent Respimat and Spiriva Respimat inhaler prices.
Inhaler prices soared in the United States, according to a March 10 U.S. News & World Report commentary by The Conversation, a nonprofit news organization, after the 2008 FDA ban on chlorofluorocarbon (CFC)-propellants led to the phase-out of CFC-containing inhalers and their replacement with hydrofluoroalkane-propellant inhalers. For the insured that meant an average out-of-pocket inhaler cost increase from $13.60 per prescription in 2004 to $25 in 2015. The current rate for the now nongeneric HFA-propelled but otherwise identical albuterol inhaler is $98. Competition from a more recently FDA-approved (2020) generic version has not been robust enough to effect meaningful price reductions, the report stated. While good insurance generally covers most of inhaler costs, the more than 25 million uninsured in 2023 faced steep market prices that put strain even on some insured, the CDC found, driving many in the United States to purchase from Mexican, Canadian, or other foreign pharmacies. The Teva QVAR REdiHaler corticosteroid inhaler, costing $9 in Germany, costs $286 in the US. Dosages, however, may not be identical. A first FDA-authorization of drug importing this past January applied only to agents for a limited number of disease states and pertained only to Florida, but may serve as a model for other states, according to the commentary.
“The announced price cap from Boehringer Ingelheim,” stated Kenneth Mendez, president and CEO of the Asthma and Allergy Foundation of America (AAFA) in a press release, “is a step toward improving access to essential asthma medicine and demonstrates that the voice of the asthma patient community is being heard.” The AAFA release noted further that asthma death rates, while declining overall, are triple in Blacks compared with Whites. Death rates, asthma rates, and rates of being uninsured or underinsured are much higher in Black and Puerto Rican populations than in Whites. The complex layers of the current US system, composed of pharmaceutical manufacturers, pharmacy benefit managers, insurance companies, employers, and federal policies often conspire against those people who need asthma drugs the most. AAFA research has shown that when drug prices become a barrier to treatment, people with asthma ration or simply discontinue their essential asthma medications. Beyond saved lives, access to asthma medications can reduce hospitalizations and lower the more than $82 billion in annual asthma costs to the US economy.
Sen. Sanders, on March 20, applauded the GSK announcement: “As Chairman of the Senate Health, Education, Labor, and Pensions Committee, I very much appreciate GlaxoSmithKline’s announcement today that Americans throughout the country with asthma and COPD will pay no more than $35 for the brand name inhalers they manufacture. I look forward to working with GSK to make sure that this decision reaches as many patients as possible.”
“Inhaled medications continue to be an essential part of the therapy for patients with asthma, COPD, and other respiratory conditions,” said Diego J. Maselli, professor and chief, Division of Pulmonary Diseases & Critical Care, UT Health at San Antonio, San Antonio, Texas, in an interview with CHEST Physician. He added, “Unfortunately, with increasing cost of these and other treatments, access has been challenging for many patients. Patients, families, and providers constantly experience frustration with the difficulties of obtaining these lifesaving medications, and cost is the main barrier. Even those with ample insurance coverage face difficult challenges, as the high prices of these medications motivate insurance carriers to constantly adjust what is the ‘preferred’ option among inhalers. Regrettably, noncompliance and nonadherence to inhaled therapies has been linked to poor patient outcomes and increased health care utilization in both asthma and COPD. Because of the high prevalence of these diseases in the US and worldwide, efforts to increase the access of these vital medications has been a priority. With the leveling of the prices of these medications across the world, we hope that there will be both improved access and, as a consequence, better patient outcomes.”
In addition to warmer weather, June will usher in changes in asthma and COPD inhaler costs for many patients, potentially reducing barriers to those seeing high prescription prices. Price ceilings have been set by some companies, likely following action earlier this year by a Senate Committee which pointed to higher costs of US inhalers compared with other countries.
Senator Sanders stated: “In my view, Americans who have asthma and COPD should not be forced to pay, in many cases, 10-70 times more for the same exact inhalers as patients in Europe and other parts of the world.”
Starting June 1, Boehringer Ingelheim will cap out-of-pocket costs for the company’s inhaler products for chronic lung disease and asthma at $35 per month, according to a March 7, 2024, press release from the German drugmaker’s US headquarters in Ridgefield, Conn. The reductions cover the full range of the company’s inhaler products for asthma and chronic obstructive pulmonary disease (COPD) including Atrovent, Combivent Respimat and Spiriva HandiHaler and Respimat, Stiolto Respimat and Striverdi Respimat. In the release, Boehringer Ingelheim USA Corporation’s President and CEO Jean-Michel Boers stated, “The US health care system is complex and often doesn’t work for patients, especially the most vulnerable. While we can’t fix the entire system alone, we are bringing forward a solution to make it fairer. We want to do our part to help patients living with COPD or asthma who struggle to pay for their medications.”
Similar announcements were made by AstraZeneca and GSK. GSK’s cap will go into effect on January 1, 2025, and includes Advair Diskus, Advair HFA, Anoro Ellipta, Arnuity Ellipta, Breo Ellipta, Incruse Ellipta, Serevent Diskus, Trelegy Ellipta, and Ventolin HFA. The AstraZeneca cap, which covers Airsupra, Bevespi Aerosphere, Breztri Aeroshpere, and Symbicort, goes into effect on June 1, 2024.
Senate statement on pricing
These companies plus Teva had received letters sent on January 8, 2024, by the members of the Senate Committee on Health, Education, Labor, and Pensions: senators Sanders, Baldwin, Luján and Markey. The letters cited enormous inhaler price discrepancies, for example $489 for Combivent Respimat in the United States but just $7 in France, and announced the conduct of an investigation into efforts by these companies to artificially inflate and manipulate prices of asthma inhalers that have been on the market for decades. A statement from Sen. Sanders’ office noted that AstraZeneca, GSK, and Teva made more than $25 billion in revenue from inhalers alone in the past 5 years (Boehringer Ingelheim does not provide public US inhaler revenue information).
Suit claims generic delay
A federal lawsuit filed in Boston on March 6, according to a Reuters brief from March 7, cited Boehringer for improperly submitting patents to the US Food and Drug Administration (FDA). The purpose of those patents, the suit charges, was to delay generic competition and inflate Combivent Respimat and Spiriva Respimat inhaler prices.
Inhaler prices soared in the United States, according to a March 10 U.S. News & World Report commentary by The Conversation, a nonprofit news organization, after the 2008 FDA ban on chlorofluorocarbon (CFC)-propellants led to the phase-out of CFC-containing inhalers and their replacement with hydrofluoroalkane-propellant inhalers. For the insured that meant an average out-of-pocket inhaler cost increase from $13.60 per prescription in 2004 to $25 in 2015. The current rate for the now nongeneric HFA-propelled but otherwise identical albuterol inhaler is $98. Competition from a more recently FDA-approved (2020) generic version has not been robust enough to effect meaningful price reductions, the report stated. While good insurance generally covers most of inhaler costs, the more than 25 million uninsured in 2023 faced steep market prices that put strain even on some insured, the CDC found, driving many in the United States to purchase from Mexican, Canadian, or other foreign pharmacies. The Teva QVAR REdiHaler corticosteroid inhaler, costing $9 in Germany, costs $286 in the US. Dosages, however, may not be identical. A first FDA-authorization of drug importing this past January applied only to agents for a limited number of disease states and pertained only to Florida, but may serve as a model for other states, according to the commentary.
“The announced price cap from Boehringer Ingelheim,” stated Kenneth Mendez, president and CEO of the Asthma and Allergy Foundation of America (AAFA) in a press release, “is a step toward improving access to essential asthma medicine and demonstrates that the voice of the asthma patient community is being heard.” The AAFA release noted further that asthma death rates, while declining overall, are triple in Blacks compared with Whites. Death rates, asthma rates, and rates of being uninsured or underinsured are much higher in Black and Puerto Rican populations than in Whites. The complex layers of the current US system, composed of pharmaceutical manufacturers, pharmacy benefit managers, insurance companies, employers, and federal policies often conspire against those people who need asthma drugs the most. AAFA research has shown that when drug prices become a barrier to treatment, people with asthma ration or simply discontinue their essential asthma medications. Beyond saved lives, access to asthma medications can reduce hospitalizations and lower the more than $82 billion in annual asthma costs to the US economy.
Sen. Sanders, on March 20, applauded the GSK announcement: “As Chairman of the Senate Health, Education, Labor, and Pensions Committee, I very much appreciate GlaxoSmithKline’s announcement today that Americans throughout the country with asthma and COPD will pay no more than $35 for the brand name inhalers they manufacture. I look forward to working with GSK to make sure that this decision reaches as many patients as possible.”
“Inhaled medications continue to be an essential part of the therapy for patients with asthma, COPD, and other respiratory conditions,” said Diego J. Maselli, professor and chief, Division of Pulmonary Diseases & Critical Care, UT Health at San Antonio, San Antonio, Texas, in an interview with CHEST Physician. He added, “Unfortunately, with increasing cost of these and other treatments, access has been challenging for many patients. Patients, families, and providers constantly experience frustration with the difficulties of obtaining these lifesaving medications, and cost is the main barrier. Even those with ample insurance coverage face difficult challenges, as the high prices of these medications motivate insurance carriers to constantly adjust what is the ‘preferred’ option among inhalers. Regrettably, noncompliance and nonadherence to inhaled therapies has been linked to poor patient outcomes and increased health care utilization in both asthma and COPD. Because of the high prevalence of these diseases in the US and worldwide, efforts to increase the access of these vital medications has been a priority. With the leveling of the prices of these medications across the world, we hope that there will be both improved access and, as a consequence, better patient outcomes.”
