Tara Haelle

DENVER – Initiating exercise therapy early on in people who develop symptoms of knee osteoarthritis – even within their first year of pain or reduced function – is associated with modestly lower pain scores and modestly better function than in those whose symptoms have lasted longer, according to a study presented at the OARSI 2023 World Congress.

Although the benefits of exercise therapy for advanced knee osteoarthritis had already been well established, this study looked specifically at benefits from exercise therapy earlier on, in patients with a shorter duration of symptoms.

“Exercise indeed seems especially beneficial in patients with shorter symptom duration and should therefore be encouraged at first symptom presentation,” Marienke van Middelkoop, PhD, of Erasmus MC Medical University in Rotterdam, the Netherlands, told attendees at the meeting, sponsored by Osteoarthritis Research Society International. “It is, however, still a challenge how we can identify patients but also how we can motivate these patients with early symptoms of osteoarthritis.” She noted that a separate pilot study had experienced difficulty recruiting people with short-term symptom duration.

The researchers compared the effect of exercise therapy and no exercise among adults at least 45 years old with knee osteoarthritis, relying on individual participant data from the STEER OA study, a meta-analysis of 31 studies that involved 4,241 participants. After excluding studies that didn’t report symptom duration, lacked a control group or consent, or focused on hip osteoarthritis, the researchers ended up with 10 studies involving 1,895 participants. These participants were stratified based on the duration of their symptoms: up to 1 year (14.4%), 1-2 years (11%), and 2 years or longer (74%).

About two-thirds of the participants were women (65.9%), with an average age of 65 years and an average body mass index (BMI) of 30.7 kg/m². Any land-based or water-based therapeutic exercise counted for the 62% of participants in the intervention group, while the control group had no exercise. Outcomes were assessed based on self-reported pain or physical function at short-term and long-term follow-up, which were as close as possible to 3 months for short-term and the closest date to 12 months for longer term. At baseline, the participants reported an average pain score of 41.7 on a 0-to-100 scale and an average physical function score of 37.4 on a 0-to-100 scale where lower scores indicate better function.

Among those doing exercise therapy, average pain scores dropped 4.56 points in the short term and 7.43 points in the long term. Short-term and long-term pain scores were lower among those whose symptom durations were shorter. For example, those with symptoms for less than a year reported a short-term pain score of 29, compared with 30 for those with 1-2 years of pain and 32 for those with at least 2 years of pain. Results were similar for long-term pain (a score of 26, compared with 28 and 33, respectively).

Participants engaging in exercise therapy also improved average function scores, with a pattern of improvement that was similar to pain scores based on patients’ symptom duration. The average short-term function score was 26 among those with less than a year of symptoms, compared with 28 for those with symptoms for 1-2 years, and 30 for those with symptoms for at least 2 years. Longer-term function scores were 21, 24, and 29, respectively, based on increasing symptom durations.

Chris Yun Lane, PT, DPT, a physical therapist and a fourth-year PhD student at the University of North Carolina at Chapel Hill, was not surprised at the exercise benefit given the extensive evidence already showing that exercise is beneficial for patients with osteoarthritis whose symptoms have lasted longer.

“Just spending a little bit of time on education, designing kind of simple exercise programs, such as walking programs, can be very helpful,” Dr. Lane said in an interview. “Of course, some of it is dependent on the patient itself, but strengthening range of motion is often very helpful.” Dr. Lane said it’s particularly important for physicians and physical therapists to emphasize the importance of exercise to their patients because that guidance doesn’t always occur as often as it should.

Ron Ellis Jr., DO, MBA, chief strategy officer of Pacira BioSciences in Tampa, Fla., noted that a lot of patients with knee osteoarthritis have weakness in their quads, so quad strengthening is “a typical part of our improvement program for patients with osteoarthritis,” he said in an interview. Dr. Ellis also referenced a session he attended the previous day that showed exercise results in reduced inflammation.

“So you may not have weight loss, but you can lower the inflammatory state of the overall body and of the specific joints,” Dr. Ellis said, “so that would support [this study’s] conclusion.”

The STEER OA study was funded by the Chartered Society of Physiotherapy Charitable Trust and the National Institute for Health Research School of Primary Care Research. Dr. van Middelkoop and Dr. Lane both reported having no relevant financial relationships.

DENVER – Initiating exercise therapy early on in people who develop symptoms of knee osteoarthritis – even within their first year of pain or reduced function – is associated with modestly lower pain scores and modestly better function than in those whose symptoms have lasted longer, according to a study presented at the OARSI 2023 World Congress.

Although the benefits of exercise therapy for advanced knee osteoarthritis had already been well established, this study looked specifically at benefits from exercise therapy earlier on, in patients with a shorter duration of symptoms.

“Exercise indeed seems especially beneficial in patients with shorter symptom duration and should therefore be encouraged at first symptom presentation,” Marienke van Middelkoop, PhD, of Erasmus MC Medical University in Rotterdam, the Netherlands, told attendees at the meeting, sponsored by Osteoarthritis Research Society International. “It is, however, still a challenge how we can identify patients but also how we can motivate these patients with early symptoms of osteoarthritis.” She noted that a separate pilot study had experienced difficulty recruiting people with short-term symptom duration.

The researchers compared the effect of exercise therapy and no exercise among adults at least 45 years old with knee osteoarthritis, relying on individual participant data from the STEER OA study, a meta-analysis of 31 studies that involved 4,241 participants. After excluding studies that didn’t report symptom duration, lacked a control group or consent, or focused on hip osteoarthritis, the researchers ended up with 10 studies involving 1,895 participants. These participants were stratified based on the duration of their symptoms: up to 1 year (14.4%), 1-2 years (11%), and 2 years or longer (74%).

About two-thirds of the participants were women (65.9%), with an average age of 65 years and an average body mass index (BMI) of 30.7 kg/m². Any land-based or water-based therapeutic exercise counted for the 62% of participants in the intervention group, while the control group had no exercise. Outcomes were assessed based on self-reported pain or physical function at short-term and long-term follow-up, which were as close as possible to 3 months for short-term and the closest date to 12 months for longer term. At baseline, the participants reported an average pain score of 41.7 on a 0-to-100 scale and an average physical function score of 37.4 on a 0-to-100 scale where lower scores indicate better function.

Among those doing exercise therapy, average pain scores dropped 4.56 points in the short term and 7.43 points in the long term. Short-term and long-term pain scores were lower among those whose symptom durations were shorter. For example, those with symptoms for less than a year reported a short-term pain score of 29, compared with 30 for those with 1-2 years of pain and 32 for those with at least 2 years of pain. Results were similar for long-term pain (a score of 26, compared with 28 and 33, respectively).

Participants engaging in exercise therapy also improved average function scores, with a pattern of improvement that was similar to pain scores based on patients’ symptom duration. The average short-term function score was 26 among those with less than a year of symptoms, compared with 28 for those with symptoms for 1-2 years, and 30 for those with symptoms for at least 2 years. Longer-term function scores were 21, 24, and 29, respectively, based on increasing symptom durations.

Chris Yun Lane, PT, DPT, a physical therapist and a fourth-year PhD student at the University of North Carolina at Chapel Hill, was not surprised at the exercise benefit given the extensive evidence already showing that exercise is beneficial for patients with osteoarthritis whose symptoms have lasted longer.

“Just spending a little bit of time on education, designing kind of simple exercise programs, such as walking programs, can be very helpful,” Dr. Lane said in an interview. “Of course, some of it is dependent on the patient itself, but strengthening range of motion is often very helpful.” Dr. Lane said it’s particularly important for physicians and physical therapists to emphasize the importance of exercise to their patients because that guidance doesn’t always occur as often as it should.

Ron Ellis Jr., DO, MBA, chief strategy officer of Pacira BioSciences in Tampa, Fla., noted that a lot of patients with knee osteoarthritis have weakness in their quads, so quad strengthening is “a typical part of our improvement program for patients with osteoarthritis,” he said in an interview. Dr. Ellis also referenced a session he attended the previous day that showed exercise results in reduced inflammation.

“So you may not have weight loss, but you can lower the inflammatory state of the overall body and of the specific joints,” Dr. Ellis said, “so that would support [this study’s] conclusion.”

The STEER OA study was funded by the Chartered Society of Physiotherapy Charitable Trust and the National Institute for Health Research School of Primary Care Research. Dr. van Middelkoop and Dr. Lane both reported having no relevant financial relationships.

DENVER – Initiating exercise therapy early on in people who develop symptoms of knee osteoarthritis – even within their first year of pain or reduced function – is associated with modestly lower pain scores and modestly better function than in those whose symptoms have lasted longer, according to a study presented at the OARSI 2023 World Congress.

Although the benefits of exercise therapy for advanced knee osteoarthritis had already been well established, this study looked specifically at benefits from exercise therapy earlier on, in patients with a shorter duration of symptoms.

“Exercise indeed seems especially beneficial in patients with shorter symptom duration and should therefore be encouraged at first symptom presentation,” Marienke van Middelkoop, PhD, of Erasmus MC Medical University in Rotterdam, the Netherlands, told attendees at the meeting, sponsored by Osteoarthritis Research Society International. “It is, however, still a challenge how we can identify patients but also how we can motivate these patients with early symptoms of osteoarthritis.” She noted that a separate pilot study had experienced difficulty recruiting people with short-term symptom duration.

The researchers compared the effect of exercise therapy and no exercise among adults at least 45 years old with knee osteoarthritis, relying on individual participant data from the STEER OA study, a meta-analysis of 31 studies that involved 4,241 participants. After excluding studies that didn’t report symptom duration, lacked a control group or consent, or focused on hip osteoarthritis, the researchers ended up with 10 studies involving 1,895 participants. These participants were stratified based on the duration of their symptoms: up to 1 year (14.4%), 1-2 years (11%), and 2 years or longer (74%).

About two-thirds of the participants were women (65.9%), with an average age of 65 years and an average body mass index (BMI) of 30.7 kg/m². Any land-based or water-based therapeutic exercise counted for the 62% of participants in the intervention group, while the control group had no exercise. Outcomes were assessed based on self-reported pain or physical function at short-term and long-term follow-up, which were as close as possible to 3 months for short-term and the closest date to 12 months for longer term. At baseline, the participants reported an average pain score of 41.7 on a 0-to-100 scale and an average physical function score of 37.4 on a 0-to-100 scale where lower scores indicate better function.

Among those doing exercise therapy, average pain scores dropped 4.56 points in the short term and 7.43 points in the long term. Short-term and long-term pain scores were lower among those whose symptom durations were shorter. For example, those with symptoms for less than a year reported a short-term pain score of 29, compared with 30 for those with 1-2 years of pain and 32 for those with at least 2 years of pain. Results were similar for long-term pain (a score of 26, compared with 28 and 33, respectively).

Participants engaging in exercise therapy also improved average function scores, with a pattern of improvement that was similar to pain scores based on patients’ symptom duration. The average short-term function score was 26 among those with less than a year of symptoms, compared with 28 for those with symptoms for 1-2 years, and 30 for those with symptoms for at least 2 years. Longer-term function scores were 21, 24, and 29, respectively, based on increasing symptom durations.

Chris Yun Lane, PT, DPT, a physical therapist and a fourth-year PhD student at the University of North Carolina at Chapel Hill, was not surprised at the exercise benefit given the extensive evidence already showing that exercise is beneficial for patients with osteoarthritis whose symptoms have lasted longer.

“Just spending a little bit of time on education, designing kind of simple exercise programs, such as walking programs, can be very helpful,” Dr. Lane said in an interview. “Of course, some of it is dependent on the patient itself, but strengthening range of motion is often very helpful.” Dr. Lane said it’s particularly important for physicians and physical therapists to emphasize the importance of exercise to their patients because that guidance doesn’t always occur as often as it should.

Ron Ellis Jr., DO, MBA, chief strategy officer of Pacira BioSciences in Tampa, Fla., noted that a lot of patients with knee osteoarthritis have weakness in their quads, so quad strengthening is “a typical part of our improvement program for patients with osteoarthritis,” he said in an interview. Dr. Ellis also referenced a session he attended the previous day that showed exercise results in reduced inflammation.

“So you may not have weight loss, but you can lower the inflammatory state of the overall body and of the specific joints,” Dr. Ellis said, “so that would support [this study’s] conclusion.”

The STEER OA study was funded by the Chartered Society of Physiotherapy Charitable Trust and the National Institute for Health Research School of Primary Care Research. Dr. van Middelkoop and Dr. Lane both reported having no relevant financial relationships.

For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

For people with inflammatory bowel disease (IBD) taking immunosuppressive medication, a third dose of a COVID-19 mRNA vaccine significantly increases neutralizing antibodies against the original SARS-CoV-2 strain, but the picture is more complicated for protection against the Omicron variant, according to a research letter published in Gastroenterology.

Though IBD patients do mount a response against Omicron, the response is substantially lower for those taking tofacitinib or infliximab, particularly infliximab monotherapy.

“As further mutations in the viral genome accumulate over time, with the attendant risk of immune evasion, it remains important to continue to reappraise vaccination strategy, including the implementation of personalized approaches for some patients, such as those treated with anti-TNF drugs and JAK inhibitors,” wrote Zhigang Liu, PhD, a research associate in the department of metabolism, digestion, and reproduction at Imperial College London, and his colleagues. “Preferential use of bivalent vaccines may be especially valuable in IBD patients taking anti-TNF agents or JAK inhibitors,” they wrote. Their study did not assess neutralizing antibodies resulting from use of the bivalent vaccine, however.

The researchers tracked 268 participants, including 49 healthy participants serving as controls, from May 2021 through March 2022. The other participants had IBD and included 51 patients taking thiopurines, 36 patients taking infliximab, 39 taking both infliximab and thiopurines, 39 taking ustekinumab, 38 taking vedolizumab, and 16 taking tofacitinib. The IBD patients were all enrolled in the SARS-CoV-2 Vaccination Immunogenicity in Immunosuppressed Inflammatory Bowel Disease Patients (VIP) cohort.

None of the participants had evidence of a SARS-CoV-2 infection at baseline. All had received two doses of an mRNA COVID-19 vaccine (all received Pfizer, except two controls who received Moderna) or two doses of the AstraZeneca vaccine as their primary vaccination. All received an mRNA vaccine for their third dose. Among the IBD patients, 137 received the AstraZeneca in their primary two-dose series, and 82 received Pfizer.

First the researchers assessed the participants’ humoral response to the vaccine against the original SARS-CoV-2 strain and against the Omicron BA.1 variant. Neutralizing antibody titers rose significantly against both strains after the third vaccine dose for all participants.

“However, 50% neutralization titer (NT50) values were significantly lower against Omicron than against the ancestral strain in all study groups, irrespective of the immunosuppressive treatment regimen,” the authors reported. NT50 values are a measure that reflect a vaccine-induced humoral immunity against SARS-CoV-2 after vaccination.

Compared to the healthy controls, individuals receiving infliximab, tofacitinib, or infliximab/thiopurine combination therapy showed significantly lower responses after the second and third vaccine doses. Thirteen patients did not generate NT50 against Omicron after the second vaccine dose, and 7 of them were on infliximab monotherapy. They represented nearly 20% of all infliximab monotherapy participants.

Next the researchers assessed the risk of a breakthrough infection according to neutralizing titer thresholds. Individuals with an NT50 less than 500 had 1.6 times greater odds of a breakthrough infection than those with an NT50 above 500, they noted. After two vaccine doses, 46% of participants with IBD had an NT50 above 500 for the ancestral strain, which rose to 85% of those with IBD after a third dose.

In the healthy control group, 35% had an NT50 under 500 after two doses, and 14% of them had a breakthrough infection, all of which were mild and none of which required hospitalization. The NT50 in healthy controls, however, was not significantly associated with risk of breakthrough infection.

“In this study, neutralizing titers elicited against the omicron variant were generally poor for all individuals and were substantially lower in recipients of infliximab, infliximab/thiopurine combination, or tofacitinib therapy,” the authors concluded. “This raises concerns about whether currently available vaccines will be sufficient to protect against continually evolving SARS-CoV-2 variants, especially in patients established on certain immunosuppressive drugs.”

The small population sizes for each subgroup based on medication was one of the study’s limitations. Another was the fact that it was underpowered to conclusively determine whether an increased risk of breakthrough infection exists in IBD patients who have lower titers of neutralizing antibodies. A limitation for generalization to U.S. patients is that just 64% of the IBD patients received the AstraZeneca vaccine, which is not offered in the United States, for their first two doses before receiving the third mRNA (Pfizer) dose.

The study was funded by Pfizer in an independent research grant and by the NIHR Biomedical Research Centres in Imperial College London and Imperial College Healthcare NHS Trust and Cambridge, and the NIHR Clinical Research Facility Cambridge.

Dr. Liu and one other author had no disclosures. The other 18 authors have a range of disclosures related to various pharmaceutical companies, including Pfizer.

An investigation of genomics data related to primary sclerosing cholangitis (PSC) in published medical literature revealed several genes likely involved in the pathogenesis of this autoimmune diseases, according to a study published in Gastro Hep Advances.

PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.

No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.

“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.

The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.

The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.

At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.

Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.

"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”

The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.

Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.

Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.

Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.

The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.

An investigation of genomics data related to primary sclerosing cholangitis (PSC) in published medical literature revealed several genes likely involved in the pathogenesis of this autoimmune diseases, according to a study published in Gastro Hep Advances.

PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.

No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.

“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.

The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.

The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.

At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.

Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.

"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”

The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.

Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.

Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.

Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.

The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.

An investigation of genomics data related to primary sclerosing cholangitis (PSC) in published medical literature revealed several genes likely involved in the pathogenesis of this autoimmune diseases, according to a study published in Gastro Hep Advances.

PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.

No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.

“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.

The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.

The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.

At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.

Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.

"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”

The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.

Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.

Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.

Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.

The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

As a toddler undergoing treatment at McMaster Children’s Hospital in Hamilton, Ont., Caroline Diorio, MD, couldn’t grasp what the nice doctors scurrying in and out of her room were doing. She just knew they were taking care of her.

Dr. Diorio had pediatric immune thrombocytopenia (ITP), a type of platelet disorder in which the immune system attacks blood platelets for usually unknown reasons.

“I remember very much how worried my parents were,” recalled Dr. Diorio, now a hematologist-oncologist at Children’s Hospital of Philadelphia. “And I remember how the tone of the doctor’s voice and the way the doctors communicated provided so much reassurance to my parents.”

