Feature

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

A version of this article first appeared on Medscape.com.

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

A version of this article first appeared on Medscape.com.

Last year, cancer screening programs around the world ground to a halt as SARS-CoV-2 infection rates surged globally. The effect of this slowdown is now becoming clear.

Thousands of cancer diagnoses are “missing,” and oncologists worry that this will lead to more advanced cancers and higher mortality for years to come.

“I feel like this is an earthquake that’s rocked our health care system. My guess is that you’ll probably still see repercussions of this over the next couple of years at least,” said Sharon Chang, MD, an attending surgical oncologist in the Permanente Medical Group, Fremont, Calif.

She was senior author of a study that analyzed the effects of the slowdown in mammography screening as a result of California’s “shelter-in-place” order on March 17, 2020. In the 2 months that followed, there were 64% fewer breast cancer diagnoses at 21 Kaiser Permanente medical centers, compared with the same period in 2019 (250 vs. 703).

In effect, approximately 450 breast cancer patients had “disappeared,” said coauthor Annie Tang, MD, a research fellow at the University of California, San Francisco, East Bay surgery program.

“What surprised me most from our data was the sheer number of breast cancer patients that were missing,” Dr. Tang said in an interview.

A similar picture has emerged elsewhere.

In Boston, an estimated 1,438 cancerous and precancerous lesions “went missing” during the first 3 months of pandemic shutdown, according to a study from the Massachusetts General Brigham health care system.

In this study, the investigators assessed screening rates for five cancers – breast cancer (mammography), prostate cancer (prostate-specific antigen testing), colorectal cancer (colonoscopy), cervical cancer (Papanicolaou tests), and lung cancer (low-dose CT).

Screening rates during the first peak of the pandemic (March 2 to June 2, 2020) were compared with those during the preceding and following 3 months and during the same 3 months in 2019.

The results showed a pronounced drop in screening rates during the peak pandemic period, compared with the three control periods. Decreases occurred for all screening tests and ranged from –60% to –82%.

There were also significant decreases in cancer diagnoses resulting from the decreases in screening tests, ranging from –19% to –78%.

“Quantifying the actual problem made us realize how much work needs to be done to get us back to prepandemic numbers,” said senior author Quoc-Dien Trinh, MD, FACS, codirector of the Dana Farber/Brigham and Women’s prostate cancer program.

In the Canadian province of Alberta, a similar decrease in cancer diagnoses occurred during the early days of the pandemic.

By the end of 2020, Alberta was “missing” approximately 2,000 cases of invasive cancers and 1,000 cases of noninvasive cancers, Doug Stewart, MD, senior medical director at the Cancer Strategic Clinical Network (SCN) of Alberta Health Services, told this news organization.

Dr. Stewart is able to track cancer diagnoses in Alberta almost in real time through a mandatory cancer registry. Within a month of shutdown, there was a 30% decrease in diagnoses of invasive cancers and a 50% decrease “in the kind of preinvasive cancers that, for the most part, are picked up by screening programs,” said Dr. Stewart.

After the health care system opened up again in the summer, Stewart said, noninvasive cancer diagnoses continued to be 20% lower than expected. There was a 10% shortfall in invasive cancer diagnoses.

The number of diagnoses had returned to normal by December 2020. However, Dr. Stewart is worried that this fact conceals a terrible truth.

The worry is over the backlog. Although the number of diagnoses is now similar to what it was before the pandemic, “people are presenting later, and maybe the cancer is more advanced,” he speculated.

His team at Alberta Health Services is assessing whether the cancers that are being diagnosed now are more advanced. Initial results are anticipated by late April 2021.

In the United Kingdom, there was a similar halt in cancer screening as a result of the country’s lockdown. Researchers now predict an uptick in cancer diagnoses.

Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, and colleagues have estimated that at least 3,500 deaths from breast, colorectal, esophageal, and lung cancer will occur during the next 5 years in England that could have been avoided had it not been for the lockdown measures necessitated by the pandemic.

Speaking to this news organization, Dr. Aggarwal warned that these numbers, which are from a modeling study published in August 2020, are “extremely conservative,” because the investigators considered diagnostic delays over only a 3-month period, the analysis involved only four cancers, and it did not reflect deferral of cancer treatment.

“It felt like it was the tip of the iceberg,” Dr. Aggarwal said. He warns that more recent data suggest that “diagnostic delays are probably worse than we predicted.”

He suspects that there is more at play than screening cancellations.

In another study conducted in the United Kingdom, data show “a falling edge of referrals” from primary care to cancer centers early in the pandemic. In that study, investigators analyzed real-time weekly hospital data from eight large British hospitals and found that urgent cancer referrals fell 70% at their lowest point.

“It really surprised me that the urgent referrals dropped so drastically,” said lead author Alvina Lai, PhD, a lecturer in health data analytics at University College London.

She attributed this in part to patients’ adherence to lockdown rules. “Patients are trying to follow government guidelines to stay home and not go to [general practitioners] unless necessary,” Dr. Lai explained in an interview.

Canada, like the United Kingdom, has a publicly funded health care system. Dr. Stewart came to a similar conclusion. “Some patients who have been diagnosed with cancer ... have told me it took them an extra couple of months to even contact the family doc, because they ... didn’t want to bother the family doctor with something that wasn’t COVID, this kind of guilt. They want to do something good for society. You know, most people are just really nice people, and they don’t want to bother the health care system if they don’t have COVID,” Dr. Stewart said.

Shelley Fuld Nasso, CEO of the National Coalition for Cancer Survivorship, a nonprofit organization based in Silver Spring, Md., agreed that screening shutdowns are not the only danger. “While we agree that screening is really important, we also want to make sure patients are following up with their physicians about symptoms that they have,” she said.

“Some of the speculation or concern about increased mortality for cancer is related to screening, but some of it is related to delayed diagnosis because of not following up on symptoms. ... What concerns me is not everyone has that ability or willingness to advocate for themselves,” she said.

Speaking at a press briefing held by the American Society for Radiation Oncology on March 30, Dr. Nasso related a case involving a patient who experienced severe arm pain. In a teleconsultation with her primary care physician, her condition was diagnosed as arthritis. She was subsequently diagnosed in the ED as having multiple myeloma.

Patients who “feel fine” may postpone their checkups to avoid going to the hospital and risking exposure to COVID-19.

“Some patients are still hesitant about returning for their mammograms or coming in if they feel a breast lump,” Dr. Tang said. “That fear of COVID-19 is still out there, and we don’t know how long patients are going to delay.”

In London, Dr. Aggarwal saw a similar response to the pandemic. “People were overestimating quite significantly what their risk of death was from acquiring COVID-19, and I think that balance was never [redressed] explicitly,” he said.

Public health initiatives to rebalance the messaging are now underway.

Public Health England and National Health Service England launched their Help Us Help You campaign in October 2020. The public information campaign urges people to speak to their doctors if they were “worried about a symptom that could be cancer.”

In Canada, the provincial government in Alberta has launched a public awareness campaign that conveys the message, “cancer has not gone away.”

“Cancer is still the No. 1 cause of potential life-years lost, despite COVID,” Dr. Stewart said. “We need to do what we can to make sure there’s no slippage in survival rates.”

Dr. Tang, Dr. Chang, Dr. Lai, Dr. Stewart, and Dr. Aggarwal have disclosed no relevant financial relationship. Dr. Trinh has received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical.

A version of this article first appeared on Medscape.com.

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

A version of this article first appeared on Medscape.com.

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

A version of this article first appeared on Medscape.com.

Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.

“TNBC is incredibly heterogeneous, which makes it challenging to treat,” said Rita Nanda, MD, director of the breast oncology program and associate professor of medicine at the University of Chicago. “We have subsets of TNBC that don’t respond to currently available therapies and, as of yet, have no identifiable therapeutic targets.”

Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy – typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.

When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).

Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.

“For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential,” said Kelly McCann, MD, PhD, a hematologist/oncologist in the department of medicine at the University of California, Los Angeles. “Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets.”
 

A targeted strategy

The Food and Drug Administration’s approval of sacituzumab govitecan, the first antibody-drug conjugate to treat metastatic TNBC, marked an important addition to the TNBC drug armamentarium. “Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease,” Dr. Nanda said.

Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells.

In the phase 1/2 ASCENT trial, the median progression-free survival was 5.5 months and overall survival was 13.0 months in 108 patients with metastatic TNBC who had received at least two therapies prior to sacituzumab govitecan.

A subsequent phase 3 trial showed progression-free survival of 5.6 months with sacituzumab govitecan and 1.7 months with physician’s choice of chemotherapy. The median overall survival was 12.1 months and 6.7 months, respectively.

But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given sacituzumab govitecan, compared with chemotherapy alone.

In other words, “patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit,” Dr. Nanda said.

Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.

Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, “trastuzumab deruxtecan represents potential in treating HER2-low TNBC,” said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

Early results from a phase 1b study showed that trastuzumab deruxtecan produced a response rate of 37% in patients with HER2-low breast cancer.

Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
 

Immunotherapy advances

Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing PD-L1. Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.

Yet, data on which patients will benefit are not so clear-cut. “These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker,” Dr. Yuan said.

Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). As with the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs. 17.6 months with nab-paclitaxel alone.

However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs. 6 months, respectively, and overall survival was 28.3 months vs. 22.1 months.

“It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel,” Dr. Nanda said. “Perhaps the negative finding has to do with how the trial was conducted, or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit.”
 

Continued efforts to understand TNBC

Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.

On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received olaparib exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.

When considering signaling pathways, the PI3K/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3K and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival – 19.1 months vs. 12.6 with placebo plus paclitaxel – with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.

But there’s more to learn about treating metastatic TNBC. “Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go,” said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York. “Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail.”

Dr. Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. “For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available,” she said.

A version of this article first appeared on Medscape.com.

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

A version of this article first appeared on Medscape.com.

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

A version of this article first appeared on Medscape.com.

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

A version of this article first appeared on Medscape.com.

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers (david.beck@nih.gov).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

jevans@mdedge.com

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers (david.beck@nih.gov).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

jevans@mdedge.com

Older men with a novel adult-onset, severe autoinflammatory syndrome known by the acronym VEXAS are likely hiding in plain sight in many adult rheumatology, hematology, and dermatology practices. New clinical features are being described to fill out the clinical profile of such patients who may be currently misdiagnosed with other conditions, according to researchers who first described the syndrome in the last quarter of 2020.

Courtesy Dr. Marcela Ferrada

VEXAS is often misdiagnosed as treatment-refractory relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, or giant cell arteritis. These seemingly unrelated disorders are actually tied together by a single thread recently unraveled by David B. Beck, MD, PhD, a clinical fellow at the National Human Genome Research Institute, and colleagues, including rheumatologist Marcela Ferrada, MD, and others at institutes of the National Institutes of Health, Bethesda, Md. The connection between these disparate clinical presentations lies in somatic mutations in UBA1, a gene that initiates cytoplasmic ubiquitylation, a process by which misfolded proteins are tagged for degradation. VEXAS appears primarily limited to men because the UBA1 gene lies on the X chromosome, although it may be possible for women to have it because of an acquired loss of X chromosome.

VEXAS is an acronym for:

• Vacuoles in bone marrow cells
• E-1 activating enzyme, which is what UBA1 encodes for
• X-linked
• Autoinflammatory
• Somatic mutation featuring hematologic mosaicism

Dr. Beck said that VEXAS is “probably affecting thousands of Americans,” but it is tough to say this early in the understanding of the disease. He estimated that the prevalence of VEXAS could be 1 per 20,000-30,000 individuals.
 

A new way of looking for disease

VEXAS has caused a major stir among geneticists because of the novel manner in which Dr. Beck and his coinvestigators made their discovery. Instead of starting out in the traditional path to discovery of a new genetic disease – that is, by looking for clinical similarities among patients with undiagnosed diseases and then conducting a search for a gene or genes that might explain the shared patient symptoms – the investigators took a genotype-first approach. They scanned the mapped genomic sequences of patients in the National Institutes of Health Undiagnosed Diseases Network, which led them to zero in on mutations in UBA1 as their top candidate.

“We targeted the ubiquitin-proteasome pathway, because it has been implicated in many autoinflammatory diseases – for example, HA20 [A20 haploinsufficiency] and CANDLE syndrome [Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature]. Many of these recurrent inflammatory diseases are caused by mutations within this pathway,” Dr. Beck said in an interview.

Next, they analyzed the genomes of patients in other NIH databases and patients from other study populations at the University College London and Leeds Teaching Hospitals NHS Trust in the United Kingdom in a search for UBA1 somatic mutations, eventually identifying 25 men with the shared features they called VEXAS. These 25 formed the basis for their initial report on the syndrome in the New England Journal of Medicine.

Most autoinflammatory diseases appear in childhood because they stem from germline mutations. VEXAS syndrome, because of somatic mutations with mosaicism, appears to manifest later in life: The median age of the initial 25-man cohort was 64 years, ranging from 45 to 80 years. It’s a severe disorder. By the time the investigators were preparing their paper for publication, 10 of the 25 patients, or 40%, had died.

“I think that somatic mutations may account for a significant percentage of severe. adult-onset rheumatologic diseases, and it may change the way we think about treating them based on having a genetic diagnosis,” Dr. Beck said.

“This approach could be expanded to look at other pathways we know are important in inflammation, or alternatively, it could be completely unbiased and look for any shared variation that occurs across undiagnosed patients with inflammatory diseases. I think that one thing that’s important about our study is that previously we had been looking for mutations that really in most cases were the same sort of germline mutations present in [pediatric] patients who have disease at early onset, but now we’re thinking about things differently. There may be a different type of genetics that drives adult-onset rheumatologic disease, and this would be somatic mutations which are not present in every cell of the body, just in the blood, and that’s why there’s just this blood-based disease.”
 

When to suspect VEXAS syndrome

Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.

Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.

Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center

Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers (david.beck@nih.gov).

In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.

Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.

Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.

First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.

Courtesy Dr. Marcela Ferrada

Myelodysplastic syndrome and hematologic abnormalities

While patients with both myelodysplastic syndrome and relapsing polychondritis have been known in the literature for many years, it’s not until now that researchers are seeing a connection between the two, Dr. Ferrada said.

A majority of the VEXAS patients in the NEJM study had a workup for myelodysplastic syndrome, but only 24% met criteria. However, many were within the spectrum of myelodysplastic disease and some did not meet criteria because their anemia was attributed to a rheumatologic diagnosis and they did not have a known genetic driver of myelodysplastic syndrome, Dr. Beck said. It also fits with this new evidence that UBA1 is probably a driver of myelodysplastic syndrome in and of itself, and that anemia and hematologic involvement are not secondary to the rheumatologic disease; they are linked to the same disease process.

Dr. Beck said that there may be a subset of patients who present with primarily hematologic manifestations, noting the NEJM study could have ascertainment bias because the researchers analyzed mainly patients presenting to their clinic with relapsing polychondritis and severe inflammation. NIH researchers also are still looking in their cohort for any association with hematologic malignancies that preceded clinical manifestations, he said.
 

More cases reported

As of early April, another 27 cases had been reported in the literature as more researchers have begun to look for patients with UBA1 mutations, some with additional presenting clinical features associated with VEXAS, including chronic progressive inflammatory arthritis, Kikuchi-Fujimoto disease, spondyloarthritis, and bacterial pneumonia.

“Many times with rare diseases, we can’t get enough patients to understand the full spectrum of the disease, but this disease seems to be far more common than we would have expected. We’re actually getting many referrals,” Dr. Beck said.

It appears so far that the range of somatic UBA1 mutations that have been discovered in VEXAS patients does make a difference in the severity of clinical presentation and could potentially be useful in prognosis, Dr. Beck said.

Right now, NIH researchers are asking patients about their natural clinical course, assessing disease activity, and determining which treatments get a response, with the ultimate goal of a treatment trial at the NIH.