In the Story of the Rubella Virus as a Source of Granulomas, the Plot Is Still Thickening
SAN DIEGO — Approximately 10 years ago in France, high throughput .
Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.
In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.
The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.
“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.
Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.
It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.
This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.
“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.
Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.
With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.
Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.
“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.
The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.
Cases now include children and adults through advanced ages.
Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.
As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.
So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.
“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.
Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.
With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.
Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.
Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.
“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.
“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.
“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.
Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.
SAN DIEGO — Approximately 10 years ago in France, high throughput .
Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.
In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.
The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.
“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.
Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.
It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.
This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.
“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.
Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.
With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.
Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.
“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.
The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.
Cases now include children and adults through advanced ages.
Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.
As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.
So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.
“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.
Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.
With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.
Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.
Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.
“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.
“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.
“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.
Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.
SAN DIEGO — Approximately 10 years ago in France, high throughput .
Based on accumulating evidence, the Centers for Disease Control and Prevention (CDC) through collaborations with others also recognized this in pediatric patients with inborn errors of immunity, and it is now appropriate for clinicians to consider this etiology when no other infectious agents can be identified, according to Karolyn A. Wanat, MD, professor of dermatology, Medical College of Wisconsin, Milwaukee, who spoke about rubella as a trigger in granulomatous disease at the meeting. “This is a huge evolving area of interest,” said Dr. Wanat, who has been the first author or coauthor on several published papers, including a review article published earlier this year.
In the earliest cases, including those reported in 2014, the cutaneous granulomas presumed to be causally related to vaccine-derived rubella virus were found only in those with a primary immunodeficiency. This is no longer the case. In a collaboration among US clinics, granulomas that had persisted for years in immunocompetent adults were identified, according to Dr. Wanat, the first author of a report on these findings in four adults in 2022. In addition, it now appears that wild-type rubella virus, like vaccine-derived rubella virus, can be the source of the antigenic response that underlies the development of rubella-associated cutaneous granulomas.
The phenotype of these granulomas is comparable to granulomas associated with other infectious agents. On dermatopathology, these commonly feature a robust granulomatous inflammation with multinucleated giant cells and lymphocytic infiltrate. Necrosis and fibrosis are also common.
“These are the types of granulomas that we would be thinking infection. If tissue cultures are negative, we would probably repeat them,” she said, suggesting that suspicion of an infectious etiology would probably remain high even after multiple negative tests.
Of the cases accruing in the United States and elsewhere, most but not all have been linked to inborn errors of immunity. In a 2020 CDC review, the risk of granulomas caused by compromised immunity, such as defects in T cell function, was estimated to be in the range of 0.6% to 2.5%, Dr. Wanat said.
It is now known that primary immunodeficiency is not a prerequisite, but this should not change the perception that the rubella vaccine, which was introduced in 1979, is effective and safe, according to Dr. Wanat. The vaccine is associated with few serious adverse events and is so effective that rubella was eliminated from the United States in 2004 and from the Americas in 2015.
This makes cases of granuloma associated with wild-type rubella virus surprising, but they appear to be exceedingly rare. Whether caused by vaccine exposure or another source, the mechanism of latent development of cutaneous granulomas is consistent with other infectious sources, and is not well understood.
“Rubella is a sneaky virus that can persist in some immunoprivileged sites indefinitely,” Dr. Wanat said. These sites include the eyes, joints, and placenta.
Many initial cases of rubella-associated granulomas occurred on the arms, presumably where the vaccine was administered, despite long intervals between exposure and lesion growth. This interval is often measured in years.
With more cases, it is now understood that involvement of other organs does occur even if the skin is the most common site of antigenic response in patients with immunodeficiency. The liver and lymph nodes represent other tissues that have been affected. Even lesions in the brain have been seen on autopsy.
Based on the benefit-to-risk ratio of a highly effective and successful vaccine, however, the association with a risk of granulomas “should not raise questions” about the value of the vaccine itself, Dr. Wanat noted.
“The proportion of patients who develop these granulomas is very, very low. Yet, the vaccine provides life-long immunity,” she said.
The discovery of granulomas associated with wild type rubella infection was “shocking” based on the supposition that the rubella virus had been eliminated, but this is just one of the unexpected discoveries as the still-evolving science has traced the story of rubella-associated granulomas over the past 10 years.
Cases now include children and adults through advanced ages.
Shedding of the virus and risk of infection to others has been studied but so far, the risk — if it exists — is very low. The evidence includes the many patients who have lived with the granulomas for years, even decades, without any known spread to others.
As for ongoing work in this area, Dr. Wanat said that a histopathological case definition for rubella-associated granulomas is being developed, and she and other investigators are actively seeking new cases to better characterize the disease.
So far, optimal treatment is not well defined. A number of strategies have had limited success or are considered impractical for routine use. One example is a stem cell transplant. In a case Dr. Wanat cited, complete resolution of the skin lesions was achieved with a transplant.
“I am not suggesting that those with localized disease in the skin should undergo a transplant, but it does support the role of the immune system and the potential for a reboot to clear the skin,” she said.
Other therapies associated with benefit in at least some patients include tumor necrosis factor (TNF) inhibitors with dapsone and ribavirin. The risk of adverse events for the latter might again limit its use, Dr. Wanat said.
With awareness, the number of granulomas found to be associated with rubella virus is expected to grow. Dr. Wanat speculated that those areas of the country that not yet have documented a case will do so over time. For idiopathic cases of cutaneous granulomas, rubella should be kept in mind, she said.
Characterizing rubella-associated cutaneous granulomas as “a public health concern,” Dr. Wanat urged clinicians to consider this etiology in lesions that match the phenotype, particularly when other more common infectious agents cannot be identified.
Asked for his perspective, Jeffrey P. North, MD, managing director of the UCSF Dermatopathology, and professor of dermatology and pathology at the University of California, San Francisco, agreed that rubella should be considered as a source of granulomas with a suspected infectious etiology when a pathogen cannot be found.
“It is likely much more common than we know as it has only been recently described and testing for it is limited. I suspected there are a lot of undiagnosed patients suffering from this disease,” Dr. North said in an interview.
“One of the important points for clinicians to consider is that while this has been reported mostly in patients with some form of immunodeficiency, there have also been patients reported to have this condition with no immunodeficiency,” he added. Even though the association between rubella and granulomas was made 10 years ago, awareness is only now spreading, which means the frequency with which rubella leads to granulomas remains uncertain.
“I think we will start to get a better idea of how common this is as more people learn about and testing for it expands,” Dr. North said.
Dr. Wanat reports no potential conflicts of interest. Dr. North reports financial relationships with AdviNow and Kiniksa Pharmaceuticals.
FROM AAD 2024
The Long, Controversial Search for a ‘Cancer Microbiome’
Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.
The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.
This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.
But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies?
Cancer Controversy
The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.
The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes.
“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.”
For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.
“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.”
The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?
This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom.
Dr. Salzberg described two major problems with Dr. Knight’s study.
“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”
Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.
Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.
Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed.
The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.
For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.
A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading.
It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.
Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed.
Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.”
Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions.
“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
Underdeveloped Technology
Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question.
For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies.
Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one.
Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said.
Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible.
“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.
Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.
Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.
“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said.
Influence on Cancer Treatment Outcomes
Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.
The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said.
Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.
“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost.
“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said.
In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said.
Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.
Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”
It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted.
No Consensus Yet
Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans.
It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges.
“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.
Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.
“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”
A version of this article appeared on Medscape.com.
Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.
The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.
This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.
But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies?
Cancer Controversy
The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.
The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes.
“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.”
For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.
“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.”
The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?
This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom.
Dr. Salzberg described two major problems with Dr. Knight’s study.
“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”
Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.
Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.
Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed.
The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.
For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.
A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading.
It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.
Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed.
Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.”
Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions.
“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
Underdeveloped Technology
Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question.
For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies.
Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one.
Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said.
Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible.
“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.
Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.
Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.
“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said.
Influence on Cancer Treatment Outcomes
Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.
The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said.
Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.
“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost.
“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said.
In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said.
Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.
Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”
It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted.
No Consensus Yet
Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans.
It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges.
“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.
Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.
“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”
A version of this article appeared on Medscape.com.
Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.
The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.
This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.
But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies?
Cancer Controversy
The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.
The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes.
“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.”
For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.
“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.”
The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?
This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom.
Dr. Salzberg described two major problems with Dr. Knight’s study.
“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”
Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.
Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.
Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed.
The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.
For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.
A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading.
It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.
Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed.
Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.”
Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions.
“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
Underdeveloped Technology
Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question.
For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies.
Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one.
Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said.
Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible.
“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.
Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.
Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.
“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said.
Influence on Cancer Treatment Outcomes
Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.
The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said.
Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.
“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost.
“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said.
In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said.
Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.
Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”
It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted.
No Consensus Yet
Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans.
It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges.
“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.
Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.
“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”
A version of this article appeared on Medscape.com.
Cervical Cancer Screening: US Clinicians Unclear About Best Practices
In 2020, the American Cancer Society (ACS) updated its cervical screening guidelines, proposing two major changes: start cervical cancer screening at age 25, rather than 21, and perform primary human papillomavirus (HPV) testing, instead of a Pap test.
First, healthcare providers in the US may be unsure how to reconcile conflicting cervical cancer screening guidelines from another major organization — the US Preventive Services Task Force (USPSTF), which published guidelines in 2018.