Dr. Diorio’s ITP resolved within a few years, but her experience left a lasting impression.

“From that moment on, I don’t remember a time that I didn’t want to be a doctor,” she said. “I had these really formative experiences with doctors who were so lovely, and I thought, ‘I want to do that.’ ”

Though she considered other specialties in medical school at the University of Toronto, Dr. Diorio kept feeling drawn back to pediatric oncology and hematology.

“I have always loved the commitment that parents have to their kids and the team approach that exists,” she said. “Hematology/oncology allowed me to take care of really sick kids but also have this long-term relationship with them and their parents, which I really value and love.”

Dr. Diorio even completed her residency at McMaster alongside one of the same physicians who had cared for her as a child, Ronald Duncan Barr, MD. “It sort of all came full circle,” she said.

Today, Dr. Diorio draws inspiration from memories of her childhood experience. “I try to recreate that and provide as much kindness and compassion as I can for patients and their families, to help when people are in this incredibly vulnerable situation,” she said.

But she takes that even further by researching new therapies for patients who have run out of options, particularly those with T-cell acute lymphoblastic leukemia (T-ALL).

For B-cell ALL and several other blood cancers, an effective option is CAR T-cell therapy, in which physicians collect T-cells from the patient, re-engineer the T cells in the lab so they recognize the proteins expressed on the surface of cancerous cells – called blasts – and then introduce the modified T-cells back into the patient. Once infused, the re-engineered T-cells attack the blasts with the tell-tale proteins.

But with T-ALL, T-cells themselves are infected with cancer, so autologous CAR T-cell therapy is not currently an option, and no allogeneic CAR T-cell therapies have been approved. Dr. Diorio is part of a cutting-edge research team led by David T. Teachey, MD, striving for breakthroughs. “She’s a brilliant clinician, extremely smart and hard-working, exceptional work ethic, great interaction with patients and families with a great bedside manner,” Dr. Teachey said of Dr. Diorio. “She’s just a superstar all around.”

Dr. Teachey first piqued Dr. Diorio’s interest in researching innovative T-ALL therapies when she arrived at CHOP as a hematology/oncology fellow in 2018 and pursued a master of science degree in translational research under his tutelage at the University of Pennsylvania. Then, for a time, the COVID-19 pandemic shut down most research.

“Caroline pivoted and was at the front line, collecting samples and helping with research on SARS-CoV-2 very early in the pandemic,” Dr. Teachey said. “She was able to then pivot back, taking the skills she learned from that work in the pandemic and applying it to what she was doing in the CAR T-cell space and T-ALL.”

Extraordinary gains in pediatric cancer over the past several decades mean that more than 80% of children diagnosed with cancer today will become long-term survivors. “The 20% of the time that we don’t get the result we want is obviously devastating,” Dr. Diorio said. “However, that’s incredibly motivating to try to make better treatments.”

Her current focus is finding a way to use CAR T-cell therapy in children with T-ALL. About 85% of children with T-ALL do well with standard first-line treatments of chemotherapy, but the 15% who relapse or have chemo-refractory disease have a far lower survival rate – less than 30%, Dr. Diorio said.

The problem with autologous CAR T-cell therapy in T-ALL is twofold: It’s difficult to sort out healthy T cells from the cancerous T cells, and the target current re-engineered T-cells go after is on healthy cells, too.

“What happens is a problem called fratricide – basically the CAR T-cells are killing their brothers,” she said. So Dr. Diorio and her colleagues are trying to modify CAR T-cell strategies to target different markers. One target they’re investigating is CD7, but using CRISPR to gene-edit out CD7 from healthy cells requires making two cuts in the DNA.

“Any time you break DNA, you have to repair it, and any time you repair it, there’s a chance of making a mistake,” Dr. Diorio said. So she used a different technique, cytosine-based editing, which requires only one cut. “You put in what you want, and it’s much more precise and less error-prone.” Cytosine-based editing also preserves T cells’ vitality; too many cuts impair T-cell growth, but that doesn’t happen with cytosine-based editing. In August of 2022, Dr. Diorio published a study demonstrating this technique while the team has continued looking for other targets that show up on cancer cells but not on healthy T-cells.

“I’m not invested in one particular strategy,” Dr. Diorio said. “I’m invested in finding a strategy that works for the maximum number of patients.”

That pragmatic approach may be why Dr. Teachey describes her as an out-of-the-box thinker.

“She brings novel ideas to the table, and not everybody who’s a physician-scientist has that ability to really think about taking things in the bench to the bedside and then back again,” Dr. Teachey said. “It’s knowing what questions are important to ask for our patients and how to study those and the research base, so that you can improve treatments for kids with leukemia.”

Their research looks promising so far. Clinical trials are in development for the CD7-targeted CAR T, and they’re collaborating with others on clinical trials for CAR-T targeting another protein, CD38. In the midst of it all, Dr. Diorio remains focused on her patients.

“It’s really a privilege to see the incredible grace people have in these very difficult circumstances,” Dr. Diorio said. “I find it really motivating to try to make things easier for people, and I try to spend every day looking for better treatments so people don’t have to go through that.”

Dr. Diorio has no disclosures. Dr. Teachey has served on the advisory boards of BEAM, Jazz, Janssen, and Sobi and has received research funding from BEAM, Jazz, Servier, and Neoimmune Tech. He has multiple patents pending on CAR-T therapy.

Patients with rheumatic disease are at least half as likely to develop long COVID after a SARS-CoV-2 infection if they have been fully vaccinated against COVID-19, according to research published in Annals of the Rheumatic Diseases (2022 Nov 28. doi: 10.1136/ard-2022-223439).

“Moreover, those who were vaccinated prior to getting COVID-19 had less pain and fatigue after their infection,” Zachary S. Wallace, MD, MSc, an assistant professor of medicine at Harvard Medical School, Boston, and a study author, said in an interview. “These findings reinforce the importance of vaccination in this population.”

Messaging around the value of COVID vaccination has been confusing for some with rheumatic disease “because our concern regarding a blunted response to vaccination has led many patients to think that they do not provide much benefit if they are on immunosuppression,” Dr. Wallace said. “In our cohort, which included many patients on immunosuppression of varying degrees, being vaccinated was quite beneficial.”

Leonard H. Calabrese, DO, director of the R.J. Fasenmyer Center for Clinical Immunology and a professor of medicine at the Cleveland Clinic, said in an interview that the study is an “extremely important contribution to our understanding of COVID-19 and its pattern of recovery in patients with immune-mediated inflammatory diseases [IMIDs].” Remaining unanswered questions are “whether patients with IMIDs develop more frequent PASC [post–acute sequelae of COVID-19] from COVID-19 and, if so, is it milder or more severe, and does it differ in its clinical phenotype?”
 

Long COVID risk assessed at 4 weeks and 3 months after infection

The researchers prospectively tracked 280 adult patients in the Mass General Brigham health care system in the greater Boston area who had systemic autoimmune rheumatic diseases and had an acute COVID-19 infection between March 2020 and July 2022. Patients were an average 53 years old, and most were White (82%) and female (80%). More than half (59%) had inflammatory arthritis, a quarter (24%) had connective tissue disease, and most others had a vasculitis condition or multiple conditions.

filadendron/E+/Getty Images

A total of 11% of patients were unvaccinated, 28% were partially vaccinated with one mRNA COVID-19 vaccine dose, and 41% were fully vaccinated with two mRNA vaccine doses or one Johnson & Johnson dose. The 116 fully vaccinated patients were considered to have a breakthrough infection while the other 164 were considered to have a nonbreakthrough infection. The breakthrough and nonbreakthrough groups were similar in terms of age, sex, race, ethnicity, smoking status, and type of rheumatic disease. Comorbidities were also similar, except obesity, which was more common in the non–breakthrough infection group (25%) than the breakthrough infection group (10%).

The researchers queried patients on their COVID-19 symptoms, how long symptoms lasted, treatments they received, and hospitalization details. COVID-19 symptoms assessed included fever, sore throat, new cough, nasal congestion/rhinorrhea, dyspnea, chest pain, rash, myalgia, fatigue/malaise, headache, nausea/vomiting, diarrhea, anosmia, dysgeusia, and joint pain.

Patients completed surveys about symptoms at 4 weeks and 3 months after infection. Long COVID, or PASC, was defined as any persistent symptom at the times assessed.
 

Vaccinated patients fared better across outcomes

At 4 weeks after infection, 41% of fully vaccinated patients had at least one persistent symptom, compared with 54% of unvaccinated or partially vaccinated patients (P = .04). At 3 months after infection, 21% of fully vaccinated patients had at least one persistent symptom, compared with 41% of unvaccinated or partially vaccinated patients (P < .0001).

Vaccinated patients were half as likely to have long COVID at 4 weeks after infection (adjusted odds ratio, 0.49) and 90% less likely to have long COVID 3 months after infection (aOR, 0.1), after adjustment for age, sex, race, comorbidities, and use of any of four immune-suppressing medications (anti-CD20 monoclonal antibodies, methotrexate, mycophenolate, or glucocorticoids).

Fully vaccinated patients with breakthrough infections had an average 21 additional days without symptoms during follow-up, compared with unvaccinated and partially vaccinated patients (P = .04).

Reduced risk of long COVID did not change for vaccinated patients after sensitivity analyses for those who did not receive nirmatrelvir/ritonavir (Paxlovid) or monoclonal antibodies, those who didn’t receive any COVID-19-related treatment, those who completed their questionnaires within 6 months after infection, and those who were not hospitalized.

“One important message is that among those who did get PASC, the severity appears similar among those with and without a breakthrough infection,” Dr. Wallace said. “This highlights the need for ongoing research to improve recognition, diagnosis, and treatment of PASC.”

Many more breakthrough infections (72%) than nonbreakthrough infections (2%) occurred during Omicron. The authors acknowledged that different variants might play a role in different long COVID risks but said such potential confounding is unlikely to fully explain the results.

“Even with data suggesting that the Omicron variants may be intrinsically less severe, vaccination still has an impact on severity of infection, rates of hospitalization, and other outcomes and thus may play a role in the risk of PASC,” lead author Naomi Patel, MD, an instructor at Harvard Medical School and a rheumatologist at Massachusetts General Hospital, said in an interview. “A study evaluating the proportions with PASC by vaccination status during the time in which a single variant is predominant, such as the early Omicron era, could help to better assess the more isolated impact of vaccination on PASC.”

Dr. Calabrese said he is convinced that Omicron infections are less likely to result in more severe forms of acute COVID than pre-Omicron infections, and he suspects Omicron infections are also less likely to result in long COVID, although less evidence currently supports this hypothesis.

Hospitalization was more common in unvaccinated/partly vaccinated patients than in vaccinated patients (27% vs. 5%; P = .001). Although pain and fatigue were lower in those with breakthrough infections, functional scores and health-related quality of life were similar in both groups.

Some symptoms significantly differed between vaccinated and unvaccinated/partly vaccinated groups, possibly caused partly by different variants. Nasal congestion was more common (73%) in those with breakthrough infections than in those with nonbreakthrough infections (46%; P < .0001). Those who were unvaccinated/partly vaccinated were significantly more likely to have loss of smell (46% vs. 22%) or taste (45% vs. 28%) or to have joint pain (11% vs. 4%).

Treatment with nirmatrelvir/ritonavir was also more common in vaccinated patients (12%) than in unvaccinated/partly vaccinated patients (1%; P < .0001), as was treatment with monoclonal antibodies (34% vs. 8%; P < .0001).

The study was limited by its low diversity and being at a single health care system, the authors said. Study coauthor Jeffrey A. Sparks, MD, MMSc, an assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, said in an interview that the group is planning additional studies as their cohort grows, including “investigating the relationships between COVID-19 and specific rheumatic diseases and immunomodulating medications, expansion of autoimmunity and systemic inflammation, and lung damage among specific patient populations.”

Dr. Calabrese said it will be important for follow-up study of the symptomatic patients to “determine how many of these patients will fit the clinical picture of long COVID or long-haul phenotypes over the months and years ahead, including documenting exertional malaise and quality of life.

This study only assessed patients who received zero, one, or two doses of a vaccine, but many patients with rheumatic disease today will likely have received booster doses. However, Dr. Calabrese said it would be difficult to quantify whether a third, fourth, or fifth dose offers additional protection from long-term COVID complications after full vaccination or hybrid vaccination.

The research was funded by the Rheumatology Research Foundation, the National Institutes of Health, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Dr. Wallace has received research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Zenas BioPharma, Horizon, Sanofi, Shionogi, Viela Bio, and Medpace. Dr. Sparks has received research support from Bristol-Myers Squibb and consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Patel has received consulting fees from FVC Health. Calabrese has consulted for Genentech, Sanofi-Regeneron, AstraZeneca, and GlaxoSmithKline.

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

Patients with rheumatic disease are at least half as likely to develop long COVID after a SARS-CoV-2 infection if they have been fully vaccinated against COVID-19, according to research published in Annals of the Rheumatic Diseases (2022 Nov 28. doi: 10.1136/ard-2022-223439).

“Moreover, those who were vaccinated prior to getting COVID-19 had less pain and fatigue after their infection,” Zachary S. Wallace, MD, MSc, an assistant professor of medicine at Harvard Medical School, Boston, and a study author, said in an interview. “These findings reinforce the importance of vaccination in this population.”

Messaging around the value of COVID vaccination has been confusing for some with rheumatic disease “because our concern regarding a blunted response to vaccination has led many patients to think that they do not provide much benefit if they are on immunosuppression,” Dr. Wallace said. “In our cohort, which included many patients on immunosuppression of varying degrees, being vaccinated was quite beneficial.”

Leonard H. Calabrese, DO, director of the R.J. Fasenmyer Center for Clinical Immunology and a professor of medicine at the Cleveland Clinic, said in an interview that the study is an “extremely important contribution to our understanding of COVID-19 and its pattern of recovery in patients with immune-mediated inflammatory diseases [IMIDs].” Remaining unanswered questions are “whether patients with IMIDs develop more frequent PASC [post–acute sequelae of COVID-19] from COVID-19 and, if so, is it milder or more severe, and does it differ in its clinical phenotype?”
 

Long COVID risk assessed at 4 weeks and 3 months after infection

The researchers prospectively tracked 280 adult patients in the Mass General Brigham health care system in the greater Boston area who had systemic autoimmune rheumatic diseases and had an acute COVID-19 infection between March 2020 and July 2022. Patients were an average 53 years old, and most were White (82%) and female (80%). More than half (59%) had inflammatory arthritis, a quarter (24%) had connective tissue disease, and most others had a vasculitis condition or multiple conditions.

filadendron/E+/Getty Images

A total of 11% of patients were unvaccinated, 28% were partially vaccinated with one mRNA COVID-19 vaccine dose, and 41% were fully vaccinated with two mRNA vaccine doses or one Johnson & Johnson dose. The 116 fully vaccinated patients were considered to have a breakthrough infection while the other 164 were considered to have a nonbreakthrough infection. The breakthrough and nonbreakthrough groups were similar in terms of age, sex, race, ethnicity, smoking status, and type of rheumatic disease. Comorbidities were also similar, except obesity, which was more common in the non–breakthrough infection group (25%) than the breakthrough infection group (10%).

The researchers queried patients on their COVID-19 symptoms, how long symptoms lasted, treatments they received, and hospitalization details. COVID-19 symptoms assessed included fever, sore throat, new cough, nasal congestion/rhinorrhea, dyspnea, chest pain, rash, myalgia, fatigue/malaise, headache, nausea/vomiting, diarrhea, anosmia, dysgeusia, and joint pain.

Patients completed surveys about symptoms at 4 weeks and 3 months after infection. Long COVID, or PASC, was defined as any persistent symptom at the times assessed.
 

Vaccinated patients fared better across outcomes

At 4 weeks after infection, 41% of fully vaccinated patients had at least one persistent symptom, compared with 54% of unvaccinated or partially vaccinated patients (P = .04). At 3 months after infection, 21% of fully vaccinated patients had at least one persistent symptom, compared with 41% of unvaccinated or partially vaccinated patients (P < .0001).

Vaccinated patients were half as likely to have long COVID at 4 weeks after infection (adjusted odds ratio, 0.49) and 90% less likely to have long COVID 3 months after infection (aOR, 0.1), after adjustment for age, sex, race, comorbidities, and use of any of four immune-suppressing medications (anti-CD20 monoclonal antibodies, methotrexate, mycophenolate, or glucocorticoids).

Fully vaccinated patients with breakthrough infections had an average 21 additional days without symptoms during follow-up, compared with unvaccinated and partially vaccinated patients (P = .04).

Reduced risk of long COVID did not change for vaccinated patients after sensitivity analyses for those who did not receive nirmatrelvir/ritonavir (Paxlovid) or monoclonal antibodies, those who didn’t receive any COVID-19-related treatment, those who completed their questionnaires within 6 months after infection, and those who were not hospitalized.

“One important message is that among those who did get PASC, the severity appears similar among those with and without a breakthrough infection,” Dr. Wallace said. “This highlights the need for ongoing research to improve recognition, diagnosis, and treatment of PASC.”

Many more breakthrough infections (72%) than nonbreakthrough infections (2%) occurred during Omicron. The authors acknowledged that different variants might play a role in different long COVID risks but said such potential confounding is unlikely to fully explain the results.

“Even with data suggesting that the Omicron variants may be intrinsically less severe, vaccination still has an impact on severity of infection, rates of hospitalization, and other outcomes and thus may play a role in the risk of PASC,” lead author Naomi Patel, MD, an instructor at Harvard Medical School and a rheumatologist at Massachusetts General Hospital, said in an interview. “A study evaluating the proportions with PASC by vaccination status during the time in which a single variant is predominant, such as the early Omicron era, could help to better assess the more isolated impact of vaccination on PASC.”

Dr. Calabrese said he is convinced that Omicron infections are less likely to result in more severe forms of acute COVID than pre-Omicron infections, and he suspects Omicron infections are also less likely to result in long COVID, although less evidence currently supports this hypothesis.

Hospitalization was more common in unvaccinated/partly vaccinated patients than in vaccinated patients (27% vs. 5%; P = .001). Although pain and fatigue were lower in those with breakthrough infections, functional scores and health-related quality of life were similar in both groups.

Some symptoms significantly differed between vaccinated and unvaccinated/partly vaccinated groups, possibly caused partly by different variants. Nasal congestion was more common (73%) in those with breakthrough infections than in those with nonbreakthrough infections (46%; P < .0001). Those who were unvaccinated/partly vaccinated were significantly more likely to have loss of smell (46% vs. 22%) or taste (45% vs. 28%) or to have joint pain (11% vs. 4%).

