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Treating rosacea: Combination therapy, benzoyl peroxide, and the ‘STOP’ mnemonic
HONOLULU – More often than not, patients with rosacea require a combination of treatments to optimize the management of the disease, according to Julie C. Harper, MD.
“We’ve been more comfortable with the idea of combination therapy for acne than we have been for rosacea,” Dr. Harper, who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “If patients are doing great on one treatment, then don’t change it. But if there’s room for improvement, think about combinations.”
Treatment options for papules and pustules include ivermectin, metronidazole, azelaic acid, sodium sulfacetamide/sulfur, modified release doxycycline, minocycline foam, and microencapsulated benzoyl peroxide, 5%. Options for persistent background erythema include brimonidine and oxymetazoline, as well as device-based treatments, which include the pulsed dye laser, the KTP laser, intense pulsed light, and electrosurgery.
Dr. Harper said that she has been especially surprised by the effectiveness of one of these options, microencapsulated benzoyl peroxide cream, 5% (Epsolay), which is approved by the Food and Drug Administration for treating inflammatory lesions of rosacea in adults. In two identical, phase 3 randomized clinical trials of patients with inflammatory rosacea lesions, those treated with microencapsulated benzoyl peroxide achieved a 68.8% reduction in inflammatory lesions at 12 weeks (including 42.5% at week 2), compared with 38%-46% of those on the vehicle, according to the April 2022 announcement of the approval from the manufacturers, Sol-Gel Technologies and Galderma.
“A common drug is playing a key role,” Dr. Harper said. “What’s the mechanism of action? I have no idea. I wonder if there may be a bacterial pathogen after all,” possibly Staphylococcus epidermidis, she added. However, she noted, “it does appear that benzoyl peroxide has an impact on Demodex, so maybe that’s the primary way it’s working.”
In her opinion, a key standout from the clinical trial data is the drug’s rapid onset of action, with a 42.5% reduction of lesions at week 2. “What makes this different is that the 5% microencapsulated benzoyl peroxide cream is wrapped up in a silica shell,” said Dr. Harper, a past president of the American Acne and Rosacea Society. “The silica shell kind of acts like a speed bump that slows the release of drug onto the skin. We think that’s what may be giving us this better tolerability.”
In an interview at the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that prior to the approval of Epsolay, benzoyl peroxide was never considered a first-line treatment for rosacea. “The problem is, the conventional formulation is irritating to the skin,” said Dr. Stein Gold, who was involved in clinical trials of Epsolay.
“The benzoyl peroxide encapsulated in the silica shell allows for a slow and steady delivery of medication to the skin in a very controlled manner. It is exceptionally good at getting rosacea under control. In the clinical trials, when we looked at the baseline irritation of the skin and followed those patients when they used the benzoyl 5% microencapsulated benzoyl peroxide cream, the irritation improved.”
‘STOP’ mnemonic
When treating her patients with rosacea, Dr. Harper incorporates the mnemonic “STOP” to these patient visits:
S: Identify signs and symptoms of rosacea.
T: Discuss triggers. “We cannot make this disease triggerless, so when you’re talking to your patients, you need to find out what’s triggering their rosacea,” she said.
O: Agree on a treatment outcome. “What is it that’s important to the patient?” she said. “They may tell you, ‘I want to be able to not be so red,’ or ‘I want to get rid of the bumps,’ or ‘I want my eyes to not feel so dry.’ ”
P: Develop a plan that helps achieve that desired outcome with patients.
Dr. Harper disclosed ties with Almirall, Cassiopeia, Cutera, Galderma, EPI, L’Oréal, Ortho Dermatologics, Sol Gel, Sun Pharmaceutical Industries, and Vyne.
Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries.
Medscape and this news organization are owned by the same parent company.
HONOLULU – More often than not, patients with rosacea require a combination of treatments to optimize the management of the disease, according to Julie C. Harper, MD.
“We’ve been more comfortable with the idea of combination therapy for acne than we have been for rosacea,” Dr. Harper, who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “If patients are doing great on one treatment, then don’t change it. But if there’s room for improvement, think about combinations.”
Treatment options for papules and pustules include ivermectin, metronidazole, azelaic acid, sodium sulfacetamide/sulfur, modified release doxycycline, minocycline foam, and microencapsulated benzoyl peroxide, 5%. Options for persistent background erythema include brimonidine and oxymetazoline, as well as device-based treatments, which include the pulsed dye laser, the KTP laser, intense pulsed light, and electrosurgery.
Dr. Harper said that she has been especially surprised by the effectiveness of one of these options, microencapsulated benzoyl peroxide cream, 5% (Epsolay), which is approved by the Food and Drug Administration for treating inflammatory lesions of rosacea in adults. In two identical, phase 3 randomized clinical trials of patients with inflammatory rosacea lesions, those treated with microencapsulated benzoyl peroxide achieved a 68.8% reduction in inflammatory lesions at 12 weeks (including 42.5% at week 2), compared with 38%-46% of those on the vehicle, according to the April 2022 announcement of the approval from the manufacturers, Sol-Gel Technologies and Galderma.
“A common drug is playing a key role,” Dr. Harper said. “What’s the mechanism of action? I have no idea. I wonder if there may be a bacterial pathogen after all,” possibly Staphylococcus epidermidis, she added. However, she noted, “it does appear that benzoyl peroxide has an impact on Demodex, so maybe that’s the primary way it’s working.”
In her opinion, a key standout from the clinical trial data is the drug’s rapid onset of action, with a 42.5% reduction of lesions at week 2. “What makes this different is that the 5% microencapsulated benzoyl peroxide cream is wrapped up in a silica shell,” said Dr. Harper, a past president of the American Acne and Rosacea Society. “The silica shell kind of acts like a speed bump that slows the release of drug onto the skin. We think that’s what may be giving us this better tolerability.”
In an interview at the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that prior to the approval of Epsolay, benzoyl peroxide was never considered a first-line treatment for rosacea. “The problem is, the conventional formulation is irritating to the skin,” said Dr. Stein Gold, who was involved in clinical trials of Epsolay.
“The benzoyl peroxide encapsulated in the silica shell allows for a slow and steady delivery of medication to the skin in a very controlled manner. It is exceptionally good at getting rosacea under control. In the clinical trials, when we looked at the baseline irritation of the skin and followed those patients when they used the benzoyl 5% microencapsulated benzoyl peroxide cream, the irritation improved.”
‘STOP’ mnemonic
When treating her patients with rosacea, Dr. Harper incorporates the mnemonic “STOP” to these patient visits:
S: Identify signs and symptoms of rosacea.
T: Discuss triggers. “We cannot make this disease triggerless, so when you’re talking to your patients, you need to find out what’s triggering their rosacea,” she said.
O: Agree on a treatment outcome. “What is it that’s important to the patient?” she said. “They may tell you, ‘I want to be able to not be so red,’ or ‘I want to get rid of the bumps,’ or ‘I want my eyes to not feel so dry.’ ”
P: Develop a plan that helps achieve that desired outcome with patients.
Dr. Harper disclosed ties with Almirall, Cassiopeia, Cutera, Galderma, EPI, L’Oréal, Ortho Dermatologics, Sol Gel, Sun Pharmaceutical Industries, and Vyne.
Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries.
Medscape and this news organization are owned by the same parent company.
HONOLULU – More often than not, patients with rosacea require a combination of treatments to optimize the management of the disease, according to Julie C. Harper, MD.
“We’ve been more comfortable with the idea of combination therapy for acne than we have been for rosacea,” Dr. Harper, who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “If patients are doing great on one treatment, then don’t change it. But if there’s room for improvement, think about combinations.”
Treatment options for papules and pustules include ivermectin, metronidazole, azelaic acid, sodium sulfacetamide/sulfur, modified release doxycycline, minocycline foam, and microencapsulated benzoyl peroxide, 5%. Options for persistent background erythema include brimonidine and oxymetazoline, as well as device-based treatments, which include the pulsed dye laser, the KTP laser, intense pulsed light, and electrosurgery.
Dr. Harper said that she has been especially surprised by the effectiveness of one of these options, microencapsulated benzoyl peroxide cream, 5% (Epsolay), which is approved by the Food and Drug Administration for treating inflammatory lesions of rosacea in adults. In two identical, phase 3 randomized clinical trials of patients with inflammatory rosacea lesions, those treated with microencapsulated benzoyl peroxide achieved a 68.8% reduction in inflammatory lesions at 12 weeks (including 42.5% at week 2), compared with 38%-46% of those on the vehicle, according to the April 2022 announcement of the approval from the manufacturers, Sol-Gel Technologies and Galderma.
“A common drug is playing a key role,” Dr. Harper said. “What’s the mechanism of action? I have no idea. I wonder if there may be a bacterial pathogen after all,” possibly Staphylococcus epidermidis, she added. However, she noted, “it does appear that benzoyl peroxide has an impact on Demodex, so maybe that’s the primary way it’s working.”
In her opinion, a key standout from the clinical trial data is the drug’s rapid onset of action, with a 42.5% reduction of lesions at week 2. “What makes this different is that the 5% microencapsulated benzoyl peroxide cream is wrapped up in a silica shell,” said Dr. Harper, a past president of the American Acne and Rosacea Society. “The silica shell kind of acts like a speed bump that slows the release of drug onto the skin. We think that’s what may be giving us this better tolerability.”
In an interview at the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that prior to the approval of Epsolay, benzoyl peroxide was never considered a first-line treatment for rosacea. “The problem is, the conventional formulation is irritating to the skin,” said Dr. Stein Gold, who was involved in clinical trials of Epsolay.
“The benzoyl peroxide encapsulated in the silica shell allows for a slow and steady delivery of medication to the skin in a very controlled manner. It is exceptionally good at getting rosacea under control. In the clinical trials, when we looked at the baseline irritation of the skin and followed those patients when they used the benzoyl 5% microencapsulated benzoyl peroxide cream, the irritation improved.”
‘STOP’ mnemonic
When treating her patients with rosacea, Dr. Harper incorporates the mnemonic “STOP” to these patient visits:
S: Identify signs and symptoms of rosacea.
T: Discuss triggers. “We cannot make this disease triggerless, so when you’re talking to your patients, you need to find out what’s triggering their rosacea,” she said.
O: Agree on a treatment outcome. “What is it that’s important to the patient?” she said. “They may tell you, ‘I want to be able to not be so red,’ or ‘I want to get rid of the bumps,’ or ‘I want my eyes to not feel so dry.’ ”
P: Develop a plan that helps achieve that desired outcome with patients.
Dr. Harper disclosed ties with Almirall, Cassiopeia, Cutera, Galderma, EPI, L’Oréal, Ortho Dermatologics, Sol Gel, Sun Pharmaceutical Industries, and Vyne.
Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries.
Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPE LIVE! HAWAII DERMATOLOGY SEMINAR
Metformin linked to reductions in COVID-19 viral load
These findings add to a multitude of benefits the drug has been shown to have in COVID infection.
COVID-OUT did not meet its primary endpoint, but it did show important secondary outcomes including a 42% reduction in ED visits and in hospitalizations and/or deaths by day 14, and a 58% reduction in hospitalizations/death by day 28. A further subanalysis has shown a 42% reduction in long COVID, compared with placebo.
“In this phase 3 randomized controlled trial, metformin showed prevention of severe COVID, prevention of long COVID, and an antiviral effect, and this is consistent with other data,” said coauthor Carolyn Bramante, MD, University of Minnesota, Minneapolis, in presenting the findings at the Conference on Retroviruses & Opportunistic Infections.
Study details
For the new subanalysis, the authors further evaluated the effects of metformin treatment on SARS-CoV-2 viral load.
A total of 1,323 patients in the study, enrolled at six centers, were randomized to treatment either with metformin 1,000 mg per day on days 2-5 and 1,500 mg per day on days 6 to 14 (n = 187), or to ivermectin 390-470 mcg/kg per day for 3 days (n = 187), fluvoxamine 50 mg twice daily for 14 days, and/or an exact-matching placebo in a 2 x 3 factorial trial design.
The subanalysis on viral load included 483 patients from the trial who were treated with metformin versus 462 who received placebo, who were all enrolled within 3 days of a documented SARS-CoV-2 infection and less than 7 days after symptom onset.
The patients had a median age of 46 years, and all had either overweight or obesity. Only about 2% had diabetes, and only patients considered low-risk were excluded from the trial, including those under age 30 and those with a body mass index under 25.
About half of patients had received a primary vaccine and about 5% had received a vaccine booster. SARS-CoV-2 variants that were prominent during the study included Alpha, Delta, and Omicron.
The viral samples available on days 1, 5, and 10 showed a mean change in viral load from baseline to follow-up; the viral load was significantly lower with metformin versus placebo (–0.64 log10 copies/mL), representing a 4.4-fold greater decrease in viral load with metformin.
The mean rate of undetectable SARS-CoV-2 viral load at day 5 was 49.9% in the metformin group versus 54.6% in the placebo group (odds ratio, 1.235), and the undetectable rate at day 10 was 14.3% in the metformin group and 22.6% in the placebo group (OR, 1.663; P = .003).
An increased antiviral effect corresponded with increases in metformin dosing on days 6 through 14. Furthermore, the antiviral effect became stronger when metformin was started earlier in the course of infection.
Of note, the antiviral effect was more pronounced among those who were not vaccinated (mean, –0.95 log copies/mL), compared with the vaccinated (mean, –0.39 log copies/mL).
The antiviral effect with metformin was similar to that seen with nirmatrelvir at day 5 and was greater than nirmatrelvir at day 10.
No similar relationships in SARS-CoV-2 viral load were observed between ivermectin or fluvoxamine and placebo.
The findings are consistent with results of other recent observational studies, including research showing metformin to be associated with reductions in COVID-19 severity in patients with prediabetes, Dr. Bramante noted.
The authors’ previous analysis looking at long COVID in the COVID-OUT study showed that metformin treatment during acute COVID significantly reduced the risk for a diagnosis of long COVID versus placebo at 300 days following randomization, with a hazard ratio of 0.59 after adjustment for the study drug and vaccination at baseline.
Dr. Bramante noted that metformin’s potential antiviral properties have long been speculated, with some of the earliest research on the drug suggesting less severe outcomes in influenza, and more recently, RNA assays suggesting effects against other RNA viruses, including the Zika virus.
In terms of COVID, Dr. Bramante noted that the drug has plenty of potentially favorable benefits.
“Metformin is very safe and is known to have very few contraindications, so the next steps could be to consider looking at this in terms of a combination therapy,” she said.
‘Data from other studies are conflicting’
Commenting on the study, Diane V. Havlir, MD, cautioned that “metformin is currently not recommended in treatment guidelines, [and] data from other studies are conflicting; side effects can be an issue, and the study presented here was in a select population,” she said in an interview.
However, “what is both new and interesting in this presentation is the reduction of viral load, which [was observed] in the samples collected not only on days 1-5, but also days 6-14,” said Dr. Havlir, who is professor and associate chair of clinical research, department of medicine, and chief of the division of HIV, infectious diseases and global medicine and director of the AIDS Research Institute at the University of California, San Francisco.
Key questions the findings raise include whether the results correlate with clinical outcomes or transmission, and whether the findings are generalizable to other populations and settings, Dr. Havlir said.
Ultimately, “we need to continue to pursue all aspects of outpatient treatments for COVID to address questions like these for new and existing agents,” she added.
The trial received funding from the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the United Health Group. The authors and Dr. Havlir disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
These findings add to a multitude of benefits the drug has been shown to have in COVID infection.
COVID-OUT did not meet its primary endpoint, but it did show important secondary outcomes including a 42% reduction in ED visits and in hospitalizations and/or deaths by day 14, and a 58% reduction in hospitalizations/death by day 28. A further subanalysis has shown a 42% reduction in long COVID, compared with placebo.
“In this phase 3 randomized controlled trial, metformin showed prevention of severe COVID, prevention of long COVID, and an antiviral effect, and this is consistent with other data,” said coauthor Carolyn Bramante, MD, University of Minnesota, Minneapolis, in presenting the findings at the Conference on Retroviruses & Opportunistic Infections.
Study details
For the new subanalysis, the authors further evaluated the effects of metformin treatment on SARS-CoV-2 viral load.
A total of 1,323 patients in the study, enrolled at six centers, were randomized to treatment either with metformin 1,000 mg per day on days 2-5 and 1,500 mg per day on days 6 to 14 (n = 187), or to ivermectin 390-470 mcg/kg per day for 3 days (n = 187), fluvoxamine 50 mg twice daily for 14 days, and/or an exact-matching placebo in a 2 x 3 factorial trial design.
The subanalysis on viral load included 483 patients from the trial who were treated with metformin versus 462 who received placebo, who were all enrolled within 3 days of a documented SARS-CoV-2 infection and less than 7 days after symptom onset.
The patients had a median age of 46 years, and all had either overweight or obesity. Only about 2% had diabetes, and only patients considered low-risk were excluded from the trial, including those under age 30 and those with a body mass index under 25.
About half of patients had received a primary vaccine and about 5% had received a vaccine booster. SARS-CoV-2 variants that were prominent during the study included Alpha, Delta, and Omicron.
The viral samples available on days 1, 5, and 10 showed a mean change in viral load from baseline to follow-up; the viral load was significantly lower with metformin versus placebo (–0.64 log10 copies/mL), representing a 4.4-fold greater decrease in viral load with metformin.
The mean rate of undetectable SARS-CoV-2 viral load at day 5 was 49.9% in the metformin group versus 54.6% in the placebo group (odds ratio, 1.235), and the undetectable rate at day 10 was 14.3% in the metformin group and 22.6% in the placebo group (OR, 1.663; P = .003).
An increased antiviral effect corresponded with increases in metformin dosing on days 6 through 14. Furthermore, the antiviral effect became stronger when metformin was started earlier in the course of infection.
Of note, the antiviral effect was more pronounced among those who were not vaccinated (mean, –0.95 log copies/mL), compared with the vaccinated (mean, –0.39 log copies/mL).
The antiviral effect with metformin was similar to that seen with nirmatrelvir at day 5 and was greater than nirmatrelvir at day 10.
No similar relationships in SARS-CoV-2 viral load were observed between ivermectin or fluvoxamine and placebo.
The findings are consistent with results of other recent observational studies, including research showing metformin to be associated with reductions in COVID-19 severity in patients with prediabetes, Dr. Bramante noted.
The authors’ previous analysis looking at long COVID in the COVID-OUT study showed that metformin treatment during acute COVID significantly reduced the risk for a diagnosis of long COVID versus placebo at 300 days following randomization, with a hazard ratio of 0.59 after adjustment for the study drug and vaccination at baseline.
Dr. Bramante noted that metformin’s potential antiviral properties have long been speculated, with some of the earliest research on the drug suggesting less severe outcomes in influenza, and more recently, RNA assays suggesting effects against other RNA viruses, including the Zika virus.
In terms of COVID, Dr. Bramante noted that the drug has plenty of potentially favorable benefits.
“Metformin is very safe and is known to have very few contraindications, so the next steps could be to consider looking at this in terms of a combination therapy,” she said.
‘Data from other studies are conflicting’
Commenting on the study, Diane V. Havlir, MD, cautioned that “metformin is currently not recommended in treatment guidelines, [and] data from other studies are conflicting; side effects can be an issue, and the study presented here was in a select population,” she said in an interview.
However, “what is both new and interesting in this presentation is the reduction of viral load, which [was observed] in the samples collected not only on days 1-5, but also days 6-14,” said Dr. Havlir, who is professor and associate chair of clinical research, department of medicine, and chief of the division of HIV, infectious diseases and global medicine and director of the AIDS Research Institute at the University of California, San Francisco.
Key questions the findings raise include whether the results correlate with clinical outcomes or transmission, and whether the findings are generalizable to other populations and settings, Dr. Havlir said.
Ultimately, “we need to continue to pursue all aspects of outpatient treatments for COVID to address questions like these for new and existing agents,” she added.
The trial received funding from the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the United Health Group. The authors and Dr. Havlir disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
These findings add to a multitude of benefits the drug has been shown to have in COVID infection.
COVID-OUT did not meet its primary endpoint, but it did show important secondary outcomes including a 42% reduction in ED visits and in hospitalizations and/or deaths by day 14, and a 58% reduction in hospitalizations/death by day 28. A further subanalysis has shown a 42% reduction in long COVID, compared with placebo.
“In this phase 3 randomized controlled trial, metformin showed prevention of severe COVID, prevention of long COVID, and an antiviral effect, and this is consistent with other data,” said coauthor Carolyn Bramante, MD, University of Minnesota, Minneapolis, in presenting the findings at the Conference on Retroviruses & Opportunistic Infections.
Study details
For the new subanalysis, the authors further evaluated the effects of metformin treatment on SARS-CoV-2 viral load.
A total of 1,323 patients in the study, enrolled at six centers, were randomized to treatment either with metformin 1,000 mg per day on days 2-5 and 1,500 mg per day on days 6 to 14 (n = 187), or to ivermectin 390-470 mcg/kg per day for 3 days (n = 187), fluvoxamine 50 mg twice daily for 14 days, and/or an exact-matching placebo in a 2 x 3 factorial trial design.
The subanalysis on viral load included 483 patients from the trial who were treated with metformin versus 462 who received placebo, who were all enrolled within 3 days of a documented SARS-CoV-2 infection and less than 7 days after symptom onset.