Although the ACS guidelines are based on an analysis of the latest evidence,
the recommendations challenge those from the USPSTF, which dictates insurance coverage in the US. Last year, the American College of Obstetricians and Gynecologists (ACOG) aligned its guidelines with those from the USPSTF.
The USPSTF recommends average-risk individuals start Pap, not HPV, testing at age 21, and broadens the options to primary HPV testing, Pap testing, or both together starting at age 30. The ACS, on the other hand, says primary HPV testing is the preferred screening approach from the start, which should be age 25.
Because the ACS guidelines marked a notable departure from prevailing practice, a team of researchers from five US universities decided to find out if anyone was following them.
The results, published in the journal Cancer in March, revealed that most healthcare providers had not changed practice.
Lead author Rebecca Perkins, MD, MSc, and colleagues found that, among the 70 respondents, few were starting screening at age 25, and none had switched to primary HPV testing.
The survey then probed clinicians’ willingness to adopt the ACS guidelines as well as their reservations and barriers to doing so.
Notably, more than half of the survey participants said they would be willing to adopt the ACS guidelines if the best evidence supported the changes and other professional medical organizations endorsed them.
On the age change, participants highlighted a range of benefits to moving to a later screening age, including that earlier screening may not be valuable and delaying screening could reduce overtreatment.
One participant noted: “We know that cervical cancer is usually a slow‐growing, long‐term progressive disease that does not typically show up that early in life, and we also know that, if infected, oftentimes their immune system can fight off the virus. So, it sounds reasonable at first glance [to delay screening to age 25 years].”
Others, however, brought up barriers to initiating screening at age 25. Some mentioned that later screening may not work for high‐risk populations and others voiced concerns about missing high‐grade precancer or cancer. “It’s not unusual for us to see women in their early 20s that have already had 10 or 15 partners. … a lot of them smoke too … they just have a lot of bad habits that put them at more risk,” one respondent noted.
On the HPV vs Pap testing front, many participants described a growing confidence in HPV tests after trying co-testing. One participant said, “Honestly, I do look more at the HPV results than the cytology. I put more faith in knowing what their HPV status is than anything.”
The main barriers to primary HPV testing, however, included lack of autonomy when working in a large health system, concerns about the efficacy of HPV testing, and a belief that cytology was valuable.
Some clinicians were worried about missing high-grade lesions or cancer. One healthcare provider said, “My only concern with primary HPV screening is occasionally you will pick up endometrial abnormalities on a Pap that you’re not going to pick up with HPV screening.”
Logistics and finances also played a role in clinicians’ hesitancy to switch to the ACS recommendation. Labs that could handle primary HPV tests were not available to some participants, and lack of insurance coverage was a barrier for others. One respondent noted, for instance, that his institution has a “cytology infrastructure that already exists in the lab and I can’t really see them switching.”
Many survey respondents also said they were waiting for endorsement from organizations, such as ACOG and USPSTF. “We run by the USPSTF and … ACOG. We don’t run by the ACS guidelines,” one person said.
Finally, some participants were not aware of the ACS recommendations at all or the data behind them but said they would be willing to change to primary HPV testing in the future.
Overall, Dr. Perkins said she was happy to see that more than half of the respondents would be willing to shift to the ACS screening guidelines, but noted that many remain reluctant to do so until the USPSTF and ACOG change their guidelines.
“It’s really just a matter of the USPSTF and ACOG endorsing” the ACS guidelines, said Dr. Perkins, professor of obstetrics and gynecology at Boston University.
The USPSTF is currently updating its cervical screening guidelines, which could potentially help reconcile this discord between the guidelines and close the gaps in practice patterns.
The USPSTF’s review of the evidence, which led to the 2018 guidelines, did highlight the effectiveness of HPV testing. The review authors concluded that “the evidence was consistent across trials” that primary, high-risk HPV screening increased detection of grade 3 or worse cervical intraepithelial neoplasia in the initial round of screening “by as much as 2 to 3 times when compared with cytology.”
However, Joy Melnikow, MD, MPH, first author on the USPSTF evidence review, explained that the reviewers factored in access to HPV testing when making their final recommendations.
“The consideration was making sure that a recommendation could be inclusive of all providers and all populations and not restricting access for clinics that couldn’t afford or didn’t have the machine to do [HPV testing],” Dr. Melnikow, director of the Center for Healthcare Policy and Research and professor of family and community medicine at the University of California Davis, told this news organization.
The ACS, however, did not consider potential access problems in its analysis of the evidence.
Although the ACS evidence is “excellent,” Dr. Perkins said, “it’s really just a matter of the USPSTF and ACOG endorsing that, and then it seems like a lot of people are willing to make the change.”
Dr. Perkins reports no relevant financial relationships.
A version of this article appeared on Medscape.com.
In 2020, the American Cancer Society (ACS) updated its cervical screening guidelines, proposing two major changes: start cervical cancer screening at age 25, rather than 21, and perform primary human papillomavirus (HPV) testing, instead of a Pap test.
First, healthcare providers in the US may be unsure how to reconcile conflicting cervical cancer screening guidelines from another major organization — the US Preventive Services Task Force (USPSTF), which published guidelines in 2018.
Although the ACS guidelines are based on an analysis of the latest evidence,
the recommendations challenge those from the USPSTF, which dictates insurance coverage in the US. Last year, the American College of Obstetricians and Gynecologists (ACOG) aligned its guidelines with those from the USPSTF.
The USPSTF recommends average-risk individuals start Pap, not HPV, testing at age 21, and broadens the options to primary HPV testing, Pap testing, or both together starting at age 30. The ACS, on the other hand, says primary HPV testing is the preferred screening approach from the start, which should be age 25.
Because the ACS guidelines marked a notable departure from prevailing practice, a team of researchers from five US universities decided to find out if anyone was following them.
The results, published in the journal Cancer in March, revealed that most healthcare providers had not changed practice.
Lead author Rebecca Perkins, MD, MSc, and colleagues found that, among the 70 respondents, few were starting screening at age 25, and none had switched to primary HPV testing.
The survey then probed clinicians’ willingness to adopt the ACS guidelines as well as their reservations and barriers to doing so.
Notably, more than half of the survey participants said they would be willing to adopt the ACS guidelines if the best evidence supported the changes and other professional medical organizations endorsed them.
On the age change, participants highlighted a range of benefits to moving to a later screening age, including that earlier screening may not be valuable and delaying screening could reduce overtreatment.
One participant noted: “We know that cervical cancer is usually a slow‐growing, long‐term progressive disease that does not typically show up that early in life, and we also know that, if infected, oftentimes their immune system can fight off the virus. So, it sounds reasonable at first glance [to delay screening to age 25 years].”
Others, however, brought up barriers to initiating screening at age 25. Some mentioned that later screening may not work for high‐risk populations and others voiced concerns about missing high‐grade precancer or cancer. “It’s not unusual for us to see women in their early 20s that have already had 10 or 15 partners. … a lot of them smoke too … they just have a lot of bad habits that put them at more risk,” one respondent noted.
On the HPV vs Pap testing front, many participants described a growing confidence in HPV tests after trying co-testing. One participant said, “Honestly, I do look more at the HPV results than the cytology. I put more faith in knowing what their HPV status is than anything.”
The main barriers to primary HPV testing, however, included lack of autonomy when working in a large health system, concerns about the efficacy of HPV testing, and a belief that cytology was valuable.
Some clinicians were worried about missing high-grade lesions or cancer. One healthcare provider said, “My only concern with primary HPV screening is occasionally you will pick up endometrial abnormalities on a Pap that you’re not going to pick up with HPV screening.”
Logistics and finances also played a role in clinicians’ hesitancy to switch to the ACS recommendation. Labs that could handle primary HPV tests were not available to some participants, and lack of insurance coverage was a barrier for others. One respondent noted, for instance, that his institution has a “cytology infrastructure that already exists in the lab and I can’t really see them switching.”
Many survey respondents also said they were waiting for endorsement from organizations, such as ACOG and USPSTF. “We run by the USPSTF and … ACOG. We don’t run by the ACS guidelines,” one person said.
Finally, some participants were not aware of the ACS recommendations at all or the data behind them but said they would be willing to change to primary HPV testing in the future.
Overall, Dr. Perkins said she was happy to see that more than half of the respondents would be willing to shift to the ACS screening guidelines, but noted that many remain reluctant to do so until the USPSTF and ACOG change their guidelines.
“It’s really just a matter of the USPSTF and ACOG endorsing” the ACS guidelines, said Dr. Perkins, professor of obstetrics and gynecology at Boston University.
The USPSTF is currently updating its cervical screening guidelines, which could potentially help reconcile this discord between the guidelines and close the gaps in practice patterns.
The USPSTF’s review of the evidence, which led to the 2018 guidelines, did highlight the effectiveness of HPV testing. The review authors concluded that “the evidence was consistent across trials” that primary, high-risk HPV screening increased detection of grade 3 or worse cervical intraepithelial neoplasia in the initial round of screening “by as much as 2 to 3 times when compared with cytology.”
However, Joy Melnikow, MD, MPH, first author on the USPSTF evidence review, explained that the reviewers factored in access to HPV testing when making their final recommendations.
“The consideration was making sure that a recommendation could be inclusive of all providers and all populations and not restricting access for clinics that couldn’t afford or didn’t have the machine to do [HPV testing],” Dr. Melnikow, director of the Center for Healthcare Policy and Research and professor of family and community medicine at the University of California Davis, told this news organization.
The ACS, however, did not consider potential access problems in its analysis of the evidence.