Treatment with nirmatrelvir/ritonavir was also more common in vaccinated patients (12%) than in unvaccinated/partly vaccinated patients (1%; P < .0001), as was treatment with monoclonal antibodies (34% vs. 8%; P < .0001).

The study was limited by its low diversity and being at a single health care system, the authors said. Study coauthor Jeffrey A. Sparks, MD, MMSc, an assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, said in an interview that the group is planning additional studies as their cohort grows, including “investigating the relationships between COVID-19 and specific rheumatic diseases and immunomodulating medications, expansion of autoimmunity and systemic inflammation, and lung damage among specific patient populations.”

Dr. Calabrese said it will be important for follow-up study of the symptomatic patients to “determine how many of these patients will fit the clinical picture of long COVID or long-haul phenotypes over the months and years ahead, including documenting exertional malaise and quality of life.

This study only assessed patients who received zero, one, or two doses of a vaccine, but many patients with rheumatic disease today will likely have received booster doses. However, Dr. Calabrese said it would be difficult to quantify whether a third, fourth, or fifth dose offers additional protection from long-term COVID complications after full vaccination or hybrid vaccination.

The research was funded by the Rheumatology Research Foundation, the National Institutes of Health, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Dr. Wallace has received research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Zenas BioPharma, Horizon, Sanofi, Shionogi, Viela Bio, and Medpace. Dr. Sparks has received research support from Bristol-Myers Squibb and consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Patel has received consulting fees from FVC Health. Calabrese has consulted for Genentech, Sanofi-Regeneron, AstraZeneca, and GlaxoSmithKline.

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

Patients with rheumatic disease are at least half as likely to develop long COVID after a SARS-CoV-2 infection if they have been fully vaccinated against COVID-19, according to research published in Annals of the Rheumatic Diseases (2022 Nov 28. doi: 10.1136/ard-2022-223439).

“Moreover, those who were vaccinated prior to getting COVID-19 had less pain and fatigue after their infection,” Zachary S. Wallace, MD, MSc, an assistant professor of medicine at Harvard Medical School, Boston, and a study author, said in an interview. “These findings reinforce the importance of vaccination in this population.”

Messaging around the value of COVID vaccination has been confusing for some with rheumatic disease “because our concern regarding a blunted response to vaccination has led many patients to think that they do not provide much benefit if they are on immunosuppression,” Dr. Wallace said. “In our cohort, which included many patients on immunosuppression of varying degrees, being vaccinated was quite beneficial.”

Leonard H. Calabrese, DO, director of the R.J. Fasenmyer Center for Clinical Immunology and a professor of medicine at the Cleveland Clinic, said in an interview that the study is an “extremely important contribution to our understanding of COVID-19 and its pattern of recovery in patients with immune-mediated inflammatory diseases [IMIDs].” Remaining unanswered questions are “whether patients with IMIDs develop more frequent PASC [post–acute sequelae of COVID-19] from COVID-19 and, if so, is it milder or more severe, and does it differ in its clinical phenotype?”
 

Long COVID risk assessed at 4 weeks and 3 months after infection

The researchers prospectively tracked 280 adult patients in the Mass General Brigham health care system in the greater Boston area who had systemic autoimmune rheumatic diseases and had an acute COVID-19 infection between March 2020 and July 2022. Patients were an average 53 years old, and most were White (82%) and female (80%). More than half (59%) had inflammatory arthritis, a quarter (24%) had connective tissue disease, and most others had a vasculitis condition or multiple conditions.

filadendron/E+/Getty Images

A total of 11% of patients were unvaccinated, 28% were partially vaccinated with one mRNA COVID-19 vaccine dose, and 41% were fully vaccinated with two mRNA vaccine doses or one Johnson & Johnson dose. The 116 fully vaccinated patients were considered to have a breakthrough infection while the other 164 were considered to have a nonbreakthrough infection. The breakthrough and nonbreakthrough groups were similar in terms of age, sex, race, ethnicity, smoking status, and type of rheumatic disease. Comorbidities were also similar, except obesity, which was more common in the non–breakthrough infection group (25%) than the breakthrough infection group (10%).

The researchers queried patients on their COVID-19 symptoms, how long symptoms lasted, treatments they received, and hospitalization details. COVID-19 symptoms assessed included fever, sore throat, new cough, nasal congestion/rhinorrhea, dyspnea, chest pain, rash, myalgia, fatigue/malaise, headache, nausea/vomiting, diarrhea, anosmia, dysgeusia, and joint pain.

Patients completed surveys about symptoms at 4 weeks and 3 months after infection. Long COVID, or PASC, was defined as any persistent symptom at the times assessed.
 

Vaccinated patients fared better across outcomes

At 4 weeks after infection, 41% of fully vaccinated patients had at least one persistent symptom, compared with 54% of unvaccinated or partially vaccinated patients (P = .04). At 3 months after infection, 21% of fully vaccinated patients had at least one persistent symptom, compared with 41% of unvaccinated or partially vaccinated patients (P < .0001).

Vaccinated patients were half as likely to have long COVID at 4 weeks after infection (adjusted odds ratio, 0.49) and 90% less likely to have long COVID 3 months after infection (aOR, 0.1), after adjustment for age, sex, race, comorbidities, and use of any of four immune-suppressing medications (anti-CD20 monoclonal antibodies, methotrexate, mycophenolate, or glucocorticoids).

Fully vaccinated patients with breakthrough infections had an average 21 additional days without symptoms during follow-up, compared with unvaccinated and partially vaccinated patients (P = .04).

Reduced risk of long COVID did not change for vaccinated patients after sensitivity analyses for those who did not receive nirmatrelvir/ritonavir (Paxlovid) or monoclonal antibodies, those who didn’t receive any COVID-19-related treatment, those who completed their questionnaires within 6 months after infection, and those who were not hospitalized.

“One important message is that among those who did get PASC, the severity appears similar among those with and without a breakthrough infection,” Dr. Wallace said. “This highlights the need for ongoing research to improve recognition, diagnosis, and treatment of PASC.”

Many more breakthrough infections (72%) than nonbreakthrough infections (2%) occurred during Omicron. The authors acknowledged that different variants might play a role in different long COVID risks but said such potential confounding is unlikely to fully explain the results.

“Even with data suggesting that the Omicron variants may be intrinsically less severe, vaccination still has an impact on severity of infection, rates of hospitalization, and other outcomes and thus may play a role in the risk of PASC,” lead author Naomi Patel, MD, an instructor at Harvard Medical School and a rheumatologist at Massachusetts General Hospital, said in an interview. “A study evaluating the proportions with PASC by vaccination status during the time in which a single variant is predominant, such as the early Omicron era, could help to better assess the more isolated impact of vaccination on PASC.”

Dr. Calabrese said he is convinced that Omicron infections are less likely to result in more severe forms of acute COVID than pre-Omicron infections, and he suspects Omicron infections are also less likely to result in long COVID, although less evidence currently supports this hypothesis.

Hospitalization was more common in unvaccinated/partly vaccinated patients than in vaccinated patients (27% vs. 5%; P = .001). Although pain and fatigue were lower in those with breakthrough infections, functional scores and health-related quality of life were similar in both groups.

Some symptoms significantly differed between vaccinated and unvaccinated/partly vaccinated groups, possibly caused partly by different variants. Nasal congestion was more common (73%) in those with breakthrough infections than in those with nonbreakthrough infections (46%; P < .0001). Those who were unvaccinated/partly vaccinated were significantly more likely to have loss of smell (46% vs. 22%) or taste (45% vs. 28%) or to have joint pain (11% vs. 4%).

Treatment with nirmatrelvir/ritonavir was also more common in vaccinated patients (12%) than in unvaccinated/partly vaccinated patients (1%; P < .0001), as was treatment with monoclonal antibodies (34% vs. 8%; P < .0001).

The study was limited by its low diversity and being at a single health care system, the authors said. Study coauthor Jeffrey A. Sparks, MD, MMSc, an assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, said in an interview that the group is planning additional studies as their cohort grows, including “investigating the relationships between COVID-19 and specific rheumatic diseases and immunomodulating medications, expansion of autoimmunity and systemic inflammation, and lung damage among specific patient populations.”

Dr. Calabrese said it will be important for follow-up study of the symptomatic patients to “determine how many of these patients will fit the clinical picture of long COVID or long-haul phenotypes over the months and years ahead, including documenting exertional malaise and quality of life.

This study only assessed patients who received zero, one, or two doses of a vaccine, but many patients with rheumatic disease today will likely have received booster doses. However, Dr. Calabrese said it would be difficult to quantify whether a third, fourth, or fifth dose offers additional protection from long-term COVID complications after full vaccination or hybrid vaccination.

The research was funded by the Rheumatology Research Foundation, the National Institutes of Health, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Dr. Wallace has received research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Zenas BioPharma, Horizon, Sanofi, Shionogi, Viela Bio, and Medpace. Dr. Sparks has received research support from Bristol-Myers Squibb and consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Patel has received consulting fees from FVC Health. Calabrese has consulted for Genentech, Sanofi-Regeneron, AstraZeneca, and GlaxoSmithKline.

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

Black and Latinx older adults are up to three times as likely to develop Alzheimer’s disease than non-Latinx White adults and tend to experience onset at a younger age with more severe symptoms, according to Monica Rivera-Mindt, PhD, a professor of psychology at Fordham University and the Icahn School of Medicine at Mount Sinai, New York. Looking ahead, that means by 2030, nearly 40% of the 8.4 million Americans affected by Alzheimer’s disease will be Black and/or Latinx, she said. These facts were among the stark disparities in health care outcomes Dr. Rivera-Mindt discussed in her presentation on brain health equity at the 2022 annual meeting of the American Neurological Association.

Dr. Rivera-Mindt’s presentation opened the ANA’s plenary session on health disparities and inequities. The plenary, “Advancing Neurologic Equity: Challenges and Paths Forward,” did not simply enumerate racial and ethnic disparities that exist with various neurological conditions. Rather it went beyond the discussion of what disparities exist into understanding the roots of them as well as tips, tools, and resources that can aid clinicians in addressing or ameliorating them.

“Our most prevalent, most burdensome diseases in neurology disproportionately affect persons from minoritized and marginalized backgrounds,” Roy Hamilton, MD, an associate professor of neurology and physical medicine and rehabilitation at the University of Pennsylvania, Philadelphia, said. “If clinicians are unaware of these disparities or don’t have any sense of how to start to address or think about them, then they’re really missing out on an important component of their education as persons who take care of patients with brain disorders.”

Dr. Hamilton, who organized the plenary, noted that awareness of these disparities is crucial to comprehensively caring for patients.
 

Missed opportunities

“We’re talking about disadvantages that are structural and large scale, but those disadvantages play themselves out in the individual encounter,” Dr. Hamilton said. “When physicians see patients, they have to treat the whole patient in front of them,” which means being aware of the risks and factors that could affect a patient’s clinical presentation. “Being aware of disparities has practical impacts on physician judgment,” he said.

For example, recent research in multiple sclerosis (MS) has highlighted how clinicians may be missing diagnosis of this condition in non-White populations because the condition has been regarded for so long as a “White person’s” disease, Dr. Hamilton said. In non-White patients exhibiting MS symptoms, then, clinicians may have been less likely to consider MS as a possibility, thereby delaying diagnosis and treatment.

Those patterns may partly explain why the mortality rate for MS is greater in Black patients, who also show more rapid neurodegeneration than White patients with MS, Lilyana Amezcua, MD, an associate professor of neurology at the University of Southern California, Los Angeles, reported in the plenary’s second presentation.
 

Transgender issues

The third session, presented by Nicole Rosendale, MD, an assistant professor of neurology at the University of California, San Francisco, and director of the San Francisco General Hospital neurology inpatient services, examined disparities in neurology within the LGBTQ+ community through representative case studies and then offered specific ways that neurologists could make their practices more inclusive and equitable for sexual and gender minorities.

Her first case study was a 52-year-old man who presented with new-onset seizures, right hemiparesis, and aphasia. A brain biopsy consistent with adenocarcinoma eventually led his physician to discover he had metastatic breast cancer. It turned out the man was transgender and, despite a family history of breast cancer, hadn’t been advised to get breast cancer screenings.

“Breast cancer was not initially on the differential as no one had identified that the patient was transmasculine,” Dr. Rosendale said. A major challenge to providing care to transgender patients is a dearth of data on risks and screening recommendations. Another barrier is low knowledge of LGBTQ+ health among neurologists, Dr. Rosendale said while sharing findings from her 2019 study on the topic and calling for more research in LGBTQ+ populations.

Dr. Rosendale’s second case study dealt with a nonbinary patient who suffered from debilitating headaches for decades, first because they lacked access to health insurance and then because negative experiences with providers dissuaded them from seeking care. In data from the Center for American Progress she shared, 8% of LGB respondents and 22% of transgender respondents said they had avoided or delayed care because of fear of discrimination or mistreatment.

“So it’s not only access but also what experiences people are having when they go in and whether they’re actually even getting access to care or being taken care of,” Dr. Rosendale said. Other findings from the CAP found that:

• 8% of LGB patients and 29% of transgender patients reported having a clinician refuse to see them.
• 6% of LGB patients and 12% of transgender patients reported that a clinician refused to give them health care.
• 9% of LGB patients and 21% of transgender patients experienced harsh or abusive language during a health care experience.
• 7% of LGB patients and nearly a third (29%) of transgender patients experienced unwanted physical contact, such as fondling or sexual assault.

Reducing the disparities

Adys Mendizabal, MD, an assistant professor of neurology at the Institute of Society and Genetics at the University of California, Los Angeles, who attended the presentation, was grateful to see how the various lectures enriched the discussion beyond stating the fact of racial/ethnic disparities and dug into the nuances on how to think about and address these disparities. She particularly appreciated discussion about the need to go out of the way to recruit diverse patient populations for clinical trials while also providing them care.

“It is definitely complicated, but it’s not impossible for an individual neurologist or an individual department to do something to reduce some of the disparities,” Dr. Mendizabal said. “It starts with just knowing that they exist and being aware of some of the things that may be impacting care for a particular patient.”
 

Tools to counter disparity

In the final presentation, Amy Kind, MD, PhD, the associate dean for social health sciences and programs at the University of Wisconsin–Madison, rounded out the discussion by exploring social determinants of health and their influence on outcomes.

“Social determinants impact brain health, and brain health is not distributed equally,” Dr. Kind told attendees. “We have known this for decades, yet disparities persist.”

Dr. Kind described the “exposome,” a “measure of all the exposures of an individual in a lifetime and how those exposures relate to health,” according to the CDC, and then introduced a tool clinicians can use to better understand social determinants of health in specific geographic areas. The Neighborhood Atlas, which Dr. Kind described in the New England Journal of Medicine in 2018, measures 17 social determinants across small population-sensitive areas and provides an area deprivation index. A high area deprivation index is linked to a range of negative outcomes, including reshopitalization, later diagnoses, less comprehensive diagnostic evaluation, increased risk of postsurgical complications, and decreased life expectancy.

“One of the things that really stood out to me about Dr. Kind’s discussion of the use of the area deprivation index was the fact that understanding and quantifying these kinds of risks and exposures is the vehicle for creating the kinds of social changes, including policy changes, that will actually lead to addressing and mitigating some of these lifelong risks and exposures,” Dr. Hamilton said. “It is implausible to think that a specific group of people would be genetically more susceptible to basically every disease that we know,” he added. “It makes much more sense to think that groups of individuals have been subjected systematically to conditions that impair health in a variety of ways.”
 

Not just race, ethnicity, sex, and gender

Following the four presentations from researchers in health inequities was an Emerging Scholar presentation in which Jay B. Lusk, an MD/MBA candidate at Duke University, Durham, N.C., shared new research findings on the role of neighborhood disadvantage in predicting mortality from coma, stroke, and other neurologic conditions. His findings revealed that living in a neighborhood with greater deprivation substantially increased risk of mortality even after accounting for individual wealth and demographics.

Maria Eugenia Diaz-Ortiz, PhD, of the department of neurology, University of Pennsylvania, Philadelphia, said she found the five presentations to be an excellent introduction to people like herself who are in the earlier stages of learning about health equity research.

“I think they introduced various important concepts and frameworks and provided tools for people who don’t know about them,” Dr. Diaz-Ortiz said. “Then they asked important questions and provided some solutions to them.”

Dr. Diaz-Ortiz also appreciated seemingly minor but actually important details in how the speakers presented themselves, such as Dr. Rivera-Mindt opening with a land acknowledgment and her disclosures of “positionality.” The former recognized the traditional Native American custodians of the land on which she lives and works, and the latter revealed details about her as an individual – such as being the Afro-Latinx daughter of immigrants yet being cisgender, able-bodied, and U.S.-born – that show where she falls on the axis of adversity and axis of privilege.
 

Implications for research

The biggest takeaway for Dr. Diaz-Ortiz, however, came from the first Q&A session when someone asked how to increase underrepresented populations in dementia research. Dr. Rivera-Mindt described her experience engaging these communities by employing “community-based participatory research practices, which involves making yourself a part of the community and making the community active participants in the research,” Dr. Diaz-Ortiz said. “It’s an evidence-based approach that has been shown to increase participation in research not only in her work but in the work of others.”

Preaching to the choir

Dr. Diaz-Ortiz was pleased overall with the plenary but disappointed in its placement at the end of the meeting, when attendance is always lower as attendees head home.

“The people who stayed were people who already know and recognize the value of health equity work, so I think that was a missed opportunity where the session could have been included on day one or two to boost attendance and also to educate like a broader group of neurologists,” Dr. Diaz-Ortiz said in an interview.

Dr. Mendizabal felt similarly, appreciating the plenary but noting it was “definitely overdue” and that it should not be the last session. Instead, sessions on health equity should be as easy as possible to attend to bring in larger audiences. “Perhaps having that session on a Saturday or Sunday would have a higher likelihood of greater attendance than on a Tuesday,” she said. That said, Dr. Mendizabal also noticed that greater attention to health care disparities was woven into many other sessions throughout the conference, which is “the best way of addressing health equity instead of trying to just designate a session,” she said.

Dr. Mendizabal hopes that plenaries like this one and the weaving of health equity issues into presentations throughout neurology conferences continue.