Treatment

Developing better treatments for VEXAS syndrome is a priority. In the initial report on VEXAS, the researchers found that the only reliably effective therapy is high-dose corticosteroids. Dr. Ferrada said that NIH investigators have begun thinking about agents that target both the hematologic and inflammatory features of VEXAS. “Most patients get exposed to treatments that are targeted to decrease the inflammatory process, and some of these treatments help partially but not completely to decrease the amount of steroids that patients are taking. For example, one of the medications is tocilizumab. [It was used in] patients who had previous diagnosis of relapsing polychondritis, but they still had to take steroids and their hematologic manifestations keep progressing. We’re in the process of figuring out medications that may help in treating both.” Dr. Ferrada added that because the source of the mutation is in the bone marrow, transplantation may be an effective option.

Laboratory work to identify potential treatments for VEXAS in studies of model organisms could identify treatments outside of the classic anti-inflammatory agents, such as targeting certain cell types in the bone marrow or the ubiquitin-proteasome pathway, Dr. Beck said. “We think that however UBA1 works to initiate inflammation may be important not just in VEXAS but in other diseases. Rare diseases may be informing the mechanisms in common diseases.”

The VEXAS NEJM study was sponsored by the NIH Intramural Research Programs and by an EU Horizon 2020 Research and Innovation Program grant. Dr. Beck reported a patent pending on “Diagnosis and Treatment of VEXAS with Mosaic Missense Mutations in UBA1.”

jevans@mdedge.com

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

An endocrinologist in Naples, Fla., faces multiple federal charges after police found homemade explosives and bomb-making supplies, as well as numerous illegal drugs, in his home.

Police were executing a search warrant at the home of Christy Daniel Cugini, MD, 63, on March 30 when they found the items, according to Collier County Sheriff’s Office (CCSO).

“An investigation continues and more charges could be brought,” the sheriff’s office said in a statement. As of April 1, Dr. Cugini was out on bond. His next court appearance is on April 26.

A search of his bedroom turned up marijuana, tramadol, oxycodone, and hydrocodone, the sheriff’s office said. According to nbcmiami.com, police also found 560 grams of marijuana and $20,000 in cash and jewelry in a safe.

“Some of the narcotics were in pill bottles with other people’s names on them. Many of the substances were of trafficking quantities. The search also turned up numerous items of narcotic paraphernalia, including heat seal bags, a vacuum sealer, and a scale,” the CCSO report said.

Charges against Dr. Cugini include narcotics trafficking; possession of marijuana with intent to sell/manufacture/deliver; possession of more than 20 grams of marijuana; possession of a controlled substance; and possession of narcotic paraphernalia, according to the report.

He was also charged with nine counts of making/possessing a destructive device.

The CCSO bomb squad was brought in to investigate the homemade explosive devices and supplies, including potassium nitrate and ammonium nitrate – which can be used as oxidizers – PVC pipe, and flash powders used in fireworks in Dr. Cugini’s house and garage.

Newsweek reported that the bomb squad found six red cylindrical devices about 4 inches long, according to information reported in an affidavit from Collier County Officer Jeffrey Tayar. They may have been intended to be a hand-tossed improvised explosive device, Mr. Tayar wrote.

An officer also found three other devices made up of PVC pipe attached to a small wood square. A rifle round was inserted into the PVC pipe, Mr. Tayar’s report said.

“The device could be placed on the ground in such a manner as to leave the rifle round facing up,” Mr. Tayar reportedly wrote. “If downward pressure were applied on the tip of the round ... the rifle round [would] discharge, launching the projectile portion of the round upward, presumably into the foot of the subject stepping on it.”

NBC News reported that deputies said Dr. Cugini appeared to live only with his young daughter.

He initially agreed to speak with deputies but then invoked his Miranda rights and stopped answering questions, NBC said.

Dr. Cugini’s profile has been removed from the Millennium Physician Group website.

His employer offered this statement via spokesperson Liza Fernandez: “We are shocked at the allegations regarding Dr. Christy Cugini. He has been placed on administrative leave until further notice. Millennium is committed to cooperating with law enforcement and is conducting an internal investigation.”

According to U.S. News & World Report, Dr. Cugini is affiliated with NCH Baker Hospital. He received his medical degree from Ross University School of Medicine, now located in Barbados, and has been practicing for more than 20 years.

Attempts to contact Dr. Cugini were unsuccessful.

A version of this article first appeared on Medscape.com.

An endocrinologist in Naples, Fla., faces multiple federal charges after police found homemade explosives and bomb-making supplies, as well as numerous illegal drugs, in his home.

Police were executing a search warrant at the home of Christy Daniel Cugini, MD, 63, on March 30 when they found the items, according to Collier County Sheriff’s Office (CCSO).

“An investigation continues and more charges could be brought,” the sheriff’s office said in a statement. As of April 1, Dr. Cugini was out on bond. His next court appearance is on April 26.

A search of his bedroom turned up marijuana, tramadol, oxycodone, and hydrocodone, the sheriff’s office said. According to nbcmiami.com, police also found 560 grams of marijuana and $20,000 in cash and jewelry in a safe.

“Some of the narcotics were in pill bottles with other people’s names on them. Many of the substances were of trafficking quantities. The search also turned up numerous items of narcotic paraphernalia, including heat seal bags, a vacuum sealer, and a scale,” the CCSO report said.

Charges against Dr. Cugini include narcotics trafficking; possession of marijuana with intent to sell/manufacture/deliver; possession of more than 20 grams of marijuana; possession of a controlled substance; and possession of narcotic paraphernalia, according to the report.

He was also charged with nine counts of making/possessing a destructive device.

The CCSO bomb squad was brought in to investigate the homemade explosive devices and supplies, including potassium nitrate and ammonium nitrate – which can be used as oxidizers – PVC pipe, and flash powders used in fireworks in Dr. Cugini’s house and garage.

Newsweek reported that the bomb squad found six red cylindrical devices about 4 inches long, according to information reported in an affidavit from Collier County Officer Jeffrey Tayar. They may have been intended to be a hand-tossed improvised explosive device, Mr. Tayar wrote.

An officer also found three other devices made up of PVC pipe attached to a small wood square. A rifle round was inserted into the PVC pipe, Mr. Tayar’s report said.

“The device could be placed on the ground in such a manner as to leave the rifle round facing up,” Mr. Tayar reportedly wrote. “If downward pressure were applied on the tip of the round ... the rifle round [would] discharge, launching the projectile portion of the round upward, presumably into the foot of the subject stepping on it.”

NBC News reported that deputies said Dr. Cugini appeared to live only with his young daughter.

He initially agreed to speak with deputies but then invoked his Miranda rights and stopped answering questions, NBC said.

Dr. Cugini’s profile has been removed from the Millennium Physician Group website.

His employer offered this statement via spokesperson Liza Fernandez: “We are shocked at the allegations regarding Dr. Christy Cugini. He has been placed on administrative leave until further notice. Millennium is committed to cooperating with law enforcement and is conducting an internal investigation.”

According to U.S. News & World Report, Dr. Cugini is affiliated with NCH Baker Hospital. He received his medical degree from Ross University School of Medicine, now located in Barbados, and has been practicing for more than 20 years.

Attempts to contact Dr. Cugini were unsuccessful.

A version of this article first appeared on Medscape.com.

An endocrinologist in Naples, Fla., faces multiple federal charges after police found homemade explosives and bomb-making supplies, as well as numerous illegal drugs, in his home.

Police were executing a search warrant at the home of Christy Daniel Cugini, MD, 63, on March 30 when they found the items, according to Collier County Sheriff’s Office (CCSO).

“An investigation continues and more charges could be brought,” the sheriff’s office said in a statement. As of April 1, Dr. Cugini was out on bond. His next court appearance is on April 26.

A search of his bedroom turned up marijuana, tramadol, oxycodone, and hydrocodone, the sheriff’s office said. According to nbcmiami.com, police also found 560 grams of marijuana and $20,000 in cash and jewelry in a safe.

“Some of the narcotics were in pill bottles with other people’s names on them. Many of the substances were of trafficking quantities. The search also turned up numerous items of narcotic paraphernalia, including heat seal bags, a vacuum sealer, and a scale,” the CCSO report said.

Charges against Dr. Cugini include narcotics trafficking; possession of marijuana with intent to sell/manufacture/deliver; possession of more than 20 grams of marijuana; possession of a controlled substance; and possession of narcotic paraphernalia, according to the report.

He was also charged with nine counts of making/possessing a destructive device.