Although the ACS evidence is “excellent,” Dr. Perkins said, “it’s really just a matter of the USPSTF and ACOG endorsing that, and then it seems like a lot of people are willing to make the change.”
Dr. Perkins reports no relevant financial relationships.
A version of this article appeared on Medscape.com.
In 2020, the American Cancer Society (ACS) updated its cervical screening guidelines, proposing two major changes: start cervical cancer screening at age 25, rather than 21, and perform primary human papillomavirus (HPV) testing, instead of a Pap test.
First, healthcare providers in the US may be unsure how to reconcile conflicting cervical cancer screening guidelines from another major organization — the US Preventive Services Task Force (USPSTF), which published guidelines in 2018.
Although the ACS guidelines are based on an analysis of the latest evidence,
the recommendations challenge those from the USPSTF, which dictates insurance coverage in the US. Last year, the American College of Obstetricians and Gynecologists (ACOG) aligned its guidelines with those from the USPSTF.
The USPSTF recommends average-risk individuals start Pap, not HPV, testing at age 21, and broadens the options to primary HPV testing, Pap testing, or both together starting at age 30. The ACS, on the other hand, says primary HPV testing is the preferred screening approach from the start, which should be age 25.
Because the ACS guidelines marked a notable departure from prevailing practice, a team of researchers from five US universities decided to find out if anyone was following them.
The results, published in the journal Cancer in March, revealed that most healthcare providers had not changed practice.
Lead author Rebecca Perkins, MD, MSc, and colleagues found that, among the 70 respondents, few were starting screening at age 25, and none had switched to primary HPV testing.
The survey then probed clinicians’ willingness to adopt the ACS guidelines as well as their reservations and barriers to doing so.
Notably, more than half of the survey participants said they would be willing to adopt the ACS guidelines if the best evidence supported the changes and other professional medical organizations endorsed them.
On the age change, participants highlighted a range of benefits to moving to a later screening age, including that earlier screening may not be valuable and delaying screening could reduce overtreatment.
One participant noted: “We know that cervical cancer is usually a slow‐growing, long‐term progressive disease that does not typically show up that early in life, and we also know that, if infected, oftentimes their immune system can fight off the virus. So, it sounds reasonable at first glance [to delay screening to age 25 years].”
Others, however, brought up barriers to initiating screening at age 25. Some mentioned that later screening may not work for high‐risk populations and others voiced concerns about missing high‐grade precancer or cancer. “It’s not unusual for us to see women in their early 20s that have already had 10 or 15 partners. … a lot of them smoke too … they just have a lot of bad habits that put them at more risk,” one respondent noted.
On the HPV vs Pap testing front, many participants described a growing confidence in HPV tests after trying co-testing. One participant said, “Honestly, I do look more at the HPV results than the cytology. I put more faith in knowing what their HPV status is than anything.”
The main barriers to primary HPV testing, however, included lack of autonomy when working in a large health system, concerns about the efficacy of HPV testing, and a belief that cytology was valuable.
Some clinicians were worried about missing high-grade lesions or cancer. One healthcare provider said, “My only concern with primary HPV screening is occasionally you will pick up endometrial abnormalities on a Pap that you’re not going to pick up with HPV screening.”
Logistics and finances also played a role in clinicians’ hesitancy to switch to the ACS recommendation. Labs that could handle primary HPV tests were not available to some participants, and lack of insurance coverage was a barrier for others. One respondent noted, for instance, that his institution has a “cytology infrastructure that already exists in the lab and I can’t really see them switching.”
Many survey respondents also said they were waiting for endorsement from organizations, such as ACOG and USPSTF. “We run by the USPSTF and … ACOG. We don’t run by the ACS guidelines,” one person said.
Finally, some participants were not aware of the ACS recommendations at all or the data behind them but said they would be willing to change to primary HPV testing in the future.
Overall, Dr. Perkins said she was happy to see that more than half of the respondents would be willing to shift to the ACS screening guidelines, but noted that many remain reluctant to do so until the USPSTF and ACOG change their guidelines.
“It’s really just a matter of the USPSTF and ACOG endorsing” the ACS guidelines, said Dr. Perkins, professor of obstetrics and gynecology at Boston University.
The USPSTF is currently updating its cervical screening guidelines, which could potentially help reconcile this discord between the guidelines and close the gaps in practice patterns.
The USPSTF’s review of the evidence, which led to the 2018 guidelines, did highlight the effectiveness of HPV testing. The review authors concluded that “the evidence was consistent across trials” that primary, high-risk HPV screening increased detection of grade 3 or worse cervical intraepithelial neoplasia in the initial round of screening “by as much as 2 to 3 times when compared with cytology.”
However, Joy Melnikow, MD, MPH, first author on the USPSTF evidence review, explained that the reviewers factored in access to HPV testing when making their final recommendations.
“The consideration was making sure that a recommendation could be inclusive of all providers and all populations and not restricting access for clinics that couldn’t afford or didn’t have the machine to do [HPV testing],” Dr. Melnikow, director of the Center for Healthcare Policy and Research and professor of family and community medicine at the University of California Davis, told this news organization.
The ACS, however, did not consider potential access problems in its analysis of the evidence.
Although the ACS evidence is “excellent,” Dr. Perkins said, “it’s really just a matter of the USPSTF and ACOG endorsing that, and then it seems like a lot of people are willing to make the change.”
Dr. Perkins reports no relevant financial relationships.
A version of this article appeared on Medscape.com.
Potential Cure for Early BRCA-Mutated Breast Cancer?
SAN DIEGO —
In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.
“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.
It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.
The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.
Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.
The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.
Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.
Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.
At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.
In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.
The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.
However, pathological complete response rates did not appear to affect overall survival.
“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.
Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.
No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.
Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.
Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.
First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.
Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”
Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”
However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.
The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.
A version of this article appeared on Medscape.com.
SAN DIEGO —
In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.
“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.
It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.
The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.
Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.
The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.
Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.
Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.
At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.
In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.
The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.
However, pathological complete response rates did not appear to affect overall survival.
“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.
Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.
No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.
Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.
Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.
First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.
Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”
Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”
However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.
The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.
A version of this article appeared on Medscape.com.
SAN DIEGO —
In a small trial, 39 patients randomized to the regimen — a combination of standard chemotherapy with the poly(ADP-ribose)polymerase (PARP) inhibitor olaparib — were alive at 3 years vs 39 of 45 (87%) randomized to chemotherapy alone.
“A remarkable 100% of patients were still alive at 36 months, which is a significant landmark for these patients,” said chief investigator Jean Abraham, PhD, a breast oncologist at the University of Cambridge, England, who presented the findings at the American Association for Cancer Research annual meeting.
It’s a “small but very powerful signal” of “what could be a potentially curative regimen that definitely does need to be confirmed in a larger study,” Dr. Abraham added.
The study, a part of the PARTNER trial, included 84 patients with T1-2 tumors of any hormone status. Just over 70% in both arms had BRCA 1 mutations, and the rest had BRCA 2 mutations.
Past attempts at combining chemotherapy with PARP inhibitors have been hampered by excess bone marrow toxicity. To counter the problem, patients randomized to the combination therapy received olaparib 48 hours after carboplatin to give their bone marrow a chance to recover.
The median age was 38 years in the control group and 47 years in the olaparib arm. A greater proportion of patients in the control arm (42% vs 23%) had axillary node involvement.
Overall, patients received neoadjuvant carboplatin on day 1 and paclitaxel on days 1, 8, and 15 every 3 weeks for four cycles, followed by anthracycline every 3 weeks for three cycles. In the study arm, olaparib 150 mg was administered twice daily starting on day 3 continuing to day 14 during the first four cycles. Almost 90% of patients received at least 80% of their planned olaparib dose.
Despite the delay in olaparib dosing, 56.4% of patients in the combination arm required a transfusion vs 48.9% with chemotherapy alone.
At a median follow-up of 40.7 months, 96% of patients in the combination arm demonstrated event-free survival, with one patient relapsing, vs 80% in the chemotherapy-alone group, with nine patients relapsing.
In the final analysis, 64% of patients who received olaparib had a pathological complete response compared with almost 70% in the chemotherapy group, though the difference was not statistically significant.
The trial was stopped short at 50% enrollment after the data monitoring safety committee determined that olaparib add-on was unlikely to improve pathological complete response rates, the trial’s primary endpoint.
However, pathological complete response rates did not appear to affect overall survival.
“It didn’t seem to matter whether you had a non-pathological complete response, you still survived 100%” with the combination, Dr. Abraham said, adding that this is not the first study to show a disconnect between response rates and survival.
Perhaps, this disconnect could be due to “doomed cells” that look like residual disease but are, in fact, dying and unable to metastasize, she said.
No patients in the combination arm and two in the control arm received olaparib, immunotherapy, or capecitabine after surgery. Both control participants relapsed, and one died.
Toxicity was more severe for patients in the combination arm. More patients who received olaparib (76.9%) experienced a grade 3 or worse adverse event vs 60% of patients in the control arm.
Study discussant Hope S. Rugo, MD, a breast oncologist at the University of California San Francisco, highlighted a few limitations and remaining questions.
First, “this is a very small population, so small differences in the biology of the tumor, the patients, and even stage that we can’t assess in the neoadjuvant setting could make a difference that would affect event-free and overall survival,” she said.
Second, two patients with pathological complete responses relapsed in the control arm and died, “which is quite unusual,” Dr. Rugo said. “Patients who achieve a pathological complete response generally have an excellent outcome.”
Dr. Rugo noted that “gap sequencing doesn’t appear to avoid the toxicity of PARP inhibitors.”
