TOPLINE:

High-dose antipsychotics, particularly quetiapine, clozapine, and olanzapine, are linked to increased pneumonia risk in patients with schizophrenia, new data show. Monotherapy with high anticholinergic burden also raises pneumonia risk.

METHODOLOGY: 

• Using several nationwide data registers, investigators pulled data on individuals who received inpatient care for schizophrenia or schizoaffective disorder (n = 61,889) between 1972 and 2014.
• Data on drug use were gathered from a prescription register and included dispensing dates, cost, dose, package size, and drug formulation. Data on dates and causes of death were obtained from the Causes of Death register.
• After entering the cohort, follow-up started in January 1996 or after the first diagnosis of schizophrenia for those diagnosed between 1996 and 2014.
• The primary outcome was hospitalization caused by pneumonia as the main diagnosis for hospital admission.

TAKEAWAY: 

• During 22 years of follow-up, 8917 patients (14.4%) had one or more hospitalizations for pneumonia, and 1137 (12.8%) died within 30 days of admission.
• Pneumonia risk was the highest with the use of high-dose (> 440 mg/d) quetiapine (P = .003), followed by high- (≥ 330 mg/d) and medium-dose (180 to < 330 mg/d) clozapine (both P < .001) and high-dose (≥ 11 mg/d) olanzapine (P = .02).
• Compared with no antipsychotic use, antipsychotic monotherapy was associated with an increased pneumonia risk (P = .03), whereas antipsychotic polytherapy was not.
• Only the use of antipsychotics with high anticholinergic potency was associated with pneumonia risk (P < .001).

IN PRACTICE:

“Identification of antipsychotic drugs that are associated with pneumonia risk may better inform prevention programs (eg, vaccinations),” the researchers noted. “Second, the availability of pneumonia risk estimates for individual antipsychotics and for groups of antipsychotics may foster personalized prescribing guidelines.”

SOURCE:

The study was led by Jurjen Luykx, MD, Amsterdam University Medical Center, Amsterdam, the Netherlands. It was published online in JAMA Psychiatry.

LIMITATIONS:

The investigators could not correct for all possible risk factors that may increase pneumonia risk in individuals with schizophrenia, such as smoking and lifestyle habits. Also, cases of pneumonia that didn’t require hospital admission couldn’t be included in the analysis, so the findings may generalize only to cases of severe pneumonia.

DISCLOSURES:

The study was funded by the Finnish Ministry of Social Affairs and Health.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

High-dose antipsychotics, particularly quetiapine, clozapine, and olanzapine, are linked to increased pneumonia risk in patients with schizophrenia, new data show. Monotherapy with high anticholinergic burden also raises pneumonia risk.

METHODOLOGY: 

• Using several nationwide data registers, investigators pulled data on individuals who received inpatient care for schizophrenia or schizoaffective disorder (n = 61,889) between 1972 and 2014.
• Data on drug use were gathered from a prescription register and included dispensing dates, cost, dose, package size, and drug formulation. Data on dates and causes of death were obtained from the Causes of Death register.
• After entering the cohort, follow-up started in January 1996 or after the first diagnosis of schizophrenia for those diagnosed between 1996 and 2014.
• The primary outcome was hospitalization caused by pneumonia as the main diagnosis for hospital admission.

TAKEAWAY: 

• During 22 years of follow-up, 8917 patients (14.4%) had one or more hospitalizations for pneumonia, and 1137 (12.8%) died within 30 days of admission.
• Pneumonia risk was the highest with the use of high-dose (> 440 mg/d) quetiapine (P = .003), followed by high- (≥ 330 mg/d) and medium-dose (180 to < 330 mg/d) clozapine (both P < .001) and high-dose (≥ 11 mg/d) olanzapine (P = .02).
• Compared with no antipsychotic use, antipsychotic monotherapy was associated with an increased pneumonia risk (P = .03), whereas antipsychotic polytherapy was not.
• Only the use of antipsychotics with high anticholinergic potency was associated with pneumonia risk (P < .001).

IN PRACTICE:

“Identification of antipsychotic drugs that are associated with pneumonia risk may better inform prevention programs (eg, vaccinations),” the researchers noted. “Second, the availability of pneumonia risk estimates for individual antipsychotics and for groups of antipsychotics may foster personalized prescribing guidelines.”

SOURCE:

The study was led by Jurjen Luykx, MD, Amsterdam University Medical Center, Amsterdam, the Netherlands. It was published online in JAMA Psychiatry.

LIMITATIONS:

The investigators could not correct for all possible risk factors that may increase pneumonia risk in individuals with schizophrenia, such as smoking and lifestyle habits. Also, cases of pneumonia that didn’t require hospital admission couldn’t be included in the analysis, so the findings may generalize only to cases of severe pneumonia.

DISCLOSURES:

The study was funded by the Finnish Ministry of Social Affairs and Health.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

High-dose antipsychotics, particularly quetiapine, clozapine, and olanzapine, are linked to increased pneumonia risk in patients with schizophrenia, new data show. Monotherapy with high anticholinergic burden also raises pneumonia risk.

METHODOLOGY: 

• Using several nationwide data registers, investigators pulled data on individuals who received inpatient care for schizophrenia or schizoaffective disorder (n = 61,889) between 1972 and 2014.
• Data on drug use were gathered from a prescription register and included dispensing dates, cost, dose, package size, and drug formulation. Data on dates and causes of death were obtained from the Causes of Death register.
• After entering the cohort, follow-up started in January 1996 or after the first diagnosis of schizophrenia for those diagnosed between 1996 and 2014.
• The primary outcome was hospitalization caused by pneumonia as the main diagnosis for hospital admission.

TAKEAWAY: 

• During 22 years of follow-up, 8917 patients (14.4%) had one or more hospitalizations for pneumonia, and 1137 (12.8%) died within 30 days of admission.
• Pneumonia risk was the highest with the use of high-dose (> 440 mg/d) quetiapine (P = .003), followed by high- (≥ 330 mg/d) and medium-dose (180 to < 330 mg/d) clozapine (both P < .001) and high-dose (≥ 11 mg/d) olanzapine (P = .02).
• Compared with no antipsychotic use, antipsychotic monotherapy was associated with an increased pneumonia risk (P = .03), whereas antipsychotic polytherapy was not.
• Only the use of antipsychotics with high anticholinergic potency was associated with pneumonia risk (P < .001).

IN PRACTICE:

“Identification of antipsychotic drugs that are associated with pneumonia risk may better inform prevention programs (eg, vaccinations),” the researchers noted. “Second, the availability of pneumonia risk estimates for individual antipsychotics and for groups of antipsychotics may foster personalized prescribing guidelines.”

SOURCE:

The study was led by Jurjen Luykx, MD, Amsterdam University Medical Center, Amsterdam, the Netherlands. It was published online in JAMA Psychiatry.

LIMITATIONS:

The investigators could not correct for all possible risk factors that may increase pneumonia risk in individuals with schizophrenia, such as smoking and lifestyle habits. Also, cases of pneumonia that didn’t require hospital admission couldn’t be included in the analysis, so the findings may generalize only to cases of severe pneumonia.

DISCLOSURES:

The study was funded by the Finnish Ministry of Social Affairs and Health.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
 

An ADC gets its first test, and falls short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
 

Hint of Benefit from Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
 

Unlocking the Order and Timing of ADCs

Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
 

An ADC gets its first test, and falls short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
 

Hint of Benefit from Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
 

Unlocking the Order and Timing of ADCs

Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
 

An ADC gets its first test, and falls short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
 

Hint of Benefit from Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
 

Unlocking the Order and Timing of ADCs

Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.

Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.

Ted Bosworth/Medscape Medical News

The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
 

SLE Is Frequently Targeted in CAR T-Cell Studies

The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.

The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.

For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.

All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
 

Remissions Have Persisted Off All Therapies

These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.

These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.

Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.

Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.

Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.

Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.

After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
 

CAR T-Cell Studies in Autoimmune Diseases Are Proliferating

At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.

At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.

Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.

For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
 

Complete B-Cell Depletion Is Followed by Full Recovery

“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.

Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.

Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.

In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.

Ted Bosworth/Medscape Medical News

cCAR T-Cell Construct Targets Immune Reset

With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.

B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.

However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.

The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.

Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.

Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.

Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.

Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.

“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.

Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
 

Other Case Series Presented at EULAR

Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:

Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.

Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.

Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented.  Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.

August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.

A version of this article appeared on Medscape.com.

VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.

Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.

Ted Bosworth/Medscape Medical News

The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
 

SLE Is Frequently Targeted in CAR T-Cell Studies

The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.

The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.

For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.

All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
 

Remissions Have Persisted Off All Therapies

These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.

These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.

Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.

Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.

Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.

Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.

After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
 

CAR T-Cell Studies in Autoimmune Diseases Are Proliferating

At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.

At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.

Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.

For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
 

Complete B-Cell Depletion Is Followed by Full Recovery

“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.

Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.

Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.

In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.

Ted Bosworth/Medscape Medical News

cCAR T-Cell Construct Targets Immune Reset

With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.

B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.

However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.

The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.

Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.

Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.

Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.

Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.

“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.

Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
 

Other Case Series Presented at EULAR

Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:

Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.

Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.

Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented.  Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.

August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.

A version of this article appeared on Medscape.com.

VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.

Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.

Ted Bosworth/Medscape Medical News

The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
 

SLE Is Frequently Targeted in CAR T-Cell Studies

The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.

The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.

For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.

All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
 

Remissions Have Persisted Off All Therapies

These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.

These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.

Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.

Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.

Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.

Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.

After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
 

CAR T-Cell Studies in Autoimmune Diseases Are Proliferating

At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.

At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.

Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.