“After the racial reckoning in 2020, there was a big impetus and a big wave of energy in addressing health disparities in the field, and I hope that that momentum is not starting to wane,” Dr. Mendizabal said. “It’s important because not talking about is not going to make this issue go away.”

Dr. Hamilton agreed that it is important that the conversation continue and that physicians recognize the importance of understanding health care disparities and determinants of health, regardless of where they fall on the political spectrum or whether they choose to get involved in policy or advocacy.

“Irrespective of whether you think race or ethnicity or socioeconomic status are political issues or not, it is the case that you’re obligated to have an objective understanding of the factors that contribute to your patient’s health and as points of intervention,” Dr. Hamilton said. “So even if you don’t want to sit down and jot off that email to your senator, you still have to take these factors into account when you’re treating the person who’s sitting right in front of you, and that’s not political. That’s the promise of being a physician.”

Dr. Amezcua has received personal compensation for consulting, speaking, or serving on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono, and she has received research support from Biogen Idec and Bristol Myers Squibb Foundation. Dr. Kind reported support from the Alzheimer’s Association. Dr. Diaz-Ortiz is coinventor of a provisional patent submitted by the University of Pennsylvania that relates to a potential therapeutic in Parkinson’s disease. Mr. Lusk reported fellowship support from American Heart Association and travel support from the American Neurological Association. No other speakers or sources had relevant disclosures.
 

Black and Latinx older adults are up to three times as likely to develop Alzheimer’s disease than non-Latinx White adults and tend to experience onset at a younger age with more severe symptoms, according to Monica Rivera-Mindt, PhD, a professor of psychology at Fordham University and the Icahn School of Medicine at Mount Sinai, New York. Looking ahead, that means by 2030, nearly 40% of the 8.4 million Americans affected by Alzheimer’s disease will be Black and/or Latinx, she said. These facts were among the stark disparities in health care outcomes Dr. Rivera-Mindt discussed in her presentation on brain health equity at the 2022 annual meeting of the American Neurological Association.

Dr. Rivera-Mindt’s presentation opened the ANA’s plenary session on health disparities and inequities. The plenary, “Advancing Neurologic Equity: Challenges and Paths Forward,” did not simply enumerate racial and ethnic disparities that exist with various neurological conditions. Rather it went beyond the discussion of what disparities exist into understanding the roots of them as well as tips, tools, and resources that can aid clinicians in addressing or ameliorating them.

“Our most prevalent, most burdensome diseases in neurology disproportionately affect persons from minoritized and marginalized backgrounds,” Roy Hamilton, MD, an associate professor of neurology and physical medicine and rehabilitation at the University of Pennsylvania, Philadelphia, said. “If clinicians are unaware of these disparities or don’t have any sense of how to start to address or think about them, then they’re really missing out on an important component of their education as persons who take care of patients with brain disorders.”

Dr. Hamilton, who organized the plenary, noted that awareness of these disparities is crucial to comprehensively caring for patients.
 

Missed opportunities

“We’re talking about disadvantages that are structural and large scale, but those disadvantages play themselves out in the individual encounter,” Dr. Hamilton said. “When physicians see patients, they have to treat the whole patient in front of them,” which means being aware of the risks and factors that could affect a patient’s clinical presentation. “Being aware of disparities has practical impacts on physician judgment,” he said.

For example, recent research in multiple sclerosis (MS) has highlighted how clinicians may be missing diagnosis of this condition in non-White populations because the condition has been regarded for so long as a “White person’s” disease, Dr. Hamilton said. In non-White patients exhibiting MS symptoms, then, clinicians may have been less likely to consider MS as a possibility, thereby delaying diagnosis and treatment.

Those patterns may partly explain why the mortality rate for MS is greater in Black patients, who also show more rapid neurodegeneration than White patients with MS, Lilyana Amezcua, MD, an associate professor of neurology at the University of Southern California, Los Angeles, reported in the plenary’s second presentation.
 

Transgender issues

The third session, presented by Nicole Rosendale, MD, an assistant professor of neurology at the University of California, San Francisco, and director of the San Francisco General Hospital neurology inpatient services, examined disparities in neurology within the LGBTQ+ community through representative case studies and then offered specific ways that neurologists could make their practices more inclusive and equitable for sexual and gender minorities.

Her first case study was a 52-year-old man who presented with new-onset seizures, right hemiparesis, and aphasia. A brain biopsy consistent with adenocarcinoma eventually led his physician to discover he had metastatic breast cancer. It turned out the man was transgender and, despite a family history of breast cancer, hadn’t been advised to get breast cancer screenings.

“Breast cancer was not initially on the differential as no one had identified that the patient was transmasculine,” Dr. Rosendale said. A major challenge to providing care to transgender patients is a dearth of data on risks and screening recommendations. Another barrier is low knowledge of LGBTQ+ health among neurologists, Dr. Rosendale said while sharing findings from her 2019 study on the topic and calling for more research in LGBTQ+ populations.

Dr. Rosendale’s second case study dealt with a nonbinary patient who suffered from debilitating headaches for decades, first because they lacked access to health insurance and then because negative experiences with providers dissuaded them from seeking care. In data from the Center for American Progress she shared, 8% of LGB respondents and 22% of transgender respondents said they had avoided or delayed care because of fear of discrimination or mistreatment.

“So it’s not only access but also what experiences people are having when they go in and whether they’re actually even getting access to care or being taken care of,” Dr. Rosendale said. Other findings from the CAP found that:

• 8% of LGB patients and 29% of transgender patients reported having a clinician refuse to see them.
• 6% of LGB patients and 12% of transgender patients reported that a clinician refused to give them health care.
• 9% of LGB patients and 21% of transgender patients experienced harsh or abusive language during a health care experience.
• 7% of LGB patients and nearly a third (29%) of transgender patients experienced unwanted physical contact, such as fondling or sexual assault.

Reducing the disparities

Adys Mendizabal, MD, an assistant professor of neurology at the Institute of Society and Genetics at the University of California, Los Angeles, who attended the presentation, was grateful to see how the various lectures enriched the discussion beyond stating the fact of racial/ethnic disparities and dug into the nuances on how to think about and address these disparities. She particularly appreciated discussion about the need to go out of the way to recruit diverse patient populations for clinical trials while also providing them care.

“It is definitely complicated, but it’s not impossible for an individual neurologist or an individual department to do something to reduce some of the disparities,” Dr. Mendizabal said. “It starts with just knowing that they exist and being aware of some of the things that may be impacting care for a particular patient.”
 

Tools to counter disparity

In the final presentation, Amy Kind, MD, PhD, the associate dean for social health sciences and programs at the University of Wisconsin–Madison, rounded out the discussion by exploring social determinants of health and their influence on outcomes.

“Social determinants impact brain health, and brain health is not distributed equally,” Dr. Kind told attendees. “We have known this for decades, yet disparities persist.”

Dr. Kind described the “exposome,” a “measure of all the exposures of an individual in a lifetime and how those exposures relate to health,” according to the CDC, and then introduced a tool clinicians can use to better understand social determinants of health in specific geographic areas. The Neighborhood Atlas, which Dr. Kind described in the New England Journal of Medicine in 2018, measures 17 social determinants across small population-sensitive areas and provides an area deprivation index. A high area deprivation index is linked to a range of negative outcomes, including reshopitalization, later diagnoses, less comprehensive diagnostic evaluation, increased risk of postsurgical complications, and decreased life expectancy.

“One of the things that really stood out to me about Dr. Kind’s discussion of the use of the area deprivation index was the fact that understanding and quantifying these kinds of risks and exposures is the vehicle for creating the kinds of social changes, including policy changes, that will actually lead to addressing and mitigating some of these lifelong risks and exposures,” Dr. Hamilton said. “It is implausible to think that a specific group of people would be genetically more susceptible to basically every disease that we know,” he added. “It makes much more sense to think that groups of individuals have been subjected systematically to conditions that impair health in a variety of ways.”
 

Not just race, ethnicity, sex, and gender

Following the four presentations from researchers in health inequities was an Emerging Scholar presentation in which Jay B. Lusk, an MD/MBA candidate at Duke University, Durham, N.C., shared new research findings on the role of neighborhood disadvantage in predicting mortality from coma, stroke, and other neurologic conditions. His findings revealed that living in a neighborhood with greater deprivation substantially increased risk of mortality even after accounting for individual wealth and demographics.

Maria Eugenia Diaz-Ortiz, PhD, of the department of neurology, University of Pennsylvania, Philadelphia, said she found the five presentations to be an excellent introduction to people like herself who are in the earlier stages of learning about health equity research.

“I think they introduced various important concepts and frameworks and provided tools for people who don’t know about them,” Dr. Diaz-Ortiz said. “Then they asked important questions and provided some solutions to them.”

Dr. Diaz-Ortiz also appreciated seemingly minor but actually important details in how the speakers presented themselves, such as Dr. Rivera-Mindt opening with a land acknowledgment and her disclosures of “positionality.” The former recognized the traditional Native American custodians of the land on which she lives and works, and the latter revealed details about her as an individual – such as being the Afro-Latinx daughter of immigrants yet being cisgender, able-bodied, and U.S.-born – that show where she falls on the axis of adversity and axis of privilege.
 

Implications for research

The biggest takeaway for Dr. Diaz-Ortiz, however, came from the first Q&A session when someone asked how to increase underrepresented populations in dementia research. Dr. Rivera-Mindt described her experience engaging these communities by employing “community-based participatory research practices, which involves making yourself a part of the community and making the community active participants in the research,” Dr. Diaz-Ortiz said. “It’s an evidence-based approach that has been shown to increase participation in research not only in her work but in the work of others.”

Preaching to the choir

Dr. Diaz-Ortiz was pleased overall with the plenary but disappointed in its placement at the end of the meeting, when attendance is always lower as attendees head home.

“The people who stayed were people who already know and recognize the value of health equity work, so I think that was a missed opportunity where the session could have been included on day one or two to boost attendance and also to educate like a broader group of neurologists,” Dr. Diaz-Ortiz said in an interview.

Dr. Mendizabal felt similarly, appreciating the plenary but noting it was “definitely overdue” and that it should not be the last session. Instead, sessions on health equity should be as easy as possible to attend to bring in larger audiences. “Perhaps having that session on a Saturday or Sunday would have a higher likelihood of greater attendance than on a Tuesday,” she said. That said, Dr. Mendizabal also noticed that greater attention to health care disparities was woven into many other sessions throughout the conference, which is “the best way of addressing health equity instead of trying to just designate a session,” she said.

Dr. Mendizabal hopes that plenaries like this one and the weaving of health equity issues into presentations throughout neurology conferences continue.

“After the racial reckoning in 2020, there was a big impetus and a big wave of energy in addressing health disparities in the field, and I hope that that momentum is not starting to wane,” Dr. Mendizabal said. “It’s important because not talking about is not going to make this issue go away.”

Dr. Hamilton agreed that it is important that the conversation continue and that physicians recognize the importance of understanding health care disparities and determinants of health, regardless of where they fall on the political spectrum or whether they choose to get involved in policy or advocacy.

“Irrespective of whether you think race or ethnicity or socioeconomic status are political issues or not, it is the case that you’re obligated to have an objective understanding of the factors that contribute to your patient’s health and as points of intervention,” Dr. Hamilton said. “So even if you don’t want to sit down and jot off that email to your senator, you still have to take these factors into account when you’re treating the person who’s sitting right in front of you, and that’s not political. That’s the promise of being a physician.”

Dr. Amezcua has received personal compensation for consulting, speaking, or serving on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono, and she has received research support from Biogen Idec and Bristol Myers Squibb Foundation. Dr. Kind reported support from the Alzheimer’s Association. Dr. Diaz-Ortiz is coinventor of a provisional patent submitted by the University of Pennsylvania that relates to a potential therapeutic in Parkinson’s disease. Mr. Lusk reported fellowship support from American Heart Association and travel support from the American Neurological Association. No other speakers or sources had relevant disclosures.
 

Black and Latinx older adults are up to three times as likely to develop Alzheimer’s disease than non-Latinx White adults and tend to experience onset at a younger age with more severe symptoms, according to Monica Rivera-Mindt, PhD, a professor of psychology at Fordham University and the Icahn School of Medicine at Mount Sinai, New York. Looking ahead, that means by 2030, nearly 40% of the 8.4 million Americans affected by Alzheimer’s disease will be Black and/or Latinx, she said. These facts were among the stark disparities in health care outcomes Dr. Rivera-Mindt discussed in her presentation on brain health equity at the 2022 annual meeting of the American Neurological Association.

Dr. Rivera-Mindt’s presentation opened the ANA’s plenary session on health disparities and inequities. The plenary, “Advancing Neurologic Equity: Challenges and Paths Forward,” did not simply enumerate racial and ethnic disparities that exist with various neurological conditions. Rather it went beyond the discussion of what disparities exist into understanding the roots of them as well as tips, tools, and resources that can aid clinicians in addressing or ameliorating them.

“Our most prevalent, most burdensome diseases in neurology disproportionately affect persons from minoritized and marginalized backgrounds,” Roy Hamilton, MD, an associate professor of neurology and physical medicine and rehabilitation at the University of Pennsylvania, Philadelphia, said. “If clinicians are unaware of these disparities or don’t have any sense of how to start to address or think about them, then they’re really missing out on an important component of their education as persons who take care of patients with brain disorders.”

Dr. Hamilton, who organized the plenary, noted that awareness of these disparities is crucial to comprehensively caring for patients.
 

Missed opportunities

“We’re talking about disadvantages that are structural and large scale, but those disadvantages play themselves out in the individual encounter,” Dr. Hamilton said. “When physicians see patients, they have to treat the whole patient in front of them,” which means being aware of the risks and factors that could affect a patient’s clinical presentation. “Being aware of disparities has practical impacts on physician judgment,” he said.

For example, recent research in multiple sclerosis (MS) has highlighted how clinicians may be missing diagnosis of this condition in non-White populations because the condition has been regarded for so long as a “White person’s” disease, Dr. Hamilton said. In non-White patients exhibiting MS symptoms, then, clinicians may have been less likely to consider MS as a possibility, thereby delaying diagnosis and treatment.

Those patterns may partly explain why the mortality rate for MS is greater in Black patients, who also show more rapid neurodegeneration than White patients with MS, Lilyana Amezcua, MD, an associate professor of neurology at the University of Southern California, Los Angeles, reported in the plenary’s second presentation.
 

Transgender issues

The third session, presented by Nicole Rosendale, MD, an assistant professor of neurology at the University of California, San Francisco, and director of the San Francisco General Hospital neurology inpatient services, examined disparities in neurology within the LGBTQ+ community through representative case studies and then offered specific ways that neurologists could make their practices more inclusive and equitable for sexual and gender minorities.

Her first case study was a 52-year-old man who presented with new-onset seizures, right hemiparesis, and aphasia. A brain biopsy consistent with adenocarcinoma eventually led his physician to discover he had metastatic breast cancer. It turned out the man was transgender and, despite a family history of breast cancer, hadn’t been advised to get breast cancer screenings.

“Breast cancer was not initially on the differential as no one had identified that the patient was transmasculine,” Dr. Rosendale said. A major challenge to providing care to transgender patients is a dearth of data on risks and screening recommendations. Another barrier is low knowledge of LGBTQ+ health among neurologists, Dr. Rosendale said while sharing findings from her 2019 study on the topic and calling for more research in LGBTQ+ populations.

Dr. Rosendale’s second case study dealt with a nonbinary patient who suffered from debilitating headaches for decades, first because they lacked access to health insurance and then because negative experiences with providers dissuaded them from seeking care. In data from the Center for American Progress she shared, 8% of LGB respondents and 22% of transgender respondents said they had avoided or delayed care because of fear of discrimination or mistreatment.

“So it’s not only access but also what experiences people are having when they go in and whether they’re actually even getting access to care or being taken care of,” Dr. Rosendale said. Other findings from the CAP found that:

• 8% of LGB patients and 29% of transgender patients reported having a clinician refuse to see them.
• 6% of LGB patients and 12% of transgender patients reported that a clinician refused to give them health care.
• 9% of LGB patients and 21% of transgender patients experienced harsh or abusive language during a health care experience.
• 7% of LGB patients and nearly a third (29%) of transgender patients experienced unwanted physical contact, such as fondling or sexual assault.

Reducing the disparities

Adys Mendizabal, MD, an assistant professor of neurology at the Institute of Society and Genetics at the University of California, Los Angeles, who attended the presentation, was grateful to see how the various lectures enriched the discussion beyond stating the fact of racial/ethnic disparities and dug into the nuances on how to think about and address these disparities. She particularly appreciated discussion about the need to go out of the way to recruit diverse patient populations for clinical trials while also providing them care.

“It is definitely complicated, but it’s not impossible for an individual neurologist or an individual department to do something to reduce some of the disparities,” Dr. Mendizabal said. “It starts with just knowing that they exist and being aware of some of the things that may be impacting care for a particular patient.”
 

Tools to counter disparity

In the final presentation, Amy Kind, MD, PhD, the associate dean for social health sciences and programs at the University of Wisconsin–Madison, rounded out the discussion by exploring social determinants of health and their influence on outcomes.

“Social determinants impact brain health, and brain health is not distributed equally,” Dr. Kind told attendees. “We have known this for decades, yet disparities persist.”

Dr. Kind described the “exposome,” a “measure of all the exposures of an individual in a lifetime and how those exposures relate to health,” according to the CDC, and then introduced a tool clinicians can use to better understand social determinants of health in specific geographic areas. The Neighborhood Atlas, which Dr. Kind described in the New England Journal of Medicine in 2018, measures 17 social determinants across small population-sensitive areas and provides an area deprivation index. A high area deprivation index is linked to a range of negative outcomes, including reshopitalization, later diagnoses, less comprehensive diagnostic evaluation, increased risk of postsurgical complications, and decreased life expectancy.

“One of the things that really stood out to me about Dr. Kind’s discussion of the use of the area deprivation index was the fact that understanding and quantifying these kinds of risks and exposures is the vehicle for creating the kinds of social changes, including policy changes, that will actually lead to addressing and mitigating some of these lifelong risks and exposures,” Dr. Hamilton said. “It is implausible to think that a specific group of people would be genetically more susceptible to basically every disease that we know,” he added. “It makes much more sense to think that groups of individuals have been subjected systematically to conditions that impair health in a variety of ways.”
 