The patients had a median age of 46 years, and all had either overweight or obesity. Only about 2% had diabetes, and only patients considered low-risk were excluded from the trial, including those under age 30 and those with a body mass index under 25.
About half of patients had received a primary vaccine and about 5% had received a vaccine booster. SARS-CoV-2 variants that were prominent during the study included Alpha, Delta, and Omicron.
The viral samples available on days 1, 5, and 10 showed a mean change in viral load from baseline to follow-up; the viral load was significantly lower with metformin versus placebo (–0.64 log10 copies/mL), representing a 4.4-fold greater decrease in viral load with metformin.
The mean rate of undetectable SARS-CoV-2 viral load at day 5 was 49.9% in the metformin group versus 54.6% in the placebo group (odds ratio, 1.235), and the undetectable rate at day 10 was 14.3% in the metformin group and 22.6% in the placebo group (OR, 1.663; P = .003).
An increased antiviral effect corresponded with increases in metformin dosing on days 6 through 14. Furthermore, the antiviral effect became stronger when metformin was started earlier in the course of infection.
Of note, the antiviral effect was more pronounced among those who were not vaccinated (mean, –0.95 log copies/mL), compared with the vaccinated (mean, –0.39 log copies/mL).
The antiviral effect with metformin was similar to that seen with nirmatrelvir at day 5 and was greater than nirmatrelvir at day 10.
No similar relationships in SARS-CoV-2 viral load were observed between ivermectin or fluvoxamine and placebo.
The findings are consistent with results of other recent observational studies, including research showing metformin to be associated with reductions in COVID-19 severity in patients with prediabetes, Dr. Bramante noted.
The authors’ previous analysis looking at long COVID in the COVID-OUT study showed that metformin treatment during acute COVID significantly reduced the risk for a diagnosis of long COVID versus placebo at 300 days following randomization, with a hazard ratio of 0.59 after adjustment for the study drug and vaccination at baseline.
Dr. Bramante noted that metformin’s potential antiviral properties have long been speculated, with some of the earliest research on the drug suggesting less severe outcomes in influenza, and more recently, RNA assays suggesting effects against other RNA viruses, including the Zika virus.
In terms of COVID, Dr. Bramante noted that the drug has plenty of potentially favorable benefits.
“Metformin is very safe and is known to have very few contraindications, so the next steps could be to consider looking at this in terms of a combination therapy,” she said.
‘Data from other studies are conflicting’
Commenting on the study, Diane V. Havlir, MD, cautioned that “metformin is currently not recommended in treatment guidelines, [and] data from other studies are conflicting; side effects can be an issue, and the study presented here was in a select population,” she said in an interview.
However, “what is both new and interesting in this presentation is the reduction of viral load, which [was observed] in the samples collected not only on days 1-5, but also days 6-14,” said Dr. Havlir, who is professor and associate chair of clinical research, department of medicine, and chief of the division of HIV, infectious diseases and global medicine and director of the AIDS Research Institute at the University of California, San Francisco.
Key questions the findings raise include whether the results correlate with clinical outcomes or transmission, and whether the findings are generalizable to other populations and settings, Dr. Havlir said.
Ultimately, “we need to continue to pursue all aspects of outpatient treatments for COVID to address questions like these for new and existing agents,” she added.
The trial received funding from the Parsemus Foundation, the Rainwater Charitable Foundation, Fast Grants, and the United Health Group. The authors and Dr. Havlir disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM CROI 2023
CML: Preventing chemo-induced vascular toxicity
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
PARIS –
Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille (France) University Hospital, offered her recommendations at the European Days of the French Society of Cardiology Conference 2023.
In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Dr. Sarlon to state, “I firmly believe that, in some patients, these treatments make LDL cholesterol go up.” This would be the main cause of the coronary and peripheral arterial diseases that are being seen.
Therefore, “LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed,” she said.
Arterial diseases
By bringing about a marked improvement in patients’ chances of survival, TKIs “have revolutionized the management of chronic myeloid leukemia,” Dr. Sarlon added. But these treatments have side effects. The most common is high blood pressure, “an effect that attests to the efficacy of targeted therapies and that must be quickly treated” with antihypertensives.
It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. “This is a real toxicity that we need to know about, detect, and manage,” said Dr. Sarlon.
The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Dr. Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.
Dr. Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm. They noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.
Risk factors uncovered
The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower-extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).
The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.
In the case of ponatinib, the side effects are even more common – so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.
In terms of pathophysiology, the Marseilles University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. “The atheromatous plaques were found where they typically are,” with the carotid bulb being the most involved territory, according to the researchers. But they’re also found in other arteries – femoral, vertebral, even renal – “sometimes in patients without cardiovascular risk factors.”
One distinctive characteristic to keep in mind is that “lipid-rich atheromatous plaques appear very dark on imaging” and thus can go unnoticed during a Doppler ultrasound. And, Dr. Sarlon added, “surprisingly, the thickening can extend to the external carotid artery.”
Ankle-brachial index
Published last year, the first European Society of Cardiology Guidelines on Cardio-Oncology present specific baseline risk-assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.
In addition, it is advised that every 6 months an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, “even for patients at low risk for cardiovascular disease,” said Dr. Sarlon. “It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy,” all the while keeping in mind that “the target LDL-C level is 1 gram per liter.”
This article was translated from the Medscape French edition. A version of this article first appeared on Medscape.com.
What does the future of psoriasis treatment look like?
HONOLULU – During office visits with Andrew Blauvelt, MD, MBA, many patients well controlled on biologic therapy for their moderate to severe psoriasis often ask him when their scheduled injections can stop.
The most common question he hears is, “ ‘Why do I have to keep doing this? I’ve been clear for 2 or 3 years,’ ” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “We have terrific drugs for psoriasis, but how can we do better?”
Development of oral biologics. At least two companies are developing a peptide-type small molecule that blocks interleukin (IL)-17 or IL-23 signaling, but would be given as a pill, he said. Another concept in the works is a robotic pill for drug delivery. The pill, which is being developed by Rani Therapeutics, protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine, according to a report of two studies that demonstrated the safety and tolerability of the robotic pill in healthy humans.
In an animal study, the same researchers showed that delivering monoclonal antibodies with the robotic pill achieved bioavailability on par with that obtained by standard subcutaneous injections.
Identifying “super responders” who require less frequent dosing of medication. “There’s data to suggest that we can kind of back off treatment in these patients,” Dr. Blauvelt said.
Hitting treatment hard and early. “There’s a concept in medicine of hitting disease hard and hitting it early, before the disease can establish itself and cause damage,” he said.
Targeting tissue resident memory T cells. In psoriasis, the idea is that if you treat earlier, when patients are just diagnosed, “perhaps you might be able to decrease resident memory T cells that set up shop in the skin and are responsible for disease recurrences,” Dr. Blauvelt said. “Research has shown that IL-23 blockers decrease tissue resident memory T cells, and IL-17 blockers don’t. This could explain why we see long remissions in this class of drug because we’re getting at these resident memory T cells and knocking them down,” he explained. “Our hypothesis is that hitting hard and early in the treatment course with high-dose IL-23 blockade may be an effective strategy to induce long-term remissions and possible cure, what we call ‘knock-out therapy.’ ”
In a pilot study of 20 patients, Dr. Blauvelt and colleagues are evaluating whether higher initial doses of the IL-23 antagonist risankizumab (300 mg and 600 mg, 2 times and 4 times the standard initial doses for plaque psoriasis) can more effectively target resident memory T cells. “This involves dosing at weeks 0, 4, and 16, then stopping and measuring resident T cells in the tissue to see how long we can induce psoriasis remissions,” Dr. Blauvelt said.
“I have no data to share, but I think we have the potential for unprecedented PASI-100 numbers with no added safety concerns, and the potential to break away from established regular dosing patterns,” such as the possibility of yearly dosing, the possibility of long-term remissions, and the possibility of cure in some patients, he noted.
Inducing tolerance. This refers to efforts aimed at increasing regulatory T cells, which are natural T cells that calm inflammation. He described it as “revving up our natural anti-inflammatory T cells to help balance the immune system.”
Gene editing. This involves using CRISPR gene editing technology to cut genes as a way to cure disease. “What if we cut the IL-23 receptor?” Dr. Blauvelt asked. “You would get rid of that whole signaling pathway. Would the patient be fine?”
In an interview a the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that Dr. Blauvelt “has a very exciting view” of the future of psoriasis treatments. “I think that some of it will come true; we’ll have to see which,” Dr. Stein Gold said. “The idea that we might be able to change the trajectory of disease by being aggressive upfront, and possibly modify the course, is exciting. That would be a wonderful new treatment approach.”
Dr. Blauvelt disclosed ties with AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN Pharma, Athenex, Bluefin, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, Highlightll, Incyte, Innovent Bio, Janssen, Landos, Leo, Lilly, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi-Genzyme, Spherix, Sun Pharmaceuticals Industries, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor.
Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries, Ltd.
Medscape and this news organization are owned by the same parent company.
HONOLULU – During office visits with Andrew Blauvelt, MD, MBA, many patients well controlled on biologic therapy for their moderate to severe psoriasis often ask him when their scheduled injections can stop.
The most common question he hears is, “ ‘Why do I have to keep doing this? I’ve been clear for 2 or 3 years,’ ” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “We have terrific drugs for psoriasis, but how can we do better?”
Development of oral biologics. At least two companies are developing a peptide-type small molecule that blocks interleukin (IL)-17 or IL-23 signaling, but would be given as a pill, he said. Another concept in the works is a robotic pill for drug delivery. The pill, which is being developed by Rani Therapeutics, protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine, according to a report of two studies that demonstrated the safety and tolerability of the robotic pill in healthy humans.
In an animal study, the same researchers showed that delivering monoclonal antibodies with the robotic pill achieved bioavailability on par with that obtained by standard subcutaneous injections.
Identifying “super responders” who require less frequent dosing of medication. “There’s data to suggest that we can kind of back off treatment in these patients,” Dr. Blauvelt said.
Hitting treatment hard and early. “There’s a concept in medicine of hitting disease hard and hitting it early, before the disease can establish itself and cause damage,” he said.
Targeting tissue resident memory T cells. In psoriasis, the idea is that if you treat earlier, when patients are just diagnosed, “perhaps you might be able to decrease resident memory T cells that set up shop in the skin and are responsible for disease recurrences,” Dr. Blauvelt said. “Research has shown that IL-23 blockers decrease tissue resident memory T cells, and IL-17 blockers don’t. This could explain why we see long remissions in this class of drug because we’re getting at these resident memory T cells and knocking them down,” he explained. “Our hypothesis is that hitting hard and early in the treatment course with high-dose IL-23 blockade may be an effective strategy to induce long-term remissions and possible cure, what we call ‘knock-out therapy.’ ”
In a pilot study of 20 patients, Dr. Blauvelt and colleagues are evaluating whether higher initial doses of the IL-23 antagonist risankizumab (300 mg and 600 mg, 2 times and 4 times the standard initial doses for plaque psoriasis) can more effectively target resident memory T cells. “This involves dosing at weeks 0, 4, and 16, then stopping and measuring resident T cells in the tissue to see how long we can induce psoriasis remissions,” Dr. Blauvelt said.