For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
 

Complete B-Cell Depletion Is Followed by Full Recovery

“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.

Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.

Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.

In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.

Ted Bosworth/Medscape Medical News

cCAR T-Cell Construct Targets Immune Reset

With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.

B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.

However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.

The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.

Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.

Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.

Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.

Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.

“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.

Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
 

Other Case Series Presented at EULAR

Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:

Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.

Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.

Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented.  Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.

August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.

A version of this article appeared on Medscape.com.

TOPLINE:

Long-term, supervised exercise therapy significantly improves the functional ability and quality of life in patients with axial spondyloarthritis (axSpA) and severe functional limitations.
 

METHODOLOGY:

• This 52-week study evaluated the effectiveness of personalized exercise therapy in adults with axSpA and severe functional limitations.
• Overall, 214 participants were randomly allocated to either a personalized exercise therapy regimen or usual care for 52 weeks.
• The supervised exercise therapy regimen consisted of various exercises, patient education, goal setting, and physical activity promotion for up to 64 sessions.
• The primary endpoint was a change in the highest-ranked Patient-Specific Complaints Numeric Rating Scale (PSC1) score at 52 weeks, and secondary endpoints included measures of physical functioning and quality of life.

TAKEAWAY:

• At 52 weeks, the exercise group showed a greater improvement in the primary outcome measure (PSC1) than the usual-care group, with a mean difference of −1.8 (95% CI, −2.4 to −1.2).
• Exercise therapy led to significant improvements in functional disability and physical quality of life.
• No serious adverse events related to the intervention were reported, highlighting the safety of exercise therapy.

IN PRACTICE:

“If guided by a trained physical therapist applying a personalized approach, people with severe functional limitations due to an unfavorable course or comorbidities can be just as responsive to training as people with axSpA without severe limitations,” the authors wrote.
 

SOURCE:

The study was led by Maria A.T. van Wissen, Department of Orthopaedics, Leiden University Medical Center, Leiden, the Netherlands, and published online in Rheumatology.
 

LIMITATIONS:

The study’s reliance on self-reported data for axSpA treatment-related medication may have compromised accuracy. Additionally, the lack of information on medication changes during the study period could affect result interpretation.
 

DISCLOSURES:

The study was supported by grants from the Netherlands Organization for Health Research and Development; Ministry of Health, Welfare and Sport; Royal Dutch Society for Physical Therapy; and Dutch Arthritis Society. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Long-term, supervised exercise therapy significantly improves the functional ability and quality of life in patients with axial spondyloarthritis (axSpA) and severe functional limitations.
 

METHODOLOGY:

• This 52-week study evaluated the effectiveness of personalized exercise therapy in adults with axSpA and severe functional limitations.
• Overall, 214 participants were randomly allocated to either a personalized exercise therapy regimen or usual care for 52 weeks.
• The supervised exercise therapy regimen consisted of various exercises, patient education, goal setting, and physical activity promotion for up to 64 sessions.
• The primary endpoint was a change in the highest-ranked Patient-Specific Complaints Numeric Rating Scale (PSC1) score at 52 weeks, and secondary endpoints included measures of physical functioning and quality of life.

TAKEAWAY:

• At 52 weeks, the exercise group showed a greater improvement in the primary outcome measure (PSC1) than the usual-care group, with a mean difference of −1.8 (95% CI, −2.4 to −1.2).
• Exercise therapy led to significant improvements in functional disability and physical quality of life.
• No serious adverse events related to the intervention were reported, highlighting the safety of exercise therapy.

IN PRACTICE:

“If guided by a trained physical therapist applying a personalized approach, people with severe functional limitations due to an unfavorable course or comorbidities can be just as responsive to training as people with axSpA without severe limitations,” the authors wrote.
 

SOURCE:

The study was led by Maria A.T. van Wissen, Department of Orthopaedics, Leiden University Medical Center, Leiden, the Netherlands, and published online in Rheumatology.
 

LIMITATIONS:

The study’s reliance on self-reported data for axSpA treatment-related medication may have compromised accuracy. Additionally, the lack of information on medication changes during the study period could affect result interpretation.
 

DISCLOSURES:

The study was supported by grants from the Netherlands Organization for Health Research and Development; Ministry of Health, Welfare and Sport; Royal Dutch Society for Physical Therapy; and Dutch Arthritis Society. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Long-term, supervised exercise therapy significantly improves the functional ability and quality of life in patients with axial spondyloarthritis (axSpA) and severe functional limitations.
 

METHODOLOGY:

• This 52-week study evaluated the effectiveness of personalized exercise therapy in adults with axSpA and severe functional limitations.
• Overall, 214 participants were randomly allocated to either a personalized exercise therapy regimen or usual care for 52 weeks.
• The supervised exercise therapy regimen consisted of various exercises, patient education, goal setting, and physical activity promotion for up to 64 sessions.
• The primary endpoint was a change in the highest-ranked Patient-Specific Complaints Numeric Rating Scale (PSC1) score at 52 weeks, and secondary endpoints included measures of physical functioning and quality of life.

TAKEAWAY:

• At 52 weeks, the exercise group showed a greater improvement in the primary outcome measure (PSC1) than the usual-care group, with a mean difference of −1.8 (95% CI, −2.4 to −1.2).
• Exercise therapy led to significant improvements in functional disability and physical quality of life.
• No serious adverse events related to the intervention were reported, highlighting the safety of exercise therapy.

IN PRACTICE:

“If guided by a trained physical therapist applying a personalized approach, people with severe functional limitations due to an unfavorable course or comorbidities can be just as responsive to training as people with axSpA without severe limitations,” the authors wrote.
 

SOURCE:

The study was led by Maria A.T. van Wissen, Department of Orthopaedics, Leiden University Medical Center, Leiden, the Netherlands, and published online in Rheumatology.
 

LIMITATIONS:

The study’s reliance on self-reported data for axSpA treatment-related medication may have compromised accuracy. Additionally, the lack of information on medication changes during the study period could affect result interpretation.
 

DISCLOSURES:

The study was supported by grants from the Netherlands Organization for Health Research and Development; Ministry of Health, Welfare and Sport; Royal Dutch Society for Physical Therapy; and Dutch Arthritis Society. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Good news for younger children suffering from the uncommon but debilitating gastrointestinal condition eosinophilic esophagitis (EoE): A randomized placebo-controlled study found the monoclonal antibody dupilumab (Dupixent) led to histologic remission in significantly more affected children than placebo. Data from this trial led to a January US Food and Drug Administration (FDA) approval of the anti-inflammatory biologic for patients aged 1-11 years weighing at least 15 kg.

In addition, the trial, published in The New England Journal of Medicine, found that a higher-exposure dupilumab regimen (approximating the trough concentration of a 300-mg dose administered once weekly versus every 2 weeks) improved key secondary end points, according to gastroenterologist Mirna Chehade, MD, MPH, AGAF, a professor of pediatrics at Icahn School of Medicine at Mount Sinai and Mount Sinai Kravis Children’s Hospital in New York City, and colleagues.

The Trial

Conducted at one Canadian and 26 US sites, the two-part phase 3 study randomly assigned 102 EoE patients aged 1-11 years who were refractory to proton pump inhibition in a 2:2:1:1 ratio.

Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher-dose or lower-dose regimen vs placebo (two groups) for 16 weeks.

Part B was a 36-week extended active treatment period in which eligible dupilumab recipients from part A maintained their weight-tiered higher- or lower-dose regimen, whereas those in the placebo groups switched to weight-tiered higher- or lower-dose dupilumab.

The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤ 6 per high-power field) at week 16. Continued dupilumab treatment appeared to maintain its effect through week 52.

During part A, histologic remission occurred in 25 of the 37 higher-exposure patients (68%), 18 of the 31 lower-exposure patients (58%), and one of the 34 placebo patients (3%).

The difference between the higher-exposure regimen and placebo was 65 percentage points (95% confidence interval [CI], 48-81; P < .001), whereas that between the lower-exposure regimen and placebo was 55 percentage points (95% CI, 37-73; P < .001).

Higher exposure led to significant improvements in histologic, endoscopic, and transcriptomic measures over placebo. Improvements between baseline and week 52 in all patients were generally similar to those between baseline and week 16 in patients who received dupilumab in part A.

As for adverse events, in part A, the incidence of coronavirus disease, nausea, injection-site pain, and headache was at least 10 percentage points higher among dupilumab recipients at either dose than among placebo recipients. Serious adverse events were reported in three dupilumab patients during part A and in six patients overall during part B.
 

A Balanced Approach

On a cautionary note, Eric H. Chiou, MD, an assistant professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital in Houston, said that while dupilumab shows great promise, further research is needed on its cost-effectiveness in EoE.

“The cost of treatment will need to be compared relative to potential long-term savings from reduced hospitalizations, fewer complications, and improved quality of life,” said Dr. Chiou, who was not involved in the study. “A balanced approach that considers clinical efficacy, patient well-being, cost-effectiveness, and equity is essential.”

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

Good news for younger children suffering from the uncommon but debilitating gastrointestinal condition eosinophilic esophagitis (EoE): A randomized placebo-controlled study found the monoclonal antibody dupilumab (Dupixent) led to histologic remission in significantly more affected children than placebo. Data from this trial led to a January US Food and Drug Administration (FDA) approval of the anti-inflammatory biologic for patients aged 1-11 years weighing at least 15 kg.

In addition, the trial, published in The New England Journal of Medicine, found that a higher-exposure dupilumab regimen (approximating the trough concentration of a 300-mg dose administered once weekly versus every 2 weeks) improved key secondary end points, according to gastroenterologist Mirna Chehade, MD, MPH, AGAF, a professor of pediatrics at Icahn School of Medicine at Mount Sinai and Mount Sinai Kravis Children’s Hospital in New York City, and colleagues.