Not just race, ethnicity, sex, and gender

Following the four presentations from researchers in health inequities was an Emerging Scholar presentation in which Jay B. Lusk, an MD/MBA candidate at Duke University, Durham, N.C., shared new research findings on the role of neighborhood disadvantage in predicting mortality from coma, stroke, and other neurologic conditions. His findings revealed that living in a neighborhood with greater deprivation substantially increased risk of mortality even after accounting for individual wealth and demographics.

Maria Eugenia Diaz-Ortiz, PhD, of the department of neurology, University of Pennsylvania, Philadelphia, said she found the five presentations to be an excellent introduction to people like herself who are in the earlier stages of learning about health equity research.

“I think they introduced various important concepts and frameworks and provided tools for people who don’t know about them,” Dr. Diaz-Ortiz said. “Then they asked important questions and provided some solutions to them.”

Dr. Diaz-Ortiz also appreciated seemingly minor but actually important details in how the speakers presented themselves, such as Dr. Rivera-Mindt opening with a land acknowledgment and her disclosures of “positionality.” The former recognized the traditional Native American custodians of the land on which she lives and works, and the latter revealed details about her as an individual – such as being the Afro-Latinx daughter of immigrants yet being cisgender, able-bodied, and U.S.-born – that show where she falls on the axis of adversity and axis of privilege.
 

Implications for research

The biggest takeaway for Dr. Diaz-Ortiz, however, came from the first Q&A session when someone asked how to increase underrepresented populations in dementia research. Dr. Rivera-Mindt described her experience engaging these communities by employing “community-based participatory research practices, which involves making yourself a part of the community and making the community active participants in the research,” Dr. Diaz-Ortiz said. “It’s an evidence-based approach that has been shown to increase participation in research not only in her work but in the work of others.”

Preaching to the choir

Dr. Diaz-Ortiz was pleased overall with the plenary but disappointed in its placement at the end of the meeting, when attendance is always lower as attendees head home.

“The people who stayed were people who already know and recognize the value of health equity work, so I think that was a missed opportunity where the session could have been included on day one or two to boost attendance and also to educate like a broader group of neurologists,” Dr. Diaz-Ortiz said in an interview.

Dr. Mendizabal felt similarly, appreciating the plenary but noting it was “definitely overdue” and that it should not be the last session. Instead, sessions on health equity should be as easy as possible to attend to bring in larger audiences. “Perhaps having that session on a Saturday or Sunday would have a higher likelihood of greater attendance than on a Tuesday,” she said. That said, Dr. Mendizabal also noticed that greater attention to health care disparities was woven into many other sessions throughout the conference, which is “the best way of addressing health equity instead of trying to just designate a session,” she said.

Dr. Mendizabal hopes that plenaries like this one and the weaving of health equity issues into presentations throughout neurology conferences continue.

“After the racial reckoning in 2020, there was a big impetus and a big wave of energy in addressing health disparities in the field, and I hope that that momentum is not starting to wane,” Dr. Mendizabal said. “It’s important because not talking about is not going to make this issue go away.”

Dr. Hamilton agreed that it is important that the conversation continue and that physicians recognize the importance of understanding health care disparities and determinants of health, regardless of where they fall on the political spectrum or whether they choose to get involved in policy or advocacy.

“Irrespective of whether you think race or ethnicity or socioeconomic status are political issues or not, it is the case that you’re obligated to have an objective understanding of the factors that contribute to your patient’s health and as points of intervention,” Dr. Hamilton said. “So even if you don’t want to sit down and jot off that email to your senator, you still have to take these factors into account when you’re treating the person who’s sitting right in front of you, and that’s not political. That’s the promise of being a physician.”

Dr. Amezcua has received personal compensation for consulting, speaking, or serving on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono, and she has received research support from Biogen Idec and Bristol Myers Squibb Foundation. Dr. Kind reported support from the Alzheimer’s Association. Dr. Diaz-Ortiz is coinventor of a provisional patent submitted by the University of Pennsylvania that relates to a potential therapeutic in Parkinson’s disease. Mr. Lusk reported fellowship support from American Heart Association and travel support from the American Neurological Association. No other speakers or sources had relevant disclosures.
 

Mailing invitations for hepatocellular carcinoma (HCC) surveillance screening to patients with cirrhosis increased ultrasound uptake by 13 percentage points, but the majority of patients still did not receive the recommended semiannual screenings, according to findings published in Clinical Gastroenterology and Hepatology.

“These data highlight the need for more intensive interventions to further increase surveillance,” wrote Amit Singal, MD, of University of Texas Southwestern Medical Center and Parkland Health Hospital System in Dallas, and colleagues. “The underuse of HCC surveillance has been attributed to a combination of patient- and provider-level barriers, which can serve as future additional intervention targets.” These include transportation and financial barriers and possibly new blood-based screening modalities when they become available, thereby removing the need for a separate ultrasound appointment.

According to one study, more than 90% of hepatocellular carcinoma cases occur in people with chronic liver disease, and the cancer is a leading cause of death in those with compensated cirrhosis. Multiple medical associations therefore recommend an abdominal ultrasound every 6 months with or without alpha-fetoprotein (AFP) for surveillance in at-risk patients, including anyone with cirrhosis of any kind, but too few patients receive these surveillance ultrasounds, the authors write.

The researchers therefore conducted a pragmatic randomized clinical trial from March 2018 to September 2019 to compare surveillance ultrasound uptake for two groups of people with cirrhosis: 1,436 people who were mailed invitations to get a surveillance ultrasound and 1,436 people who received usual care, with surveillance recommended only at usual visits. The patients all received care at one of three health systems: a tertiary care referral center, a safety net health system, and a Veterans Affairs medical center. The primary outcome was semiannual surveillance in the patients over 1 year.

The researchers identified patients using ICD-9 and ICD-10 codes for cirrhosis and cirrhosis complications, as well as those with suspected but undocumented cirrhosis based on electronic medical record notes such as an elevated Fibrosis-4 index. They confirmed the diagnoses with chart review, confirmed that the patients had at least one outpatient visit in the previous year, and excluded those in whom surveillance is not recommended, who lacked contact information, or who spoke a language besides English or Spanish.

The mailing was a one-page letter in English and Spanish, written at a low literacy level, that explained hepatocellular carcinoma risk and recommended surveillance. Those who didn’t respond to the mailed invitation within 2 weeks received a reminder call to undergo surveillance, and those who scheduled an ultrasound received a reminder call about a week before the visit. Primary and subspecialty providers were blinded to the patients’ study arm assignments.

“We conducted the study as a pragmatic trial whereby patients in either arm could also be offered HCC surveillance by primary or specialty care providers during clinic visits,” the researchers wrote. “The frequency of the clinic visits and provider discussions regarding HCC surveillance were conducted per usual care and not dictated by the study protocol.”

Two-thirds of the patients (67.7%) were men, with a median age of 61.2 years. Just over a third (37.0%) were white, 31.9% were Hispanic, and 27.6% were Black. More than half the patients had hepatitis C (56.4%), 18.1% had alcohol-related liver disease, 14.5% had nonalcoholic fatty liver disease, and 2.4% had hepatitis B. Most of the patients had compensated cirrhosis, including 36.7% with ascites and 17.1% with hepatic encephalopathy.

Nearly a quarter of the patients in the outreach arm (23%) could not be contacted or lacked working phone numbers, but they remained in the intent-to-screen analysis. Just over a third of the patients who received mailed outreach (35.1%; 95% confidence interval, 32.6%-37.6%) received semiannual surveillance, compared to 21.9% (95% CI, 19.8%-24.2%) of the usual-care patients. The increased surveillance in the outreach group applied to most subgroups, including race/ethnicity and cirrhosis severity based on the Child-Turcotte-Pugh class.

“However, we observed site-level differences in the intervention effect, with significant increases in semiannual surveillance at the VA and safety net health systems (both P < .001) but not at the tertiary care referral center (P = .52),” the authors wrote. “In a post hoc subgroup analysis among patients with at least 1 primary care or gastroenterology outpatient visit during the study period, mailed outreach continued to increase semiannual surveillance, compared with usual care (46.8% vs. 32.7%; P < .001).”

Despite the improved rates from the intervention, the majority of patients still did not receive semiannual surveillance across all three sites, and almost 30% underwent no surveillance the entire year.

The research was funded by the National Cancer Institute, the Cancer Prevention Research Institute of Texas, and the Center for Innovations in Quality, Effectiveness and Safety. Dr. Singal has consulted for or served on the advisory boards of Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, and GRAIL. The other authors had no industry disclosures.

Mailing invitations for hepatocellular carcinoma (HCC) surveillance screening to patients with cirrhosis increased ultrasound uptake by 13 percentage points, but the majority of patients still did not receive the recommended semiannual screenings, according to findings published in Clinical Gastroenterology and Hepatology.

“These data highlight the need for more intensive interventions to further increase surveillance,” wrote Amit Singal, MD, of University of Texas Southwestern Medical Center and Parkland Health Hospital System in Dallas, and colleagues. “The underuse of HCC surveillance has been attributed to a combination of patient- and provider-level barriers, which can serve as future additional intervention targets.” These include transportation and financial barriers and possibly new blood-based screening modalities when they become available, thereby removing the need for a separate ultrasound appointment.

According to one study, more than 90% of hepatocellular carcinoma cases occur in people with chronic liver disease, and the cancer is a leading cause of death in those with compensated cirrhosis. Multiple medical associations therefore recommend an abdominal ultrasound every 6 months with or without alpha-fetoprotein (AFP) for surveillance in at-risk patients, including anyone with cirrhosis of any kind, but too few patients receive these surveillance ultrasounds, the authors write.

The researchers therefore conducted a pragmatic randomized clinical trial from March 2018 to September 2019 to compare surveillance ultrasound uptake for two groups of people with cirrhosis: 1,436 people who were mailed invitations to get a surveillance ultrasound and 1,436 people who received usual care, with surveillance recommended only at usual visits. The patients all received care at one of three health systems: a tertiary care referral center, a safety net health system, and a Veterans Affairs medical center. The primary outcome was semiannual surveillance in the patients over 1 year.

The researchers identified patients using ICD-9 and ICD-10 codes for cirrhosis and cirrhosis complications, as well as those with suspected but undocumented cirrhosis based on electronic medical record notes such as an elevated Fibrosis-4 index. They confirmed the diagnoses with chart review, confirmed that the patients had at least one outpatient visit in the previous year, and excluded those in whom surveillance is not recommended, who lacked contact information, or who spoke a language besides English or Spanish.

The mailing was a one-page letter in English and Spanish, written at a low literacy level, that explained hepatocellular carcinoma risk and recommended surveillance. Those who didn’t respond to the mailed invitation within 2 weeks received a reminder call to undergo surveillance, and those who scheduled an ultrasound received a reminder call about a week before the visit. Primary and subspecialty providers were blinded to the patients’ study arm assignments.

“We conducted the study as a pragmatic trial whereby patients in either arm could also be offered HCC surveillance by primary or specialty care providers during clinic visits,” the researchers wrote. “The frequency of the clinic visits and provider discussions regarding HCC surveillance were conducted per usual care and not dictated by the study protocol.”

Two-thirds of the patients (67.7%) were men, with a median age of 61.2 years. Just over a third (37.0%) were white, 31.9% were Hispanic, and 27.6% were Black. More than half the patients had hepatitis C (56.4%), 18.1% had alcohol-related liver disease, 14.5% had nonalcoholic fatty liver disease, and 2.4% had hepatitis B. Most of the patients had compensated cirrhosis, including 36.7% with ascites and 17.1% with hepatic encephalopathy.

Nearly a quarter of the patients in the outreach arm (23%) could not be contacted or lacked working phone numbers, but they remained in the intent-to-screen analysis. Just over a third of the patients who received mailed outreach (35.1%; 95% confidence interval, 32.6%-37.6%) received semiannual surveillance, compared to 21.9% (95% CI, 19.8%-24.2%) of the usual-care patients. The increased surveillance in the outreach group applied to most subgroups, including race/ethnicity and cirrhosis severity based on the Child-Turcotte-Pugh class.

“However, we observed site-level differences in the intervention effect, with significant increases in semiannual surveillance at the VA and safety net health systems (both P < .001) but not at the tertiary care referral center (P = .52),” the authors wrote. “In a post hoc subgroup analysis among patients with at least 1 primary care or gastroenterology outpatient visit during the study period, mailed outreach continued to increase semiannual surveillance, compared with usual care (46.8% vs. 32.7%; P < .001).”

Despite the improved rates from the intervention, the majority of patients still did not receive semiannual surveillance across all three sites, and almost 30% underwent no surveillance the entire year.

The research was funded by the National Cancer Institute, the Cancer Prevention Research Institute of Texas, and the Center for Innovations in Quality, Effectiveness and Safety. Dr. Singal has consulted for or served on the advisory boards of Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, and GRAIL. The other authors had no industry disclosures.

Mailing invitations for hepatocellular carcinoma (HCC) surveillance screening to patients with cirrhosis increased ultrasound uptake by 13 percentage points, but the majority of patients still did not receive the recommended semiannual screenings, according to findings published in Clinical Gastroenterology and Hepatology.

“These data highlight the need for more intensive interventions to further increase surveillance,” wrote Amit Singal, MD, of University of Texas Southwestern Medical Center and Parkland Health Hospital System in Dallas, and colleagues. “The underuse of HCC surveillance has been attributed to a combination of patient- and provider-level barriers, which can serve as future additional intervention targets.” These include transportation and financial barriers and possibly new blood-based screening modalities when they become available, thereby removing the need for a separate ultrasound appointment.

According to one study, more than 90% of hepatocellular carcinoma cases occur in people with chronic liver disease, and the cancer is a leading cause of death in those with compensated cirrhosis. Multiple medical associations therefore recommend an abdominal ultrasound every 6 months with or without alpha-fetoprotein (AFP) for surveillance in at-risk patients, including anyone with cirrhosis of any kind, but too few patients receive these surveillance ultrasounds, the authors write.

The researchers therefore conducted a pragmatic randomized clinical trial from March 2018 to September 2019 to compare surveillance ultrasound uptake for two groups of people with cirrhosis: 1,436 people who were mailed invitations to get a surveillance ultrasound and 1,436 people who received usual care, with surveillance recommended only at usual visits. The patients all received care at one of three health systems: a tertiary care referral center, a safety net health system, and a Veterans Affairs medical center. The primary outcome was semiannual surveillance in the patients over 1 year.

The researchers identified patients using ICD-9 and ICD-10 codes for cirrhosis and cirrhosis complications, as well as those with suspected but undocumented cirrhosis based on electronic medical record notes such as an elevated Fibrosis-4 index. They confirmed the diagnoses with chart review, confirmed that the patients had at least one outpatient visit in the previous year, and excluded those in whom surveillance is not recommended, who lacked contact information, or who spoke a language besides English or Spanish.

The mailing was a one-page letter in English and Spanish, written at a low literacy level, that explained hepatocellular carcinoma risk and recommended surveillance. Those who didn’t respond to the mailed invitation within 2 weeks received a reminder call to undergo surveillance, and those who scheduled an ultrasound received a reminder call about a week before the visit. Primary and subspecialty providers were blinded to the patients’ study arm assignments.

“We conducted the study as a pragmatic trial whereby patients in either arm could also be offered HCC surveillance by primary or specialty care providers during clinic visits,” the researchers wrote. “The frequency of the clinic visits and provider discussions regarding HCC surveillance were conducted per usual care and not dictated by the study protocol.”

Two-thirds of the patients (67.7%) were men, with a median age of 61.2 years. Just over a third (37.0%) were white, 31.9% were Hispanic, and 27.6% were Black. More than half the patients had hepatitis C (56.4%), 18.1% had alcohol-related liver disease, 14.5% had nonalcoholic fatty liver disease, and 2.4% had hepatitis B. Most of the patients had compensated cirrhosis, including 36.7% with ascites and 17.1% with hepatic encephalopathy.

Nearly a quarter of the patients in the outreach arm (23%) could not be contacted or lacked working phone numbers, but they remained in the intent-to-screen analysis. Just over a third of the patients who received mailed outreach (35.1%; 95% confidence interval, 32.6%-37.6%) received semiannual surveillance, compared to 21.9% (95% CI, 19.8%-24.2%) of the usual-care patients. The increased surveillance in the outreach group applied to most subgroups, including race/ethnicity and cirrhosis severity based on the Child-Turcotte-Pugh class.

“However, we observed site-level differences in the intervention effect, with significant increases in semiannual surveillance at the VA and safety net health systems (both P < .001) but not at the tertiary care referral center (P = .52),” the authors wrote. “In a post hoc subgroup analysis among patients with at least 1 primary care or gastroenterology outpatient visit during the study period, mailed outreach continued to increase semiannual surveillance, compared with usual care (46.8% vs. 32.7%; P < .001).”

Despite the improved rates from the intervention, the majority of patients still did not receive semiannual surveillance across all three sites, and almost 30% underwent no surveillance the entire year.

The research was funded by the National Cancer Institute, the Cancer Prevention Research Institute of Texas, and the Center for Innovations in Quality, Effectiveness and Safety. Dr. Singal has consulted for or served on the advisory boards of Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, and GRAIL. The other authors had no industry disclosures.

Up to 10 different menopausal symptoms were linked to an increased risk of cardiovascular disease when they were moderate to severe in women who initially had no evidence of cardiovascular disease, according to research presented at the North American Menopause Society annual meeting in Atlanta.

“The take-home message is that severe menopausal symptoms may increase the risk of cardiovascular disease,” Matthew Nudy, MD, an assistant professor of medicine at the Heart and Vascular Institute at Penn State University, Hershey, said in an interview about his findings. “Physicians and patients should be aware of this association. Women with severe symptoms may be more likely to see their physician, and this would be an ideal time to have their cardiovascular risk assessed.”

Margaret Nachtigall, MD, a clinical associate professor of obstetrics and gynecology at New York University and at NYU Langone Health, noted that these findings lined up with other studies showing an increased risk of cardiovascular disease in patients who have more symptoms, especially hot flashes.

“Other recent studies showed that an increase in severity of hot flush is associated with worse blood vessel function, leading to heart disease,” Dr. Nachtigall, who was not involved with the study, said in an interview. “The next step that makes sense is to try to eliminate these symptoms and hope that, in turn, would lower cardiovascular disease and improve survival.”