However, she said, “the efficacy results are intriguing” and would need confirmation in a larger randomized trial, perhaps with newer, more selective PARP inhibitors.
The work was funded by AstraZeneca, maker of olaparib. Researchers included AstraZeneca employees. Dr. Abraham is an adviser to and disclosed grants, travel costs, and honoraria from the company. Dr. Rugo disclosed research funding from AstraZeneca and other companies.
A version of this article appeared on Medscape.com.
FROM AACR 2024
Major Gaps in Care and Management of Neurologic Diseases
DENVER –
Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
National Neurologist Shortage
The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.
“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.
“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added.
Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted.
Analyzing Trends in Specialist Referrals
Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.
They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.
Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).
Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.
“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.
Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral.
Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral.
Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.”
Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found.
For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.
Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.
She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
Neurology Challenges
Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.
This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.
With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.
In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.
The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.
The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.
Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.
Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.
Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.
A version of this article appeared on Medscape.com.
DENVER –
Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
National Neurologist Shortage
The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.
“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.
“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added.
Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted.
Analyzing Trends in Specialist Referrals
Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.
They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.
Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).
Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.
“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.
Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral.
Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral.
Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.”
Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found.
For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.
Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.
She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
Neurology Challenges
Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.
This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.
With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.
In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.
The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.
The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.
Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.
Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.
Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.
A version of this article appeared on Medscape.com.
DENVER –
Investigators led by Nikki Win, PhD, medical manager/team lead, OMNI Scientific Strategy and Collaborations, US Medical Affairs, Genentech/Roche, found that patients with Parkinson’s disease were referred to a specialist most often, followed by those with MS and those with AD.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
National Neurologist Shortage
The national neurologist shortage, coupled with the growing incidence of Alzheimer’s disease, Parkinson’s disease, MS, and other conditions has led the AAN and other organizations to call for expanding the role of primary care physicians in the diagnosis and management of neurologic disorders, the leading global cause of disability.
“These neurological conditions are increasing in prevalence and there’s a limited number of neurologists, so we wanted to understand what this looks like in the US,” Dr. Win said.
“There is a need to understand the patient journey from primary care to neurology care, from presentation of a suspected neurological disorder to diagnosis, referral to a specialist, and the time elapsed before the specialist visit for Alzheimer’s disease, MS, and Parkinson’s disease in the US,” Dr. Win added.
Timely and accurate diagnoses of neurologic disorders can optimize treatment outcomes. Because many of these diseases are first detected during a visit with a primary care physician, it is important to understand the timeline from the initial visit to a specialist referral, the investigators noted.
Analyzing Trends in Specialist Referrals
Using claims data from the Optum Normative Health Information database, researchers identified 48,525 adults with Alzheimer’s disease, 26,431 with Parkinson’s disease, and 8169 with MS who received a diagnosis from a primary care physician between 2016 and 2021.
They examined the proportion, timing, and demographic factors associated with referrals from primary care clinicians or other healthcare providers to specialists including neurologists, neurosurgeons, psychiatrists, and geriatric medicine specialists.
Results showed that patients with Parkinson’s disease were referred to a specialist most often (53%), followed by those with MS (42%) and those with Alzheimer’s disease (27%).
Individuals with Alzheimer’s disease waited the longest for a specialist referral, with a median of 10 months between the time of referral and the first specialist visit compared with 5.7 months for patients with Parkinson’s disease and 2.6 months for MS patients.
“Some patients with common conditions like Alzheimer’s disease, MS, and Parkinson’s disease don’t see a neurologist, and when they do, it can take as long as 10 months,” said Dr. Win.
Using zip code heatmaps, researchers found that the proportion of referrals for all neurologic disorders was higher in the Midwest and Northeast, whereas patients in the South and West were less likely to receive a referral.
Referrals for Alzheimer’s disease were low nationwide, except for some areas of Michigan and New England. California had the lowest referral rate for MS, followed by regions in the South and Northeast. Patients with Parkinson’s disease living in the Midwest and Northeast were more likely than those in the West to receive a specialist referral.
Previous studies have reported regional shortages of neurologists, said Dr. Win. “Our data seem to correlate that in terms of the areas with lower referral patterns, but as to whether that is causative or correlative, we don’t know.”
Odds of referral were also influenced by demographic characteristics such as sex, age, race, and ethnicity, investigators found.
For example, there were fewer referrals with increasing age across all three neurologic disorders, and men were more likely than women to be referred for Alzheimer’s disease and Parkinson’s disease. Compared with White patients, Parkinson’s disease referrals were less likely among African American, Asian, and Hispanic patients and Alzheimer’s disease referrals were less common among Asian and Hispanic patients.
Insurance status also affected referrals. People with MS and Parkinson’s disease who had commercial insurance were referred more often than were those with Medicare Advantage, said Dr. Win.
She also noted, “Additional research is needed to understand how being referred or not being referred to a neurologist actually impacts patient treatment, care and outcomes.”
Neurology Challenges
Commenting on the research, Thomas Vidic, MD, a community neurologist in Elkhart, Indiana, and clinical professor of neurology at Indiana University School of Medicine at South Bend, said that he was surprised by the variation in wait times for patients.
This, he said, could reflect a study limitation or a higher comfort level among primary care doctors in treating dementia.
With respect to MS, Dr. Vidic said that he believes primary care physicians may not be uncertain about prescribing the approved medications for the disease because there are so many of them.
In addition, patients with Alzheimer’s disease are older and perhaps less accepting of being referred to a specialist that may be hours away.
The bottom line for Dr. Vidic, though, is the lack of specialists. “It comes back to the fact we’re not doing a good job of having community neurologists available to take care of these problems,” he said.
The issue of community neurologist shortages was underlined by the study’s findings about geographic gaps in specialist referrals across the country, he said.
Neurologists make up about 2% of the medical workforce and this has remained static for some time, Dr. Vidic noted. Meanwhile, people are living longer and developing more neurologic diseases.
Dr. Vidic also pointed to the lack of neurology training programs. “There has not been a significant change in the number of programs in the last 10-15 years,” he said.
Study funding was not disclosed. Dr. Win reports receiving personal compensation for serving as an employee of Genentech and has stock in Genentech. Dr. Vidic reports no relevant financial disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
New Contraindications to Coadministration of Atazanavir
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) this week recommended new contraindications on the coadministration of the protease inhibitor atazanavir (Reyataz, Bristol-Myers Squibb) with antineoplastic agents encorafenib and ivosidenib (atazanavir may significantly increase blood levels and thus side effects), and with the anticonvulsants carbamazepine, phenobarbital, and phenytoin (which may decrease serum levels of atazanavir).
The new rules alter sections 4.3 and 4.5 of the summary of product characteristics (SmPC) to reclassify drug–drug interactions with the new contraindications.
Atazanavir is an orally administered drug, used in combination with low-dose ritonavir (Norvir) to boost its pharmacokinetics. It is indicated for the treatment of HIV-1 infected adults and pediatric patients 3 months of age and older in combination with other antiretroviral medicinal products. A combination preparation boosted with cobicistat (Evotaz) is also available.
The drug is an azapeptide HIV-1 protease inhibitor (PI) that selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells. This prevents the virus from multiplying and slows the spread of infection. Based on available virological and clinical data from adult patients, no benefit is expected in patients with HIV strains resistant to multiple protease inhibitors (four or more PI mutations).
Therapy with atazanavir is intended to be initiated by a physician experienced in the management of HIV infection, with the choice of atazanavir in treatment-experienced adult and pediatric patients based on individual viral resistance testing and the patient’s treatment history. The standard dose is 300 mg atazanavir taken with 100 mg ritonavir once daily with food.
Atazanavir is already contraindicated in combination or coadministration with a wide variety of other agents:
- Coadministration with simvastatin or lovastatin [statins – risk of increased blood levels with atazanavir].
- Combination with the anti-TB antibiotic rifampicin.
- Combination with the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension only.
- Coadministration with substrates of the CYP3A4 isoform of cytochrome P450 that have narrow therapeutic windows (eg, quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, oral midazolam, lomitapide, and ergot alkaloids).
- Coadministration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (hepatitis C drug combination; atazanavir increases its blood levels).
- Coadministration with glecaprevir/pibrentasvir fixed dose combination (hepatitis C drug combination; increased hepatotoxicity due to increased bilirubin concentration).
- Coadministration with products containing St. John’s wort (Hypericum perforatum).
The EMA said detailed recommendations for the use of atazanavir will be described in the updated SmPC, which will be published in the revised European public assessment report after a decision on this change to the marketing authorization has been granted by the European Commission.
A version of this article appeared on Medscape.com.
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) this week recommended new contraindications on the coadministration of the protease inhibitor atazanavir (Reyataz, Bristol-Myers Squibb) with antineoplastic agents encorafenib and ivosidenib (atazanavir may significantly increase blood levels and thus side effects), and with the anticonvulsants carbamazepine, phenobarbital, and phenytoin (which may decrease serum levels of atazanavir).
The new rules alter sections 4.3 and 4.5 of the summary of product characteristics (SmPC) to reclassify drug–drug interactions with the new contraindications.
Atazanavir is an orally administered drug, used in combination with low-dose ritonavir (Norvir) to boost its pharmacokinetics. It is indicated for the treatment of HIV-1 infected adults and pediatric patients 3 months of age and older in combination with other antiretroviral medicinal products. A combination preparation boosted with cobicistat (Evotaz) is also available.
The drug is an azapeptide HIV-1 protease inhibitor (PI) that selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells. This prevents the virus from multiplying and slows the spread of infection. Based on available virological and clinical data from adult patients, no benefit is expected in patients with HIV strains resistant to multiple protease inhibitors (four or more PI mutations).