The CCSO bomb squad was brought in to investigate the homemade explosive devices and supplies, including potassium nitrate and ammonium nitrate – which can be used as oxidizers – PVC pipe, and flash powders used in fireworks in Dr. Cugini’s house and garage.

Newsweek reported that the bomb squad found six red cylindrical devices about 4 inches long, according to information reported in an affidavit from Collier County Officer Jeffrey Tayar. They may have been intended to be a hand-tossed improvised explosive device, Mr. Tayar wrote.

An officer also found three other devices made up of PVC pipe attached to a small wood square. A rifle round was inserted into the PVC pipe, Mr. Tayar’s report said.

“The device could be placed on the ground in such a manner as to leave the rifle round facing up,” Mr. Tayar reportedly wrote. “If downward pressure were applied on the tip of the round ... the rifle round [would] discharge, launching the projectile portion of the round upward, presumably into the foot of the subject stepping on it.”

NBC News reported that deputies said Dr. Cugini appeared to live only with his young daughter.

He initially agreed to speak with deputies but then invoked his Miranda rights and stopped answering questions, NBC said.

Dr. Cugini’s profile has been removed from the Millennium Physician Group website.

His employer offered this statement via spokesperson Liza Fernandez: “We are shocked at the allegations regarding Dr. Christy Cugini. He has been placed on administrative leave until further notice. Millennium is committed to cooperating with law enforcement and is conducting an internal investigation.”

According to U.S. News & World Report, Dr. Cugini is affiliated with NCH Baker Hospital. He received his medical degree from Ross University School of Medicine, now located in Barbados, and has been practicing for more than 20 years.

Attempts to contact Dr. Cugini were unsuccessful.

A version of this article first appeared on Medscape.com.

New cases of COVID-19 in children in the United States fell slightly, but even that small dip was enough to reverse 2 straight weeks of increases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

New cases totaled 63,862 for the latest reporting week, March 26 to April 1, compared with 64,029 for the previous week, the AAP and the CHA said in their weekly COVID-19 report. For the week ending April 1, children represented 18.1% of all new cases reported in the United States, down from a pandemic-high 19.1% the week before.

COVID-19 cases in children now total just under 3.47 million, which works out to 13.4% of reported cases for all ages and 4,610 cases per 100,000 children since the beginning of the pandemic, the AAP and the CHA said based on data from 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

Among those jurisdictions, Vermont has the highest proportion of its cases occurring in children at 21.0%, and North Dakota has the highest cumulative rate at 8,958 cases per 100,000 children. Looking at those states from the bottoms of their respective lists are Florida, where children aged 0-14 years represent 8.4% of all cases, and Hawaii, with 1,133 cases per 100,000 children aged 0-17 years, the AAP/CHA report shows.

The data on more serious illness show that Minnesota has the highest proportion of hospitalizations occurring in children at 3.1%, while New York City has the highest hospitalization rate among infected children, 2.0%. Among the other 23 states reporting on such admissions, children make up only 1.3% of hospitalizations in Florida and in New Hampshire, which also has the lowest hospitalization rate at 0.1%, the AAP and CHA said.

Five more deaths were reported in children during the week ending April 1, bringing the total to 284 in the 43 states, along with New York City, Puerto Rico, and Guam, that are sharing age-distribution data on mortality.

rfranki@mdedge.com

New cases of COVID-19 in children in the United States fell slightly, but even that small dip was enough to reverse 2 straight weeks of increases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

New cases totaled 63,862 for the latest reporting week, March 26 to April 1, compared with 64,029 for the previous week, the AAP and the CHA said in their weekly COVID-19 report. For the week ending April 1, children represented 18.1% of all new cases reported in the United States, down from a pandemic-high 19.1% the week before.

COVID-19 cases in children now total just under 3.47 million, which works out to 13.4% of reported cases for all ages and 4,610 cases per 100,000 children since the beginning of the pandemic, the AAP and the CHA said based on data from 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

Among those jurisdictions, Vermont has the highest proportion of its cases occurring in children at 21.0%, and North Dakota has the highest cumulative rate at 8,958 cases per 100,000 children. Looking at those states from the bottoms of their respective lists are Florida, where children aged 0-14 years represent 8.4% of all cases, and Hawaii, with 1,133 cases per 100,000 children aged 0-17 years, the AAP/CHA report shows.

The data on more serious illness show that Minnesota has the highest proportion of hospitalizations occurring in children at 3.1%, while New York City has the highest hospitalization rate among infected children, 2.0%. Among the other 23 states reporting on such admissions, children make up only 1.3% of hospitalizations in Florida and in New Hampshire, which also has the lowest hospitalization rate at 0.1%, the AAP and CHA said.

Five more deaths were reported in children during the week ending April 1, bringing the total to 284 in the 43 states, along with New York City, Puerto Rico, and Guam, that are sharing age-distribution data on mortality.

rfranki@mdedge.com

New cases of COVID-19 in children in the United States fell slightly, but even that small dip was enough to reverse 2 straight weeks of increases, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

New cases totaled 63,862 for the latest reporting week, March 26 to April 1, compared with 64,029 for the previous week, the AAP and the CHA said in their weekly COVID-19 report. For the week ending April 1, children represented 18.1% of all new cases reported in the United States, down from a pandemic-high 19.1% the week before.

COVID-19 cases in children now total just under 3.47 million, which works out to 13.4% of reported cases for all ages and 4,610 cases per 100,000 children since the beginning of the pandemic, the AAP and the CHA said based on data from 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

Among those jurisdictions, Vermont has the highest proportion of its cases occurring in children at 21.0%, and North Dakota has the highest cumulative rate at 8,958 cases per 100,000 children. Looking at those states from the bottoms of their respective lists are Florida, where children aged 0-14 years represent 8.4% of all cases, and Hawaii, with 1,133 cases per 100,000 children aged 0-17 years, the AAP/CHA report shows.

The data on more serious illness show that Minnesota has the highest proportion of hospitalizations occurring in children at 3.1%, while New York City has the highest hospitalization rate among infected children, 2.0%. Among the other 23 states reporting on such admissions, children make up only 1.3% of hospitalizations in Florida and in New Hampshire, which also has the lowest hospitalization rate at 0.1%, the AAP and CHA said.

Five more deaths were reported in children during the week ending April 1, bringing the total to 284 in the 43 states, along with New York City, Puerto Rico, and Guam, that are sharing age-distribution data on mortality.

rfranki@mdedge.com

In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.

eskymaks/iStock/Getty Images

Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.

Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.

Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.

Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.

To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
 

Global legal status

In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.

In the United States, classic psychedelics remain schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.

France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.

In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.

Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.

“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.

Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.

Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.

However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
 

Potential indications

Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.

In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.

In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.

In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.

Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.

Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
 

Environment is key

Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.

Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.

Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”

For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.

“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.

Dr. Gründer agreed.

“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.

Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.

“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
 

Risks, abuse potential

The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.

It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”

Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.

“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”

Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.

“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”

Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.

Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.

Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.

Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.

“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
 

Psychologically challenging

The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.

Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.

For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.

Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.

The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.

Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
 

Patient education

Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.

Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.

Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.

There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.

Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
 

Working out treatment protocols

Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.

Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.

In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.

For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.

With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.

The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.

“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.

Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.

“Most get better,” he said, “but the majority of depression comes back over a period of months.”

Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.

“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”

All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.

“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”

A version of this article first appeared on Medscape.com.

In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.

eskymaks/iStock/Getty Images

Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.

Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.

Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.

Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.

To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
 

Global legal status

In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.

In the United States, classic psychedelics remain schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.

France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.

In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.

Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.

“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.

Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.

Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.

However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
 

Potential indications

Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.

In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.

In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.

In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.

Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.

Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
 

Environment is key

Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.

Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.

Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”

For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.

“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.

Dr. Gründer agreed.

“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.

Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.

“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
 

Risks, abuse potential

The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.

It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”

Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.

“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”

Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.

“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”

Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.

Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.

Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.

Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.

“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
 

Psychologically challenging

The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.

Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.

For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.

Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.

The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.

Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
 

Patient education

Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.

Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.

Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.

There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.

Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
 

Working out treatment protocols

Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.

Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.

In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.

For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.

With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.

The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.

“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.

Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.

“Most get better,” he said, “but the majority of depression comes back over a period of months.”

Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.

“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”

All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.

“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”

A version of this article first appeared on Medscape.com.

In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.

eskymaks/iStock/Getty Images

Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.

Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.

Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.

Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.

To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
 

Global legal status

In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.

In the United States, classic psychedelics remain schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.

France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.

In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.

Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.

“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.

Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.

Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.

However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
 

Potential indications

Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.

In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.

In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.

In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.

Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.

Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
 

Environment is key

Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.

Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.

Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”

For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.

“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.

Dr. Gründer agreed.

“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.

Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.

“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
 

Risks, abuse potential

The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.

It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”

Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.

“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”

Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.

“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”

Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.

Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.

Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.

Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.

“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
 

Psychologically challenging

The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.

Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.

For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.

Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.

The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.

Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
 

Patient education

Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.

Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.

Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.

There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.

Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
 

Working out treatment protocols

Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.

Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.

In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.

For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.

With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.

The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.

“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.

Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.

“Most get better,” he said, “but the majority of depression comes back over a period of months.”

Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.

“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”

All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.

“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”

A version of this article first appeared on Medscape.com.

More than 10 years after the withdrawal of the weight-loss drug Mediator (benfluorex) from the market in France, the Paris Court issued its judgment on March 29, 2021, against Servier Laboratories and the French National Agency for the Safety of Medicines and Health Products (ANSM).

Servier Laboratories was convicted of “aggravated deception” and fined 2.7 million euros (approximately $3.2 million) but were found not guilty of fraud. ANSM will also have to pay a fine.

Mediator was brought to the market in 1976 for the treatment of hyperlipidemia and for overweight patients with type 2 diabetes but was used off label as an appetite suppressant. It was taken by 5 million people and was only removed from the market in France in 2009 because of its toxic effects.

Mediator was taken off the market in Spain 6 years earlier, and in Switzerland 12 years earlier, and more than 30 years before in Belgium. It was never marketed in the United States.

The number of deaths because of heart valve damage related to the drug in France has been estimated at 220-300 in the short term (2.5 years) and 1,300-1,800 in the long term. In addition, the drug has been responsible for 3,100-4,200 hospital admissions for valvular insufficiency and pulmonary arterial hypertension.

“Despite knowing the risks for very many years ... [Servier Laboratories] never took the necessary measures and thus deceived” consumers of Mediator, declared the president of the criminal court, Sylvie Daunois.

Servier has “weakened confidence in the health system,” she added.

“I am very happy that ‘aggravated deception,’ the heart of the case, has been recognized and condemned,” Irène Frachon, MD, a pulmonologist at Brest (France) University Hospital and whistleblower on the Mediator scandal, said in an interview.

However, Dr. Frachon continued: “The major problem, putting a toxic agent on the market for years, is a given. But the weakness of the sentences gives a mixed message.

“The judgment is too cautious in its punishments,” she added, pointing out that, “in the case of contaminated blood, there were prison sentences.”
 

Servier deceived doctors and patients

The French trial in September 2019 was extraordinary, with about 100 witnesses, nearly 400 lawyers, and 5,000 victims.

On June 23, 2020, the prosecutor, Aude Le Guilcher, requested at the end of her indictment that the six companies of the Servier group be fined, notably for “deception, homicide, involuntary injuries, and fraud,” to the tune of 20.3 million euros (approximately $23.8 million).

Against the former No. 2 of Servier, Jean-Philippe Seta, Ms. Le Guilcher requested 5 years in prison, with 2 years suspended, and a 200,000 euro (approximately $235,000) fine.

The same sum was requested against ANSM for homicide and unintentional injuries.

In the end, Mr. Seta, the former right hand of Jacques Servier, who died in 2004, was sentenced to 4 years in prison, suspended. For their part, ANSM was fined 303,000 euros(approximately $350,000).

It is now clearly established that Servier Laboratories knowingly concealed the similarity of Mediator to the fenfluramine family of compounds, which was banned in 1990 because of adverse effects.

The group also deceived doctors who prescribed the drug and patients who took it by hiding its toxicity.
 

Mediator should never have been authorized for use

In terms of the fraud charges, the prosecutor estimated that the losses incurred by the primary health insurance industry were in the region of several hundred million euros.

She argued that Mediator should never have been reimbursed, as “it should never have benefited from market authorization, which it received solely due to the fraudulent actions of the company.”

But because of the statute of limitations, this argument was not heard, explained Dr. Frachon, “and the same is true of conflicts of interest, where limitations led to them being discharged.

“We understand the legal difficulties, but it’s a shame in terms of the signal sent.”

“I hope the medical world will learn the lesson and not continue with ‘business as usual’ with people who are delinquents. I think it will be essential to restore public confidence,” concluded Dr. Frachon.

No conflicts of interest or funding were declared.

A version of this article first appeared on Medscape.com.

More than 10 years after the withdrawal of the weight-loss drug Mediator (benfluorex) from the market in France, the Paris Court issued its judgment on March 29, 2021, against Servier Laboratories and the French National Agency for the Safety of Medicines and Health Products (ANSM).

Servier Laboratories was convicted of “aggravated deception” and fined 2.7 million euros (approximately $3.2 million) but were found not guilty of fraud. ANSM will also have to pay a fine.

Mediator was brought to the market in 1976 for the treatment of hyperlipidemia and for overweight patients with type 2 diabetes but was used off label as an appetite suppressant. It was taken by 5 million people and was only removed from the market in France in 2009 because of its toxic effects.

Mediator was taken off the market in Spain 6 years earlier, and in Switzerland 12 years earlier, and more than 30 years before in Belgium. It was never marketed in the United States.

The number of deaths because of heart valve damage related to the drug in France has been estimated at 220-300 in the short term (2.5 years) and 1,300-1,800 in the long term. In addition, the drug has been responsible for 3,100-4,200 hospital admissions for valvular insufficiency and pulmonary arterial hypertension.

“Despite knowing the risks for very many years ... [Servier Laboratories] never took the necessary measures and thus deceived” consumers of Mediator, declared the president of the criminal court, Sylvie Daunois.

Servier has “weakened confidence in the health system,” she added.

“I am very happy that ‘aggravated deception,’ the heart of the case, has been recognized and condemned,” Irène Frachon, MD, a pulmonologist at Brest (France) University Hospital and whistleblower on the Mediator scandal, said in an interview.

However, Dr. Frachon continued: “The major problem, putting a toxic agent on the market for years, is a given. But the weakness of the sentences gives a mixed message.

“The judgment is too cautious in its punishments,” she added, pointing out that, “in the case of contaminated blood, there were prison sentences.”
 

Servier deceived doctors and patients

The French trial in September 2019 was extraordinary, with about 100 witnesses, nearly 400 lawyers, and 5,000 victims.

On June 23, 2020, the prosecutor, Aude Le Guilcher, requested at the end of her indictment that the six companies of the Servier group be fined, notably for “deception, homicide, involuntary injuries, and fraud,” to the tune of 20.3 million euros (approximately $23.8 million).

Against the former No. 2 of Servier, Jean-Philippe Seta, Ms. Le Guilcher requested 5 years in prison, with 2 years suspended, and a 200,000 euro (approximately $235,000) fine.

The same sum was requested against ANSM for homicide and unintentional injuries.

In the end, Mr. Seta, the former right hand of Jacques Servier, who died in 2004, was sentenced to 4 years in prison, suspended. For their part, ANSM was fined 303,000 euros(approximately $350,000).

It is now clearly established that Servier Laboratories knowingly concealed the similarity of Mediator to the fenfluramine family of compounds, which was banned in 1990 because of adverse effects.

The group also deceived doctors who prescribed the drug and patients who took it by hiding its toxicity.
 

Mediator should never have been authorized for use

In terms of the fraud charges, the prosecutor estimated that the losses incurred by the primary health insurance industry were in the region of several hundred million euros.

She argued that Mediator should never have been reimbursed, as “it should never have benefited from market authorization, which it received solely due to the fraudulent actions of the company.”

But because of the statute of limitations, this argument was not heard, explained Dr. Frachon, “and the same is true of conflicts of interest, where limitations led to them being discharged.

“We understand the legal difficulties, but it’s a shame in terms of the signal sent.”

“I hope the medical world will learn the lesson and not continue with ‘business as usual’ with people who are delinquents. I think it will be essential to restore public confidence,” concluded Dr. Frachon.

No conflicts of interest or funding were declared.

