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Sublingual immunotherapy stops onset and worsening of asthma
PARIS – The EfficAPSI study showed with real-world data that sublingual immunotherapy (SLIT) reduces the risks for asthma onset and the worsening of asthma symptoms for patients with allergic rhinitis. The research was presented at the 18th French-language allergy conference.
These results confirm that allergen immunotherapy, or “desensitization,” is indeed an etiologic treatment of this allergic condition.
SLIT encompasses personalized solutions created for an individual specifically for allergies to dust mites, grass, birch, cats, and so on. These preparations are commonly used by allergy specialists when establishing an AIT treatment plan.
In 2017, the French Health Authority published a report indicating that there was insufficient clinical proof regarding the efficacy of SLIT. It subsequently removed injectable forms of these allergen extracts from the list of drugs reimbursed by the state and reduced state reimbursement of sublingual SLIT preparations from 30% to 15%, a step it confirmed in March 2018 and that led to outrage from allergy specialists. The chair of the French allergy society at the time, Jocelyne Just, MD, PhD, argued that conducting double-blind, placebo-controlled studies for all types (grass pollen, birch pollen, dust mites, asthma, allergic rhinitis, subcutaneous injections, sublingual treatments, tablets, liquid preparations) would take decades. Furthermore, meta-analyses on the subject, despite being heterogeneous and unable to answer all questions, are indeed pointing to the effectiveness of SLIT. To supplement existing data and to answer the queries raised by the HAS, several studies have been launched, including EfficAPSI.
The pharmacoepidemiologic EfficAPSI study is the largest retrospective, real-world, longitudinal cohort study ever carried out regarding liquid SLIT using data stored in the French National Health Data System (SNDS). The primary objective of the study was to evaluate the real-world impact of liquid SLIT on the onset and worsening of asthma for patients with allergic rhinitis and to evaluate the impact of sublingual treatments on public health.
A cohort analysis of patients treated with SLIT and control patients treated for allergic rhinitis with or without treatment for asthma was carried out. The patients treated with SLIT for at least 2 consecutive years were anonymously selected from the SNDS using the Stallergenes Greer prescription database.
In all, 99,538 patients who received SLIT were compared with 333,082 control patients (those who had received treatment for allergic rhinitis without taking SLIT). Participants were stratified according to their treatment history for asthma and were paired using a propensity score to minimize comparison bias.
The main definition of the onset of asthma included the first prescription of an asthma medication, hospital admission for asthma, or a diagnosis of chronic asthma. The secondary definition omitted the prescription of any treatment, and the third (sensitive and specific) took into consideration an initial prescription of omalizumab or a prescription of three inhaled corticosteroids (ICSs) associated with or without a long-acting beta-2 agonist (LABA) for a period of 1 year, admission to the hospital, or chronic asthma.
Asthma risk reduced
Among patients with allergic rhinitis without preexisting asthma, liquid SLIT was associated with a significantly lower risk of asthma onset in comparison with the control group (primary hazard ratio: 0.77; secondary HR: 0.66; and tertiary HR: 0.62).
The risk reductions were significant and were consistent regardless of the allergens analyzed (tertiary HR, dust mites: 0.57; grass: 0.52) for all age groups. These new results that were based on the tertiary definition corroborate the results from the primary and secondary definitions.
said study co-author Philippe Devillier, MD, PhD, research director at the respiratory tract diseases center of Foch Hospital, Paris. “These results are consistent with previous studies in the same French health care database, as well as in a German database with SLIT preparations in tablet form. This not only confirms the soundness of the methodology but also the benefit of liquid SLIT as an etiological treatment of respiratory allergies.”
Risk for worsening
Furthermore, in the same study, liquid SLIT treatment was associated with a 27% reduced risk for worsening asthma and a 36% reduced risk for severe asthma. Among patients with allergic rhinitis and preexisting asthma, liquid SLIT was associated with a significantly lower risk for worsening of asthma, compared with the control group (primary HR: 0.73; secondary HR: 0.61; and tertiary HR: 0.64). The primary definition was an initial prescription of an ICS-LABA combination in a patient treated with ICS alone, severe exacerbation of asthma symptoms, hospital admission, or a diagnosis of chronic asthma.