Therapy with atazanavir is intended to be initiated by a physician experienced in the management of HIV infection, with the choice of atazanavir in treatment-experienced adult and pediatric patients based on individual viral resistance testing and the patient’s treatment history. The standard dose is 300 mg atazanavir taken with 100 mg ritonavir once daily with food.
Atazanavir is already contraindicated in combination or coadministration with a wide variety of other agents:
- Coadministration with simvastatin or lovastatin [statins – risk of increased blood levels with atazanavir].
- Combination with the anti-TB antibiotic rifampicin.
- Combination with the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension only.
- Coadministration with substrates of the CYP3A4 isoform of cytochrome P450 that have narrow therapeutic windows (eg, quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, oral midazolam, lomitapide, and ergot alkaloids).
- Coadministration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (hepatitis C drug combination; atazanavir increases its blood levels).
- Coadministration with glecaprevir/pibrentasvir fixed dose combination (hepatitis C drug combination; increased hepatotoxicity due to increased bilirubin concentration).
- Coadministration with products containing St. John’s wort (Hypericum perforatum).
The EMA said detailed recommendations for the use of atazanavir will be described in the updated SmPC, which will be published in the revised European public assessment report after a decision on this change to the marketing authorization has been granted by the European Commission.
A version of this article appeared on Medscape.com.
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) this week recommended new contraindications on the coadministration of the protease inhibitor atazanavir (Reyataz, Bristol-Myers Squibb) with antineoplastic agents encorafenib and ivosidenib (atazanavir may significantly increase blood levels and thus side effects), and with the anticonvulsants carbamazepine, phenobarbital, and phenytoin (which may decrease serum levels of atazanavir).
The new rules alter sections 4.3 and 4.5 of the summary of product characteristics (SmPC) to reclassify drug–drug interactions with the new contraindications.
Atazanavir is an orally administered drug, used in combination with low-dose ritonavir (Norvir) to boost its pharmacokinetics. It is indicated for the treatment of HIV-1 infected adults and pediatric patients 3 months of age and older in combination with other antiretroviral medicinal products. A combination preparation boosted with cobicistat (Evotaz) is also available.
The drug is an azapeptide HIV-1 protease inhibitor (PI) that selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells. This prevents the virus from multiplying and slows the spread of infection. Based on available virological and clinical data from adult patients, no benefit is expected in patients with HIV strains resistant to multiple protease inhibitors (four or more PI mutations).
Therapy with atazanavir is intended to be initiated by a physician experienced in the management of HIV infection, with the choice of atazanavir in treatment-experienced adult and pediatric patients based on individual viral resistance testing and the patient’s treatment history. The standard dose is 300 mg atazanavir taken with 100 mg ritonavir once daily with food.
Atazanavir is already contraindicated in combination or coadministration with a wide variety of other agents:
- Coadministration with simvastatin or lovastatin [statins – risk of increased blood levels with atazanavir].
- Combination with the anti-TB antibiotic rifampicin.
- Combination with the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension only.
- Coadministration with substrates of the CYP3A4 isoform of cytochrome P450 that have narrow therapeutic windows (eg, quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, oral midazolam, lomitapide, and ergot alkaloids).
- Coadministration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (hepatitis C drug combination; atazanavir increases its blood levels).
- Coadministration with glecaprevir/pibrentasvir fixed dose combination (hepatitis C drug combination; increased hepatotoxicity due to increased bilirubin concentration).
- Coadministration with products containing St. John’s wort (Hypericum perforatum).
The EMA said detailed recommendations for the use of atazanavir will be described in the updated SmPC, which will be published in the revised European public assessment report after a decision on this change to the marketing authorization has been granted by the European Commission.
A version of this article appeared on Medscape.com.
Updated Sjögren Disease Guideline Advises Doing ‘the Little Things Well’
LIVERPOOL, ENGLAND — An updated guideline from the British Society for Rheumatology (BSR) on the management of Sjögren disease asks rheumatologists and other clinicians caring for patients with the condition to “do the little things well” rather than overly focusing on rheumatologic treatments. The guideline’s new format provides recommendations for specific clinical questions and now also includes recommendations for managing the disease in children and adolescents.
“The original guideline was published in 2017, and things move on very rapidly,” consultant rheumatologist Elizabeth Price, MBBCh, PhD, said ahead of her presentation of the updated guideline at the annual meeting of the British Society for Rheumatology.
“We approached the update in a slightly different way,” said Dr. Price, who works at Great Western Hospital NHS Foundation Trust in Swindon, England. She was the chair of the new guideline’s working group and convenes the BSR’s Special Interest Group for Sjögren disease.
Previously, the approach was to look at the management of Sjögren disease affecting the eyes, mouth, salivary glands, and, in turn, systemic disease. “This time we posed questions that we felt needed to be asked, interrogated the literature, and then used that to come up with our recommendations,” Dr. Price said.
The answers to those questions were used to form the 19 recommendations that now make up the guideline. These cover four key areas on the management of Sjögren disease: confirming the diagnosis, treating the symptoms, managing systemic disease, and considering special situations such as planned pregnancy and comorbidities. There is also lifestyle advice and information about where to get good patient education.
What’s in a Name?
The BSR guideline on the management of adult and juvenile onset Sjögren disease is published in Rheumatology and is available via the BSR website, where it is accompanied by a short summary sheet.
The most notable change perhaps is the name the guideline now uses, Dr. Price said at BSR 2024. “We have been bold and called it Sjögren disease.” Previously, the guideline used the term primary Sjögren’s syndrome, but there has been a “move away from using eponymous syndromes and dropping s’s and apostrophes,” she explained.
Another significant change is that advice on managing Sjögren disease in children and adolescents is now included where appropriate, meaning that the British guideline is now the first to cover Sjögren disease “across the ages,” Dr. Price said.
A pediatric/adolescent rheumatologist joined the guideline working group, which already consisted of several adult rheumatologists, ophthalmologists, and a dentistry consultant. The group now comprises 22 members total, including a general practitioner, an oncologist, a renal physician, an occupational therapist, two patients with Sjögren disease, and a librarian.
Confirming the Diagnosis
The first questions asked to help form the new recommendations were around confirming a diagnosis of Sjögren disease, such as what is the diagnostic accuracy of antinuclear antibodies (ANAs), extractable nuclear antigens (ENAs), and other novel antigens in Sjögren disease? And what is the diagnostic accuracy of salivary gland ultrasound, imaging in general, and salivary gland or lacrimal gland biopsies?
The resulting recommendations advised not to measure ANAs in the absence of clinical indicators of Sjögren disease or any other connective tissue disease but to use it to screen if there was a clinical suspicion. And ENAs should be measured even if the ANAs were negative and there is a high index of suspicion.
In terms of imaging, ultrasound of the salivary glands was thought to be useful, but other imaging was not recommended for routine practice at the current time. Minor lip but not lacrimal gland biopsies were recommended if clinical and serologic features were not enough to make a diagnosis.
Lymphoma Worries
The 2017 version of the guideline did not include information about lymphoma, but this is the thing that most patients with Sjögren disease will worry about, Dr. Price said. “They all look it up on YouTube, they all come back and tell me that they are really worried they’ll develop it.”
The question that was therefore posed was whether there were any measurable biomarkers that could predict the development of lymphoma in adults and children. Seven predictors were found, the strongest being a low level of complement C4 alone or together with low levels of C3. Other predictors were salivary gland enlargement, lymphadenopathy, anti-Ro/La and rheumatoid factor autoantibodies, cryoglobulinemia, monoclonal gammopathy, and a high focus score.
All of these predictors put someone in a higher risk category for lymphoma. If two or fewer of those features are present, the lifetime risk is “probably below 2%,” Dr. Price said. However, if all seven are present, the lifetime risk is “approaching 100%.”
The recommendation made on the basis of these findings is that people with Sjögren disease need to be offered early further investigation if they present with any new salivary gland swelling or other symptoms that might suggest the development of lymphoma. In this regard, a labial salivary gland biopsy might provide additional prognostic information.
‘Do the Little Things Well’
“You have to do the little things well,” Dr. Price said. “Many of the patients [who] come to see me for a second opinion have not been prescribed the right eye drops, have not been given advice on dental care,” with their management taking “too much on the rheumatological treatments.”
Rheumatologists are of course not trained or expected to be experts in ophthalmology or dentistry, but “you need to look at their mouth and you do need to examine their eyes, and you do need to give them some advice,” Dr. Price advised.
Thankfully, that is where the updated guidelines should help, with a recommendation that people with Sjögren disease should use preservative-free eye drops every 2-3 hours.
“It’s vital you avoid preservatives, because preservatives flatten the corneal surface and reduce the surface area and can cause inflammation in their own right,” Dr. Price cautioned, adding that there are plenty of suitable eye drop formulations available.
In regard to helping with dry mouth symptoms, the recommendation is to use a saliva substitute for symptomatic relief. For vaginal dryness, the recommendation is to consider advising topical nonhormonal vaginal moisturizers plus estrogen creams or pessaries in peri- or postmenopausal women with significant vaginal dryness.
“Very important, however, is to maintain a neutral pH, an alkaline environment in the mouth because acid damages dental enamel,” Dr. Price said. Conversely, an acidic vaginal moisturizer is needed to treat vaginal dryness.