“I have no data to share, but I think we have the potential for unprecedented PASI-100 numbers with no added safety concerns, and the potential to break away from established regular dosing patterns,” such as the possibility of yearly dosing, the possibility of long-term remissions, and the possibility of cure in some patients, he noted.
Inducing tolerance. This refers to efforts aimed at increasing regulatory T cells, which are natural T cells that calm inflammation. He described it as “revving up our natural anti-inflammatory T cells to help balance the immune system.”
Gene editing. This involves using CRISPR gene editing technology to cut genes as a way to cure disease. “What if we cut the IL-23 receptor?” Dr. Blauvelt asked. “You would get rid of that whole signaling pathway. Would the patient be fine?”
In an interview a the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that Dr. Blauvelt “has a very exciting view” of the future of psoriasis treatments. “I think that some of it will come true; we’ll have to see which,” Dr. Stein Gold said. “The idea that we might be able to change the trajectory of disease by being aggressive upfront, and possibly modify the course, is exciting. That would be a wonderful new treatment approach.”
Dr. Blauvelt disclosed ties with AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN Pharma, Athenex, Bluefin, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, Highlightll, Incyte, Innovent Bio, Janssen, Landos, Leo, Lilly, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi-Genzyme, Spherix, Sun Pharmaceuticals Industries, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor.
Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries, Ltd.
Medscape and this news organization are owned by the same parent company.
HONOLULU – During office visits with Andrew Blauvelt, MD, MBA, many patients well controlled on biologic therapy for their moderate to severe psoriasis often ask him when their scheduled injections can stop.
The most common question he hears is, “ ‘Why do I have to keep doing this? I’ve been clear for 2 or 3 years,’ ” Dr. Blauvelt, president of Oregon Medical Research Center, Portland, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “We have terrific drugs for psoriasis, but how can we do better?”
Development of oral biologics. At least two companies are developing a peptide-type small molecule that blocks interleukin (IL)-17 or IL-23 signaling, but would be given as a pill, he said. Another concept in the works is a robotic pill for drug delivery. The pill, which is being developed by Rani Therapeutics, protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine, according to a report of two studies that demonstrated the safety and tolerability of the robotic pill in healthy humans.
In an animal study, the same researchers showed that delivering monoclonal antibodies with the robotic pill achieved bioavailability on par with that obtained by standard subcutaneous injections.
Identifying “super responders” who require less frequent dosing of medication. “There’s data to suggest that we can kind of back off treatment in these patients,” Dr. Blauvelt said.
Hitting treatment hard and early. “There’s a concept in medicine of hitting disease hard and hitting it early, before the disease can establish itself and cause damage,” he said.
Targeting tissue resident memory T cells. In psoriasis, the idea is that if you treat earlier, when patients are just diagnosed, “perhaps you might be able to decrease resident memory T cells that set up shop in the skin and are responsible for disease recurrences,” Dr. Blauvelt said. “Research has shown that IL-23 blockers decrease tissue resident memory T cells, and IL-17 blockers don’t. This could explain why we see long remissions in this class of drug because we’re getting at these resident memory T cells and knocking them down,” he explained. “Our hypothesis is that hitting hard and early in the treatment course with high-dose IL-23 blockade may be an effective strategy to induce long-term remissions and possible cure, what we call ‘knock-out therapy.’ ”
In a pilot study of 20 patients, Dr. Blauvelt and colleagues are evaluating whether higher initial doses of the IL-23 antagonist risankizumab (300 mg and 600 mg, 2 times and 4 times the standard initial doses for plaque psoriasis) can more effectively target resident memory T cells. “This involves dosing at weeks 0, 4, and 16, then stopping and measuring resident T cells in the tissue to see how long we can induce psoriasis remissions,” Dr. Blauvelt said.
“I have no data to share, but I think we have the potential for unprecedented PASI-100 numbers with no added safety concerns, and the potential to break away from established regular dosing patterns,” such as the possibility of yearly dosing, the possibility of long-term remissions, and the possibility of cure in some patients, he noted.
Inducing tolerance. This refers to efforts aimed at increasing regulatory T cells, which are natural T cells that calm inflammation. He described it as “revving up our natural anti-inflammatory T cells to help balance the immune system.”
Gene editing. This involves using CRISPR gene editing technology to cut genes as a way to cure disease. “What if we cut the IL-23 receptor?” Dr. Blauvelt asked. “You would get rid of that whole signaling pathway. Would the patient be fine?”
In an interview a the meeting, Linda Stein Gold, MD, director of clinical research and division head of dermatology at the Henry Ford Health System, Detroit, said that Dr. Blauvelt “has a very exciting view” of the future of psoriasis treatments. “I think that some of it will come true; we’ll have to see which,” Dr. Stein Gold said. “The idea that we might be able to change the trajectory of disease by being aggressive upfront, and possibly modify the course, is exciting. That would be a wonderful new treatment approach.”
Dr. Blauvelt disclosed ties with AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, AnaptysBio, Arcutis, Arena, ASLAN Pharma, Athenex, Bluefin, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Dermavant, EcoR1, Escient, Evelo, Evommune, Forte, Galderma, Highlightll, Incyte, Innovent Bio, Janssen, Landos, Leo, Lilly, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi-Genzyme, Spherix, Sun Pharmaceuticals Industries, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor.
Dr. Stein Gold disclosed ties with Almirall, Cutera, Dermata, Galderma, Novartis, Ortho Dermatologics, and Sun Pharmaceutical Industries, Ltd.
Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPE LIVE! HAWAII DERMATOLOGY SEMINAR
Eight-week TB treatment strategy shows potential
A strategy for the
“We found that if we use the strategy of a bedaquiline-linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was noninferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference held during the Conference on Retroviruses & Opportunistic Infections.
“The total time on treatment was reduced by half – instead of 160 days, it was 85 days for the total duration.”
Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that, although more needs to be understood, the high number of responses is nevertheless encouraging.
“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Dr. Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research, Baltimore, said in an interview.
Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.
The current global standard for TB treatment, practiced for 4 decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.
Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.
These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors asserted.
TRUNCATE-TB
To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3, prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.
The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel five-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).
Two of the regimens were dropped because of logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.
Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.
Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.
For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet noninferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting noninferiority criterion).
The mean total duration of treatment through week 96 in the standard treatment group was 180 days versus 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline-linezolid group.
The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.
In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.
Of note, only two patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Dr. Paton said was “encouraging,” because of concerns about resistance to that drug.
‘Unfavorable’ composite also evaluated
In an updated analysis of the study that Dr. Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome – a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.
The rate remained lowest in the standard 24-week therapy group (3.9%) versus 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.
Though the lower rate with the standard treatment was expected, Dr. Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.
“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”
Dr. Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.
“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said.
“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”
The authors of an accompanying editorial further commented that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.
“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” wrote Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, N.J., and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”
The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”
The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; as well as a grant from the UK Research and Innovation Medical Research Council. Dr. Dartois reported no relevant financial relationships. Dr. Chaisson had no disclosures to report.
A version of this article originally appeared on Medscape.com.
A strategy for the
“We found that if we use the strategy of a bedaquiline-linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was noninferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference held during the Conference on Retroviruses & Opportunistic Infections.
“The total time on treatment was reduced by half – instead of 160 days, it was 85 days for the total duration.”
Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that, although more needs to be understood, the high number of responses is nevertheless encouraging.
“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Dr. Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research, Baltimore, said in an interview.
Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.
The current global standard for TB treatment, practiced for 4 decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.
Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.
These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors asserted.
TRUNCATE-TB
To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3, prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.
The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel five-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).
Two of the regimens were dropped because of logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.
Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.
Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.
For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet noninferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting noninferiority criterion).
The mean total duration of treatment through week 96 in the standard treatment group was 180 days versus 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline-linezolid group.
The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.
In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.
Of note, only two patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Dr. Paton said was “encouraging,” because of concerns about resistance to that drug.
‘Unfavorable’ composite also evaluated
In an updated analysis of the study that Dr. Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome – a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.
The rate remained lowest in the standard 24-week therapy group (3.9%) versus 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.
Though the lower rate with the standard treatment was expected, Dr. Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.
“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”
Dr. Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.
“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said.
“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”
The authors of an accompanying editorial further commented that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.
“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” wrote Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, N.J., and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”
The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”
The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; as well as a grant from the UK Research and Innovation Medical Research Council. Dr. Dartois reported no relevant financial relationships. Dr. Chaisson had no disclosures to report.
A version of this article originally appeared on Medscape.com.
A strategy for the
“We found that if we use the strategy of a bedaquiline-linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was noninferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference held during the Conference on Retroviruses & Opportunistic Infections.
“The total time on treatment was reduced by half – instead of 160 days, it was 85 days for the total duration.”
Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that, although more needs to be understood, the high number of responses is nevertheless encouraging.
“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Dr. Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research, Baltimore, said in an interview.
Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.
The current global standard for TB treatment, practiced for 4 decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.
Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.
These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors asserted.
TRUNCATE-TB
To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3, prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.
The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel five-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).
Two of the regimens were dropped because of logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.
Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.
Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.
For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet noninferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting noninferiority criterion).
The mean total duration of treatment through week 96 in the standard treatment group was 180 days versus 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline-linezolid group.
The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.
In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.
Of note, only two patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Dr. Paton said was “encouraging,” because of concerns about resistance to that drug.
‘Unfavorable’ composite also evaluated
In an updated analysis of the study that Dr. Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome – a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.
The rate remained lowest in the standard 24-week therapy group (3.9%) versus 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.
Though the lower rate with the standard treatment was expected, Dr. Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.
“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”
Dr. Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.
“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said.
“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”
The authors of an accompanying editorial further commented that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.
“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” wrote Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, N.J., and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”
The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”
The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; as well as a grant from the UK Research and Innovation Medical Research Council. Dr. Dartois reported no relevant financial relationships. Dr. Chaisson had no disclosures to report.
A version of this article originally appeared on Medscape.com.
FROM CROI 2023
How to manage isotretinoin’s bothersome mucocutaneous side effects
HONOLULU –
“If they don’t have dry lips, you have to wonder if they’re even absorbing isotretinoin,” Dr. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “Everyone is going to get dry lips.”
According to a retrospective review of 1,743 patients started on isotretinoin, other common mucocutaneous side effects include eczema, nose bleeds, and eye problems. Emerging research suggests that there may be a role for oral omega-3 in decreasing such side effects of the drug. In a case control study, 118 patients were randomized to isotretinoin alone or isotretinoin plus 1 g/day of oral omega-3 for 16 weeks. At week 16, the rate of dry lips was 26% in the isoretinoin only group compared with 14% in the combination group; similar trends were seen with dry nose (11% vs. 0 %, respectively) and dry skin (11% vs. 2%).