A version of this article first appeared on Medscape.com.

More than 10 years after the withdrawal of the weight-loss drug Mediator (benfluorex) from the market in France, the Paris Court issued its judgment on March 29, 2021, against Servier Laboratories and the French National Agency for the Safety of Medicines and Health Products (ANSM).

Servier Laboratories was convicted of “aggravated deception” and fined 2.7 million euros (approximately $3.2 million) but were found not guilty of fraud. ANSM will also have to pay a fine.

Mediator was brought to the market in 1976 for the treatment of hyperlipidemia and for overweight patients with type 2 diabetes but was used off label as an appetite suppressant. It was taken by 5 million people and was only removed from the market in France in 2009 because of its toxic effects.

Mediator was taken off the market in Spain 6 years earlier, and in Switzerland 12 years earlier, and more than 30 years before in Belgium. It was never marketed in the United States.

The number of deaths because of heart valve damage related to the drug in France has been estimated at 220-300 in the short term (2.5 years) and 1,300-1,800 in the long term. In addition, the drug has been responsible for 3,100-4,200 hospital admissions for valvular insufficiency and pulmonary arterial hypertension.

“Despite knowing the risks for very many years ... [Servier Laboratories] never took the necessary measures and thus deceived” consumers of Mediator, declared the president of the criminal court, Sylvie Daunois.

Servier has “weakened confidence in the health system,” she added.

“I am very happy that ‘aggravated deception,’ the heart of the case, has been recognized and condemned,” Irène Frachon, MD, a pulmonologist at Brest (France) University Hospital and whistleblower on the Mediator scandal, said in an interview.

However, Dr. Frachon continued: “The major problem, putting a toxic agent on the market for years, is a given. But the weakness of the sentences gives a mixed message.

“The judgment is too cautious in its punishments,” she added, pointing out that, “in the case of contaminated blood, there were prison sentences.”
 

Servier deceived doctors and patients

The French trial in September 2019 was extraordinary, with about 100 witnesses, nearly 400 lawyers, and 5,000 victims.

On June 23, 2020, the prosecutor, Aude Le Guilcher, requested at the end of her indictment that the six companies of the Servier group be fined, notably for “deception, homicide, involuntary injuries, and fraud,” to the tune of 20.3 million euros (approximately $23.8 million).

Against the former No. 2 of Servier, Jean-Philippe Seta, Ms. Le Guilcher requested 5 years in prison, with 2 years suspended, and a 200,000 euro (approximately $235,000) fine.

The same sum was requested against ANSM for homicide and unintentional injuries.

In the end, Mr. Seta, the former right hand of Jacques Servier, who died in 2004, was sentenced to 4 years in prison, suspended. For their part, ANSM was fined 303,000 euros(approximately $350,000).

It is now clearly established that Servier Laboratories knowingly concealed the similarity of Mediator to the fenfluramine family of compounds, which was banned in 1990 because of adverse effects.

The group also deceived doctors who prescribed the drug and patients who took it by hiding its toxicity.
 

Mediator should never have been authorized for use

In terms of the fraud charges, the prosecutor estimated that the losses incurred by the primary health insurance industry were in the region of several hundred million euros.

She argued that Mediator should never have been reimbursed, as “it should never have benefited from market authorization, which it received solely due to the fraudulent actions of the company.”

But because of the statute of limitations, this argument was not heard, explained Dr. Frachon, “and the same is true of conflicts of interest, where limitations led to them being discharged.

“We understand the legal difficulties, but it’s a shame in terms of the signal sent.”

“I hope the medical world will learn the lesson and not continue with ‘business as usual’ with people who are delinquents. I think it will be essential to restore public confidence,” concluded Dr. Frachon.

No conflicts of interest or funding were declared.

A version of this article first appeared on Medscape.com.

News of actor/comedian Pete Davidson expressing relief after finally receiving a diagnosis of borderline personality disorder (BPD) prompted a recent Twitter discussion among physicians regarding the ongoing debate on whether or not to tell a patient he or she has this diagnosis.

“I’ve heard from [many] trainees that they were told never to tell a patient they had BPD, but I can hardly think of anything more paternalistic and stigmatizing,” Amy Barnhorst, MD, vice chair of community psychiatry at University of California, Davis, tweeted.

“Most patients, when I explain it to them, have this kind of reaction – they feel relieved and understood,” she added.

“I was told that as well [not to tell] in one of my practicum placements,” one respondent who identified herself as a clinical/forensic psychologist tweeted back. “I said it anyway and the person was relieved there was a name for what they were living with.”

However, others disagreed with Dr. Barnhorst, noting that BPD is a very serious, stigmatizing, and challenging disorder to treat and, because of this, may cause patients to lose hope.

Still, Dr. Barnhorst stands by her position. Although “there is a negative stigma against a diagnosis of BPD,” that idea more often comes from the clinician instead of the patient, she said.

“I’ve never had a patient say, ‘how dare you call me that!’ like it was an insult,” she said in an interview. Not disclosing a diagnosis “is like you’re not trusting a patient to be a reasonable adult human about this.”
 

‘Hard diagnosis’

Although BPD is a “hard diagnosis, we would never withhold a diagnosis of cancer or liver disease or something else we knew patients didn’t want but that we were going to try and treat them for,” said Dr. Barnhorst.

BPD is linked to significant morbidity because of its common association with comorbid conditions, such as major depressive disorder, substance use disorders, and dysthymia. A history of self-harm is present in 70%-75% of these patients and some estimates suggest up to 9% of individuals with BPD die by suicide.

In an article published in Innovations in Clinical Neuroscience investigators discussed “ethical and clinical questions psychiatrists should consider” when treating BPD, including whether a diagnosis should be shared with a patient.

After such a diagnosis a patient may “react intensely in negative ways and these responses may be easily triggered,” the researchers wrote.

“A propensity that will likely cause psychiatrists anguish, however, is BPD patients’ increased likelihood of attempting suicide,” they added. Part of the problem has been that, in the past, it was thought that a BPD prognosis was untreatable. However, the researchers note that is no longer the case.

Still, Kaz Nelson, MD, associate professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis, has labeled BPD a so-called “asterisk” disorder.  

As she wrote in a recent blog, “We tell patients when they meet criteria for a medical diagnosis.* We show compassion and nonjudgmentalism to patients.* We do not discriminate against patients.*” However, the asterisk for each of these statements is: *Except for those with BPD.
 

Ongoing debate

Starting around the 1980s, the DSM listed personality disorders under the No. 2 Axis, which is for conditions with symptoms that are “not mitigatable,” said Dr. Nelson.

“It really started as well-meaning therapists who care about their patients who wanted to develop some precision in understanding people, and them starting to notice some patterns that can get in the way of optimal function,” she said in an interview.

The thought was not to disclose these diagnoses “because that was for you to understand, and for the patient to discover these patterns over time in the course of your work together,” Dr. Nelson added.

Although treatment for BPD used to be virtually nonexistent, there is now hope – especially with dialectic-behavior therapy (DBT), which uses mindfulness to teach patients how to control emotions and improve relationships.

According to the National Education Alliance for BPD, other useful treatments include mentalization-based therapy, transference-focused therapy, and “good psychiatric management.” Although there are currently no approved medications for BPD, some drugs are used to treat comorbid conditions such as depression or anxiety.

“We now know that people recover, and the whole paradigm has been turned on its head,” Dr. Nelson said. For example, “we no longer categorize these things as treatable or untreatable, which was a very positive move.”

So why is the field still debating the issue of diagnosis disclosure?

“To this day there are different psychiatrists and some medical school curricula that continue to teach that personality disorders are long-term, fixed, and nontreatable – and that it’s kind of disparaging to give this kind of diagnosis to a patient,” Dr. Nelson said.

Dr. Nelson, also the vice chair for education at the University of Minnesota, Minneapolis, medical school, reported that there “we acknowledge BPD’s painful history and that there are these misconceptions. They’re going to be on the front line of combating discrimination and the idea that if you see a patient with possible BPD coming you should run. That’s just unacceptable.”

Dr. Nelson noted that the idea of disclosing a BPD diagnosis is less controversial now than in the past, but “the whole thing is still under debate, and treatment guidelines [on BPD] are old and expired.”