Dental hygiene is important. Regular brushing with a fluoride-based toothpaste is advised. The use of xylitol-containing products has been shown to reduce bacteria known to increase the risk for dental decay. Telling patients not to eat between meals is also simple but important advice.
“We do recommend that patients are assessed holistically,” Dr. Price said, noting that they should be offered access to cognitive-behavioral therapy and exercise therapies to help with the symptoms of fatigue and joint pain.
Watch Out for Comorbidities
Sjögren disease is associated with many comorbidities, some of which might be predicted from the age and demographics of the people who are normally affected.
“This is on the whole an older, female population, so you see a lot of osteoarthritis, gastroesophageal reflux, and hypertension,” Dr. Price said. “However, you may not be aware that 1 in 5 of these patients develop thyroid disease,” and there is a higher rate of celiac disease and primary biliary cholangitis than is seen in the general background population.
The recommendation, therefore, is to “be aware of and consider screening for commonly associated conditions, as guided by age and/or clinical presentation.” As such, it’s recommended that baseline and repeated investigations that look for signs of comorbidity are performed, such as thyroid function assessment and liver function tests, to name two.
Treatment Recommendations
As in the original guideline, the treatment of systemic disease is discussed, but the advice has been overhauled with the availability of new data.
The updated guidance notes that a trial of hydroxychloroquine for 6-12 months is the recommended treatment approach for people with fatigue and systemic symptoms.
Systemic steroids may be used in the short-term for specific indications but should not be offered routinely.
Conventional immunosuppressive or biologic drugs and immunoglobulins are not currently recommended outside of managing specific systemic complications.
In juvenile cases, the treatment of recurrent swollen parotid glands that are not due to infection or stone disease should include a short course of a nonsteroidal anti-inflammatory drug or a short course of oral steroids. This should be combined with massage followed by washouts with saline or steroids. In refractory cases, escalation to anti–B-cell–targeted therapies may be considered in select situations.
View on Updates
Patient advocate Bridget Crampton, who leads the helpline team at Sjögren’s UK (formerly the British Sjögren’s Syndrome Association), commented on the importance of the guidelines during a roundtable held by the BSR.
“I think it will help [patients] make better use of their own appointments. So, they’ll know what treatments might be offered. They’ll know what they want to talk about at their appointments,” she said.
Ms. Crampton, who has lived with Sjögren disease herself for the past 20 years, added: “I think it’s important for patients that we have guidelines like this. It means that all clinicians can easily access information. My hope is that it might standardize care across the UK a little bit more.”
No specific funding was received to create the guidelines, be that from any bodies in the public, commercial, or not-for-profit sectors. No conflicts of interests were expressed by any of the experts quoted in this article.
A version of this article appeared on Medscape.com.
LIVERPOOL, ENGLAND — An updated guideline from the British Society for Rheumatology (BSR) on the management of Sjögren disease asks rheumatologists and other clinicians caring for patients with the condition to “do the little things well” rather than overly focusing on rheumatologic treatments. The guideline’s new format provides recommendations for specific clinical questions and now also includes recommendations for managing the disease in children and adolescents.
“The original guideline was published in 2017, and things move on very rapidly,” consultant rheumatologist Elizabeth Price, MBBCh, PhD, said ahead of her presentation of the updated guideline at the annual meeting of the British Society for Rheumatology.
“We approached the update in a slightly different way,” said Dr. Price, who works at Great Western Hospital NHS Foundation Trust in Swindon, England. She was the chair of the new guideline’s working group and convenes the BSR’s Special Interest Group for Sjögren disease.
Previously, the approach was to look at the management of Sjögren disease affecting the eyes, mouth, salivary glands, and, in turn, systemic disease. “This time we posed questions that we felt needed to be asked, interrogated the literature, and then used that to come up with our recommendations,” Dr. Price said.
The answers to those questions were used to form the 19 recommendations that now make up the guideline. These cover four key areas on the management of Sjögren disease: confirming the diagnosis, treating the symptoms, managing systemic disease, and considering special situations such as planned pregnancy and comorbidities. There is also lifestyle advice and information about where to get good patient education.
What’s in a Name?
The BSR guideline on the management of adult and juvenile onset Sjögren disease is published in Rheumatology and is available via the BSR website, where it is accompanied by a short summary sheet.
The most notable change perhaps is the name the guideline now uses, Dr. Price said at BSR 2024. “We have been bold and called it Sjögren disease.” Previously, the guideline used the term primary Sjögren’s syndrome, but there has been a “move away from using eponymous syndromes and dropping s’s and apostrophes,” she explained.
Another significant change is that advice on managing Sjögren disease in children and adolescents is now included where appropriate, meaning that the British guideline is now the first to cover Sjögren disease “across the ages,” Dr. Price said.
A pediatric/adolescent rheumatologist joined the guideline working group, which already consisted of several adult rheumatologists, ophthalmologists, and a dentistry consultant. The group now comprises 22 members total, including a general practitioner, an oncologist, a renal physician, an occupational therapist, two patients with Sjögren disease, and a librarian.
Confirming the Diagnosis
The first questions asked to help form the new recommendations were around confirming a diagnosis of Sjögren disease, such as what is the diagnostic accuracy of antinuclear antibodies (ANAs), extractable nuclear antigens (ENAs), and other novel antigens in Sjögren disease? And what is the diagnostic accuracy of salivary gland ultrasound, imaging in general, and salivary gland or lacrimal gland biopsies?
The resulting recommendations advised not to measure ANAs in the absence of clinical indicators of Sjögren disease or any other connective tissue disease but to use it to screen if there was a clinical suspicion. And ENAs should be measured even if the ANAs were negative and there is a high index of suspicion.
In terms of imaging, ultrasound of the salivary glands was thought to be useful, but other imaging was not recommended for routine practice at the current time. Minor lip but not lacrimal gland biopsies were recommended if clinical and serologic features were not enough to make a diagnosis.
Lymphoma Worries
The 2017 version of the guideline did not include information about lymphoma, but this is the thing that most patients with Sjögren disease will worry about, Dr. Price said. “They all look it up on YouTube, they all come back and tell me that they are really worried they’ll develop it.”
The question that was therefore posed was whether there were any measurable biomarkers that could predict the development of lymphoma in adults and children. Seven predictors were found, the strongest being a low level of complement C4 alone or together with low levels of C3. Other predictors were salivary gland enlargement, lymphadenopathy, anti-Ro/La and rheumatoid factor autoantibodies, cryoglobulinemia, monoclonal gammopathy, and a high focus score.
All of these predictors put someone in a higher risk category for lymphoma. If two or fewer of those features are present, the lifetime risk is “probably below 2%,” Dr. Price said. However, if all seven are present, the lifetime risk is “approaching 100%.”
The recommendation made on the basis of these findings is that people with Sjögren disease need to be offered early further investigation if they present with any new salivary gland swelling or other symptoms that might suggest the development of lymphoma. In this regard, a labial salivary gland biopsy might provide additional prognostic information.
‘Do the Little Things Well’
“You have to do the little things well,” Dr. Price said. “Many of the patients [who] come to see me for a second opinion have not been prescribed the right eye drops, have not been given advice on dental care,” with their management taking “too much on the rheumatological treatments.”
Rheumatologists are of course not trained or expected to be experts in ophthalmology or dentistry, but “you need to look at their mouth and you do need to examine their eyes, and you do need to give them some advice,” Dr. Price advised.
Thankfully, that is where the updated guidelines should help, with a recommendation that people with Sjögren disease should use preservative-free eye drops every 2-3 hours.
“It’s vital you avoid preservatives, because preservatives flatten the corneal surface and reduce the surface area and can cause inflammation in their own right,” Dr. Price cautioned, adding that there are plenty of suitable eye drop formulations available.
In regard to helping with dry mouth symptoms, the recommendation is to use a saliva substitute for symptomatic relief. For vaginal dryness, the recommendation is to consider advising topical nonhormonal vaginal moisturizers plus estrogen creams or pessaries in peri- or postmenopausal women with significant vaginal dryness.
“Very important, however, is to maintain a neutral pH, an alkaline environment in the mouth because acid damages dental enamel,” Dr. Price said. Conversely, an acidic vaginal moisturizer is needed to treat vaginal dryness.
Dental hygiene is important. Regular brushing with a fluoride-based toothpaste is advised. The use of xylitol-containing products has been shown to reduce bacteria known to increase the risk for dental decay. Telling patients not to eat between meals is also simple but important advice.
“We do recommend that patients are assessed holistically,” Dr. Price said, noting that they should be offered access to cognitive-behavioral therapy and exercise therapies to help with the symptoms of fatigue and joint pain.
Watch Out for Comorbidities
Sjögren disease is associated with many comorbidities, some of which might be predicted from the age and demographics of the people who are normally affected.
“This is on the whole an older, female population, so you see a lot of osteoarthritis, gastroesophageal reflux, and hypertension,” Dr. Price said. “However, you may not be aware that 1 in 5 of these patients develop thyroid disease,” and there is a higher rate of celiac disease and primary biliary cholangitis than is seen in the general background population.
The recommendation, therefore, is to “be aware of and consider screening for commonly associated conditions, as guided by age and/or clinical presentation.” As such, it’s recommended that baseline and repeated investigations that look for signs of comorbidity are performed, such as thyroid function assessment and liver function tests, to name two.
Treatment Recommendations
As in the original guideline, the treatment of systemic disease is discussed, but the advice has been overhauled with the availability of new data.
The updated guidance notes that a trial of hydroxychloroquine for 6-12 months is the recommended treatment approach for people with fatigue and systemic symptoms.