The Trial

Conducted at one Canadian and 26 US sites, the two-part phase 3 study randomly assigned 102 EoE patients aged 1-11 years who were refractory to proton pump inhibition in a 2:2:1:1 ratio.

Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher-dose or lower-dose regimen vs placebo (two groups) for 16 weeks.

Part B was a 36-week extended active treatment period in which eligible dupilumab recipients from part A maintained their weight-tiered higher- or lower-dose regimen, whereas those in the placebo groups switched to weight-tiered higher- or lower-dose dupilumab.

The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤ 6 per high-power field) at week 16. Continued dupilumab treatment appeared to maintain its effect through week 52.

During part A, histologic remission occurred in 25 of the 37 higher-exposure patients (68%), 18 of the 31 lower-exposure patients (58%), and one of the 34 placebo patients (3%).

The difference between the higher-exposure regimen and placebo was 65 percentage points (95% confidence interval [CI], 48-81; P < .001), whereas that between the lower-exposure regimen and placebo was 55 percentage points (95% CI, 37-73; P < .001).

Higher exposure led to significant improvements in histologic, endoscopic, and transcriptomic measures over placebo. Improvements between baseline and week 52 in all patients were generally similar to those between baseline and week 16 in patients who received dupilumab in part A.

As for adverse events, in part A, the incidence of coronavirus disease, nausea, injection-site pain, and headache was at least 10 percentage points higher among dupilumab recipients at either dose than among placebo recipients. Serious adverse events were reported in three dupilumab patients during part A and in six patients overall during part B.
 

A Balanced Approach

On a cautionary note, Eric H. Chiou, MD, an assistant professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital in Houston, said that while dupilumab shows great promise, further research is needed on its cost-effectiveness in EoE.

“The cost of treatment will need to be compared relative to potential long-term savings from reduced hospitalizations, fewer complications, and improved quality of life,” said Dr. Chiou, who was not involved in the study. “A balanced approach that considers clinical efficacy, patient well-being, cost-effectiveness, and equity is essential.”

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

Good news for younger children suffering from the uncommon but debilitating gastrointestinal condition eosinophilic esophagitis (EoE): A randomized placebo-controlled study found the monoclonal antibody dupilumab (Dupixent) led to histologic remission in significantly more affected children than placebo. Data from this trial led to a January US Food and Drug Administration (FDA) approval of the anti-inflammatory biologic for patients aged 1-11 years weighing at least 15 kg.

In addition, the trial, published in The New England Journal of Medicine, found that a higher-exposure dupilumab regimen (approximating the trough concentration of a 300-mg dose administered once weekly versus every 2 weeks) improved key secondary end points, according to gastroenterologist Mirna Chehade, MD, MPH, AGAF, a professor of pediatrics at Icahn School of Medicine at Mount Sinai and Mount Sinai Kravis Children’s Hospital in New York City, and colleagues.

The Trial

Conducted at one Canadian and 26 US sites, the two-part phase 3 study randomly assigned 102 EoE patients aged 1-11 years who were refractory to proton pump inhibition in a 2:2:1:1 ratio.

Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher-dose or lower-dose regimen vs placebo (two groups) for 16 weeks.

Part B was a 36-week extended active treatment period in which eligible dupilumab recipients from part A maintained their weight-tiered higher- or lower-dose regimen, whereas those in the placebo groups switched to weight-tiered higher- or lower-dose dupilumab.

The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤ 6 per high-power field) at week 16. Continued dupilumab treatment appeared to maintain its effect through week 52.

During part A, histologic remission occurred in 25 of the 37 higher-exposure patients (68%), 18 of the 31 lower-exposure patients (58%), and one of the 34 placebo patients (3%).

The difference between the higher-exposure regimen and placebo was 65 percentage points (95% confidence interval [CI], 48-81; P < .001), whereas that between the lower-exposure regimen and placebo was 55 percentage points (95% CI, 37-73; P < .001).

Higher exposure led to significant improvements in histologic, endoscopic, and transcriptomic measures over placebo. Improvements between baseline and week 52 in all patients were generally similar to those between baseline and week 16 in patients who received dupilumab in part A.

As for adverse events, in part A, the incidence of coronavirus disease, nausea, injection-site pain, and headache was at least 10 percentage points higher among dupilumab recipients at either dose than among placebo recipients. Serious adverse events were reported in three dupilumab patients during part A and in six patients overall during part B.
 

A Balanced Approach

On a cautionary note, Eric H. Chiou, MD, an assistant professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital in Houston, said that while dupilumab shows great promise, further research is needed on its cost-effectiveness in EoE.

“The cost of treatment will need to be compared relative to potential long-term savings from reduced hospitalizations, fewer complications, and improved quality of life,” said Dr. Chiou, who was not involved in the study. “A balanced approach that considers clinical efficacy, patient well-being, cost-effectiveness, and equity is essential.”

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

Nonphysician operators (NPOs) using laser and energy-based devices are accounting for an increasing share of malpractice lawsuits in dermatology, and when they use these devices in a dermatologic practice or a dermatologist-owned medical spa, the dermatologist can be on the hook for liability. Dermatologists can protect themselves by understanding malpractice trends and taking preventive steps, such as making sure NPOs have appropriate training and using a rigorous informed consent process, according to a dermatology resident and a dermatologist who have researched recent trends in dermatology lawsuits.

“It’s really important that physicians recognize their responsibility when delegating procedures to nonphysician operators and the physician’s role in supervision of these procedures,” Scott Stratman, MD, MPH, a dermatology resident at the Icahn School of Medicine at Mount Sinai, New York City, told this news organization. He led a  study recently published in the Journal of the American Academy of Dermatology, which found that the majority (52%) of malpractice cases for cutaneous energy-based device procedures in the LexisNexis database from 1985 to September 2023 involved NPOs. The study did not break the data down between different types of NPOs.

Dr. Stratman

Trends in Dermatology Malpractice

This follows a similar trend reported in a 2014 study led by Mathew M. Avram, MD, JD, director of the MGH Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston. The study analyzed liability claims related to cutaneous laser surgery performed by nonphysicians from January 1999 to December 2012.

“With nonphysician litigation data, we saw trend lines beginning in 2008 where the proportion of cases began to increase,” Dr. Avram said at the American Society for Laser Medicine and Surgery (ASLMS) meeting on April 12, 2024. “Over a period of 2008-2012, it went from 36% of cases to about 78%,” he said.

About a quarter (23.4%) of those were in medical offices; 76.6% were in nontraditional settings such as medical spas, he added. The proportion of NPOs was similar in a 2022 study that looked at causes of litigation in cutaneous laser surgery from 2012 to 2020, Dr. Avram said. Again, neither study broke down cases involving NPOs by specific type, but the 2014 study reported that 64% of cases by NPOs occurred outside of a traditional medical setting.

“So it seems that the location and potentially the supervision are issues that are important to patient safety,” Dr. Avram said at the meeting. While state laws regarding laser delegation vary widely, “depending on where you practice, it’s incumbent upon you to know that.”

Dr. Avram and colleagues were also the authors of a study published in June in Dermatologic Surgery that looked at the reasons behind ligations involving dermatologists in a retrospective analysis of 48 state and federal cases between 2011 and 2022. The majority of cases — 54.2% — were for unexpected harm, followed by wrong or delayed diagnoses, which accounted for a third of litigations.

Dr. Stratman’s study found that laser hair removal was the most common procedure for malpractice claims in dermatology among cutaneous energy-based device procedures. Complications from energy-based devices included burns, scarring, and pigmentation changes.

The growth of malpractice suits involving NPOs could be because NPOs are performing a greater proportion of dermatologic procedures, “particularly those practicing without direct supervision, such as in the context of a medical spa,” Dr. Stratman said in the interview. “Again, this highlights a physician’s responsibility in delegating these kinds of procedures to NPOs.”
 

Training Is a Must — But Not Standardized

Comprehensive training for physicians, staff, NPOs, and physicians “is all necessary and paramount in order to diminish adverse outcomes and legal risk, and then, of course, all these practitioners, be it staff or [NPOs], and, of course, physicians, are all held to the same standard of care,” Dr. Stratman said.

However, he added, “There is really no standardized training to operate these devices. That being said, it’s really important to know that both providers and facility owners have a significant obligation to their patients to make sure that their staff in their centers are appropriately trained.”

Training not only involves protocols and procedures but also how to handle patient interactions, Dr. Stratman said.

The legal concept of respondeat superior applies when nonphysicians participate in a patient’s care, Dr. Avram said at the ASLMS meeting. The physician is held liable for a nonphysician’s “negligence provided he or she is an employee receiving a salary [and] benefits and is performing within the scope of his or her duty,” regardless of whether the physician saw the patient or not at that visit, he said. Again, supervision of nonphysician laser procedures varies from state to state, he added.

“So the take-home point is to provide excellent training and appropriate supervision, and if you’re the owner of that practice, you are liable in the event of negligence even though you never were part of the treatment,” Dr. Avram said.

Ins and Outs of Informed Consent

When a patient outcome is less than desirable, or at least less than what the patient expected, a transparent and thorough informed consent process can protect the practice and physician, Dr. Avram said at the meeting.

“Malpractice and consent have nothing to do with each other,” he said. “Consent is getting permission to do a procedure. It’s needed actually for any medical intervention that you perform. What you need to do is to provide information to enable the patient or guardian or to choose knowledgeably among reasonable medical alternatives. This places the patient in control of the course of their medical treatment.”