Criteria for BPD were not updated when the DSM-5 was published in 2013, and that needs to be fixed, Dr. Nelson added. “In the meantime, we’re trying to get the word out that it’s okay to interact with people about the diagnosis, discuss treatment plans, and manage it as one would with any other psychiatric or medical illness.”
 

An evolution, not a debate

Paul Appelbaum, MD, past president of the American Psychiatric Association and current chair of the organization’s DSM steering committee, said in an interview that he hasn’t been involved in any recent debate on this issue.

“I think practice has changed to the point where the general practice is to discuss patient diagnoses with [patients] openly. Patients appreciate that and psychiatrists have come to see the advantages of it,” said Dr. Appelbaum, a professor of psychiatry, medicine, and law at Columbia University, New York.

Dr. Appelbaum noted that patients also increasingly have access to their medical records, “so the reality is that it’s no longer possible in many cases to withhold a diagnosis.”

“I don’t think it’s a debate; I think it’s been an evolution,” he said. “Maybe not everyone is entirely on board yet but there has been a sea change in psychiatric practices.”

Asked whether there needs to be some type of guideline update or statement released by the APA regarding BPD, Dr. Appelbaum said he doesn’t think the overall issue is BPD specific but applies to all psychiatric diagnoses.

“To the extent that there are still practitioners today that are telling students or residents [not to disclose], I would guess that they were trained a very long time ago and have not adapted to the new world,” he said.

“I don’t want to speak for the APA, but speaking for myself: I certainly encourage residents that I teach to be open about a diagnosis. It’s not just clinically helpful in some cases, it’s also ethically required from the perspective of allowing patients to make appropriate decisions about their treatment. And arguably it’s legally required as well, as part of the informed consent requirement,” Dr. Appelbaum said.

Regarding DSM updates, he noted that the committee “looks to the field to propose to us additions or changes to the DSM that are warranted by data that have been gathered since the DSM-5 came out.” There is a process set up on the DSM’s website to review such proposals.

In addition, Dr. Appelbaum said that there have been discussions about using a new model “that focuses on dimensions rather than on discreet categories” in order to classify personality disorders.

“There’s a group out there that is formulating a proposal that they will submit to us” on this, he added. “That’s the major discussion that is going on right now and it would clearly have implications for borderline as well as all the other personality disorders.”

In a statement, the APA said practice guidelines for BPD are currently under review and that the organization does not have a “position statement” on BPD for clinicians. The last update to its guideline was in the early 2000s.

A version of this article first appeared on Medscape.com.

News of actor/comedian Pete Davidson expressing relief after finally receiving a diagnosis of borderline personality disorder (BPD) prompted a recent Twitter discussion among physicians regarding the ongoing debate on whether or not to tell a patient he or she has this diagnosis.

“I’ve heard from [many] trainees that they were told never to tell a patient they had BPD, but I can hardly think of anything more paternalistic and stigmatizing,” Amy Barnhorst, MD, vice chair of community psychiatry at University of California, Davis, tweeted.

“Most patients, when I explain it to them, have this kind of reaction – they feel relieved and understood,” she added.

“I was told that as well [not to tell] in one of my practicum placements,” one respondent who identified herself as a clinical/forensic psychologist tweeted back. “I said it anyway and the person was relieved there was a name for what they were living with.”

However, others disagreed with Dr. Barnhorst, noting that BPD is a very serious, stigmatizing, and challenging disorder to treat and, because of this, may cause patients to lose hope.

Still, Dr. Barnhorst stands by her position. Although “there is a negative stigma against a diagnosis of BPD,” that idea more often comes from the clinician instead of the patient, she said.

“I’ve never had a patient say, ‘how dare you call me that!’ like it was an insult,” she said in an interview. Not disclosing a diagnosis “is like you’re not trusting a patient to be a reasonable adult human about this.”
 

‘Hard diagnosis’

Although BPD is a “hard diagnosis, we would never withhold a diagnosis of cancer or liver disease or something else we knew patients didn’t want but that we were going to try and treat them for,” said Dr. Barnhorst.

BPD is linked to significant morbidity because of its common association with comorbid conditions, such as major depressive disorder, substance use disorders, and dysthymia. A history of self-harm is present in 70%-75% of these patients and some estimates suggest up to 9% of individuals with BPD die by suicide.

In an article published in Innovations in Clinical Neuroscience investigators discussed “ethical and clinical questions psychiatrists should consider” when treating BPD, including whether a diagnosis should be shared with a patient.

After such a diagnosis a patient may “react intensely in negative ways and these responses may be easily triggered,” the researchers wrote.

“A propensity that will likely cause psychiatrists anguish, however, is BPD patients’ increased likelihood of attempting suicide,” they added. Part of the problem has been that, in the past, it was thought that a BPD prognosis was untreatable. However, the researchers note that is no longer the case.

Still, Kaz Nelson, MD, associate professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis, has labeled BPD a so-called “asterisk” disorder.  

As she wrote in a recent blog, “We tell patients when they meet criteria for a medical diagnosis.* We show compassion and nonjudgmentalism to patients.* We do not discriminate against patients.*” However, the asterisk for each of these statements is: *Except for those with BPD.
 

Ongoing debate

Starting around the 1980s, the DSM listed personality disorders under the No. 2 Axis, which is for conditions with symptoms that are “not mitigatable,” said Dr. Nelson.

“It really started as well-meaning therapists who care about their patients who wanted to develop some precision in understanding people, and them starting to notice some patterns that can get in the way of optimal function,” she said in an interview.

The thought was not to disclose these diagnoses “because that was for you to understand, and for the patient to discover these patterns over time in the course of your work together,” Dr. Nelson added.

Although treatment for BPD used to be virtually nonexistent, there is now hope – especially with dialectic-behavior therapy (DBT), which uses mindfulness to teach patients how to control emotions and improve relationships.

According to the National Education Alliance for BPD, other useful treatments include mentalization-based therapy, transference-focused therapy, and “good psychiatric management.” Although there are currently no approved medications for BPD, some drugs are used to treat comorbid conditions such as depression or anxiety.

“We now know that people recover, and the whole paradigm has been turned on its head,” Dr. Nelson said. For example, “we no longer categorize these things as treatable or untreatable, which was a very positive move.”

So why is the field still debating the issue of diagnosis disclosure?

“To this day there are different psychiatrists and some medical school curricula that continue to teach that personality disorders are long-term, fixed, and nontreatable – and that it’s kind of disparaging to give this kind of diagnosis to a patient,” Dr. Nelson said.

Dr. Nelson, also the vice chair for education at the University of Minnesota, Minneapolis, medical school, reported that there “we acknowledge BPD’s painful history and that there are these misconceptions. They’re going to be on the front line of combating discrimination and the idea that if you see a patient with possible BPD coming you should run. That’s just unacceptable.”

Dr. Nelson noted that the idea of disclosing a BPD diagnosis is less controversial now than in the past, but “the whole thing is still under debate, and treatment guidelines [on BPD] are old and expired.”

Criteria for BPD were not updated when the DSM-5 was published in 2013, and that needs to be fixed, Dr. Nelson added. “In the meantime, we’re trying to get the word out that it’s okay to interact with people about the diagnosis, discuss treatment plans, and manage it as one would with any other psychiatric or medical illness.”
 

An evolution, not a debate

Paul Appelbaum, MD, past president of the American Psychiatric Association and current chair of the organization’s DSM steering committee, said in an interview that he hasn’t been involved in any recent debate on this issue.

“I think practice has changed to the point where the general practice is to discuss patient diagnoses with [patients] openly. Patients appreciate that and psychiatrists have come to see the advantages of it,” said Dr. Appelbaum, a professor of psychiatry, medicine, and law at Columbia University, New York.

Dr. Appelbaum noted that patients also increasingly have access to their medical records, “so the reality is that it’s no longer possible in many cases to withhold a diagnosis.”

“I don’t think it’s a debate; I think it’s been an evolution,” he said. “Maybe not everyone is entirely on board yet but there has been a sea change in psychiatric practices.”

Asked whether there needs to be some type of guideline update or statement released by the APA regarding BPD, Dr. Appelbaum said he doesn’t think the overall issue is BPD specific but applies to all psychiatric diagnoses.