The researchers compared menopausal symptoms with cardiovascular outcomes and all-cause mortality in an observational cohort of 80,278 postmenopausal women for a median 8.2 years of follow-up. None of the women, all enrolled in the Women’s Health Initiative, had known cardiovascular disease at baseline. They had an average age of 63 years and average body mass index (BMI) of 25.9 at baseline. Most participants were White (86.7%), with 7% being Black and 4.1% Hispanic. Cardiovascular disease was a composite outcome that included hospitalized myocardial infarction, definite silent myocardial infarction, coronary death, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization.

The researchers used a four-item Likert scale (0-3) to assess the severity of 15 symptoms experienced within the past 4 weeks at baseline: “night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, [feeling] restless or fidgety, and difficulty concentrating.”

The associations were adjusted for the following covariates: race/ethnicity, blood pressure, education, smoking status, bilateral oophorectomy, menopausal hormone therapy use (never/past/current), sleep duration, statin use, history of high cholesterol, aspirin use, use of antihypertensives, treated diabetes, and family history of heart attack. Continuous variables included age, age at menopause, BMI, blood pressure, and physical activity levels. Because of the high number of multiple comparisons, the researchers also used a Bonferroni correction to reduce the risk of spurious statistical significance.

The researchers found some clustering of symptoms. Among women who had at least two moderate or severe menopausal symptoms, more than half frequently woke up at night, had joint pain, or felt tired, the researchers reported. Those symptoms were also the most commonly reported ones overall. Younger women, between ages 50 and 59, were more likely than older women (60-79 years old) to experience vasomotor symptoms and all cognitive affective symptoms except forgetfulness.

The researchers identified 10 symptoms whose severity was significantly associated with cardiovascular disease. Compared to having no symptoms at all, the following moderate or severe symptoms were associated with an increased risk of a cardiovascular event after adjustment for covariates and corrected for multiple comparisons: night sweats – a 19% increased risk (P = .03), waking up several times at night – 11% increased risk (P = .05), joint pain or stiffness – 27% increased risk (P < .001), heart racing or skipping beats – 55% increased risk (P < .001), dizziness – 34% increased risk (P < .001), feeling tired – 35% increased risk (P < .001), forgetfulness – 25% increased risk (P < .001), mood swings – 21% increased risk (P = .02), feeling restless or fidgety – 29% increased risk (P < .001), and difficulty concentrating – 31% increased risk (P < .001)

In addition, all-cause mortality was associated with these symptoms when they were moderate or severe: heart racing or skipping beats (32% increased risk of all-cause mortality; hazard ratio, 1.32; P =.006), dizziness (HR, 1.58; P < .001), tremors (HR, 1.44; P < .001), feeling tired (HR, 1.26; P < .001), forgetfulness (HR, 1.29; P = .01), mood swings (HR, 1.35; P = .02), feeling restless or fidgety (HR, 1.35; P < .001), and difficulty concentrating (HR, 1.47; P < .001).

The symptom with the greatest association with all-cause mortality was dizziness, which was associated with an increased risk of 58% when rated moderate or severe. Any dizziness at all was linked to a 12% increased risk of cardiovascular disease, compared with no dizziness. Machine learning with the LASSO method determined that the symptoms most predictive of cardiovascular disease were dizziness, heart racing, feeling tired, and joint pain. The symptoms most associated with all-cause mortality, based on the machine learning algorithm, were dizziness, tremors, and feeling tired.

Dr. Nudy said that their study did not look at mitigation strategies. “Women should discuss with their physician the best methods for cardiovascular risk reduction,” he said. He also cautioned that severe menopausal symptoms can also indicate other health conditions that may require investigation.

“It is certainly possible some symptoms may represent other medical conditions we were unable to control for and may not be directly related to menopause,” such as autoimmune diseases, endocrine abnormalities, or subclinical cardiovascular disease, he said. Additional limitations of the study included an older cohort and retrospective assessment of menopausal symptoms only at baseline. In addition, ”we did not assess the cardiovascular risk among women whose symptoms persisted versus resolved during the study period,” Dr. Nudy said.

Dr. Nachtigall said a key message is that people who are experiencing these symptoms should try to get treatment for them and attempt to alleviate them, hopefully reducing the risk of heart disease and death.

”Estrogen treatment is one excellent option for some individuals and should be considered in the appropriate person,” Dr. Nachtigall said. “If estrogen treatment is to be considered, it should be given closer to menopause, within the first 10 years after menopause and in younger individuals (under 59) at start.”

Dr. Nachtigall referred to the NAMS 2022 position statement concluding that, for healthy women within 10 years of menopause who have bothersome menopause symptoms, “the benefits of hormone therapy outweigh its risks, with fewer cardiovascular events in younger versus older women.”

”Menopause and having menopausal symptoms is an opportunity for clinicians and patients to have a conversation about appropriate individualized management options,” Dr. Nachtigall said.

Women may also be able to mitigate their cardiovascular risk with regular exercise, eating a healthy diet, not smoking, and getting adequate sleep, Dr. Nachtigall said. But these healthy behaviors may not adequately treat moderate or severe menopausal symptoms.

“Some health care providers have said that because menopause happens naturally, individuals should just accept the symptoms and try to wait it out and not get treatment, but this study, as well as others, makes it clear that it actually may be beneficial to treat the symptoms,” Dr. Nachtigall said.

The research used no external funding. Dr. Nudy and Dr. Nachtigall had no disclosures.

Up to 10 different menopausal symptoms were linked to an increased risk of cardiovascular disease when they were moderate to severe in women who initially had no evidence of cardiovascular disease, according to research presented at the North American Menopause Society annual meeting in Atlanta.

“The take-home message is that severe menopausal symptoms may increase the risk of cardiovascular disease,” Matthew Nudy, MD, an assistant professor of medicine at the Heart and Vascular Institute at Penn State University, Hershey, said in an interview about his findings. “Physicians and patients should be aware of this association. Women with severe symptoms may be more likely to see their physician, and this would be an ideal time to have their cardiovascular risk assessed.”

Margaret Nachtigall, MD, a clinical associate professor of obstetrics and gynecology at New York University and at NYU Langone Health, noted that these findings lined up with other studies showing an increased risk of cardiovascular disease in patients who have more symptoms, especially hot flashes.

“Other recent studies showed that an increase in severity of hot flush is associated with worse blood vessel function, leading to heart disease,” Dr. Nachtigall, who was not involved with the study, said in an interview. “The next step that makes sense is to try to eliminate these symptoms and hope that, in turn, would lower cardiovascular disease and improve survival.”

The researchers compared menopausal symptoms with cardiovascular outcomes and all-cause mortality in an observational cohort of 80,278 postmenopausal women for a median 8.2 years of follow-up. None of the women, all enrolled in the Women’s Health Initiative, had known cardiovascular disease at baseline. They had an average age of 63 years and average body mass index (BMI) of 25.9 at baseline. Most participants were White (86.7%), with 7% being Black and 4.1% Hispanic. Cardiovascular disease was a composite outcome that included hospitalized myocardial infarction, definite silent myocardial infarction, coronary death, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization.

The researchers used a four-item Likert scale (0-3) to assess the severity of 15 symptoms experienced within the past 4 weeks at baseline: “night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, [feeling] restless or fidgety, and difficulty concentrating.”

The associations were adjusted for the following covariates: race/ethnicity, blood pressure, education, smoking status, bilateral oophorectomy, menopausal hormone therapy use (never/past/current), sleep duration, statin use, history of high cholesterol, aspirin use, use of antihypertensives, treated diabetes, and family history of heart attack. Continuous variables included age, age at menopause, BMI, blood pressure, and physical activity levels. Because of the high number of multiple comparisons, the researchers also used a Bonferroni correction to reduce the risk of spurious statistical significance.

The researchers found some clustering of symptoms. Among women who had at least two moderate or severe menopausal symptoms, more than half frequently woke up at night, had joint pain, or felt tired, the researchers reported. Those symptoms were also the most commonly reported ones overall. Younger women, between ages 50 and 59, were more likely than older women (60-79 years old) to experience vasomotor symptoms and all cognitive affective symptoms except forgetfulness.

The researchers identified 10 symptoms whose severity was significantly associated with cardiovascular disease. Compared to having no symptoms at all, the following moderate or severe symptoms were associated with an increased risk of a cardiovascular event after adjustment for covariates and corrected for multiple comparisons: night sweats – a 19% increased risk (P = .03), waking up several times at night – 11% increased risk (P = .05), joint pain or stiffness – 27% increased risk (P < .001), heart racing or skipping beats – 55% increased risk (P < .001), dizziness – 34% increased risk (P < .001), feeling tired – 35% increased risk (P < .001), forgetfulness – 25% increased risk (P < .001), mood swings – 21% increased risk (P = .02), feeling restless or fidgety – 29% increased risk (P < .001), and difficulty concentrating – 31% increased risk (P < .001)

In addition, all-cause mortality was associated with these symptoms when they were moderate or severe: heart racing or skipping beats (32% increased risk of all-cause mortality; hazard ratio, 1.32; P =.006), dizziness (HR, 1.58; P < .001), tremors (HR, 1.44; P < .001), feeling tired (HR, 1.26; P < .001), forgetfulness (HR, 1.29; P = .01), mood swings (HR, 1.35; P = .02), feeling restless or fidgety (HR, 1.35; P < .001), and difficulty concentrating (HR, 1.47; P < .001).

The symptom with the greatest association with all-cause mortality was dizziness, which was associated with an increased risk of 58% when rated moderate or severe. Any dizziness at all was linked to a 12% increased risk of cardiovascular disease, compared with no dizziness. Machine learning with the LASSO method determined that the symptoms most predictive of cardiovascular disease were dizziness, heart racing, feeling tired, and joint pain. The symptoms most associated with all-cause mortality, based on the machine learning algorithm, were dizziness, tremors, and feeling tired.

Dr. Nudy said that their study did not look at mitigation strategies. “Women should discuss with their physician the best methods for cardiovascular risk reduction,” he said. He also cautioned that severe menopausal symptoms can also indicate other health conditions that may require investigation.

“It is certainly possible some symptoms may represent other medical conditions we were unable to control for and may not be directly related to menopause,” such as autoimmune diseases, endocrine abnormalities, or subclinical cardiovascular disease, he said. Additional limitations of the study included an older cohort and retrospective assessment of menopausal symptoms only at baseline. In addition, ”we did not assess the cardiovascular risk among women whose symptoms persisted versus resolved during the study period,” Dr. Nudy said.

Dr. Nachtigall said a key message is that people who are experiencing these symptoms should try to get treatment for them and attempt to alleviate them, hopefully reducing the risk of heart disease and death.

”Estrogen treatment is one excellent option for some individuals and should be considered in the appropriate person,” Dr. Nachtigall said. “If estrogen treatment is to be considered, it should be given closer to menopause, within the first 10 years after menopause and in younger individuals (under 59) at start.”

Dr. Nachtigall referred to the NAMS 2022 position statement concluding that, for healthy women within 10 years of menopause who have bothersome menopause symptoms, “the benefits of hormone therapy outweigh its risks, with fewer cardiovascular events in younger versus older women.”

”Menopause and having menopausal symptoms is an opportunity for clinicians and patients to have a conversation about appropriate individualized management options,” Dr. Nachtigall said.

Women may also be able to mitigate their cardiovascular risk with regular exercise, eating a healthy diet, not smoking, and getting adequate sleep, Dr. Nachtigall said. But these healthy behaviors may not adequately treat moderate or severe menopausal symptoms.

“Some health care providers have said that because menopause happens naturally, individuals should just accept the symptoms and try to wait it out and not get treatment, but this study, as well as others, makes it clear that it actually may be beneficial to treat the symptoms,” Dr. Nachtigall said.

The research used no external funding. Dr. Nudy and Dr. Nachtigall had no disclosures.

Up to 10 different menopausal symptoms were linked to an increased risk of cardiovascular disease when they were moderate to severe in women who initially had no evidence of cardiovascular disease, according to research presented at the North American Menopause Society annual meeting in Atlanta.

“The take-home message is that severe menopausal symptoms may increase the risk of cardiovascular disease,” Matthew Nudy, MD, an assistant professor of medicine at the Heart and Vascular Institute at Penn State University, Hershey, said in an interview about his findings. “Physicians and patients should be aware of this association. Women with severe symptoms may be more likely to see their physician, and this would be an ideal time to have their cardiovascular risk assessed.”

Margaret Nachtigall, MD, a clinical associate professor of obstetrics and gynecology at New York University and at NYU Langone Health, noted that these findings lined up with other studies showing an increased risk of cardiovascular disease in patients who have more symptoms, especially hot flashes.

“Other recent studies showed that an increase in severity of hot flush is associated with worse blood vessel function, leading to heart disease,” Dr. Nachtigall, who was not involved with the study, said in an interview. “The next step that makes sense is to try to eliminate these symptoms and hope that, in turn, would lower cardiovascular disease and improve survival.”

The researchers compared menopausal symptoms with cardiovascular outcomes and all-cause mortality in an observational cohort of 80,278 postmenopausal women for a median 8.2 years of follow-up. None of the women, all enrolled in the Women’s Health Initiative, had known cardiovascular disease at baseline. They had an average age of 63 years and average body mass index (BMI) of 25.9 at baseline. Most participants were White (86.7%), with 7% being Black and 4.1% Hispanic. Cardiovascular disease was a composite outcome that included hospitalized myocardial infarction, definite silent myocardial infarction, coronary death, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization.

The researchers used a four-item Likert scale (0-3) to assess the severity of 15 symptoms experienced within the past 4 weeks at baseline: “night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, [feeling] restless or fidgety, and difficulty concentrating.”

The associations were adjusted for the following covariates: race/ethnicity, blood pressure, education, smoking status, bilateral oophorectomy, menopausal hormone therapy use (never/past/current), sleep duration, statin use, history of high cholesterol, aspirin use, use of antihypertensives, treated diabetes, and family history of heart attack. Continuous variables included age, age at menopause, BMI, blood pressure, and physical activity levels. Because of the high number of multiple comparisons, the researchers also used a Bonferroni correction to reduce the risk of spurious statistical significance.

The researchers found some clustering of symptoms. Among women who had at least two moderate or severe menopausal symptoms, more than half frequently woke up at night, had joint pain, or felt tired, the researchers reported. Those symptoms were also the most commonly reported ones overall. Younger women, between ages 50 and 59, were more likely than older women (60-79 years old) to experience vasomotor symptoms and all cognitive affective symptoms except forgetfulness.

The researchers identified 10 symptoms whose severity was significantly associated with cardiovascular disease. Compared to having no symptoms at all, the following moderate or severe symptoms were associated with an increased risk of a cardiovascular event after adjustment for covariates and corrected for multiple comparisons: night sweats – a 19% increased risk (P = .03), waking up several times at night – 11% increased risk (P = .05), joint pain or stiffness – 27% increased risk (P < .001), heart racing or skipping beats – 55% increased risk (P < .001), dizziness – 34% increased risk (P < .001), feeling tired – 35% increased risk (P < .001), forgetfulness – 25% increased risk (P < .001), mood swings – 21% increased risk (P = .02), feeling restless or fidgety – 29% increased risk (P < .001), and difficulty concentrating – 31% increased risk (P < .001)

In addition, all-cause mortality was associated with these symptoms when they were moderate or severe: heart racing or skipping beats (32% increased risk of all-cause mortality; hazard ratio, 1.32; P =.006), dizziness (HR, 1.58; P < .001), tremors (HR, 1.44; P < .001), feeling tired (HR, 1.26; P < .001), forgetfulness (HR, 1.29; P = .01), mood swings (HR, 1.35; P = .02), feeling restless or fidgety (HR, 1.35; P < .001), and difficulty concentrating (HR, 1.47; P < .001).

The symptom with the greatest association with all-cause mortality was dizziness, which was associated with an increased risk of 58% when rated moderate or severe. Any dizziness at all was linked to a 12% increased risk of cardiovascular disease, compared with no dizziness. Machine learning with the LASSO method determined that the symptoms most predictive of cardiovascular disease were dizziness, heart racing, feeling tired, and joint pain. The symptoms most associated with all-cause mortality, based on the machine learning algorithm, were dizziness, tremors, and feeling tired.

Dr. Nudy said that their study did not look at mitigation strategies. “Women should discuss with their physician the best methods for cardiovascular risk reduction,” he said. He also cautioned that severe menopausal symptoms can also indicate other health conditions that may require investigation.

“It is certainly possible some symptoms may represent other medical conditions we were unable to control for and may not be directly related to menopause,” such as autoimmune diseases, endocrine abnormalities, or subclinical cardiovascular disease, he said. Additional limitations of the study included an older cohort and retrospective assessment of menopausal symptoms only at baseline. In addition, ”we did not assess the cardiovascular risk among women whose symptoms persisted versus resolved during the study period,” Dr. Nudy said.

Dr. Nachtigall said a key message is that people who are experiencing these symptoms should try to get treatment for them and attempt to alleviate them, hopefully reducing the risk of heart disease and death.

”Estrogen treatment is one excellent option for some individuals and should be considered in the appropriate person,” Dr. Nachtigall said. “If estrogen treatment is to be considered, it should be given closer to menopause, within the first 10 years after menopause and in younger individuals (under 59) at start.”

Dr. Nachtigall referred to the NAMS 2022 position statement concluding that, for healthy women within 10 years of menopause who have bothersome menopause symptoms, “the benefits of hormone therapy outweigh its risks, with fewer cardiovascular events in younger versus older women.”

”Menopause and having menopausal symptoms is an opportunity for clinicians and patients to have a conversation about appropriate individualized management options,” Dr. Nachtigall said.

Women may also be able to mitigate their cardiovascular risk with regular exercise, eating a healthy diet, not smoking, and getting adequate sleep, Dr. Nachtigall said. But these healthy behaviors may not adequately treat moderate or severe menopausal symptoms.

“Some health care providers have said that because menopause happens naturally, individuals should just accept the symptoms and try to wait it out and not get treatment, but this study, as well as others, makes it clear that it actually may be beneficial to treat the symptoms,” Dr. Nachtigall said.

The research used no external funding. Dr. Nudy and Dr. Nachtigall had no disclosures.

The relationship between estrogen levels and heart health makes it particularly important for clinicians to be aware of those patients who might be at risk for cardiovascular disease despite not having other traditional risk factors, according to a presentation Oct. 12 at the North American Menopause Society annual meeting in Atlanta.

”Endogenous estrogens are protective for cardiovascular disease in premenopausal women,” Chrisandra L. Shufelt, MD, chair of the division of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Fla., told attendees. Yet, “a substantial population of young women are dying prematurely from cardiovascular disease,” with rates of cardiovascular death increasing in women aged 35-44 even as rates have decreased in postmenopausal women and in men. One potential reason may be premature estrogen loss.