The information conveyed to the patient should include the diagnosis, the medical causes, the nature and purpose of the treatment, and the risks and alternatives of procedure, “particularly if they’re high risk,” Dr. Avram said.

“Failure to obtain informed consent constitutes a civil battery, and the physician is liable for civil damages,” he said. “The patient need only show that he or she was not informed of the medical nature of the medical touching; physical injury is not necessary.”

A battery could occur if a procedure extends beyond the scope or area of treatment the patient agreed to — for example, extending a liposuction to an area that wasn’t originally targeted, or extending a laser procedure to an area of the body as a presumed favor to the patient. “It does not require a standard of care or an expert witness,” Dr. Avram said. “One only needs to show nonconsensual touching.”

Informed consents should include plain language, he said. “The whole idea is the patient understands what the risks and benefits are,” Dr. Avram said. “You don’t need to use medical jargon.” As an example, he suggested using the term “blisters” instead of “bullae.” If the treatment involves an off-label procedure, include that too, he said.

He also advised avoiding blanket authorizations. “Courts disfavor them,” he noted. “They need more specificity. So those are not valid.”

Dr. Stratman added that providers should think about the setting in which they obtain informed consent. “It’s really important that providers are consenting their patients in private and quiet places, free from distractions, that they accommodate patients who might have disabilities or limitations in English proficiency, using a teach-back method to help patients understand or demonstrate their understanding of the procedure in order to gauge comprehension,” he said.

Both Dr. Avram and Dr. Stratman pointed out that another strategy to prevent malpractice is to build trusting patient-provider relationships. “The patient-provider relationship is paramount not only to the success of the procedure but to the clinical visit as a whole,” Dr. Stratman said.

That’s a two-way street, he added. Patients should be able to trust that their provider provides them with the best treatment based on their own history, and providers should also be able to trust that patients are providing them with an accurate history, asking relevant questions, or expressing any level of apprehension about the procedure or visit. “The patient-provider relationship is everything,” Dr. Stratman said.

Dr. Stratman and Dr. Avram had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Nonphysician operators (NPOs) using laser and energy-based devices are accounting for an increasing share of malpractice lawsuits in dermatology, and when they use these devices in a dermatologic practice or a dermatologist-owned medical spa, the dermatologist can be on the hook for liability. Dermatologists can protect themselves by understanding malpractice trends and taking preventive steps, such as making sure NPOs have appropriate training and using a rigorous informed consent process, according to a dermatology resident and a dermatologist who have researched recent trends in dermatology lawsuits.

“It’s really important that physicians recognize their responsibility when delegating procedures to nonphysician operators and the physician’s role in supervision of these procedures,” Scott Stratman, MD, MPH, a dermatology resident at the Icahn School of Medicine at Mount Sinai, New York City, told this news organization. He led a  study recently published in the Journal of the American Academy of Dermatology, which found that the majority (52%) of malpractice cases for cutaneous energy-based device procedures in the LexisNexis database from 1985 to September 2023 involved NPOs. The study did not break the data down between different types of NPOs.

Dr. Stratman

Trends in Dermatology Malpractice

This follows a similar trend reported in a 2014 study led by Mathew M. Avram, MD, JD, director of the MGH Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston. The study analyzed liability claims related to cutaneous laser surgery performed by nonphysicians from January 1999 to December 2012.

“With nonphysician litigation data, we saw trend lines beginning in 2008 where the proportion of cases began to increase,” Dr. Avram said at the American Society for Laser Medicine and Surgery (ASLMS) meeting on April 12, 2024. “Over a period of 2008-2012, it went from 36% of cases to about 78%,” he said.

About a quarter (23.4%) of those were in medical offices; 76.6% were in nontraditional settings such as medical spas, he added. The proportion of NPOs was similar in a 2022 study that looked at causes of litigation in cutaneous laser surgery from 2012 to 2020, Dr. Avram said. Again, neither study broke down cases involving NPOs by specific type, but the 2014 study reported that 64% of cases by NPOs occurred outside of a traditional medical setting.

“So it seems that the location and potentially the supervision are issues that are important to patient safety,” Dr. Avram said at the meeting. While state laws regarding laser delegation vary widely, “depending on where you practice, it’s incumbent upon you to know that.”

Dr. Avram and colleagues were also the authors of a study published in June in Dermatologic Surgery that looked at the reasons behind ligations involving dermatologists in a retrospective analysis of 48 state and federal cases between 2011 and 2022. The majority of cases — 54.2% — were for unexpected harm, followed by wrong or delayed diagnoses, which accounted for a third of litigations.

Dr. Stratman’s study found that laser hair removal was the most common procedure for malpractice claims in dermatology among cutaneous energy-based device procedures. Complications from energy-based devices included burns, scarring, and pigmentation changes.

The growth of malpractice suits involving NPOs could be because NPOs are performing a greater proportion of dermatologic procedures, “particularly those practicing without direct supervision, such as in the context of a medical spa,” Dr. Stratman said in the interview. “Again, this highlights a physician’s responsibility in delegating these kinds of procedures to NPOs.”
 

Training Is a Must — But Not Standardized

Comprehensive training for physicians, staff, NPOs, and physicians “is all necessary and paramount in order to diminish adverse outcomes and legal risk, and then, of course, all these practitioners, be it staff or [NPOs], and, of course, physicians, are all held to the same standard of care,” Dr. Stratman said.

However, he added, “There is really no standardized training to operate these devices. That being said, it’s really important to know that both providers and facility owners have a significant obligation to their patients to make sure that their staff in their centers are appropriately trained.”

Training not only involves protocols and procedures but also how to handle patient interactions, Dr. Stratman said.

The legal concept of respondeat superior applies when nonphysicians participate in a patient’s care, Dr. Avram said at the ASLMS meeting. The physician is held liable for a nonphysician’s “negligence provided he or she is an employee receiving a salary [and] benefits and is performing within the scope of his or her duty,” regardless of whether the physician saw the patient or not at that visit, he said. Again, supervision of nonphysician laser procedures varies from state to state, he added.

“So the take-home point is to provide excellent training and appropriate supervision, and if you’re the owner of that practice, you are liable in the event of negligence even though you never were part of the treatment,” Dr. Avram said.

Ins and Outs of Informed Consent

When a patient outcome is less than desirable, or at least less than what the patient expected, a transparent and thorough informed consent process can protect the practice and physician, Dr. Avram said at the meeting.

“Malpractice and consent have nothing to do with each other,” he said. “Consent is getting permission to do a procedure. It’s needed actually for any medical intervention that you perform. What you need to do is to provide information to enable the patient or guardian or to choose knowledgeably among reasonable medical alternatives. This places the patient in control of the course of their medical treatment.”

The information conveyed to the patient should include the diagnosis, the medical causes, the nature and purpose of the treatment, and the risks and alternatives of procedure, “particularly if they’re high risk,” Dr. Avram said.

“Failure to obtain informed consent constitutes a civil battery, and the physician is liable for civil damages,” he said. “The patient need only show that he or she was not informed of the medical nature of the medical touching; physical injury is not necessary.”

A battery could occur if a procedure extends beyond the scope or area of treatment the patient agreed to — for example, extending a liposuction to an area that wasn’t originally targeted, or extending a laser procedure to an area of the body as a presumed favor to the patient. “It does not require a standard of care or an expert witness,” Dr. Avram said. “One only needs to show nonconsensual touching.”

Informed consents should include plain language, he said. “The whole idea is the patient understands what the risks and benefits are,” Dr. Avram said. “You don’t need to use medical jargon.” As an example, he suggested using the term “blisters” instead of “bullae.” If the treatment involves an off-label procedure, include that too, he said.

He also advised avoiding blanket authorizations. “Courts disfavor them,” he noted. “They need more specificity. So those are not valid.”

Dr. Stratman added that providers should think about the setting in which they obtain informed consent. “It’s really important that providers are consenting their patients in private and quiet places, free from distractions, that they accommodate patients who might have disabilities or limitations in English proficiency, using a teach-back method to help patients understand or demonstrate their understanding of the procedure in order to gauge comprehension,” he said.

Both Dr. Avram and Dr. Stratman pointed out that another strategy to prevent malpractice is to build trusting patient-provider relationships. “The patient-provider relationship is paramount not only to the success of the procedure but to the clinical visit as a whole,” Dr. Stratman said.

That’s a two-way street, he added. Patients should be able to trust that their provider provides them with the best treatment based on their own history, and providers should also be able to trust that patients are providing them with an accurate history, asking relevant questions, or expressing any level of apprehension about the procedure or visit. “The patient-provider relationship is everything,” Dr. Stratman said.

Dr. Stratman and Dr. Avram had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Nonphysician operators (NPOs) using laser and energy-based devices are accounting for an increasing share of malpractice lawsuits in dermatology, and when they use these devices in a dermatologic practice or a dermatologist-owned medical spa, the dermatologist can be on the hook for liability. Dermatologists can protect themselves by understanding malpractice trends and taking preventive steps, such as making sure NPOs have appropriate training and using a rigorous informed consent process, according to a dermatology resident and a dermatologist who have researched recent trends in dermatology lawsuits.

“It’s really important that physicians recognize their responsibility when delegating procedures to nonphysician operators and the physician’s role in supervision of these procedures,” Scott Stratman, MD, MPH, a dermatology resident at the Icahn School of Medicine at Mount Sinai, New York City, told this news organization. He led a  study recently published in the Journal of the American Academy of Dermatology, which found that the majority (52%) of malpractice cases for cutaneous energy-based device procedures in the LexisNexis database from 1985 to September 2023 involved NPOs. The study did not break the data down between different types of NPOs.