“To the extent that there are still practitioners today that are telling students or residents [not to disclose], I would guess that they were trained a very long time ago and have not adapted to the new world,” he said.

“I don’t want to speak for the APA, but speaking for myself: I certainly encourage residents that I teach to be open about a diagnosis. It’s not just clinically helpful in some cases, it’s also ethically required from the perspective of allowing patients to make appropriate decisions about their treatment. And arguably it’s legally required as well, as part of the informed consent requirement,” Dr. Appelbaum said.

Regarding DSM updates, he noted that the committee “looks to the field to propose to us additions or changes to the DSM that are warranted by data that have been gathered since the DSM-5 came out.” There is a process set up on the DSM’s website to review such proposals.

In addition, Dr. Appelbaum said that there have been discussions about using a new model “that focuses on dimensions rather than on discreet categories” in order to classify personality disorders.

“There’s a group out there that is formulating a proposal that they will submit to us” on this, he added. “That’s the major discussion that is going on right now and it would clearly have implications for borderline as well as all the other personality disorders.”

In a statement, the APA said practice guidelines for BPD are currently under review and that the organization does not have a “position statement” on BPD for clinicians. The last update to its guideline was in the early 2000s.

A version of this article first appeared on Medscape.com.

News of actor/comedian Pete Davidson expressing relief after finally receiving a diagnosis of borderline personality disorder (BPD) prompted a recent Twitter discussion among physicians regarding the ongoing debate on whether or not to tell a patient he or she has this diagnosis.

“I’ve heard from [many] trainees that they were told never to tell a patient they had BPD, but I can hardly think of anything more paternalistic and stigmatizing,” Amy Barnhorst, MD, vice chair of community psychiatry at University of California, Davis, tweeted.

“Most patients, when I explain it to them, have this kind of reaction – they feel relieved and understood,” she added.

“I was told that as well [not to tell] in one of my practicum placements,” one respondent who identified herself as a clinical/forensic psychologist tweeted back. “I said it anyway and the person was relieved there was a name for what they were living with.”

However, others disagreed with Dr. Barnhorst, noting that BPD is a very serious, stigmatizing, and challenging disorder to treat and, because of this, may cause patients to lose hope.

Still, Dr. Barnhorst stands by her position. Although “there is a negative stigma against a diagnosis of BPD,” that idea more often comes from the clinician instead of the patient, she said.

“I’ve never had a patient say, ‘how dare you call me that!’ like it was an insult,” she said in an interview. Not disclosing a diagnosis “is like you’re not trusting a patient to be a reasonable adult human about this.”
 

‘Hard diagnosis’

Although BPD is a “hard diagnosis, we would never withhold a diagnosis of cancer or liver disease or something else we knew patients didn’t want but that we were going to try and treat them for,” said Dr. Barnhorst.

BPD is linked to significant morbidity because of its common association with comorbid conditions, such as major depressive disorder, substance use disorders, and dysthymia. A history of self-harm is present in 70%-75% of these patients and some estimates suggest up to 9% of individuals with BPD die by suicide.

In an article published in Innovations in Clinical Neuroscience investigators discussed “ethical and clinical questions psychiatrists should consider” when treating BPD, including whether a diagnosis should be shared with a patient.

After such a diagnosis a patient may “react intensely in negative ways and these responses may be easily triggered,” the researchers wrote.

“A propensity that will likely cause psychiatrists anguish, however, is BPD patients’ increased likelihood of attempting suicide,” they added. Part of the problem has been that, in the past, it was thought that a BPD prognosis was untreatable. However, the researchers note that is no longer the case.

Still, Kaz Nelson, MD, associate professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis, has labeled BPD a so-called “asterisk” disorder.  

As she wrote in a recent blog, “We tell patients when they meet criteria for a medical diagnosis.* We show compassion and nonjudgmentalism to patients.* We do not discriminate against patients.*” However, the asterisk for each of these statements is: *Except for those with BPD.
 

Ongoing debate

Starting around the 1980s, the DSM listed personality disorders under the No. 2 Axis, which is for conditions with symptoms that are “not mitigatable,” said Dr. Nelson.

“It really started as well-meaning therapists who care about their patients who wanted to develop some precision in understanding people, and them starting to notice some patterns that can get in the way of optimal function,” she said in an interview.

The thought was not to disclose these diagnoses “because that was for you to understand, and for the patient to discover these patterns over time in the course of your work together,” Dr. Nelson added.

Although treatment for BPD used to be virtually nonexistent, there is now hope – especially with dialectic-behavior therapy (DBT), which uses mindfulness to teach patients how to control emotions and improve relationships.

According to the National Education Alliance for BPD, other useful treatments include mentalization-based therapy, transference-focused therapy, and “good psychiatric management.” Although there are currently no approved medications for BPD, some drugs are used to treat comorbid conditions such as depression or anxiety.

“We now know that people recover, and the whole paradigm has been turned on its head,” Dr. Nelson said. For example, “we no longer categorize these things as treatable or untreatable, which was a very positive move.”

So why is the field still debating the issue of diagnosis disclosure?

“To this day there are different psychiatrists and some medical school curricula that continue to teach that personality disorders are long-term, fixed, and nontreatable – and that it’s kind of disparaging to give this kind of diagnosis to a patient,” Dr. Nelson said.

Dr. Nelson, also the vice chair for education at the University of Minnesota, Minneapolis, medical school, reported that there “we acknowledge BPD’s painful history and that there are these misconceptions. They’re going to be on the front line of combating discrimination and the idea that if you see a patient with possible BPD coming you should run. That’s just unacceptable.”

Dr. Nelson noted that the idea of disclosing a BPD diagnosis is less controversial now than in the past, but “the whole thing is still under debate, and treatment guidelines [on BPD] are old and expired.”

Criteria for BPD were not updated when the DSM-5 was published in 2013, and that needs to be fixed, Dr. Nelson added. “In the meantime, we’re trying to get the word out that it’s okay to interact with people about the diagnosis, discuss treatment plans, and manage it as one would with any other psychiatric or medical illness.”
 

An evolution, not a debate

Paul Appelbaum, MD, past president of the American Psychiatric Association and current chair of the organization’s DSM steering committee, said in an interview that he hasn’t been involved in any recent debate on this issue.

“I think practice has changed to the point where the general practice is to discuss patient diagnoses with [patients] openly. Patients appreciate that and psychiatrists have come to see the advantages of it,” said Dr. Appelbaum, a professor of psychiatry, medicine, and law at Columbia University, New York.

Dr. Appelbaum noted that patients also increasingly have access to their medical records, “so the reality is that it’s no longer possible in many cases to withhold a diagnosis.”

“I don’t think it’s a debate; I think it’s been an evolution,” he said. “Maybe not everyone is entirely on board yet but there has been a sea change in psychiatric practices.”

Asked whether there needs to be some type of guideline update or statement released by the APA regarding BPD, Dr. Appelbaum said he doesn’t think the overall issue is BPD specific but applies to all psychiatric diagnoses.

“To the extent that there are still practitioners today that are telling students or residents [not to disclose], I would guess that they were trained a very long time ago and have not adapted to the new world,” he said.

“I don’t want to speak for the APA, but speaking for myself: I certainly encourage residents that I teach to be open about a diagnosis. It’s not just clinically helpful in some cases, it’s also ethically required from the perspective of allowing patients to make appropriate decisions about their treatment. And arguably it’s legally required as well, as part of the informed consent requirement,” Dr. Appelbaum said.

Regarding DSM updates, he noted that the committee “looks to the field to propose to us additions or changes to the DSM that are warranted by data that have been gathered since the DSM-5 came out.” There is a process set up on the DSM’s website to review such proposals.

In addition, Dr. Appelbaum said that there have been discussions about using a new model “that focuses on dimensions rather than on discreet categories” in order to classify personality disorders.

“There’s a group out there that is formulating a proposal that they will submit to us” on this, he added. “That’s the major discussion that is going on right now and it would clearly have implications for borderline as well as all the other personality disorders.”

In a statement, the APA said practice guidelines for BPD are currently under review and that the organization does not have a “position statement” on BPD for clinicians. The last update to its guideline was in the early 2000s.

A version of this article first appeared on Medscape.com.