Dr. Shufelt reminded attendees of four major causes of premature estrogen loss: Natural premature menopause, surgical menopause, chemotherapy-induced menopause, and premature ovarian insufficiency. But she would go on to discuss a less widely recognized condition, functional hypothalamic amenorrhea, that also may be contributing to increased cardiovascular risk.

First, Dr. Shufelt reviewed the evidence supporting the relationship between estrogen and cardiovascular health, starting with the Framingham study’s findings that cardiovascular disease is approximately two to four times more common in postmenopausal women than in premenopausal women, depending on the age range.

“Menopause at an early age, particularly under the age of 40, matters,” Dr. Shufelt said. “So we should be discussing this with our patients.”

Surgical menopause makes a difference to cardiovascular health as well, she said. In women under age 35, for example, the risk of a nonfatal heart attack in those with a bilateral oophorectomy was 7.7 times greater than in women who retained both ovaries and their uterus, and 1.5 times greater in women who had a hysterectomy without bilateral oophorectomy.

In a 2019 study, surgical premature menopause was associated with an 87% increased risk of heart disease even after researchers accounted for age, cardiovascular risk factors, and some forms of hormone therapy. The increased risk from natural premature menopause, on the other hand, was lower – a 36% increased risk of heart disease – compared with those producing endogenous hormones. Although randomized controlled trials are unavailable and unlikely to be done, the Nurses’ Health Study and the Danish Nurses Cohort Study, both observational studies, found that heart disease risk was diminished in those taking hormone therapy after surgical premature menopause.

Recommendations for premature or early menopause, from a wide range of different medical societies including NAMS, are that women without contraindications be given estrogen-based hormone therapy until the average age of natural menopause. Though not included in the same guidance, research has also shown that estrogen after oophorectomy does not increase the risk of breast cancer in women with a BRCA1 mutation, Dr. Shufelt said. Hormone therapy for premature or early menopause should adequately replace the levels women have lost and that means younger menopausal women often need higher doses than what older women receive, such as 2 mg/day of oral estradiol rather than the standard doses of 0.5 or 1 mg/day.
 

Functional hypothalamic amenorrhea and cardiovascular risk

Dr. Shufelt then discussed functional hypothalamic amenorrhea (hypogonadotropic hypogonadism), a common type of secondary amenorrhea that affects at least 1.4 million U.S. women. Diagnosis includes lack of a period for at least 3 months in someone who previously menstruated plus lab values below 50 pg/mL for estradiol, below 10 mIU/L for follicle stimulating hormone, and below 10 mIU/L for luteinizing hormone. Causes of this reversible form of infertility can include stress, overexercising, undereating, or some combination of these, plus an underlying genetic predisposition.

“After ruling out polycystic ovary syndrome, prolactinoma, and thyroid dysfunction, clinicians need to consider the diagnosis of hypothalamic amenorrhea,” Dr. Shufelt said. This condition goes beyond low estrogen levels: Women have elevated cortisol, low thyroid levels, low leptin levels, and increased ghrelin.

”This is not going away,” Dr. Shufelt said, sharing data on stress levels among U.S. adults, particularly Gen Z and millennial adults, noting that the ongoing “national mental health crisis” may be contributing to functional hypothalamic amenorrhea.

A 2020 substudy from the Nurses’ Health Study II found an increased risk of premature death in those who didn’t have a period or always had irregular periods starting as early as 14-17 years old. The increased risk of premature death rose with age in those with irregular or absent cycles – a 37% higher risk in 18- to 22-year-olds and a 39% increased risk in 29- to 46-year-olds.

But clinicians aren’t adequately identifying the “phenotype of the hypothalamic women,” Dr. Shufelt said, despite research showing overlap between hypothalamic amenorrhea and a higher risk of cardiovascular disease. Hypothalamic amenorrhea is so understudied that the last original research on the topic was in 2008, Dr. Shufelt said in an interview. ”No research except mine has been done to evaluate heart health in these young women,” she said.

Dr. Shufelt described a study she led involving 30 women with functional hypothalamic amenorrhea, 29 women with normal menstrual cycles, and 30 women who were recently menopausal and not on hormone therapy. The women with hypothalamic amenorrhea had average stress levels but their depression scores were higher than those of the other two groups.

The results showed that women with hypothalamic amenorrhea had lower estradiol and leptin levels and higher testosterone levels compared with the control group, and they had higher cortisol levels than those of both groups. Despite having similar body mass indexes as the control and menopausal groups, women with hypothalamic amenorrhea had lower blood pressure than that of the other two groups, yet they had higher cholesterol levels than those of the control group. EndoPAT^© (Itamar Medical) testing showed that they had poor vascular function.

“In fact, one-third of the women [with hypothalamic amenorrhea] entered the trial with a diagnosis of what would be considered endothelial dysfunction,” Dr. Shufelt said. “Our results demonstrated significantly higher circulating levels of serum proinflammatory cytokines in the women with hypothalamic amenorrhea compared to eumenorrheic controls.”

Dr. Shufelt’s team then tested whether giving estradiol to the women with hypothalamic amenorrhea for 12 weeks would improve their vascular health, but they saw no significant differences between the women who received estrogen and those who received placebo.

“Endothelial function is partly mediated by estrogen, and it was expected that giving back estrogen would ‘fix’ the endothelium, but that is not what happened,” Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado at Denver, Aurora, said in interview. “The mechanisms that maintain vascular function in women are not limited to hormones,” said Dr. Santoro, who was not involved in Dr. Shufelt’s study but attended her lecture. “We need to think beyond the simple model of estrogen-good, no-estrogen-bad.”

Dr. Santoro noted how easy it is to overlook the women who may have cardiovascular risk because of hypothalamic amenorrhea.

“Because many women with functional hypothalamic amenorrhea are super athletic and do not have the typical features of people with cardiometabolic disease – such as glucose intolerance, obesity, abnormal cholesterol or triglycerides, or high blood pressure – clinicians tend to think of them as healthy and to think that simply giving back hormones will fix the problems with bone density and vascular function, but that is not enough,” Dr. Santoro said. “The cognitive-behavioral therapy model for treatment of women with functional hypothalamic amenorrhea addresses the stress-related factors that drive the disorder, and this needs to be considered the standard of care for treatment.”

Stephanie S. Faubion, MD, professor of medicine and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Fla., who was not involved in Dr. Shufelt’s presentation, also emphasized the importance of recognizing functional hypothalamic amenorrhea.

“This is an underrecognized entity to begin with, and the fact that these women appear to be at increased risk for vascular dysfunction and potentially increased risk for cardiovascular disease down the road makes it even more important for clinicians to identify them and provide interventions early on,” Dr. Faubion said in an interview. “These women need to be identified and the etiology of the amenorrhea addressed, whether it relates to overexercising, being underweight, or experiencing significant stressors that have led to the loss of menstrual cycles.”

Dr. Shufelt’s research was funded by the National Institutes of Health. She had no disclosures. Dr. Santoro is a member of the scientific advisory board for Astellas, Menogenix, Amazon Ember, and Que Oncology, and she consults for Ansh Labs. Dr. Faubion had no disclosures.

The relationship between estrogen levels and heart health makes it particularly important for clinicians to be aware of those patients who might be at risk for cardiovascular disease despite not having other traditional risk factors, according to a presentation Oct. 12 at the North American Menopause Society annual meeting in Atlanta.

”Endogenous estrogens are protective for cardiovascular disease in premenopausal women,” Chrisandra L. Shufelt, MD, chair of the division of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Fla., told attendees. Yet, “a substantial population of young women are dying prematurely from cardiovascular disease,” with rates of cardiovascular death increasing in women aged 35-44 even as rates have decreased in postmenopausal women and in men. One potential reason may be premature estrogen loss.

Dr. Shufelt reminded attendees of four major causes of premature estrogen loss: Natural premature menopause, surgical menopause, chemotherapy-induced menopause, and premature ovarian insufficiency. But she would go on to discuss a less widely recognized condition, functional hypothalamic amenorrhea, that also may be contributing to increased cardiovascular risk.

First, Dr. Shufelt reviewed the evidence supporting the relationship between estrogen and cardiovascular health, starting with the Framingham study’s findings that cardiovascular disease is approximately two to four times more common in postmenopausal women than in premenopausal women, depending on the age range.

“Menopause at an early age, particularly under the age of 40, matters,” Dr. Shufelt said. “So we should be discussing this with our patients.”

Surgical menopause makes a difference to cardiovascular health as well, she said. In women under age 35, for example, the risk of a nonfatal heart attack in those with a bilateral oophorectomy was 7.7 times greater than in women who retained both ovaries and their uterus, and 1.5 times greater in women who had a hysterectomy without bilateral oophorectomy.

In a 2019 study, surgical premature menopause was associated with an 87% increased risk of heart disease even after researchers accounted for age, cardiovascular risk factors, and some forms of hormone therapy. The increased risk from natural premature menopause, on the other hand, was lower – a 36% increased risk of heart disease – compared with those producing endogenous hormones. Although randomized controlled trials are unavailable and unlikely to be done, the Nurses’ Health Study and the Danish Nurses Cohort Study, both observational studies, found that heart disease risk was diminished in those taking hormone therapy after surgical premature menopause.

Recommendations for premature or early menopause, from a wide range of different medical societies including NAMS, are that women without contraindications be given estrogen-based hormone therapy until the average age of natural menopause. Though not included in the same guidance, research has also shown that estrogen after oophorectomy does not increase the risk of breast cancer in women with a BRCA1 mutation, Dr. Shufelt said. Hormone therapy for premature or early menopause should adequately replace the levels women have lost and that means younger menopausal women often need higher doses than what older women receive, such as 2 mg/day of oral estradiol rather than the standard doses of 0.5 or 1 mg/day.
 

Functional hypothalamic amenorrhea and cardiovascular risk

Dr. Shufelt then discussed functional hypothalamic amenorrhea (hypogonadotropic hypogonadism), a common type of secondary amenorrhea that affects at least 1.4 million U.S. women. Diagnosis includes lack of a period for at least 3 months in someone who previously menstruated plus lab values below 50 pg/mL for estradiol, below 10 mIU/L for follicle stimulating hormone, and below 10 mIU/L for luteinizing hormone. Causes of this reversible form of infertility can include stress, overexercising, undereating, or some combination of these, plus an underlying genetic predisposition.

“After ruling out polycystic ovary syndrome, prolactinoma, and thyroid dysfunction, clinicians need to consider the diagnosis of hypothalamic amenorrhea,” Dr. Shufelt said. This condition goes beyond low estrogen levels: Women have elevated cortisol, low thyroid levels, low leptin levels, and increased ghrelin.

”This is not going away,” Dr. Shufelt said, sharing data on stress levels among U.S. adults, particularly Gen Z and millennial adults, noting that the ongoing “national mental health crisis” may be contributing to functional hypothalamic amenorrhea.

A 2020 substudy from the Nurses’ Health Study II found an increased risk of premature death in those who didn’t have a period or always had irregular periods starting as early as 14-17 years old. The increased risk of premature death rose with age in those with irregular or absent cycles – a 37% higher risk in 18- to 22-year-olds and a 39% increased risk in 29- to 46-year-olds.

But clinicians aren’t adequately identifying the “phenotype of the hypothalamic women,” Dr. Shufelt said, despite research showing overlap between hypothalamic amenorrhea and a higher risk of cardiovascular disease. Hypothalamic amenorrhea is so understudied that the last original research on the topic was in 2008, Dr. Shufelt said in an interview. ”No research except mine has been done to evaluate heart health in these young women,” she said.

Dr. Shufelt described a study she led involving 30 women with functional hypothalamic amenorrhea, 29 women with normal menstrual cycles, and 30 women who were recently menopausal and not on hormone therapy. The women with hypothalamic amenorrhea had average stress levels but their depression scores were higher than those of the other two groups.

The results showed that women with hypothalamic amenorrhea had lower estradiol and leptin levels and higher testosterone levels compared with the control group, and they had higher cortisol levels than those of both groups. Despite having similar body mass indexes as the control and menopausal groups, women with hypothalamic amenorrhea had lower blood pressure than that of the other two groups, yet they had higher cholesterol levels than those of the control group. EndoPAT^© (Itamar Medical) testing showed that they had poor vascular function.

“In fact, one-third of the women [with hypothalamic amenorrhea] entered the trial with a diagnosis of what would be considered endothelial dysfunction,” Dr. Shufelt said. “Our results demonstrated significantly higher circulating levels of serum proinflammatory cytokines in the women with hypothalamic amenorrhea compared to eumenorrheic controls.”

Dr. Shufelt’s team then tested whether giving estradiol to the women with hypothalamic amenorrhea for 12 weeks would improve their vascular health, but they saw no significant differences between the women who received estrogen and those who received placebo.

“Endothelial function is partly mediated by estrogen, and it was expected that giving back estrogen would ‘fix’ the endothelium, but that is not what happened,” Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado at Denver, Aurora, said in interview. “The mechanisms that maintain vascular function in women are not limited to hormones,” said Dr. Santoro, who was not involved in Dr. Shufelt’s study but attended her lecture. “We need to think beyond the simple model of estrogen-good, no-estrogen-bad.”

Dr. Santoro noted how easy it is to overlook the women who may have cardiovascular risk because of hypothalamic amenorrhea.

“Because many women with functional hypothalamic amenorrhea are super athletic and do not have the typical features of people with cardiometabolic disease – such as glucose intolerance, obesity, abnormal cholesterol or triglycerides, or high blood pressure – clinicians tend to think of them as healthy and to think that simply giving back hormones will fix the problems with bone density and vascular function, but that is not enough,” Dr. Santoro said. “The cognitive-behavioral therapy model for treatment of women with functional hypothalamic amenorrhea addresses the stress-related factors that drive the disorder, and this needs to be considered the standard of care for treatment.”

Stephanie S. Faubion, MD, professor of medicine and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Fla., who was not involved in Dr. Shufelt’s presentation, also emphasized the importance of recognizing functional hypothalamic amenorrhea.

“This is an underrecognized entity to begin with, and the fact that these women appear to be at increased risk for vascular dysfunction and potentially increased risk for cardiovascular disease down the road makes it even more important for clinicians to identify them and provide interventions early on,” Dr. Faubion said in an interview. “These women need to be identified and the etiology of the amenorrhea addressed, whether it relates to overexercising, being underweight, or experiencing significant stressors that have led to the loss of menstrual cycles.”

Dr. Shufelt’s research was funded by the National Institutes of Health. She had no disclosures. Dr. Santoro is a member of the scientific advisory board for Astellas, Menogenix, Amazon Ember, and Que Oncology, and she consults for Ansh Labs. Dr. Faubion had no disclosures.

The relationship between estrogen levels and heart health makes it particularly important for clinicians to be aware of those patients who might be at risk for cardiovascular disease despite not having other traditional risk factors, according to a presentation Oct. 12 at the North American Menopause Society annual meeting in Atlanta.

”Endogenous estrogens are protective for cardiovascular disease in premenopausal women,” Chrisandra L. Shufelt, MD, chair of the division of general internal medicine and associate director of the Women’s Health Research Center at Mayo Clinic in Jacksonville, Fla., told attendees. Yet, “a substantial population of young women are dying prematurely from cardiovascular disease,” with rates of cardiovascular death increasing in women aged 35-44 even as rates have decreased in postmenopausal women and in men. One potential reason may be premature estrogen loss.

Dr. Shufelt reminded attendees of four major causes of premature estrogen loss: Natural premature menopause, surgical menopause, chemotherapy-induced menopause, and premature ovarian insufficiency. But she would go on to discuss a less widely recognized condition, functional hypothalamic amenorrhea, that also may be contributing to increased cardiovascular risk.

First, Dr. Shufelt reviewed the evidence supporting the relationship between estrogen and cardiovascular health, starting with the Framingham study’s findings that cardiovascular disease is approximately two to four times more common in postmenopausal women than in premenopausal women, depending on the age range.

“Menopause at an early age, particularly under the age of 40, matters,” Dr. Shufelt said. “So we should be discussing this with our patients.”

Surgical menopause makes a difference to cardiovascular health as well, she said. In women under age 35, for example, the risk of a nonfatal heart attack in those with a bilateral oophorectomy was 7.7 times greater than in women who retained both ovaries and their uterus, and 1.5 times greater in women who had a hysterectomy without bilateral oophorectomy.

In a 2019 study, surgical premature menopause was associated with an 87% increased risk of heart disease even after researchers accounted for age, cardiovascular risk factors, and some forms of hormone therapy. The increased risk from natural premature menopause, on the other hand, was lower – a 36% increased risk of heart disease – compared with those producing endogenous hormones. Although randomized controlled trials are unavailable and unlikely to be done, the Nurses’ Health Study and the Danish Nurses Cohort Study, both observational studies, found that heart disease risk was diminished in those taking hormone therapy after surgical premature menopause.

Recommendations for premature or early menopause, from a wide range of different medical societies including NAMS, are that women without contraindications be given estrogen-based hormone therapy until the average age of natural menopause. Though not included in the same guidance, research has also shown that estrogen after oophorectomy does not increase the risk of breast cancer in women with a BRCA1 mutation, Dr. Shufelt said. Hormone therapy for premature or early menopause should adequately replace the levels women have lost and that means younger menopausal women often need higher doses than what older women receive, such as 2 mg/day of oral estradiol rather than the standard doses of 0.5 or 1 mg/day.
 

Functional hypothalamic amenorrhea and cardiovascular risk

Dr. Shufelt then discussed functional hypothalamic amenorrhea (hypogonadotropic hypogonadism), a common type of secondary amenorrhea that affects at least 1.4 million U.S. women. Diagnosis includes lack of a period for at least 3 months in someone who previously menstruated plus lab values below 50 pg/mL for estradiol, below 10 mIU/L for follicle stimulating hormone, and below 10 mIU/L for luteinizing hormone. Causes of this reversible form of infertility can include stress, overexercising, undereating, or some combination of these, plus an underlying genetic predisposition.

“After ruling out polycystic ovary syndrome, prolactinoma, and thyroid dysfunction, clinicians need to consider the diagnosis of hypothalamic amenorrhea,” Dr. Shufelt said. This condition goes beyond low estrogen levels: Women have elevated cortisol, low thyroid levels, low leptin levels, and increased ghrelin.