Dr. Stratman

Trends in Dermatology Malpractice

This follows a similar trend reported in a 2014 study led by Mathew M. Avram, MD, JD, director of the MGH Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston. The study analyzed liability claims related to cutaneous laser surgery performed by nonphysicians from January 1999 to December 2012.

“With nonphysician litigation data, we saw trend lines beginning in 2008 where the proportion of cases began to increase,” Dr. Avram said at the American Society for Laser Medicine and Surgery (ASLMS) meeting on April 12, 2024. “Over a period of 2008-2012, it went from 36% of cases to about 78%,” he said.

About a quarter (23.4%) of those were in medical offices; 76.6% were in nontraditional settings such as medical spas, he added. The proportion of NPOs was similar in a 2022 study that looked at causes of litigation in cutaneous laser surgery from 2012 to 2020, Dr. Avram said. Again, neither study broke down cases involving NPOs by specific type, but the 2014 study reported that 64% of cases by NPOs occurred outside of a traditional medical setting.

“So it seems that the location and potentially the supervision are issues that are important to patient safety,” Dr. Avram said at the meeting. While state laws regarding laser delegation vary widely, “depending on where you practice, it’s incumbent upon you to know that.”

Dr. Avram and colleagues were also the authors of a study published in June in Dermatologic Surgery that looked at the reasons behind ligations involving dermatologists in a retrospective analysis of 48 state and federal cases between 2011 and 2022. The majority of cases — 54.2% — were for unexpected harm, followed by wrong or delayed diagnoses, which accounted for a third of litigations.

Dr. Stratman’s study found that laser hair removal was the most common procedure for malpractice claims in dermatology among cutaneous energy-based device procedures. Complications from energy-based devices included burns, scarring, and pigmentation changes.

The growth of malpractice suits involving NPOs could be because NPOs are performing a greater proportion of dermatologic procedures, “particularly those practicing without direct supervision, such as in the context of a medical spa,” Dr. Stratman said in the interview. “Again, this highlights a physician’s responsibility in delegating these kinds of procedures to NPOs.”
 

Training Is a Must — But Not Standardized

Comprehensive training for physicians, staff, NPOs, and physicians “is all necessary and paramount in order to diminish adverse outcomes and legal risk, and then, of course, all these practitioners, be it staff or [NPOs], and, of course, physicians, are all held to the same standard of care,” Dr. Stratman said.

However, he added, “There is really no standardized training to operate these devices. That being said, it’s really important to know that both providers and facility owners have a significant obligation to their patients to make sure that their staff in their centers are appropriately trained.”

Training not only involves protocols and procedures but also how to handle patient interactions, Dr. Stratman said.

The legal concept of respondeat superior applies when nonphysicians participate in a patient’s care, Dr. Avram said at the ASLMS meeting. The physician is held liable for a nonphysician’s “negligence provided he or she is an employee receiving a salary [and] benefits and is performing within the scope of his or her duty,” regardless of whether the physician saw the patient or not at that visit, he said. Again, supervision of nonphysician laser procedures varies from state to state, he added.

“So the take-home point is to provide excellent training and appropriate supervision, and if you’re the owner of that practice, you are liable in the event of negligence even though you never were part of the treatment,” Dr. Avram said.

Ins and Outs of Informed Consent

When a patient outcome is less than desirable, or at least less than what the patient expected, a transparent and thorough informed consent process can protect the practice and physician, Dr. Avram said at the meeting.

“Malpractice and consent have nothing to do with each other,” he said. “Consent is getting permission to do a procedure. It’s needed actually for any medical intervention that you perform. What you need to do is to provide information to enable the patient or guardian or to choose knowledgeably among reasonable medical alternatives. This places the patient in control of the course of their medical treatment.”

The information conveyed to the patient should include the diagnosis, the medical causes, the nature and purpose of the treatment, and the risks and alternatives of procedure, “particularly if they’re high risk,” Dr. Avram said.

“Failure to obtain informed consent constitutes a civil battery, and the physician is liable for civil damages,” he said. “The patient need only show that he or she was not informed of the medical nature of the medical touching; physical injury is not necessary.”

A battery could occur if a procedure extends beyond the scope or area of treatment the patient agreed to — for example, extending a liposuction to an area that wasn’t originally targeted, or extending a laser procedure to an area of the body as a presumed favor to the patient. “It does not require a standard of care or an expert witness,” Dr. Avram said. “One only needs to show nonconsensual touching.”

Informed consents should include plain language, he said. “The whole idea is the patient understands what the risks and benefits are,” Dr. Avram said. “You don’t need to use medical jargon.” As an example, he suggested using the term “blisters” instead of “bullae.” If the treatment involves an off-label procedure, include that too, he said.

He also advised avoiding blanket authorizations. “Courts disfavor them,” he noted. “They need more specificity. So those are not valid.”

Dr. Stratman added that providers should think about the setting in which they obtain informed consent. “It’s really important that providers are consenting their patients in private and quiet places, free from distractions, that they accommodate patients who might have disabilities or limitations in English proficiency, using a teach-back method to help patients understand or demonstrate their understanding of the procedure in order to gauge comprehension,” he said.

Both Dr. Avram and Dr. Stratman pointed out that another strategy to prevent malpractice is to build trusting patient-provider relationships. “The patient-provider relationship is paramount not only to the success of the procedure but to the clinical visit as a whole,” Dr. Stratman said.

That’s a two-way street, he added. Patients should be able to trust that their provider provides them with the best treatment based on their own history, and providers should also be able to trust that patients are providing them with an accurate history, asking relevant questions, or expressing any level of apprehension about the procedure or visit. “The patient-provider relationship is everything,” Dr. Stratman said.

Dr. Stratman and Dr. Avram had no relevant disclosures.
 

A version of this article appeared on Medscape.com.

As Pride Month drew to a close, the Supreme Court made a shocking announcement. For the first time in the history of the court, it is willing to hear a legal challenge regarding gender-affirming care for minors. The justices will review whether a 2023 Tennessee law, SB1, which bans hormone therapy, puberty blockers, and surgery for transgender minors, is unconstitutional. This is the first time the Supreme Court will directly weigh in on gender-affirming care.

There are few topics as politically and medically divisive as gender-affirming care for minors. When the World Professional Association for Transgender Health (WPATH) released its updated Standards of Care, SOC8, one of the noticeable changes to the document was its approach to caring for transgender children and adolescents.

Dr. Brandt

Before I highlight these recommendations and the ensuing controversy, it is imperative to establish proper terminology. Unfortunately, medical and legal terms often differ. Both activists and opponents use these terms interchangeably, which makes discourse about an already emotionally charged topic extremely difficult. From a legal perspective, the terms “minor” and “child” often refer to individuals under the age of majority. In the United States, the age of majority is 18. However, the term child also has a well-established medical definition. A child is an individual between the stages of infancy and puberty. Adolescence is a transitional period marked by the onset of puberty until adulthood (typically the age of majority). As medical providers, understanding these definitions is essential to identifying misinformation pertaining to this type of healthcare.

For the purposes of this article, I will be adhering to the medical terminology. Now, I want to be very clear. WPATH does not endorse surgical procedures on children. Furthermore, surgeons are not performing gender-affirming surgeries on children. On adolescents, rarely. But children, never.

According to the updated SOC8, the only acceptable gender-affirming intervention for children is psychosocial support.¹ This does not include puberty blockers, hormones, or surgery, but rather allowing a child to explore their gender identity by experimenting with different clothing, toys, hairstyles, and even an alternative name that aligns more closely with their gender identity.¹

It is only after children reach adolescence that medical, and in rare cases, surgical interventions, can be considered. Puberty blockers are appropriate for patients who have started puberty and experience gender dysphoria. These medications are reversible, and their purpose is to temporarily pause puberty to allow the adolescent to further explore their gender identity.

The most significant side effect of puberty blockers is decreased bone density.¹ As a result, providers typically do not prescribe these medications for more than 2-3 years. After discontinuation of the medication, bone density returns to baseline.¹ If the adolescent’s gender identity is marked and sustained over time, hormone therapy, such as testosterone or estrogen is then considered. Unlike puberty blockers, these medications can have permanent side effects. Testosterone use can lead to irreversible hair growth, alopecia, clitoromegaly, and voice deepening, while estrogen can cause permanent breast growth and halt sperm production.¹ Future fertility and these side effects are discussed with the patient in detail prior to the initiation of these medications.

Contrary to the current political narrative, gender-affirming care for children and adolescents is not taken lightly. These individuals often receive years of multidisciplinary assessments, with a focus on gender identity development, social development and support, and diagnostic assessment of possible co-occurring mental health or developmental concerns and capacity for decision making.¹ The clinical visits also occur with parental support and consent.

WPATH SOC8 also delineates the provider qualifications for health care professionals assessing these patients. Providers must be licensed by their statutory bodies and hold a postgraduate degree by a nationally accredited statutory institution; receive theoretical and evidence-based training and develop expertise in child, adolescent, and family mental health across the developmental spectrum; receive training and have expertise in gender identity development and gender diversity in children and adolescence; have the ability to assess capacity to assent/consent; receive training and develop expertise in autism spectrum disorders and other neurodevelopmental presentations; and to continue engaging in professional development in all areas relevant to gender-diverse children, adolescents, and families.¹

The most controversial aspect of gender-affirming care for children and adolescents relates to surgical treatment. While the rates of gender-affirming surgeries have increased for this age group over the years, the overall rate of gender-affirming surgery for adolescents is markedly lower compared with other adolescents seeking cosmetic surgeries and compared with transgender adults undergoing gender-affirming surgery.