“The risk reductions were significant and consistent for the allergens analyzed,” said study co-author Pascal Demoly, MD, PhD, head of pulmonology at Montpellier University Hospital, France (tertiary HR, dust mites: 0.66; grass: 0.59; birch: 0.34; and cats: 0.77). “This was across all age groups,” he added.
“The results of the EfficAPSI real-world study on health data from the SNDS are consistent with outcomes from clinical trials, suggestive of a reduced risk of asthma onset in patients with allergic rhinitis receiving liquid SLIT, as well as a reduced risk of worsening of preexisting asthma,” said Devillier. “SLIT, in this case in the form of a liquid, thus appears to be an effective etiological treatment, since the use of symptomatic drugs, in particular preventer inhalers, but also reliever inhalers, is lower in patients treated with SLIT over at least two consecutive years, compared with paired control subjects. And it’s the same for the risk of treating asthma in nonasthmatic patients at the start of the study. EfficAPSI is the largest study using data from a comprehensive state drug reimbursement database, allowing us to assess the impact of liquid SLIT on public health. These results, also obtained with other allergen preparations, particularly in tablet form in French and German studies using data from health care databases, demonstrate the consistency of the data regarding the efficacy of SLIT.”
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
PARIS – The EfficAPSI study showed with real-world data that sublingual immunotherapy (SLIT) reduces the risks for asthma onset and the worsening of asthma symptoms for patients with allergic rhinitis. The research was presented at the 18th French-language allergy conference.
These results confirm that allergen immunotherapy, or “desensitization,” is indeed an etiologic treatment of this allergic condition.
SLIT encompasses personalized solutions created for an individual specifically for allergies to dust mites, grass, birch, cats, and so on. These preparations are commonly used by allergy specialists when establishing an AIT treatment plan.
In 2017, the French Health Authority published a report indicating that there was insufficient clinical proof regarding the efficacy of SLIT. It subsequently removed injectable forms of these allergen extracts from the list of drugs reimbursed by the state and reduced state reimbursement of sublingual SLIT preparations from 30% to 15%, a step it confirmed in March 2018 and that led to outrage from allergy specialists. The chair of the French allergy society at the time, Jocelyne Just, MD, PhD, argued that conducting double-blind, placebo-controlled studies for all types (grass pollen, birch pollen, dust mites, asthma, allergic rhinitis, subcutaneous injections, sublingual treatments, tablets, liquid preparations) would take decades. Furthermore, meta-analyses on the subject, despite being heterogeneous and unable to answer all questions, are indeed pointing to the effectiveness of SLIT. To supplement existing data and to answer the queries raised by the HAS, several studies have been launched, including EfficAPSI.
The pharmacoepidemiologic EfficAPSI study is the largest retrospective, real-world, longitudinal cohort study ever carried out regarding liquid SLIT using data stored in the French National Health Data System (SNDS). The primary objective of the study was to evaluate the real-world impact of liquid SLIT on the onset and worsening of asthma for patients with allergic rhinitis and to evaluate the impact of sublingual treatments on public health.
A cohort analysis of patients treated with SLIT and control patients treated for allergic rhinitis with or without treatment for asthma was carried out. The patients treated with SLIT for at least 2 consecutive years were anonymously selected from the SNDS using the Stallergenes Greer prescription database.
In all, 99,538 patients who received SLIT were compared with 333,082 control patients (those who had received treatment for allergic rhinitis without taking SLIT). Participants were stratified according to their treatment history for asthma and were paired using a propensity score to minimize comparison bias.
The main definition of the onset of asthma included the first prescription of an asthma medication, hospital admission for asthma, or a diagnosis of chronic asthma. The secondary definition omitted the prescription of any treatment, and the third (sensitive and specific) took into consideration an initial prescription of omalizumab or a prescription of three inhaled corticosteroids (ICSs) associated with or without a long-acting beta-2 agonist (LABA) for a period of 1 year, admission to the hospital, or chronic asthma.