“Omega-3 is a simple thing that we can think about recommending for patients,” Dr. Barbieri said. “It’s very safe, inexpensive, and it may help us manage these common sides effect we run into.”
Another potential side effect of isotretinoin that he characterized as underappreciated is chronic dry eye and other ocular changes. One retrospective cohort study of 14,682 adolescents and young adults in Israel found that use of the drug resulted in reduced tear production and reduced tear quality. In another study, a review and meta-analysis of 21 publications involving 1,105 eyes of 842 patients, isotretinoin use was associated with increased conjunctival fluorescein staining, decreased corneal thickness, and worse patient-reported ocular surface disease index scores.
“These changes may be mediated by meibomian gland dysfunction and atrophy,” Dr. Barbieri said. “Fortunately, many of these tear film changes appear to resolve after treatment. Those changes in corneal thickness do seem to get better. That’s reassuring.”
In a study of 54 patients treated with isotretinoin, tear production and quality returned to baseline within 6 months of treatment completion. “But some changes in the meibomian gland may be persistent,” Dr. Barbieri said. “At 6 and 12 months after the end of treatment, you can still see changes in the meibomian glands of patients who were treated with a standard course of 120 to 150 mg/kg isotretinoin,” he said, referring to the results of a study of 88 patients .
One study investigated the effects of omega-3 fatty acids and punctal plugs on tear film and ocular surface parameters in 90 patients receiving systemic isotretinoin therapy. They were divided into three groups: Those who received a soft preloaded silicone plug that was inserted in the inferior punctum of both eyes and received oral omega-3 fatty acid capsules twice daily for a total dose of 1,040 mg/day for 6 months; those who received a soft preloaded silicone plug and oral placebo, and those who received isotretinoin alone. At 6 months’ follow-up, those who were treated with omega-3 combined with the preloaded silicone plug had better meibomian gland function than did those who received isotretinoin alone or isotretinoin with the preloaded silicone plug.
Dr. Barbieri also noted that antihistamines may play a role in enhancing the effect of isotretinoin. In one study, 20 patients were treated with isotretinoin 0.4 mg/kg per day and 20 patients were also treated with an antihistamine, desloratadine 5 mg/day for 12 weeks. At week 12, patients in the group treated with isotretinoin and the antihistamine showed a more statistically significant decrease in acne lesion counts, compared with the isotretinoin-only group (reductions of 44.8% vs. 17.8%, respectively, in noninflammatory lesions; 55.8% vs. 22.9% in inflammatory lesions, and 45.6% vs. 18.7% in total lesions (P < .05 for all associations).
A subsequent larger study yielded similar findings. There were also lower rates of initial flaring and higher rates of patient satisfaction in the antihistamine groups in both studies.
In an interview at the meeting, Lawrence F. Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, described Dr. Barbieri as “a leader in taking a comprehensive view on what the history and latest information is on isotretinoin. His fresh approach is something everyone should consider and figure out what they can use in their practice.”
Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Galderma, and Ortho Dermatologics. Medscape and this news organization are owned by the same parent company.
HONOLULU –
“If they don’t have dry lips, you have to wonder if they’re even absorbing isotretinoin,” Dr. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “Everyone is going to get dry lips.”
According to a retrospective review of 1,743 patients started on isotretinoin, other common mucocutaneous side effects include eczema, nose bleeds, and eye problems. Emerging research suggests that there may be a role for oral omega-3 in decreasing such side effects of the drug. In a case control study, 118 patients were randomized to isotretinoin alone or isotretinoin plus 1 g/day of oral omega-3 for 16 weeks. At week 16, the rate of dry lips was 26% in the isoretinoin only group compared with 14% in the combination group; similar trends were seen with dry nose (11% vs. 0 %, respectively) and dry skin (11% vs. 2%).
“Omega-3 is a simple thing that we can think about recommending for patients,” Dr. Barbieri said. “It’s very safe, inexpensive, and it may help us manage these common sides effect we run into.”
Another potential side effect of isotretinoin that he characterized as underappreciated is chronic dry eye and other ocular changes. One retrospective cohort study of 14,682 adolescents and young adults in Israel found that use of the drug resulted in reduced tear production and reduced tear quality. In another study, a review and meta-analysis of 21 publications involving 1,105 eyes of 842 patients, isotretinoin use was associated with increased conjunctival fluorescein staining, decreased corneal thickness, and worse patient-reported ocular surface disease index scores.
“These changes may be mediated by meibomian gland dysfunction and atrophy,” Dr. Barbieri said. “Fortunately, many of these tear film changes appear to resolve after treatment. Those changes in corneal thickness do seem to get better. That’s reassuring.”
In a study of 54 patients treated with isotretinoin, tear production and quality returned to baseline within 6 months of treatment completion. “But some changes in the meibomian gland may be persistent,” Dr. Barbieri said. “At 6 and 12 months after the end of treatment, you can still see changes in the meibomian glands of patients who were treated with a standard course of 120 to 150 mg/kg isotretinoin,” he said, referring to the results of a study of 88 patients .
One study investigated the effects of omega-3 fatty acids and punctal plugs on tear film and ocular surface parameters in 90 patients receiving systemic isotretinoin therapy. They were divided into three groups: Those who received a soft preloaded silicone plug that was inserted in the inferior punctum of both eyes and received oral omega-3 fatty acid capsules twice daily for a total dose of 1,040 mg/day for 6 months; those who received a soft preloaded silicone plug and oral placebo, and those who received isotretinoin alone. At 6 months’ follow-up, those who were treated with omega-3 combined with the preloaded silicone plug had better meibomian gland function than did those who received isotretinoin alone or isotretinoin with the preloaded silicone plug.
Dr. Barbieri also noted that antihistamines may play a role in enhancing the effect of isotretinoin. In one study, 20 patients were treated with isotretinoin 0.4 mg/kg per day and 20 patients were also treated with an antihistamine, desloratadine 5 mg/day for 12 weeks. At week 12, patients in the group treated with isotretinoin and the antihistamine showed a more statistically significant decrease in acne lesion counts, compared with the isotretinoin-only group (reductions of 44.8% vs. 17.8%, respectively, in noninflammatory lesions; 55.8% vs. 22.9% in inflammatory lesions, and 45.6% vs. 18.7% in total lesions (P < .05 for all associations).
A subsequent larger study yielded similar findings. There were also lower rates of initial flaring and higher rates of patient satisfaction in the antihistamine groups in both studies.
In an interview at the meeting, Lawrence F. Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, described Dr. Barbieri as “a leader in taking a comprehensive view on what the history and latest information is on isotretinoin. His fresh approach is something everyone should consider and figure out what they can use in their practice.”
Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Galderma, and Ortho Dermatologics. Medscape and this news organization are owned by the same parent company.
HONOLULU –
“If they don’t have dry lips, you have to wonder if they’re even absorbing isotretinoin,” Dr. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “Everyone is going to get dry lips.”
According to a retrospective review of 1,743 patients started on isotretinoin, other common mucocutaneous side effects include eczema, nose bleeds, and eye problems. Emerging research suggests that there may be a role for oral omega-3 in decreasing such side effects of the drug. In a case control study, 118 patients were randomized to isotretinoin alone or isotretinoin plus 1 g/day of oral omega-3 for 16 weeks. At week 16, the rate of dry lips was 26% in the isoretinoin only group compared with 14% in the combination group; similar trends were seen with dry nose (11% vs. 0 %, respectively) and dry skin (11% vs. 2%).
“Omega-3 is a simple thing that we can think about recommending for patients,” Dr. Barbieri said. “It’s very safe, inexpensive, and it may help us manage these common sides effect we run into.”
Another potential side effect of isotretinoin that he characterized as underappreciated is chronic dry eye and other ocular changes. One retrospective cohort study of 14,682 adolescents and young adults in Israel found that use of the drug resulted in reduced tear production and reduced tear quality. In another study, a review and meta-analysis of 21 publications involving 1,105 eyes of 842 patients, isotretinoin use was associated with increased conjunctival fluorescein staining, decreased corneal thickness, and worse patient-reported ocular surface disease index scores.
“These changes may be mediated by meibomian gland dysfunction and atrophy,” Dr. Barbieri said. “Fortunately, many of these tear film changes appear to resolve after treatment. Those changes in corneal thickness do seem to get better. That’s reassuring.”
In a study of 54 patients treated with isotretinoin, tear production and quality returned to baseline within 6 months of treatment completion. “But some changes in the meibomian gland may be persistent,” Dr. Barbieri said. “At 6 and 12 months after the end of treatment, you can still see changes in the meibomian glands of patients who were treated with a standard course of 120 to 150 mg/kg isotretinoin,” he said, referring to the results of a study of 88 patients .
One study investigated the effects of omega-3 fatty acids and punctal plugs on tear film and ocular surface parameters in 90 patients receiving systemic isotretinoin therapy. They were divided into three groups: Those who received a soft preloaded silicone plug that was inserted in the inferior punctum of both eyes and received oral omega-3 fatty acid capsules twice daily for a total dose of 1,040 mg/day for 6 months; those who received a soft preloaded silicone plug and oral placebo, and those who received isotretinoin alone. At 6 months’ follow-up, those who were treated with omega-3 combined with the preloaded silicone plug had better meibomian gland function than did those who received isotretinoin alone or isotretinoin with the preloaded silicone plug.
Dr. Barbieri also noted that antihistamines may play a role in enhancing the effect of isotretinoin. In one study, 20 patients were treated with isotretinoin 0.4 mg/kg per day and 20 patients were also treated with an antihistamine, desloratadine 5 mg/day for 12 weeks. At week 12, patients in the group treated with isotretinoin and the antihistamine showed a more statistically significant decrease in acne lesion counts, compared with the isotretinoin-only group (reductions of 44.8% vs. 17.8%, respectively, in noninflammatory lesions; 55.8% vs. 22.9% in inflammatory lesions, and 45.6% vs. 18.7% in total lesions (P < .05 for all associations).
A subsequent larger study yielded similar findings. There were also lower rates of initial flaring and higher rates of patient satisfaction in the antihistamine groups in both studies.
In an interview at the meeting, Lawrence F. Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, described Dr. Barbieri as “a leader in taking a comprehensive view on what the history and latest information is on isotretinoin. His fresh approach is something everyone should consider and figure out what they can use in their practice.”
Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Galderma, and Ortho Dermatologics. Medscape and this news organization are owned by the same parent company.
AT THE MEDSCAPE LIVE! HAWAII DERMATOLOGY SEMINAR
Expert discusses pros, cons of molecular tests for melanoma
SAN DIEGO – , according to Gregory A. Hosler, MD, PhD.