In a cohort study conducted between 2016 to 2020, 48,019 patients were identified who had undergone gender-affirming surgery.² Only 3678 or 7.7% of patients were aged between 12 and 18, with the most common procedure being chest/breast surgery.² So, under about 1000 cases per year were gender-affirming surgeries on patients under 18.

During 2020 alone, the number of cisgender adolescents between the ages of 13 and 19 who underwent breast augmentation and breast reduction was 3233 and 4666, respectively.³ The outrage about gender-affirming surgeries on transgender youth, yet the silence on cosmetic procedures in this same age group, speaks volumes.

All surgeries on adolescents should be taken seriously and with caution, regardless of gender identity. However, current legislation disproportionately targets only transgender youth. For whatever reason, surgeries on transgender individuals are labeled as “body mutilation,” whereas surgeries on cisgender youth are not even discussed. Such inflammatory rhetoric and complete lack of empathy impedes the common goal of all parties: what is in the best interest of the minor? Unfortunately, in a few short months, the answer to this question will be determined by a group of nine justices who have no experience in medicine or transgender health care, instead of by medical experts and the parents who care for these individuals.
 

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pennsylvania. She has no conflicts of interest.
 

References

1. Coleman E et al. Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgender Health. 2022;23(sup):S1-S259.

2. Wright JD et al. National estimates of gender affirming surgery in the US. JAMA Netw Open. 2023 Aug 1;6(8):e2330348.

3. American Society of Plastic Surgeons. Plastic Surgery Statistics Report. ASPS National Clearinghouse of Plastic Surgery Procedural Statistics. 2020.

As Pride Month drew to a close, the Supreme Court made a shocking announcement. For the first time in the history of the court, it is willing to hear a legal challenge regarding gender-affirming care for minors. The justices will review whether a 2023 Tennessee law, SB1, which bans hormone therapy, puberty blockers, and surgery for transgender minors, is unconstitutional. This is the first time the Supreme Court will directly weigh in on gender-affirming care.

There are few topics as politically and medically divisive as gender-affirming care for minors. When the World Professional Association for Transgender Health (WPATH) released its updated Standards of Care, SOC8, one of the noticeable changes to the document was its approach to caring for transgender children and adolescents.

Dr. Brandt

Before I highlight these recommendations and the ensuing controversy, it is imperative to establish proper terminology. Unfortunately, medical and legal terms often differ. Both activists and opponents use these terms interchangeably, which makes discourse about an already emotionally charged topic extremely difficult. From a legal perspective, the terms “minor” and “child” often refer to individuals under the age of majority. In the United States, the age of majority is 18. However, the term child also has a well-established medical definition. A child is an individual between the stages of infancy and puberty. Adolescence is a transitional period marked by the onset of puberty until adulthood (typically the age of majority). As medical providers, understanding these definitions is essential to identifying misinformation pertaining to this type of healthcare.

For the purposes of this article, I will be adhering to the medical terminology. Now, I want to be very clear. WPATH does not endorse surgical procedures on children. Furthermore, surgeons are not performing gender-affirming surgeries on children. On adolescents, rarely. But children, never.

According to the updated SOC8, the only acceptable gender-affirming intervention for children is psychosocial support.¹ This does not include puberty blockers, hormones, or surgery, but rather allowing a child to explore their gender identity by experimenting with different clothing, toys, hairstyles, and even an alternative name that aligns more closely with their gender identity.¹

It is only after children reach adolescence that medical, and in rare cases, surgical interventions, can be considered. Puberty blockers are appropriate for patients who have started puberty and experience gender dysphoria. These medications are reversible, and their purpose is to temporarily pause puberty to allow the adolescent to further explore their gender identity.

The most significant side effect of puberty blockers is decreased bone density.¹ As a result, providers typically do not prescribe these medications for more than 2-3 years. After discontinuation of the medication, bone density returns to baseline.¹ If the adolescent’s gender identity is marked and sustained over time, hormone therapy, such as testosterone or estrogen is then considered. Unlike puberty blockers, these medications can have permanent side effects. Testosterone use can lead to irreversible hair growth, alopecia, clitoromegaly, and voice deepening, while estrogen can cause permanent breast growth and halt sperm production.¹ Future fertility and these side effects are discussed with the patient in detail prior to the initiation of these medications.

Contrary to the current political narrative, gender-affirming care for children and adolescents is not taken lightly. These individuals often receive years of multidisciplinary assessments, with a focus on gender identity development, social development and support, and diagnostic assessment of possible co-occurring mental health or developmental concerns and capacity for decision making.¹ The clinical visits also occur with parental support and consent.

WPATH SOC8 also delineates the provider qualifications for health care professionals assessing these patients. Providers must be licensed by their statutory bodies and hold a postgraduate degree by a nationally accredited statutory institution; receive theoretical and evidence-based training and develop expertise in child, adolescent, and family mental health across the developmental spectrum; receive training and have expertise in gender identity development and gender diversity in children and adolescence; have the ability to assess capacity to assent/consent; receive training and develop expertise in autism spectrum disorders and other neurodevelopmental presentations; and to continue engaging in professional development in all areas relevant to gender-diverse children, adolescents, and families.¹

The most controversial aspect of gender-affirming care for children and adolescents relates to surgical treatment. While the rates of gender-affirming surgeries have increased for this age group over the years, the overall rate of gender-affirming surgery for adolescents is markedly lower compared with other adolescents seeking cosmetic surgeries and compared with transgender adults undergoing gender-affirming surgery.

In a cohort study conducted between 2016 to 2020, 48,019 patients were identified who had undergone gender-affirming surgery.² Only 3678 or 7.7% of patients were aged between 12 and 18, with the most common procedure being chest/breast surgery.² So, under about 1000 cases per year were gender-affirming surgeries on patients under 18.

During 2020 alone, the number of cisgender adolescents between the ages of 13 and 19 who underwent breast augmentation and breast reduction was 3233 and 4666, respectively.³ The outrage about gender-affirming surgeries on transgender youth, yet the silence on cosmetic procedures in this same age group, speaks volumes.

All surgeries on adolescents should be taken seriously and with caution, regardless of gender identity. However, current legislation disproportionately targets only transgender youth. For whatever reason, surgeries on transgender individuals are labeled as “body mutilation,” whereas surgeries on cisgender youth are not even discussed. Such inflammatory rhetoric and complete lack of empathy impedes the common goal of all parties: what is in the best interest of the minor? Unfortunately, in a few short months, the answer to this question will be determined by a group of nine justices who have no experience in medicine or transgender health care, instead of by medical experts and the parents who care for these individuals.
 

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pennsylvania. She has no conflicts of interest.
 

References

1. Coleman E et al. Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgender Health. 2022;23(sup):S1-S259.

2. Wright JD et al. National estimates of gender affirming surgery in the US. JAMA Netw Open. 2023 Aug 1;6(8):e2330348.

3. American Society of Plastic Surgeons. Plastic Surgery Statistics Report. ASPS National Clearinghouse of Plastic Surgery Procedural Statistics. 2020.

As Pride Month drew to a close, the Supreme Court made a shocking announcement. For the first time in the history of the court, it is willing to hear a legal challenge regarding gender-affirming care for minors. The justices will review whether a 2023 Tennessee law, SB1, which bans hormone therapy, puberty blockers, and surgery for transgender minors, is unconstitutional. This is the first time the Supreme Court will directly weigh in on gender-affirming care.

There are few topics as politically and medically divisive as gender-affirming care for minors. When the World Professional Association for Transgender Health (WPATH) released its updated Standards of Care, SOC8, one of the noticeable changes to the document was its approach to caring for transgender children and adolescents.

Dr. Brandt

Before I highlight these recommendations and the ensuing controversy, it is imperative to establish proper terminology. Unfortunately, medical and legal terms often differ. Both activists and opponents use these terms interchangeably, which makes discourse about an already emotionally charged topic extremely difficult. From a legal perspective, the terms “minor” and “child” often refer to individuals under the age of majority. In the United States, the age of majority is 18. However, the term child also has a well-established medical definition. A child is an individual between the stages of infancy and puberty. Adolescence is a transitional period marked by the onset of puberty until adulthood (typically the age of majority). As medical providers, understanding these definitions is essential to identifying misinformation pertaining to this type of healthcare.

For the purposes of this article, I will be adhering to the medical terminology. Now, I want to be very clear. WPATH does not endorse surgical procedures on children. Furthermore, surgeons are not performing gender-affirming surgeries on children. On adolescents, rarely. But children, never.

According to the updated SOC8, the only acceptable gender-affirming intervention for children is psychosocial support.¹ This does not include puberty blockers, hormones, or surgery, but rather allowing a child to explore their gender identity by experimenting with different clothing, toys, hairstyles, and even an alternative name that aligns more closely with their gender identity.¹

It is only after children reach adolescence that medical, and in rare cases, surgical interventions, can be considered. Puberty blockers are appropriate for patients who have started puberty and experience gender dysphoria. These medications are reversible, and their purpose is to temporarily pause puberty to allow the adolescent to further explore their gender identity.

The most significant side effect of puberty blockers is decreased bone density.¹ As a result, providers typically do not prescribe these medications for more than 2-3 years. After discontinuation of the medication, bone density returns to baseline.¹ If the adolescent’s gender identity is marked and sustained over time, hormone therapy, such as testosterone or estrogen is then considered. Unlike puberty blockers, these medications can have permanent side effects. Testosterone use can lead to irreversible hair growth, alopecia, clitoromegaly, and voice deepening, while estrogen can cause permanent breast growth and halt sperm production.¹ Future fertility and these side effects are discussed with the patient in detail prior to the initiation of these medications.