”This is not going away,” Dr. Shufelt said, sharing data on stress levels among U.S. adults, particularly Gen Z and millennial adults, noting that the ongoing “national mental health crisis” may be contributing to functional hypothalamic amenorrhea.

A 2020 substudy from the Nurses’ Health Study II found an increased risk of premature death in those who didn’t have a period or always had irregular periods starting as early as 14-17 years old. The increased risk of premature death rose with age in those with irregular or absent cycles – a 37% higher risk in 18- to 22-year-olds and a 39% increased risk in 29- to 46-year-olds.

But clinicians aren’t adequately identifying the “phenotype of the hypothalamic women,” Dr. Shufelt said, despite research showing overlap between hypothalamic amenorrhea and a higher risk of cardiovascular disease. Hypothalamic amenorrhea is so understudied that the last original research on the topic was in 2008, Dr. Shufelt said in an interview. ”No research except mine has been done to evaluate heart health in these young women,” she said.

Dr. Shufelt described a study she led involving 30 women with functional hypothalamic amenorrhea, 29 women with normal menstrual cycles, and 30 women who were recently menopausal and not on hormone therapy. The women with hypothalamic amenorrhea had average stress levels but their depression scores were higher than those of the other two groups.

The results showed that women with hypothalamic amenorrhea had lower estradiol and leptin levels and higher testosterone levels compared with the control group, and they had higher cortisol levels than those of both groups. Despite having similar body mass indexes as the control and menopausal groups, women with hypothalamic amenorrhea had lower blood pressure than that of the other two groups, yet they had higher cholesterol levels than those of the control group. EndoPAT^© (Itamar Medical) testing showed that they had poor vascular function.

“In fact, one-third of the women [with hypothalamic amenorrhea] entered the trial with a diagnosis of what would be considered endothelial dysfunction,” Dr. Shufelt said. “Our results demonstrated significantly higher circulating levels of serum proinflammatory cytokines in the women with hypothalamic amenorrhea compared to eumenorrheic controls.”

Dr. Shufelt’s team then tested whether giving estradiol to the women with hypothalamic amenorrhea for 12 weeks would improve their vascular health, but they saw no significant differences between the women who received estrogen and those who received placebo.

“Endothelial function is partly mediated by estrogen, and it was expected that giving back estrogen would ‘fix’ the endothelium, but that is not what happened,” Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado at Denver, Aurora, said in interview. “The mechanisms that maintain vascular function in women are not limited to hormones,” said Dr. Santoro, who was not involved in Dr. Shufelt’s study but attended her lecture. “We need to think beyond the simple model of estrogen-good, no-estrogen-bad.”

Dr. Santoro noted how easy it is to overlook the women who may have cardiovascular risk because of hypothalamic amenorrhea.

“Because many women with functional hypothalamic amenorrhea are super athletic and do not have the typical features of people with cardiometabolic disease – such as glucose intolerance, obesity, abnormal cholesterol or triglycerides, or high blood pressure – clinicians tend to think of them as healthy and to think that simply giving back hormones will fix the problems with bone density and vascular function, but that is not enough,” Dr. Santoro said. “The cognitive-behavioral therapy model for treatment of women with functional hypothalamic amenorrhea addresses the stress-related factors that drive the disorder, and this needs to be considered the standard of care for treatment.”

Stephanie S. Faubion, MD, professor of medicine and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Fla., who was not involved in Dr. Shufelt’s presentation, also emphasized the importance of recognizing functional hypothalamic amenorrhea.

“This is an underrecognized entity to begin with, and the fact that these women appear to be at increased risk for vascular dysfunction and potentially increased risk for cardiovascular disease down the road makes it even more important for clinicians to identify them and provide interventions early on,” Dr. Faubion said in an interview. “These women need to be identified and the etiology of the amenorrhea addressed, whether it relates to overexercising, being underweight, or experiencing significant stressors that have led to the loss of menstrual cycles.”

Dr. Shufelt’s research was funded by the National Institutes of Health. She had no disclosures. Dr. Santoro is a member of the scientific advisory board for Astellas, Menogenix, Amazon Ember, and Que Oncology, and she consults for Ansh Labs. Dr. Faubion had no disclosures.

Adults with obesity who do not respond adequately to lifestyle interventions alone should be offered one of four suggested medications to treat obesity, with preference for semaglutide before others, according to new guidelines published by the American Gastroenterological Association in Gastroenterology.

Recommended first-line medications include semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-buproprion ER, based on moderate-certainty evidence. Also recommended, albeit based on lower-certainty evidence, are phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient for Gelesis100 superabsorbent hydrogel.

The substantial increase in obesity prevalence in the United States – from 30.5% to 41.9% in just the 2 decades from 2000 to 2020 – has likely contributed to increases in various obesity-related complications, wrote Eduardo Grunvald, MD, of the University of California San Diego, and colleagues. These include cardiovascular disease, stroke, type 2 diabetes mellitus, nonalcoholic steatohepatitis, obstructive sleep apnea, osteoarthritis, and certain types of cancer, such as colorectal cancer.

“Lifestyle intervention is the foundation in the management of obesity, but it has limited effectiveness and durability for most individuals,” the authors wrote. Despite a range of highly effective pharmacological therapies developed for long-term management of obesity, these agents are not widely used in routine clinical care, and practice variability is wide. There is a “small number of providers responsible for more than 90% of the prescriptions, partly due to lack of familiarity and limited access and insurance coverage,” the authors wrote.

A multidisciplinary panel of 10 experts and one patient representative, therefore, developed the guidelines by first prioritizing key clinical questions, identifying patient-centered outcomes, and conducting an evidence review of the following interventions: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 superabsorbent hydrogel. The guideline panel then developed management recommendations and provided clinical practice considerations regarding each of the pharmacologic interventions.

The authors focused on adults, noting that pharmacologic treatment of childhood obesity is beyond the scope of these guidelines. The evidence synthesis yielded nine recommendations for the pharmacological management of obesity by gastroenterologists, primary care clinicians, endocrinologists, and other providers caring for patients with overweight or obesity. The target audience of the guidelines, however, includes patients and policymakers, the authors wrote.

“These guidelines are not intended to impose a standard of care, but rather, they provide the basis for rational, informed decisions for patients and health care professionals,” the authors wrote. “No recommendation can include all the unique individual circumstances that must be considered when making recommendations for individual patients. However, discussions around benefits and harms can be used for shared decision-making, especially for conditional recommendations where patients’ values and preferences are important to consider.”

The panel conducted a systematic review and meta-analysis of randomized controlled trials of Food and Drug Administration–approved obesity medications through Jan. 1, 2022. Though they primarily included studies with at least 48 weeks follow-up, they included studies with a follow-up of less than a year if one with 48 weeks’ outcomes did not exist.

The first of the nine recommendations was to add pharmacological agents to lifestyle interventions in treating adults with obesity or overweight and weight-related complications who have not adequately responded to lifestyle interventions alone. This strong recommendation was based on moderate-certainty evidence.

“Antiobesity medications generally need to be used chronically, and the selection of the medication or intervention should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs, and access to the therapy,” the authors wrote. Average difference in total body weight loss with the addition of medication to lifestyle interventions was 3%-10.8%, depending on the drug. Treatment discontinuation ranged from 34 to 219 per 1,000 people in treatment groups, but adverse event rates were low.

The panel’s second recommendation suggested prioritizing of semaglutide along with lifestyle interventions based on the large magnitude of its net benefit. The remaining recommendations describes the use of each of the other medications based on their respective magnitude of effect and risk for adverse events.

Important considerations

“These medications treat a biological disease, not a lifestyle problem,” Dr. Grunvald said in a prepared statement. “Obesity is a disease that often does not respond to lifestyle interventions alone in the long term. Using medications as an option to assist with weight loss can improve weight-related complications like joint pain, diabetes, fatty liver, and hypertension.”

The authors acknowledged that cost remains a concern for the use of these therapies, especially among vulnerable populations. They also noted that the medications should not be used in pregnant individuals or those with bulimia nervosa, and they should be used with caution in people with other eating disorders. Patients with type 2 diabetes taking insulin or sulfonylureas and patients taking antihypertensives may require dosage adjustments since these obesity medications may increase risk of hypoglycemia for the former and decrease blood pressure for the latter.

The panel advised against orlistat, although it added that ”patients who place a high value on the potential small weight loss benefit and low value on gastrointestinal side effects may reasonably choose treatment with orlistat.” Those patients should take a multivitamin daily that contains vitamins A, D, E, and K at least 2 hours apart from orlistat.

The lack of available evidence for Gelesis100 oral superabsorbent hydrogel led the panel to suggest its use only in the context of a clinical trial.

The AGA will update these guidelines no later than 2025 and may issue rapid guidance updates until then as new evidence comes to light.

The guidelines did not receive any external funding, being fully funded by the AGA. The guideline chair and guideline methodologists had no relevant or direct conflicts of interest. All conflict of interest disclosures are maintained by the AGA office.

Adults with obesity who do not respond adequately to lifestyle interventions alone should be offered one of four suggested medications to treat obesity, with preference for semaglutide before others, according to new guidelines published by the American Gastroenterological Association in Gastroenterology.

Recommended first-line medications include semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-buproprion ER, based on moderate-certainty evidence. Also recommended, albeit based on lower-certainty evidence, are phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient for Gelesis100 superabsorbent hydrogel.

The substantial increase in obesity prevalence in the United States – from 30.5% to 41.9% in just the 2 decades from 2000 to 2020 – has likely contributed to increases in various obesity-related complications, wrote Eduardo Grunvald, MD, of the University of California San Diego, and colleagues. These include cardiovascular disease, stroke, type 2 diabetes mellitus, nonalcoholic steatohepatitis, obstructive sleep apnea, osteoarthritis, and certain types of cancer, such as colorectal cancer.

“Lifestyle intervention is the foundation in the management of obesity, but it has limited effectiveness and durability for most individuals,” the authors wrote. Despite a range of highly effective pharmacological therapies developed for long-term management of obesity, these agents are not widely used in routine clinical care, and practice variability is wide. There is a “small number of providers responsible for more than 90% of the prescriptions, partly due to lack of familiarity and limited access and insurance coverage,” the authors wrote.

A multidisciplinary panel of 10 experts and one patient representative, therefore, developed the guidelines by first prioritizing key clinical questions, identifying patient-centered outcomes, and conducting an evidence review of the following interventions: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 superabsorbent hydrogel. The guideline panel then developed management recommendations and provided clinical practice considerations regarding each of the pharmacologic interventions.

The authors focused on adults, noting that pharmacologic treatment of childhood obesity is beyond the scope of these guidelines. The evidence synthesis yielded nine recommendations for the pharmacological management of obesity by gastroenterologists, primary care clinicians, endocrinologists, and other providers caring for patients with overweight or obesity. The target audience of the guidelines, however, includes patients and policymakers, the authors wrote.

“These guidelines are not intended to impose a standard of care, but rather, they provide the basis for rational, informed decisions for patients and health care professionals,” the authors wrote. “No recommendation can include all the unique individual circumstances that must be considered when making recommendations for individual patients. However, discussions around benefits and harms can be used for shared decision-making, especially for conditional recommendations where patients’ values and preferences are important to consider.”

The panel conducted a systematic review and meta-analysis of randomized controlled trials of Food and Drug Administration–approved obesity medications through Jan. 1, 2022. Though they primarily included studies with at least 48 weeks follow-up, they included studies with a follow-up of less than a year if one with 48 weeks’ outcomes did not exist.

The first of the nine recommendations was to add pharmacological agents to lifestyle interventions in treating adults with obesity or overweight and weight-related complications who have not adequately responded to lifestyle interventions alone. This strong recommendation was based on moderate-certainty evidence.

“Antiobesity medications generally need to be used chronically, and the selection of the medication or intervention should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs, and access to the therapy,” the authors wrote. Average difference in total body weight loss with the addition of medication to lifestyle interventions was 3%-10.8%, depending on the drug. Treatment discontinuation ranged from 34 to 219 per 1,000 people in treatment groups, but adverse event rates were low.

The panel’s second recommendation suggested prioritizing of semaglutide along with lifestyle interventions based on the large magnitude of its net benefit. The remaining recommendations describes the use of each of the other medications based on their respective magnitude of effect and risk for adverse events.

Important considerations

“These medications treat a biological disease, not a lifestyle problem,” Dr. Grunvald said in a prepared statement. “Obesity is a disease that often does not respond to lifestyle interventions alone in the long term. Using medications as an option to assist with weight loss can improve weight-related complications like joint pain, diabetes, fatty liver, and hypertension.”

The authors acknowledged that cost remains a concern for the use of these therapies, especially among vulnerable populations. They also noted that the medications should not be used in pregnant individuals or those with bulimia nervosa, and they should be used with caution in people with other eating disorders. Patients with type 2 diabetes taking insulin or sulfonylureas and patients taking antihypertensives may require dosage adjustments since these obesity medications may increase risk of hypoglycemia for the former and decrease blood pressure for the latter.

The panel advised against orlistat, although it added that ”patients who place a high value on the potential small weight loss benefit and low value on gastrointestinal side effects may reasonably choose treatment with orlistat.” Those patients should take a multivitamin daily that contains vitamins A, D, E, and K at least 2 hours apart from orlistat.

The lack of available evidence for Gelesis100 oral superabsorbent hydrogel led the panel to suggest its use only in the context of a clinical trial.

The AGA will update these guidelines no later than 2025 and may issue rapid guidance updates until then as new evidence comes to light.

The guidelines did not receive any external funding, being fully funded by the AGA. The guideline chair and guideline methodologists had no relevant or direct conflicts of interest. All conflict of interest disclosures are maintained by the AGA office.

Adults with obesity who do not respond adequately to lifestyle interventions alone should be offered one of four suggested medications to treat obesity, with preference for semaglutide before others, according to new guidelines published by the American Gastroenterological Association in Gastroenterology.

Recommended first-line medications include semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-buproprion ER, based on moderate-certainty evidence. Also recommended, albeit based on lower-certainty evidence, are phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient for Gelesis100 superabsorbent hydrogel.

The substantial increase in obesity prevalence in the United States – from 30.5% to 41.9% in just the 2 decades from 2000 to 2020 – has likely contributed to increases in various obesity-related complications, wrote Eduardo Grunvald, MD, of the University of California San Diego, and colleagues. These include cardiovascular disease, stroke, type 2 diabetes mellitus, nonalcoholic steatohepatitis, obstructive sleep apnea, osteoarthritis, and certain types of cancer, such as colorectal cancer.

“Lifestyle intervention is the foundation in the management of obesity, but it has limited effectiveness and durability for most individuals,” the authors wrote. Despite a range of highly effective pharmacological therapies developed for long-term management of obesity, these agents are not widely used in routine clinical care, and practice variability is wide. There is a “small number of providers responsible for more than 90% of the prescriptions, partly due to lack of familiarity and limited access and insurance coverage,” the authors wrote.

A multidisciplinary panel of 10 experts and one patient representative, therefore, developed the guidelines by first prioritizing key clinical questions, identifying patient-centered outcomes, and conducting an evidence review of the following interventions: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 superabsorbent hydrogel. The guideline panel then developed management recommendations and provided clinical practice considerations regarding each of the pharmacologic interventions.

The authors focused on adults, noting that pharmacologic treatment of childhood obesity is beyond the scope of these guidelines. The evidence synthesis yielded nine recommendations for the pharmacological management of obesity by gastroenterologists, primary care clinicians, endocrinologists, and other providers caring for patients with overweight or obesity. The target audience of the guidelines, however, includes patients and policymakers, the authors wrote.

“These guidelines are not intended to impose a standard of care, but rather, they provide the basis for rational, informed decisions for patients and health care professionals,” the authors wrote. “No recommendation can include all the unique individual circumstances that must be considered when making recommendations for individual patients. However, discussions around benefits and harms can be used for shared decision-making, especially for conditional recommendations where patients’ values and preferences are important to consider.”

The panel conducted a systematic review and meta-analysis of randomized controlled trials of Food and Drug Administration–approved obesity medications through Jan. 1, 2022. Though they primarily included studies with at least 48 weeks follow-up, they included studies with a follow-up of less than a year if one with 48 weeks’ outcomes did not exist.

The first of the nine recommendations was to add pharmacological agents to lifestyle interventions in treating adults with obesity or overweight and weight-related complications who have not adequately responded to lifestyle interventions alone. This strong recommendation was based on moderate-certainty evidence.

“Antiobesity medications generally need to be used chronically, and the selection of the medication or intervention should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs, and access to the therapy,” the authors wrote. Average difference in total body weight loss with the addition of medication to lifestyle interventions was 3%-10.8%, depending on the drug. Treatment discontinuation ranged from 34 to 219 per 1,000 people in treatment groups, but adverse event rates were low.

The panel’s second recommendation suggested prioritizing of semaglutide along with lifestyle interventions based on the large magnitude of its net benefit. The remaining recommendations describes the use of each of the other medications based on their respective magnitude of effect and risk for adverse events.

Important considerations

“These medications treat a biological disease, not a lifestyle problem,” Dr. Grunvald said in a prepared statement. “Obesity is a disease that often does not respond to lifestyle interventions alone in the long term. Using medications as an option to assist with weight loss can improve weight-related complications like joint pain, diabetes, fatty liver, and hypertension.”

The authors acknowledged that cost remains a concern for the use of these therapies, especially among vulnerable populations. They also noted that the medications should not be used in pregnant individuals or those with bulimia nervosa, and they should be used with caution in people with other eating disorders. Patients with type 2 diabetes taking insulin or sulfonylureas and patients taking antihypertensives may require dosage adjustments since these obesity medications may increase risk of hypoglycemia for the former and decrease blood pressure for the latter.

The panel advised against orlistat, although it added that ”patients who place a high value on the potential small weight loss benefit and low value on gastrointestinal side effects may reasonably choose treatment with orlistat.” Those patients should take a multivitamin daily that contains vitamins A, D, E, and K at least 2 hours apart from orlistat.

The lack of available evidence for Gelesis100 oral superabsorbent hydrogel led the panel to suggest its use only in the context of a clinical trial.

The AGA will update these guidelines no later than 2025 and may issue rapid guidance updates until then as new evidence comes to light.

The guidelines did not receive any external funding, being fully funded by the AGA. The guideline chair and guideline methodologists had no relevant or direct conflicts of interest. All conflict of interest disclosures are maintained by the AGA office.