At the annual Cutaneous Malignancy Update, Dr. Hosler, director of dermatopathology for ProPath, highlighted the following molecular tests currently used for the diagnosis of challenging melanocytic lesions:
Comparative genomic hybridization (CGH). This technique allows for the detection of chromosomal copy number changes throughout the tumor genome. “With CGH, test (tumor) DNA and normal DNA are differentially labeled and compared to a reference library. Gains and losses of portions of the tumor genome are determined by comparing the relative signals from these two groups,” said Dr. Hosler, clinical professor of pathology and dermatology at the University of Texas Southwestern Medical Center, Dallas.
“In the past, your library was a metaphase of spread of chromosomes, which introduced technical challenges and made performance of the assay labor intensive. Because of this, CGH is not routinely performed by clinical laboratories and is used more as an exploratory/research technique.”
Array CGH (also known as SNP array). Newer versions of CGH use short DNA sequences that are tiled onto a chip. “The interesting thing about these chips is that you can purchase them or design them on your own,” Dr. Hosler said. “The chips may cover the entire genome or cover specific areas of the genome at higher resolution.” One upside of array CGH, he continued, is that it allows one to detect essentially all gains or losses of chromosomal material in a single reaction. “It is not subject to the artifacts associated with cutting thin sections like with fluorescence in situ hybridization (FISH); it can detect copy number neutral loss of heterozygosity, and it is more scalable,” Dr. Hosler said at the meeting, which was hosted by Scripps MD Anderson Cancer Center.
One downside of array CGH is that does not allow one to analyze specific cells, “so if you have a tumor that’s heterogeneous, the assay is agnostic to this and spits out a result based on all the material provided,” he said. “You can’t parse out different areas of the lesion. It also does not track balanced translocations.” In addition, he said, “there are also questions about reimbursement and these are lab-developed tests, so each lab’s assay is different. Finally, it requires specialized equipment and expertise for interpretation.”
FISH. First-generation melanoma FISH assays, which became available in 2009, used six probes and four colors and had a sensitivity of about 87% and specificity of about 95%, Dr. Hosler said, but there were problems with those assays, particularly related to Spitz nevi. Spitz nevi often duplicate their chromosomes, “so instead of being diploid they’re tetraploid,” he said.
“The second-generation melanoma FISH assays addressed this by adding centromeres to the assay, and targeted probes could be compared to the centromeres on the same chromosome to determine if these were true copy number gains, due to genetic instability, or gains or losses of entire arms or whole chromosomes. This modification and the addition of new targets really improved upon the sensitivity and specificity (94% and 98%, respectively),” he said, noting that this assay is widely used.
Upsides of melanoma FISH assays are that they are a “fairly routine methodology” in large clinical laboratories, he said, and that many labs are familiar with interpretation. “I would say the biggest advantage to FISH is its ability to analyze specific cells, which is useful with small or heterogeneous tumors,” Dr. Hosler said. “Also, there is a genetic reimbursement code for it, and it yields diagnostic and potentially prognostic information.” For example, certain copy number changes have shown to portend a worse prognosis if they’re present in a melanocytic tumor, including alterations in CDKN2A, CCND1, MYC, topoisomerase, and BAP1.
Downsides of melanoma FISH assays are that they are expensive, labor-intensive, and require experts to interpret the results. “The stacking and truncation of cell nuclei innate to paraffin-embedded FISH make interpretation difficult,” he said. “Also, all colors cannot be viewed simultaneously, and each lab’s assay potentially is different, requiring validation. These are not [Food and Drug Administration]-approved tests.”
Next generation sequencing (NGS). Also known as high-throughput sequencing, this technique allows for the generation of millions of sequencing reads that are aligned to a standard human genome, and likely represents the wave of the future. “With NGS you can increase breadth, so you can sequence the entire genome if you want, but you can also increase depth, meaning increasing the number of reads over a single target of the genome,” Dr. Hosler said. “That’s useful if you’re looking for a low frequency mutation.”
For example, NGS allows one to detect alterations of BRAF and KIT and other potentially actionable alterations. It can also be used to detect mutations in benign and malignant melanocytic lesions, including historically diagnostically challenging Spitz and desmoplastic subgroups. Several different NGS technologies exist, and there are different strategies behind each assay, including whole genome sequencing, whole exome sequencing, transcriptome sequencing, and targeted panels. “I’ve seen panels of 10 and I’ve seen panels of 1,500; there’s a wide range,” Dr. Hosler said. “The biggest challenge with NGS, currently, is that it’s difficult to interpret. Trying to figure out what’s important and what’s not important can be challenging. Often you need a team of people who are experts in bioinformatics to interpret these results.”
Slow turnaround time is another downside. “It can take a month to get results, and sometimes clinicians don’t want to wait that long, especially if they think a lesion is melanoma, so that’s an area of focus for NGS laboratories,” he said. “And there are questions on reimbursement. If you run NGS on every unusual melanocytic lesion, that’s not a good use of health care dollars. Who’s paying for it? I don’t have an answer for you. It’s all over the map right now. Each lab’s test and billing practice is different.”
Dr. Hosler reported having no relevant financial disclosures. ProPath is a nationwide pathology practice.
SAN DIEGO – , according to Gregory A. Hosler, MD, PhD.
At the annual Cutaneous Malignancy Update, Dr. Hosler, director of dermatopathology for ProPath, highlighted the following molecular tests currently used for the diagnosis of challenging melanocytic lesions:
Comparative genomic hybridization (CGH). This technique allows for the detection of chromosomal copy number changes throughout the tumor genome. “With CGH, test (tumor) DNA and normal DNA are differentially labeled and compared to a reference library. Gains and losses of portions of the tumor genome are determined by comparing the relative signals from these two groups,” said Dr. Hosler, clinical professor of pathology and dermatology at the University of Texas Southwestern Medical Center, Dallas.
“In the past, your library was a metaphase of spread of chromosomes, which introduced technical challenges and made performance of the assay labor intensive. Because of this, CGH is not routinely performed by clinical laboratories and is used more as an exploratory/research technique.”
Array CGH (also known as SNP array). Newer versions of CGH use short DNA sequences that are tiled onto a chip. “The interesting thing about these chips is that you can purchase them or design them on your own,” Dr. Hosler said. “The chips may cover the entire genome or cover specific areas of the genome at higher resolution.” One upside of array CGH, he continued, is that it allows one to detect essentially all gains or losses of chromosomal material in a single reaction. “It is not subject to the artifacts associated with cutting thin sections like with fluorescence in situ hybridization (FISH); it can detect copy number neutral loss of heterozygosity, and it is more scalable,” Dr. Hosler said at the meeting, which was hosted by Scripps MD Anderson Cancer Center.
One downside of array CGH is that does not allow one to analyze specific cells, “so if you have a tumor that’s heterogeneous, the assay is agnostic to this and spits out a result based on all the material provided,” he said. “You can’t parse out different areas of the lesion. It also does not track balanced translocations.” In addition, he said, “there are also questions about reimbursement and these are lab-developed tests, so each lab’s assay is different. Finally, it requires specialized equipment and expertise for interpretation.”
FISH. First-generation melanoma FISH assays, which became available in 2009, used six probes and four colors and had a sensitivity of about 87% and specificity of about 95%, Dr. Hosler said, but there were problems with those assays, particularly related to Spitz nevi. Spitz nevi often duplicate their chromosomes, “so instead of being diploid they’re tetraploid,” he said.
“The second-generation melanoma FISH assays addressed this by adding centromeres to the assay, and targeted probes could be compared to the centromeres on the same chromosome to determine if these were true copy number gains, due to genetic instability, or gains or losses of entire arms or whole chromosomes. This modification and the addition of new targets really improved upon the sensitivity and specificity (94% and 98%, respectively),” he said, noting that this assay is widely used.
Upsides of melanoma FISH assays are that they are a “fairly routine methodology” in large clinical laboratories, he said, and that many labs are familiar with interpretation. “I would say the biggest advantage to FISH is its ability to analyze specific cells, which is useful with small or heterogeneous tumors,” Dr. Hosler said. “Also, there is a genetic reimbursement code for it, and it yields diagnostic and potentially prognostic information.” For example, certain copy number changes have shown to portend a worse prognosis if they’re present in a melanocytic tumor, including alterations in CDKN2A, CCND1, MYC, topoisomerase, and BAP1.
Downsides of melanoma FISH assays are that they are expensive, labor-intensive, and require experts to interpret the results. “The stacking and truncation of cell nuclei innate to paraffin-embedded FISH make interpretation difficult,” he said. “Also, all colors cannot be viewed simultaneously, and each lab’s assay potentially is different, requiring validation. These are not [Food and Drug Administration]-approved tests.”
Next generation sequencing (NGS). Also known as high-throughput sequencing, this technique allows for the generation of millions of sequencing reads that are aligned to a standard human genome, and likely represents the wave of the future. “With NGS you can increase breadth, so you can sequence the entire genome if you want, but you can also increase depth, meaning increasing the number of reads over a single target of the genome,” Dr. Hosler said. “That’s useful if you’re looking for a low frequency mutation.”
For example, NGS allows one to detect alterations of BRAF and KIT and other potentially actionable alterations. It can also be used to detect mutations in benign and malignant melanocytic lesions, including historically diagnostically challenging Spitz and desmoplastic subgroups. Several different NGS technologies exist, and there are different strategies behind each assay, including whole genome sequencing, whole exome sequencing, transcriptome sequencing, and targeted panels. “I’ve seen panels of 10 and I’ve seen panels of 1,500; there’s a wide range,” Dr. Hosler said. “The biggest challenge with NGS, currently, is that it’s difficult to interpret. Trying to figure out what’s important and what’s not important can be challenging. Often you need a team of people who are experts in bioinformatics to interpret these results.”
Slow turnaround time is another downside. “It can take a month to get results, and sometimes clinicians don’t want to wait that long, especially if they think a lesion is melanoma, so that’s an area of focus for NGS laboratories,” he said. “And there are questions on reimbursement. If you run NGS on every unusual melanocytic lesion, that’s not a good use of health care dollars. Who’s paying for it? I don’t have an answer for you. It’s all over the map right now. Each lab’s test and billing practice is different.”
Dr. Hosler reported having no relevant financial disclosures. ProPath is a nationwide pathology practice.
SAN DIEGO – , according to Gregory A. Hosler, MD, PhD.
At the annual Cutaneous Malignancy Update, Dr. Hosler, director of dermatopathology for ProPath, highlighted the following molecular tests currently used for the diagnosis of challenging melanocytic lesions:
Comparative genomic hybridization (CGH). This technique allows for the detection of chromosomal copy number changes throughout the tumor genome. “With CGH, test (tumor) DNA and normal DNA are differentially labeled and compared to a reference library. Gains and losses of portions of the tumor genome are determined by comparing the relative signals from these two groups,” said Dr. Hosler, clinical professor of pathology and dermatology at the University of Texas Southwestern Medical Center, Dallas.