Contrary to the current political narrative, gender-affirming care for children and adolescents is not taken lightly. These individuals often receive years of multidisciplinary assessments, with a focus on gender identity development, social development and support, and diagnostic assessment of possible co-occurring mental health or developmental concerns and capacity for decision making.¹ The clinical visits also occur with parental support and consent.

WPATH SOC8 also delineates the provider qualifications for health care professionals assessing these patients. Providers must be licensed by their statutory bodies and hold a postgraduate degree by a nationally accredited statutory institution; receive theoretical and evidence-based training and develop expertise in child, adolescent, and family mental health across the developmental spectrum; receive training and have expertise in gender identity development and gender diversity in children and adolescence; have the ability to assess capacity to assent/consent; receive training and develop expertise in autism spectrum disorders and other neurodevelopmental presentations; and to continue engaging in professional development in all areas relevant to gender-diverse children, adolescents, and families.¹

The most controversial aspect of gender-affirming care for children and adolescents relates to surgical treatment. While the rates of gender-affirming surgeries have increased for this age group over the years, the overall rate of gender-affirming surgery for adolescents is markedly lower compared with other adolescents seeking cosmetic surgeries and compared with transgender adults undergoing gender-affirming surgery.

In a cohort study conducted between 2016 to 2020, 48,019 patients were identified who had undergone gender-affirming surgery.² Only 3678 or 7.7% of patients were aged between 12 and 18, with the most common procedure being chest/breast surgery.² So, under about 1000 cases per year were gender-affirming surgeries on patients under 18.

During 2020 alone, the number of cisgender adolescents between the ages of 13 and 19 who underwent breast augmentation and breast reduction was 3233 and 4666, respectively.³ The outrage about gender-affirming surgeries on transgender youth, yet the silence on cosmetic procedures in this same age group, speaks volumes.

All surgeries on adolescents should be taken seriously and with caution, regardless of gender identity. However, current legislation disproportionately targets only transgender youth. For whatever reason, surgeries on transgender individuals are labeled as “body mutilation,” whereas surgeries on cisgender youth are not even discussed. Such inflammatory rhetoric and complete lack of empathy impedes the common goal of all parties: what is in the best interest of the minor? Unfortunately, in a few short months, the answer to this question will be determined by a group of nine justices who have no experience in medicine or transgender health care, instead of by medical experts and the parents who care for these individuals.
 

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pennsylvania. She has no conflicts of interest.
 

References

1. Coleman E et al. Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgender Health. 2022;23(sup):S1-S259.

2. Wright JD et al. National estimates of gender affirming surgery in the US. JAMA Netw Open. 2023 Aug 1;6(8):e2330348.

3. American Society of Plastic Surgeons. Plastic Surgery Statistics Report. ASPS National Clearinghouse of Plastic Surgery Procedural Statistics. 2020.

TOPLINE:

Compared with transarterial chemoembolization (TACE) alone, the combination of sorafenib and TACE may improve overall and progression-free survival in patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) with positive microvascular invasion.

METHODOLOGY:

• Recurrent intermediate-stage HCC has a poor prognosis, and TACE alone has yielded “unsatisfactory survival benefits,” the study authors explained. Retrospective studies suggest that combining sorafenib and TACE may be a better therapeutic option.
• Sorafenib, an inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, may have a synergistic effect alongside TACE after hepatectomy in patients with positive microvascular invasion.
• To investigate further, 162 patients (median age, 55 years; 93% men) with recurrent intermediate-stage HCC and positive microvascular invasion were randomly allocated to sorafenib plus TACE or TACE alone.
• The trial was conducted at five hospitals in China from October 2019 to December 2021.

TAKEAWAY:

• Median overall survival was significantly longer with sorafenib plus TACE than with TACE alone (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001).
• The overall survival rate at 24 months was 44.4% in the combination group vs 24.2% in the TACE group, and the rate at 36 months was 26.9% and 13.6%, respectively.
• The combination of sorafenib and TACE also significantly prolonged progression-free survival (median 16.2 months vs 11.8 months; HR, 0.54; P < .001) and led to a significantly better objective response rate (80.2% vs 58.0%; P = .002).
• Any-grade adverse events were more common in the combination arm, but all responded well to treatment, and no unexpected adverse events or treatment-related deaths occurred. The most common grade 3 or 4 adverse events in both arms included increased alanine aminotransferase (19.8% in both) and increased aspartate aminotransferase (23.5% in the combination group vs 18.5% in the TACE arm).

IN PRACTICE:

“These findings suggest that combined [sorafenib plus TACE] treatment should be considered for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive microvascular invasion,” the authors wrote.

SOURCE:

The study, with first author Wenzhe Fan, MD, from The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, was published online in JAMA Oncology.

LIMITATIONS:

The open-label design may introduce potential bias, although the results were confirmed by a masked independent imaging review. The study population was primarily from an endemic region with high rates of chronic hepatitis B virus infection, which may limit generalizability to populations with different etiologies of HCC, such as hepatitis C in Western countries.

DISCLOSURES:

Funding was provided by the National Natural Science Foundation of China and the Outstanding Youth Fund of the National Natural Science Foundation of China. The authors reported no conflicts of interest.

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

TOPLINE:

Compared with transarterial chemoembolization (TACE) alone, the combination of sorafenib and TACE may improve overall and progression-free survival in patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) with positive microvascular invasion.

METHODOLOGY:

• Recurrent intermediate-stage HCC has a poor prognosis, and TACE alone has yielded “unsatisfactory survival benefits,” the study authors explained. Retrospective studies suggest that combining sorafenib and TACE may be a better therapeutic option.
• Sorafenib, an inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, may have a synergistic effect alongside TACE after hepatectomy in patients with positive microvascular invasion.
• To investigate further, 162 patients (median age, 55 years; 93% men) with recurrent intermediate-stage HCC and positive microvascular invasion were randomly allocated to sorafenib plus TACE or TACE alone.
• The trial was conducted at five hospitals in China from October 2019 to December 2021.

TAKEAWAY:

• Median overall survival was significantly longer with sorafenib plus TACE than with TACE alone (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001).
• The overall survival rate at 24 months was 44.4% in the combination group vs 24.2% in the TACE group, and the rate at 36 months was 26.9% and 13.6%, respectively.
• The combination of sorafenib and TACE also significantly prolonged progression-free survival (median 16.2 months vs 11.8 months; HR, 0.54; P < .001) and led to a significantly better objective response rate (80.2% vs 58.0%; P = .002).
• Any-grade adverse events were more common in the combination arm, but all responded well to treatment, and no unexpected adverse events or treatment-related deaths occurred. The most common grade 3 or 4 adverse events in both arms included increased alanine aminotransferase (19.8% in both) and increased aspartate aminotransferase (23.5% in the combination group vs 18.5% in the TACE arm).

IN PRACTICE:

“These findings suggest that combined [sorafenib plus TACE] treatment should be considered for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive microvascular invasion,” the authors wrote.

SOURCE:

The study, with first author Wenzhe Fan, MD, from The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, was published online in JAMA Oncology.

LIMITATIONS:

The open-label design may introduce potential bias, although the results were confirmed by a masked independent imaging review. The study population was primarily from an endemic region with high rates of chronic hepatitis B virus infection, which may limit generalizability to populations with different etiologies of HCC, such as hepatitis C in Western countries.

DISCLOSURES:

Funding was provided by the National Natural Science Foundation of China and the Outstanding Youth Fund of the National Natural Science Foundation of China. The authors reported no conflicts of interest.

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

TOPLINE:

Compared with transarterial chemoembolization (TACE) alone, the combination of sorafenib and TACE may improve overall and progression-free survival in patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) with positive microvascular invasion.

METHODOLOGY:

• Recurrent intermediate-stage HCC has a poor prognosis, and TACE alone has yielded “unsatisfactory survival benefits,” the study authors explained. Retrospective studies suggest that combining sorafenib and TACE may be a better therapeutic option.
• Sorafenib, an inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, may have a synergistic effect alongside TACE after hepatectomy in patients with positive microvascular invasion.
• To investigate further, 162 patients (median age, 55 years; 93% men) with recurrent intermediate-stage HCC and positive microvascular invasion were randomly allocated to sorafenib plus TACE or TACE alone.
• The trial was conducted at five hospitals in China from October 2019 to December 2021.

TAKEAWAY:

• Median overall survival was significantly longer with sorafenib plus TACE than with TACE alone (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001).
• The overall survival rate at 24 months was 44.4% in the combination group vs 24.2% in the TACE group, and the rate at 36 months was 26.9% and 13.6%, respectively.
• The combination of sorafenib and TACE also significantly prolonged progression-free survival (median 16.2 months vs 11.8 months; HR, 0.54; P < .001) and led to a significantly better objective response rate (80.2% vs 58.0%; P = .002).
• Any-grade adverse events were more common in the combination arm, but all responded well to treatment, and no unexpected adverse events or treatment-related deaths occurred. The most common grade 3 or 4 adverse events in both arms included increased alanine aminotransferase (19.8% in both) and increased aspartate aminotransferase (23.5% in the combination group vs 18.5% in the TACE arm).

IN PRACTICE:

“These findings suggest that combined [sorafenib plus TACE] treatment should be considered for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive microvascular invasion,” the authors wrote.

SOURCE:

The study, with first author Wenzhe Fan, MD, from The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, was published online in JAMA Oncology.

LIMITATIONS:

The open-label design may introduce potential bias, although the results were confirmed by a masked independent imaging review. The study population was primarily from an endemic region with high rates of chronic hepatitis B virus infection, which may limit generalizability to populations with different etiologies of HCC, such as hepatitis C in Western countries.