Asthma risk reduced
Among patients with allergic rhinitis without preexisting asthma, liquid SLIT was associated with a significantly lower risk of asthma onset in comparison with the control group (primary hazard ratio: 0.77; secondary HR: 0.66; and tertiary HR: 0.62).
The risk reductions were significant and were consistent regardless of the allergens analyzed (tertiary HR, dust mites: 0.57; grass: 0.52) for all age groups. These new results that were based on the tertiary definition corroborate the results from the primary and secondary definitions.
said study co-author Philippe Devillier, MD, PhD, research director at the respiratory tract diseases center of Foch Hospital, Paris. “These results are consistent with previous studies in the same French health care database, as well as in a German database with SLIT preparations in tablet form. This not only confirms the soundness of the methodology but also the benefit of liquid SLIT as an etiological treatment of respiratory allergies.”
Risk for worsening
Furthermore, in the same study, liquid SLIT treatment was associated with a 27% reduced risk for worsening asthma and a 36% reduced risk for severe asthma. Among patients with allergic rhinitis and preexisting asthma, liquid SLIT was associated with a significantly lower risk for worsening of asthma, compared with the control group (primary HR: 0.73; secondary HR: 0.61; and tertiary HR: 0.64). The primary definition was an initial prescription of an ICS-LABA combination in a patient treated with ICS alone, severe exacerbation of asthma symptoms, hospital admission, or a diagnosis of chronic asthma.
“The risk reductions were significant and consistent for the allergens analyzed,” said study co-author Pascal Demoly, MD, PhD, head of pulmonology at Montpellier University Hospital, France (tertiary HR, dust mites: 0.66; grass: 0.59; birch: 0.34; and cats: 0.77). “This was across all age groups,” he added.
“The results of the EfficAPSI real-world study on health data from the SNDS are consistent with outcomes from clinical trials, suggestive of a reduced risk of asthma onset in patients with allergic rhinitis receiving liquid SLIT, as well as a reduced risk of worsening of preexisting asthma,” said Devillier. “SLIT, in this case in the form of a liquid, thus appears to be an effective etiological treatment, since the use of symptomatic drugs, in particular preventer inhalers, but also reliever inhalers, is lower in patients treated with SLIT over at least two consecutive years, compared with paired control subjects. And it’s the same for the risk of treating asthma in nonasthmatic patients at the start of the study. EfficAPSI is the largest study using data from a comprehensive state drug reimbursement database, allowing us to assess the impact of liquid SLIT on public health. These results, also obtained with other allergen preparations, particularly in tablet form in French and German studies using data from health care databases, demonstrate the consistency of the data regarding the efficacy of SLIT.”
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
PARIS – The EfficAPSI study showed with real-world data that sublingual immunotherapy (SLIT) reduces the risks for asthma onset and the worsening of asthma symptoms for patients with allergic rhinitis. The research was presented at the 18th French-language allergy conference.
These results confirm that allergen immunotherapy, or “desensitization,” is indeed an etiologic treatment of this allergic condition.
SLIT encompasses personalized solutions created for an individual specifically for allergies to dust mites, grass, birch, cats, and so on. These preparations are commonly used by allergy specialists when establishing an AIT treatment plan.
In 2017, the French Health Authority published a report indicating that there was insufficient clinical proof regarding the efficacy of SLIT. It subsequently removed injectable forms of these allergen extracts from the list of drugs reimbursed by the state and reduced state reimbursement of sublingual SLIT preparations from 30% to 15%, a step it confirmed in March 2018 and that led to outrage from allergy specialists. The chair of the French allergy society at the time, Jocelyne Just, MD, PhD, argued that conducting double-blind, placebo-controlled studies for all types (grass pollen, birch pollen, dust mites, asthma, allergic rhinitis, subcutaneous injections, sublingual treatments, tablets, liquid preparations) would take decades. Furthermore, meta-analyses on the subject, despite being heterogeneous and unable to answer all questions, are indeed pointing to the effectiveness of SLIT. To supplement existing data and to answer the queries raised by the HAS, several studies have been launched, including EfficAPSI.