“In the past, your library was a metaphase of spread of chromosomes, which introduced technical challenges and made performance of the assay labor intensive. Because of this, CGH is not routinely performed by clinical laboratories and is used more as an exploratory/research technique.”
Array CGH (also known as SNP array). Newer versions of CGH use short DNA sequences that are tiled onto a chip. “The interesting thing about these chips is that you can purchase them or design them on your own,” Dr. Hosler said. “The chips may cover the entire genome or cover specific areas of the genome at higher resolution.” One upside of array CGH, he continued, is that it allows one to detect essentially all gains or losses of chromosomal material in a single reaction. “It is not subject to the artifacts associated with cutting thin sections like with fluorescence in situ hybridization (FISH); it can detect copy number neutral loss of heterozygosity, and it is more scalable,” Dr. Hosler said at the meeting, which was hosted by Scripps MD Anderson Cancer Center.
One downside of array CGH is that does not allow one to analyze specific cells, “so if you have a tumor that’s heterogeneous, the assay is agnostic to this and spits out a result based on all the material provided,” he said. “You can’t parse out different areas of the lesion. It also does not track balanced translocations.” In addition, he said, “there are also questions about reimbursement and these are lab-developed tests, so each lab’s assay is different. Finally, it requires specialized equipment and expertise for interpretation.”
FISH. First-generation melanoma FISH assays, which became available in 2009, used six probes and four colors and had a sensitivity of about 87% and specificity of about 95%, Dr. Hosler said, but there were problems with those assays, particularly related to Spitz nevi. Spitz nevi often duplicate their chromosomes, “so instead of being diploid they’re tetraploid,” he said.
“The second-generation melanoma FISH assays addressed this by adding centromeres to the assay, and targeted probes could be compared to the centromeres on the same chromosome to determine if these were true copy number gains, due to genetic instability, or gains or losses of entire arms or whole chromosomes. This modification and the addition of new targets really improved upon the sensitivity and specificity (94% and 98%, respectively),” he said, noting that this assay is widely used.
Upsides of melanoma FISH assays are that they are a “fairly routine methodology” in large clinical laboratories, he said, and that many labs are familiar with interpretation. “I would say the biggest advantage to FISH is its ability to analyze specific cells, which is useful with small or heterogeneous tumors,” Dr. Hosler said. “Also, there is a genetic reimbursement code for it, and it yields diagnostic and potentially prognostic information.” For example, certain copy number changes have shown to portend a worse prognosis if they’re present in a melanocytic tumor, including alterations in CDKN2A, CCND1, MYC, topoisomerase, and BAP1.
Downsides of melanoma FISH assays are that they are expensive, labor-intensive, and require experts to interpret the results. “The stacking and truncation of cell nuclei innate to paraffin-embedded FISH make interpretation difficult,” he said. “Also, all colors cannot be viewed simultaneously, and each lab’s assay potentially is different, requiring validation. These are not [Food and Drug Administration]-approved tests.”
Next generation sequencing (NGS). Also known as high-throughput sequencing, this technique allows for the generation of millions of sequencing reads that are aligned to a standard human genome, and likely represents the wave of the future. “With NGS you can increase breadth, so you can sequence the entire genome if you want, but you can also increase depth, meaning increasing the number of reads over a single target of the genome,” Dr. Hosler said. “That’s useful if you’re looking for a low frequency mutation.”
For example, NGS allows one to detect alterations of BRAF and KIT and other potentially actionable alterations. It can also be used to detect mutations in benign and malignant melanocytic lesions, including historically diagnostically challenging Spitz and desmoplastic subgroups. Several different NGS technologies exist, and there are different strategies behind each assay, including whole genome sequencing, whole exome sequencing, transcriptome sequencing, and targeted panels. “I’ve seen panels of 10 and I’ve seen panels of 1,500; there’s a wide range,” Dr. Hosler said. “The biggest challenge with NGS, currently, is that it’s difficult to interpret. Trying to figure out what’s important and what’s not important can be challenging. Often you need a team of people who are experts in bioinformatics to interpret these results.”
Slow turnaround time is another downside. “It can take a month to get results, and sometimes clinicians don’t want to wait that long, especially if they think a lesion is melanoma, so that’s an area of focus for NGS laboratories,” he said. “And there are questions on reimbursement. If you run NGS on every unusual melanocytic lesion, that’s not a good use of health care dollars. Who’s paying for it? I don’t have an answer for you. It’s all over the map right now. Each lab’s test and billing practice is different.”
Dr. Hosler reported having no relevant financial disclosures. ProPath is a nationwide pathology practice.
AT MELANOMA 2023
Telemedicine usage still high among rheumatologists as interest wanes in other specialties
There was an explosion in the use of telemedicine during the COVID-19 pandemic, but usage has stabilized and varies between specialties. However, telemedicine use is still somewhat high among rheumatologists, according to speakers at the 2023 Rheumatology Winter Clinical Symposium.
Speaking in general about the future of rheumatology, Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, said it is up to rheumatologists to adapt to the changing winds in the specialty.
“The future is going to happen no matter what, so the question is, are you going to go along with it? Are you going to be a part of it? Are you going to be resistant to it?” Dr. Cush asked attendees. “Your recent experience with COVID would tell you maybe what your path is going to be if you’re dying to get back to the way it once was.”
Rheumatologists can expect changes in where they work, how they’re paid, increases in their workload, and new innovations in connecting with patients, he said.
“You’re going to be integrating a new style of medicine, you’re going to be digitally connected,” he explained. “All these networks are going to be working together to make you supposedly better at what you do, or maybe they’re working together to make you obsolete – and I think you better start protecting your space.”
One major area of change, telemedicine, already occurred as a result of the COVID-19 pandemic and will “begin to dominate” over the next decade, Dr. Cush said. An analysis conducted by consulting firm McKinsey & Company found telehealth usage increased 78-fold between February and April 2020 before leveling off at a 38-fold higher rate, compared with prepandemic levels. In the same analysis, rheumatology ranked third in terms of telehealth usage claims behind psychiatry and substance use disorder treatment, Dr. Cush observed, as other specialties have “fallen off quite a bit.”
“The common denominators are chronic care, cognitive care, nonprocedural care, pattern recognition, and monitoring, and this is what you do,” he said. “This is why, in many ways, for you to abandon telemedicine I think is a gigantic mistake.”
Changes to telemedicine
The most immediate change to telemedicine will come when the Biden administration officially ends the COVID-19 public health emergency in May 2023, and temporary telehealth services will be extended for approximately 5 months after the end of the public health emergency. Legislation passed by Congress will ensure some of the flexibilities in telemedicine will be extended until the end of December 2024.
Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said he sees telemedicine as persisting even after the official COVID-19 public health emergency ends. “There’s a lot of push from the American Medical Association, from the American College of Physicians. You’re going to see people – this will not go away because [there’s] also going to be that demand.”
Despite decreased usage since April 2020, telehealth was estimated to be a $60 billion industry in 2022 and will likely increase over the next decade, Dr. Cush noted. “I question [the decline] because I think it still is a major part of your [future in] 2033.”
The number of physicians who have at least three licenses to practice in other U.S. states increased from 50,454 in 2010 to 72,752 in 2020, and that trend will continue, Dr. Wells explained. It is now becoming easier for physicians to become licensed in other states with companies like CompHealth that offer services to simplify obtaining medical licenses with states that participate in the Interstate Medical Licensure Compact.
“It’s a telemedicine easy pass,” Dr. Cush said.
Concerns in telemedicine
Commenting on the presentation, Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery (HSS), both in New York, pointed out that because telemedicine is governed by U.S. states, rather than the federal government, a physician needs to be licensed in the state where the patient is located. While many states relaxed their restrictions during COVID-19, as states began tightening their restrictions later, “many physicians didn’t want to have three licenses,” he said.
“There’s an expense in getting three licenses. There’s an expense in obtaining it and maintaining it, and the reimbursement for the telemedicine visit did not reach that expectation,” Dr. Gibofsky explained. With the exception of the orthopedic surgeons at HSS who practice in New York and a satellite office in Florida, none of the surgeons at his center have obtained more than one license to practice telemedicine in other states.
“Our volume of telemedicine at HSS has remained about the same at 30%, but fewer physicians are doing it because they don’t want to maintain multiple licensures,” he said. “So don’t overlook the role of legal concerns in terms of who’s going to be allowed to do what where. Your talk was great in terms of an exuberance of what’s going to be available, but it’s not going to relieve the physician from the burden of being responsible for their use.”
Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, asked the presenters about the balance between seeing patients for virtual and in-person visits. “The question is what’s the sweet spot? Are there people you’re willing to see virtually forever?” he asked, noting that he has patients scheduling telemedicine visits that he hasn’t seen since before the COVID-19 pandemic.
“That’s not going to work for me. At some point, you have to lay hands on people,” he said.
Dr. Wells said his current practice is 40% virtual, and his staff converts potential no-shows into a telemedicine consultation over the phone. “My no-show rate has gone down to zero. Somebody’s scheduled for a visit, they don’t show up, my [medical assistants] get them on the phone, they put them on hold, tee up the refills. I turn them into a telephone call,” he said. “We don’t accept the no-show at all because we can do a telephone [consultation].”
In Dr. Cush’s practice, he alternates telemedicine visits with in-person visits. “If you come back for two videos in a row, you’re catching hell from me for that,” he said. Responding to how Dr. Wells incorporates telemedicine into his practice, Dr. Cush said many rheumatologists “don’t have the setups to support the care, and that’s why it’s hard to do and that’s why we’re not as great as we could be.”
“This is the way we were trained. We’re used to seeing these patients in the clinic that often. Not every single patient needs to be seen that frequently if they’re stable and doing fine,” Dr. Wells countered.
Dr. Cush and Dr. Wells reported having financial relationships with numerous pharmaceutical companies.
There was an explosion in the use of telemedicine during the COVID-19 pandemic, but usage has stabilized and varies between specialties. However, telemedicine use is still somewhat high among rheumatologists, according to speakers at the 2023 Rheumatology Winter Clinical Symposium.
Speaking in general about the future of rheumatology, Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, said it is up to rheumatologists to adapt to the changing winds in the specialty.
“The future is going to happen no matter what, so the question is, are you going to go along with it? Are you going to be a part of it? Are you going to be resistant to it?” Dr. Cush asked attendees. “Your recent experience with COVID would tell you maybe what your path is going to be if you’re dying to get back to the way it once was.”
Rheumatologists can expect changes in where they work, how they’re paid, increases in their workload, and new innovations in connecting with patients, he said.
“You’re going to be integrating a new style of medicine, you’re going to be digitally connected,” he explained. “All these networks are going to be working together to make you supposedly better at what you do, or maybe they’re working together to make you obsolete – and I think you better start protecting your space.”