DISCLOSURES:

Funding was provided by the National Natural Science Foundation of China and the Outstanding Youth Fund of the National Natural Science Foundation of China. The authors reported no conflicts of interest.

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

Patients who live in areas with high levels of sun exposure may require higher than normal doses of botulinum toxin A to the glabella to achieve maximal results, findings from a comparative cohort study suggested.

“Botulinum toxin A to the glabella is a popular cosmetic intervention,” researchers led by Kim L. Borsky, MD, MBBS, of the Department of Plastic and Reconstructive Surgery at Stoke Mandeville Hospital, Aylesbury, England, and colleagues wrote in their study, which was published in Plastic and Reconstructive Surgery. “Functional musculature differences may arise from chronic behavioral adjustment to high sun exposure levels, requiring greater doses. This could affect clinical practice globally.”

To investigate the effect of climate on real-world doses of the product, the researchers enrolled 523 women aged 35-60 years who received glabellar botulinum toxin treatment at two centers between 2012 and 2019: one in the United Kingdom and one in Malta. They evaluated data on 292 patients treated during the summer months at the Malta center (classified as the high sun-exposure group), and 231 patients treated during the winter months at the UK center (classified as the low sun-exposure group). The primary outcomes of interest were the required top-up doses and the total dose to achieve full paralysis. Smokers were excluded from the analysis, as were those who did not seek maximal paralysis, those documented as not compliant with posttreatment advice, and those with colds or fevers. They used univariable and multivariable analyses to compare the high vs low sun-exposure groups.

The researchers found that 68.5% of women in the high-sun group required a top-up dose to achieve full paralysis, compared with 61.5% in the low-sun group, a difference that did not reach statistical significance (P = .1032). All patients achieved full paralysis with the treatment protocol used. However, in the high-sun group, the mean top-up dose was significantly higher than that in the low-sun group (a mean of 9.30 vs 7.06 units, respectively; P = .0009), as was the mean total dose (a mean of 29.23 vs 27.25 units; P = .0031).

“Patients subject to less sun exposure require a lower dose than patients with high sun exposure, and this was present and persisted when controlling for potential confounders,” the researchers wrote. “Although robustly demonstrated, the difference in doses seen here was small, and so may not directly impact at a health economic level, as the difference would not necessarily change the number of vials used. However, it may be of relevance to training and protocolization of treatments. Rigid protocols about doses and distributions may lead to undertreatment if applied in sunnier climates.”

They acknowledged certain limitations of their study, including its unblinded design and the fact that they did not evaluate or control for ethnicity. They also characterized the population of Malta as “very homogeneous, mainly made up of Maltese with less than 5% foreigners,” while the demographics of the United Kingdom and especially London, where the injections were performed, “are much more diverse.”

Asked to comment on the results, Pooja Sodha, MD, director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington, DC, said that the study highlights the importance of tailoring neuromodulator treatment to the individual patient based not just on gender but also on lifestyle and climate. “The conclusion [of the study] is logical, but it’s encouraging that the data supports this,” Dr. Sodha told this news organization. “The potential confounders, such as injection technique (5 point vs 3 point), nonblinding of the evaluator, history of prior treatments, and variation in treatment effect by different botulinum toxin products may be important as well in how we consider this data in practice.”

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Neither the researchers nor Dr. Sodha reported having financial disclosures.

A version of this article appeared on Medscape.com.

Patients who live in areas with high levels of sun exposure may require higher than normal doses of botulinum toxin A to the glabella to achieve maximal results, findings from a comparative cohort study suggested.

“Botulinum toxin A to the glabella is a popular cosmetic intervention,” researchers led by Kim L. Borsky, MD, MBBS, of the Department of Plastic and Reconstructive Surgery at Stoke Mandeville Hospital, Aylesbury, England, and colleagues wrote in their study, which was published in Plastic and Reconstructive Surgery. “Functional musculature differences may arise from chronic behavioral adjustment to high sun exposure levels, requiring greater doses. This could affect clinical practice globally.”

To investigate the effect of climate on real-world doses of the product, the researchers enrolled 523 women aged 35-60 years who received glabellar botulinum toxin treatment at two centers between 2012 and 2019: one in the United Kingdom and one in Malta. They evaluated data on 292 patients treated during the summer months at the Malta center (classified as the high sun-exposure group), and 231 patients treated during the winter months at the UK center (classified as the low sun-exposure group). The primary outcomes of interest were the required top-up doses and the total dose to achieve full paralysis. Smokers were excluded from the analysis, as were those who did not seek maximal paralysis, those documented as not compliant with posttreatment advice, and those with colds or fevers. They used univariable and multivariable analyses to compare the high vs low sun-exposure groups.

The researchers found that 68.5% of women in the high-sun group required a top-up dose to achieve full paralysis, compared with 61.5% in the low-sun group, a difference that did not reach statistical significance (P = .1032). All patients achieved full paralysis with the treatment protocol used. However, in the high-sun group, the mean top-up dose was significantly higher than that in the low-sun group (a mean of 9.30 vs 7.06 units, respectively; P = .0009), as was the mean total dose (a mean of 29.23 vs 27.25 units; P = .0031).

“Patients subject to less sun exposure require a lower dose than patients with high sun exposure, and this was present and persisted when controlling for potential confounders,” the researchers wrote. “Although robustly demonstrated, the difference in doses seen here was small, and so may not directly impact at a health economic level, as the difference would not necessarily change the number of vials used. However, it may be of relevance to training and protocolization of treatments. Rigid protocols about doses and distributions may lead to undertreatment if applied in sunnier climates.”

They acknowledged certain limitations of their study, including its unblinded design and the fact that they did not evaluate or control for ethnicity. They also characterized the population of Malta as “very homogeneous, mainly made up of Maltese with less than 5% foreigners,” while the demographics of the United Kingdom and especially London, where the injections were performed, “are much more diverse.”

Asked to comment on the results, Pooja Sodha, MD, director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington, DC, said that the study highlights the importance of tailoring neuromodulator treatment to the individual patient based not just on gender but also on lifestyle and climate. “The conclusion [of the study] is logical, but it’s encouraging that the data supports this,” Dr. Sodha told this news organization. “The potential confounders, such as injection technique (5 point vs 3 point), nonblinding of the evaluator, history of prior treatments, and variation in treatment effect by different botulinum toxin products may be important as well in how we consider this data in practice.”

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Neither the researchers nor Dr. Sodha reported having financial disclosures.

A version of this article appeared on Medscape.com.

Patients who live in areas with high levels of sun exposure may require higher than normal doses of botulinum toxin A to the glabella to achieve maximal results, findings from a comparative cohort study suggested.

“Botulinum toxin A to the glabella is a popular cosmetic intervention,” researchers led by Kim L. Borsky, MD, MBBS, of the Department of Plastic and Reconstructive Surgery at Stoke Mandeville Hospital, Aylesbury, England, and colleagues wrote in their study, which was published in Plastic and Reconstructive Surgery. “Functional musculature differences may arise from chronic behavioral adjustment to high sun exposure levels, requiring greater doses. This could affect clinical practice globally.”

To investigate the effect of climate on real-world doses of the product, the researchers enrolled 523 women aged 35-60 years who received glabellar botulinum toxin treatment at two centers between 2012 and 2019: one in the United Kingdom and one in Malta. They evaluated data on 292 patients treated during the summer months at the Malta center (classified as the high sun-exposure group), and 231 patients treated during the winter months at the UK center (classified as the low sun-exposure group). The primary outcomes of interest were the required top-up doses and the total dose to achieve full paralysis. Smokers were excluded from the analysis, as were those who did not seek maximal paralysis, those documented as not compliant with posttreatment advice, and those with colds or fevers. They used univariable and multivariable analyses to compare the high vs low sun-exposure groups.

The researchers found that 68.5% of women in the high-sun group required a top-up dose to achieve full paralysis, compared with 61.5% in the low-sun group, a difference that did not reach statistical significance (P = .1032). All patients achieved full paralysis with the treatment protocol used. However, in the high-sun group, the mean top-up dose was significantly higher than that in the low-sun group (a mean of 9.30 vs 7.06 units, respectively; P = .0009), as was the mean total dose (a mean of 29.23 vs 27.25 units; P = .0031).

“Patients subject to less sun exposure require a lower dose than patients with high sun exposure, and this was present and persisted when controlling for potential confounders,” the researchers wrote. “Although robustly demonstrated, the difference in doses seen here was small, and so may not directly impact at a health economic level, as the difference would not necessarily change the number of vials used. However, it may be of relevance to training and protocolization of treatments. Rigid protocols about doses and distributions may lead to undertreatment if applied in sunnier climates.”

They acknowledged certain limitations of their study, including its unblinded design and the fact that they did not evaluate or control for ethnicity. They also characterized the population of Malta as “very homogeneous, mainly made up of Maltese with less than 5% foreigners,” while the demographics of the United Kingdom and especially London, where the injections were performed, “are much more diverse.”

Asked to comment on the results, Pooja Sodha, MD, director of the Center for Laser and Cosmetic Dermatology at George Washington University, Washington, DC, said that the study highlights the importance of tailoring neuromodulator treatment to the individual patient based not just on gender but also on lifestyle and climate. “The conclusion [of the study] is logical, but it’s encouraging that the data supports this,” Dr. Sodha told this news organization. “The potential confounders, such as injection technique (5 point vs 3 point), nonblinding of the evaluator, history of prior treatments, and variation in treatment effect by different botulinum toxin products may be important as well in how we consider this data in practice.”

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Neither the researchers nor Dr. Sodha reported having financial disclosures.

A version of this article appeared on Medscape.com.