Systemic steroids may be used in the short-term for specific indications but should not be offered routinely.
Conventional immunosuppressive or biologic drugs and immunoglobulins are not currently recommended outside of managing specific systemic complications.
In juvenile cases, the treatment of recurrent swollen parotid glands that are not due to infection or stone disease should include a short course of a nonsteroidal anti-inflammatory drug or a short course of oral steroids. This should be combined with massage followed by washouts with saline or steroids. In refractory cases, escalation to anti–B-cell–targeted therapies may be considered in select situations.
View on Updates
Patient advocate Bridget Crampton, who leads the helpline team at Sjögren’s UK (formerly the British Sjögren’s Syndrome Association), commented on the importance of the guidelines during a roundtable held by the BSR.
“I think it will help [patients] make better use of their own appointments. So, they’ll know what treatments might be offered. They’ll know what they want to talk about at their appointments,” she said.
Ms. Crampton, who has lived with Sjögren disease herself for the past 20 years, added: “I think it’s important for patients that we have guidelines like this. It means that all clinicians can easily access information. My hope is that it might standardize care across the UK a little bit more.”
No specific funding was received to create the guidelines, be that from any bodies in the public, commercial, or not-for-profit sectors. No conflicts of interests were expressed by any of the experts quoted in this article.
A version of this article appeared on Medscape.com.
LIVERPOOL, ENGLAND — An updated guideline from the British Society for Rheumatology (BSR) on the management of Sjögren disease asks rheumatologists and other clinicians caring for patients with the condition to “do the little things well” rather than overly focusing on rheumatologic treatments. The guideline’s new format provides recommendations for specific clinical questions and now also includes recommendations for managing the disease in children and adolescents.
“The original guideline was published in 2017, and things move on very rapidly,” consultant rheumatologist Elizabeth Price, MBBCh, PhD, said ahead of her presentation of the updated guideline at the annual meeting of the British Society for Rheumatology.
“We approached the update in a slightly different way,” said Dr. Price, who works at Great Western Hospital NHS Foundation Trust in Swindon, England. She was the chair of the new guideline’s working group and convenes the BSR’s Special Interest Group for Sjögren disease.
Previously, the approach was to look at the management of Sjögren disease affecting the eyes, mouth, salivary glands, and, in turn, systemic disease. “This time we posed questions that we felt needed to be asked, interrogated the literature, and then used that to come up with our recommendations,” Dr. Price said.
The answers to those questions were used to form the 19 recommendations that now make up the guideline. These cover four key areas on the management of Sjögren disease: confirming the diagnosis, treating the symptoms, managing systemic disease, and considering special situations such as planned pregnancy and comorbidities. There is also lifestyle advice and information about where to get good patient education.
What’s in a Name?
The BSR guideline on the management of adult and juvenile onset Sjögren disease is published in Rheumatology and is available via the BSR website, where it is accompanied by a short summary sheet.
The most notable change perhaps is the name the guideline now uses, Dr. Price said at BSR 2024. “We have been bold and called it Sjögren disease.” Previously, the guideline used the term primary Sjögren’s syndrome, but there has been a “move away from using eponymous syndromes and dropping s’s and apostrophes,” she explained.
Another significant change is that advice on managing Sjögren disease in children and adolescents is now included where appropriate, meaning that the British guideline is now the first to cover Sjögren disease “across the ages,” Dr. Price said.
A pediatric/adolescent rheumatologist joined the guideline working group, which already consisted of several adult rheumatologists, ophthalmologists, and a dentistry consultant. The group now comprises 22 members total, including a general practitioner, an oncologist, a renal physician, an occupational therapist, two patients with Sjögren disease, and a librarian.
Confirming the Diagnosis
The first questions asked to help form the new recommendations were around confirming a diagnosis of Sjögren disease, such as what is the diagnostic accuracy of antinuclear antibodies (ANAs), extractable nuclear antigens (ENAs), and other novel antigens in Sjögren disease? And what is the diagnostic accuracy of salivary gland ultrasound, imaging in general, and salivary gland or lacrimal gland biopsies?
The resulting recommendations advised not to measure ANAs in the absence of clinical indicators of Sjögren disease or any other connective tissue disease but to use it to screen if there was a clinical suspicion. And ENAs should be measured even if the ANAs were negative and there is a high index of suspicion.
In terms of imaging, ultrasound of the salivary glands was thought to be useful, but other imaging was not recommended for routine practice at the current time. Minor lip but not lacrimal gland biopsies were recommended if clinical and serologic features were not enough to make a diagnosis.
Lymphoma Worries
The 2017 version of the guideline did not include information about lymphoma, but this is the thing that most patients with Sjögren disease will worry about, Dr. Price said. “They all look it up on YouTube, they all come back and tell me that they are really worried they’ll develop it.”
The question that was therefore posed was whether there were any measurable biomarkers that could predict the development of lymphoma in adults and children. Seven predictors were found, the strongest being a low level of complement C4 alone or together with low levels of C3. Other predictors were salivary gland enlargement, lymphadenopathy, anti-Ro/La and rheumatoid factor autoantibodies, cryoglobulinemia, monoclonal gammopathy, and a high focus score.
All of these predictors put someone in a higher risk category for lymphoma. If two or fewer of those features are present, the lifetime risk is “probably below 2%,” Dr. Price said. However, if all seven are present, the lifetime risk is “approaching 100%.”
The recommendation made on the basis of these findings is that people with Sjögren disease need to be offered early further investigation if they present with any new salivary gland swelling or other symptoms that might suggest the development of lymphoma. In this regard, a labial salivary gland biopsy might provide additional prognostic information.
‘Do the Little Things Well’
“You have to do the little things well,” Dr. Price said. “Many of the patients [who] come to see me for a second opinion have not been prescribed the right eye drops, have not been given advice on dental care,” with their management taking “too much on the rheumatological treatments.”
Rheumatologists are of course not trained or expected to be experts in ophthalmology or dentistry, but “you need to look at their mouth and you do need to examine their eyes, and you do need to give them some advice,” Dr. Price advised.
Thankfully, that is where the updated guidelines should help, with a recommendation that people with Sjögren disease should use preservative-free eye drops every 2-3 hours.
“It’s vital you avoid preservatives, because preservatives flatten the corneal surface and reduce the surface area and can cause inflammation in their own right,” Dr. Price cautioned, adding that there are plenty of suitable eye drop formulations available.
In regard to helping with dry mouth symptoms, the recommendation is to use a saliva substitute for symptomatic relief. For vaginal dryness, the recommendation is to consider advising topical nonhormonal vaginal moisturizers plus estrogen creams or pessaries in peri- or postmenopausal women with significant vaginal dryness.
“Very important, however, is to maintain a neutral pH, an alkaline environment in the mouth because acid damages dental enamel,” Dr. Price said. Conversely, an acidic vaginal moisturizer is needed to treat vaginal dryness.
Dental hygiene is important. Regular brushing with a fluoride-based toothpaste is advised. The use of xylitol-containing products has been shown to reduce bacteria known to increase the risk for dental decay. Telling patients not to eat between meals is also simple but important advice.
“We do recommend that patients are assessed holistically,” Dr. Price said, noting that they should be offered access to cognitive-behavioral therapy and exercise therapies to help with the symptoms of fatigue and joint pain.
Watch Out for Comorbidities
Sjögren disease is associated with many comorbidities, some of which might be predicted from the age and demographics of the people who are normally affected.
“This is on the whole an older, female population, so you see a lot of osteoarthritis, gastroesophageal reflux, and hypertension,” Dr. Price said. “However, you may not be aware that 1 in 5 of these patients develop thyroid disease,” and there is a higher rate of celiac disease and primary biliary cholangitis than is seen in the general background population.
The recommendation, therefore, is to “be aware of and consider screening for commonly associated conditions, as guided by age and/or clinical presentation.” As such, it’s recommended that baseline and repeated investigations that look for signs of comorbidity are performed, such as thyroid function assessment and liver function tests, to name two.
Treatment Recommendations
As in the original guideline, the treatment of systemic disease is discussed, but the advice has been overhauled with the availability of new data.
The updated guidance notes that a trial of hydroxychloroquine for 6-12 months is the recommended treatment approach for people with fatigue and systemic symptoms.
Systemic steroids may be used in the short-term for specific indications but should not be offered routinely.
Conventional immunosuppressive or biologic drugs and immunoglobulins are not currently recommended outside of managing specific systemic complications.
In juvenile cases, the treatment of recurrent swollen parotid glands that are not due to infection or stone disease should include a short course of a nonsteroidal anti-inflammatory drug or a short course of oral steroids. This should be combined with massage followed by washouts with saline or steroids. In refractory cases, escalation to anti–B-cell–targeted therapies may be considered in select situations.
View on Updates
Patient advocate Bridget Crampton, who leads the helpline team at Sjögren’s UK (formerly the British Sjögren’s Syndrome Association), commented on the importance of the guidelines during a roundtable held by the BSR.
“I think it will help [patients] make better use of their own appointments. So, they’ll know what treatments might be offered. They’ll know what they want to talk about at their appointments,” she said.
Ms. Crampton, who has lived with Sjögren disease herself for the past 20 years, added: “I think it’s important for patients that we have guidelines like this. It means that all clinicians can easily access information. My hope is that it might standardize care across the UK a little bit more.”
No specific funding was received to create the guidelines, be that from any bodies in the public, commercial, or not-for-profit sectors. No conflicts of interests were expressed by any of the experts quoted in this article.
A version of this article appeared on Medscape.com.
FROM BSR 2024