One major area of change, telemedicine, already occurred as a result of the COVID-19 pandemic and will “begin to dominate” over the next decade, Dr. Cush said. An analysis conducted by consulting firm McKinsey & Company found telehealth usage increased 78-fold between February and April 2020 before leveling off at a 38-fold higher rate, compared with prepandemic levels. In the same analysis, rheumatology ranked third in terms of telehealth usage claims behind psychiatry and substance use disorder treatment, Dr. Cush observed, as other specialties have “fallen off quite a bit.”
“The common denominators are chronic care, cognitive care, nonprocedural care, pattern recognition, and monitoring, and this is what you do,” he said. “This is why, in many ways, for you to abandon telemedicine I think is a gigantic mistake.”
Changes to telemedicine
The most immediate change to telemedicine will come when the Biden administration officially ends the COVID-19 public health emergency in May 2023, and temporary telehealth services will be extended for approximately 5 months after the end of the public health emergency. Legislation passed by Congress will ensure some of the flexibilities in telemedicine will be extended until the end of December 2024.
Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said he sees telemedicine as persisting even after the official COVID-19 public health emergency ends. “There’s a lot of push from the American Medical Association, from the American College of Physicians. You’re going to see people – this will not go away because [there’s] also going to be that demand.”
Despite decreased usage since April 2020, telehealth was estimated to be a $60 billion industry in 2022 and will likely increase over the next decade, Dr. Cush noted. “I question [the decline] because I think it still is a major part of your [future in] 2033.”
The number of physicians who have at least three licenses to practice in other U.S. states increased from 50,454 in 2010 to 72,752 in 2020, and that trend will continue, Dr. Wells explained. It is now becoming easier for physicians to become licensed in other states with companies like CompHealth that offer services to simplify obtaining medical licenses with states that participate in the Interstate Medical Licensure Compact.
“It’s a telemedicine easy pass,” Dr. Cush said.
Concerns in telemedicine
Commenting on the presentation, Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery (HSS), both in New York, pointed out that because telemedicine is governed by U.S. states, rather than the federal government, a physician needs to be licensed in the state where the patient is located. While many states relaxed their restrictions during COVID-19, as states began tightening their restrictions later, “many physicians didn’t want to have three licenses,” he said.
“There’s an expense in getting three licenses. There’s an expense in obtaining it and maintaining it, and the reimbursement for the telemedicine visit did not reach that expectation,” Dr. Gibofsky explained. With the exception of the orthopedic surgeons at HSS who practice in New York and a satellite office in Florida, none of the surgeons at his center have obtained more than one license to practice telemedicine in other states.
“Our volume of telemedicine at HSS has remained about the same at 30%, but fewer physicians are doing it because they don’t want to maintain multiple licensures,” he said. “So don’t overlook the role of legal concerns in terms of who’s going to be allowed to do what where. Your talk was great in terms of an exuberance of what’s going to be available, but it’s not going to relieve the physician from the burden of being responsible for their use.”
Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, asked the presenters about the balance between seeing patients for virtual and in-person visits. “The question is what’s the sweet spot? Are there people you’re willing to see virtually forever?” he asked, noting that he has patients scheduling telemedicine visits that he hasn’t seen since before the COVID-19 pandemic.
“That’s not going to work for me. At some point, you have to lay hands on people,” he said.
Dr. Wells said his current practice is 40% virtual, and his staff converts potential no-shows into a telemedicine consultation over the phone. “My no-show rate has gone down to zero. Somebody’s scheduled for a visit, they don’t show up, my [medical assistants] get them on the phone, they put them on hold, tee up the refills. I turn them into a telephone call,” he said. “We don’t accept the no-show at all because we can do a telephone [consultation].”
In Dr. Cush’s practice, he alternates telemedicine visits with in-person visits. “If you come back for two videos in a row, you’re catching hell from me for that,” he said. Responding to how Dr. Wells incorporates telemedicine into his practice, Dr. Cush said many rheumatologists “don’t have the setups to support the care, and that’s why it’s hard to do and that’s why we’re not as great as we could be.”
“This is the way we were trained. We’re used to seeing these patients in the clinic that often. Not every single patient needs to be seen that frequently if they’re stable and doing fine,” Dr. Wells countered.
Dr. Cush and Dr. Wells reported having financial relationships with numerous pharmaceutical companies.
There was an explosion in the use of telemedicine during the COVID-19 pandemic, but usage has stabilized and varies between specialties. However, telemedicine use is still somewhat high among rheumatologists, according to speakers at the 2023 Rheumatology Winter Clinical Symposium.
Speaking in general about the future of rheumatology, Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, said it is up to rheumatologists to adapt to the changing winds in the specialty.
“The future is going to happen no matter what, so the question is, are you going to go along with it? Are you going to be a part of it? Are you going to be resistant to it?” Dr. Cush asked attendees. “Your recent experience with COVID would tell you maybe what your path is going to be if you’re dying to get back to the way it once was.”
Rheumatologists can expect changes in where they work, how they’re paid, increases in their workload, and new innovations in connecting with patients, he said.
“You’re going to be integrating a new style of medicine, you’re going to be digitally connected,” he explained. “All these networks are going to be working together to make you supposedly better at what you do, or maybe they’re working together to make you obsolete – and I think you better start protecting your space.”
One major area of change, telemedicine, already occurred as a result of the COVID-19 pandemic and will “begin to dominate” over the next decade, Dr. Cush said. An analysis conducted by consulting firm McKinsey & Company found telehealth usage increased 78-fold between February and April 2020 before leveling off at a 38-fold higher rate, compared with prepandemic levels. In the same analysis, rheumatology ranked third in terms of telehealth usage claims behind psychiatry and substance use disorder treatment, Dr. Cush observed, as other specialties have “fallen off quite a bit.”
“The common denominators are chronic care, cognitive care, nonprocedural care, pattern recognition, and monitoring, and this is what you do,” he said. “This is why, in many ways, for you to abandon telemedicine I think is a gigantic mistake.”
Changes to telemedicine
The most immediate change to telemedicine will come when the Biden administration officially ends the COVID-19 public health emergency in May 2023, and temporary telehealth services will be extended for approximately 5 months after the end of the public health emergency. Legislation passed by Congress will ensure some of the flexibilities in telemedicine will be extended until the end of December 2024.
Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said he sees telemedicine as persisting even after the official COVID-19 public health emergency ends. “There’s a lot of push from the American Medical Association, from the American College of Physicians. You’re going to see people – this will not go away because [there’s] also going to be that demand.”
Despite decreased usage since April 2020, telehealth was estimated to be a $60 billion industry in 2022 and will likely increase over the next decade, Dr. Cush noted. “I question [the decline] because I think it still is a major part of your [future in] 2033.”
The number of physicians who have at least three licenses to practice in other U.S. states increased from 50,454 in 2010 to 72,752 in 2020, and that trend will continue, Dr. Wells explained. It is now becoming easier for physicians to become licensed in other states with companies like CompHealth that offer services to simplify obtaining medical licenses with states that participate in the Interstate Medical Licensure Compact.
“It’s a telemedicine easy pass,” Dr. Cush said.
Concerns in telemedicine
Commenting on the presentation, Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery (HSS), both in New York, pointed out that because telemedicine is governed by U.S. states, rather than the federal government, a physician needs to be licensed in the state where the patient is located. While many states relaxed their restrictions during COVID-19, as states began tightening their restrictions later, “many physicians didn’t want to have three licenses,” he said.
“There’s an expense in getting three licenses. There’s an expense in obtaining it and maintaining it, and the reimbursement for the telemedicine visit did not reach that expectation,” Dr. Gibofsky explained. With the exception of the orthopedic surgeons at HSS who practice in New York and a satellite office in Florida, none of the surgeons at his center have obtained more than one license to practice telemedicine in other states.
“Our volume of telemedicine at HSS has remained about the same at 30%, but fewer physicians are doing it because they don’t want to maintain multiple licensures,” he said. “So don’t overlook the role of legal concerns in terms of who’s going to be allowed to do what where. Your talk was great in terms of an exuberance of what’s going to be available, but it’s not going to relieve the physician from the burden of being responsible for their use.”
Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, asked the presenters about the balance between seeing patients for virtual and in-person visits. “The question is what’s the sweet spot? Are there people you’re willing to see virtually forever?” he asked, noting that he has patients scheduling telemedicine visits that he hasn’t seen since before the COVID-19 pandemic.
“That’s not going to work for me. At some point, you have to lay hands on people,” he said.
Dr. Wells said his current practice is 40% virtual, and his staff converts potential no-shows into a telemedicine consultation over the phone. “My no-show rate has gone down to zero. Somebody’s scheduled for a visit, they don’t show up, my [medical assistants] get them on the phone, they put them on hold, tee up the refills. I turn them into a telephone call,” he said. “We don’t accept the no-show at all because we can do a telephone [consultation].”
In Dr. Cush’s practice, he alternates telemedicine visits with in-person visits. “If you come back for two videos in a row, you’re catching hell from me for that,” he said. Responding to how Dr. Wells incorporates telemedicine into his practice, Dr. Cush said many rheumatologists “don’t have the setups to support the care, and that’s why it’s hard to do and that’s why we’re not as great as we could be.”
“This is the way we were trained. We’re used to seeing these patients in the clinic that often. Not every single patient needs to be seen that frequently if they’re stable and doing fine,” Dr. Wells countered.
Dr. Cush and Dr. Wells reported having financial relationships with numerous pharmaceutical companies.
FROM RWCS 2023
Rucaparib benefit in BRCA+ prostate cancer confirmed
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Endovascular therapy benefits large infarction: ANGEL-ASPECT
The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.
Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.
“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.
The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.
Will change practice
Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.
Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.
“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”
But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “
This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.
The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.
The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
ANGEL-ASPECT
As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.
The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).
Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).
The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.
Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.
IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.
A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.
When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
Better functional outcome
The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).
The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.
Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.
“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”
As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).
The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).
The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)
Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).
The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.
Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.
These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.
“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
Welcome news
An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.
From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.
“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”
The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.
Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.
“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.
The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.
Will change practice
Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.
Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.
“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”
But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “
This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.
The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.
The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
ANGEL-ASPECT
As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.
The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).
Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).
The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.
Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.
IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.
A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.
When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
Better functional outcome
The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).
The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.
Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.
“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”
As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).
The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).
The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)
Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).
The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.
Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.
These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.
“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
Welcome news
An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.
From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.
“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”
The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.
Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.
“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.
The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.
Will change practice
Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.
Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.
“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”
But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “
This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.
The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.
The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
ANGEL-ASPECT
As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.
The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).
Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).
The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.
Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.
IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.
A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.
When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
Better functional outcome
The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).
The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.
Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.
“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”
As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).
The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).
The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)
Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).
The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.
Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.
These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.
“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
Welcome news
An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.
From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.
“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”
The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023