The pharmacoepidemiologic EfficAPSI study is the largest retrospective, real-world, longitudinal cohort study ever carried out regarding liquid SLIT using data stored in the French National Health Data System (SNDS). The primary objective of the study was to evaluate the real-world impact of liquid SLIT on the onset and worsening of asthma for patients with allergic rhinitis and to evaluate the impact of sublingual treatments on public health.
A cohort analysis of patients treated with SLIT and control patients treated for allergic rhinitis with or without treatment for asthma was carried out. The patients treated with SLIT for at least 2 consecutive years were anonymously selected from the SNDS using the Stallergenes Greer prescription database.
In all, 99,538 patients who received SLIT were compared with 333,082 control patients (those who had received treatment for allergic rhinitis without taking SLIT). Participants were stratified according to their treatment history for asthma and were paired using a propensity score to minimize comparison bias.
The main definition of the onset of asthma included the first prescription of an asthma medication, hospital admission for asthma, or a diagnosis of chronic asthma. The secondary definition omitted the prescription of any treatment, and the third (sensitive and specific) took into consideration an initial prescription of omalizumab or a prescription of three inhaled corticosteroids (ICSs) associated with or without a long-acting beta-2 agonist (LABA) for a period of 1 year, admission to the hospital, or chronic asthma.
Asthma risk reduced
Among patients with allergic rhinitis without preexisting asthma, liquid SLIT was associated with a significantly lower risk of asthma onset in comparison with the control group (primary hazard ratio: 0.77; secondary HR: 0.66; and tertiary HR: 0.62).
The risk reductions were significant and were consistent regardless of the allergens analyzed (tertiary HR, dust mites: 0.57; grass: 0.52) for all age groups. These new results that were based on the tertiary definition corroborate the results from the primary and secondary definitions.
said study co-author Philippe Devillier, MD, PhD, research director at the respiratory tract diseases center of Foch Hospital, Paris. “These results are consistent with previous studies in the same French health care database, as well as in a German database with SLIT preparations in tablet form. This not only confirms the soundness of the methodology but also the benefit of liquid SLIT as an etiological treatment of respiratory allergies.”
Risk for worsening
Furthermore, in the same study, liquid SLIT treatment was associated with a 27% reduced risk for worsening asthma and a 36% reduced risk for severe asthma. Among patients with allergic rhinitis and preexisting asthma, liquid SLIT was associated with a significantly lower risk for worsening of asthma, compared with the control group (primary HR: 0.73; secondary HR: 0.61; and tertiary HR: 0.64). The primary definition was an initial prescription of an ICS-LABA combination in a patient treated with ICS alone, severe exacerbation of asthma symptoms, hospital admission, or a diagnosis of chronic asthma.
“The risk reductions were significant and consistent for the allergens analyzed,” said study co-author Pascal Demoly, MD, PhD, head of pulmonology at Montpellier University Hospital, France (tertiary HR, dust mites: 0.66; grass: 0.59; birch: 0.34; and cats: 0.77). “This was across all age groups,” he added.
“The results of the EfficAPSI real-world study on health data from the SNDS are consistent with outcomes from clinical trials, suggestive of a reduced risk of asthma onset in patients with allergic rhinitis receiving liquid SLIT, as well as a reduced risk of worsening of preexisting asthma,” said Devillier. “SLIT, in this case in the form of a liquid, thus appears to be an effective etiological treatment, since the use of symptomatic drugs, in particular preventer inhalers, but also reliever inhalers, is lower in patients treated with SLIT over at least two consecutive years, compared with paired control subjects. And it’s the same for the risk of treating asthma in nonasthmatic patients at the start of the study. EfficAPSI is the largest study using data from a comprehensive state drug reimbursement database, allowing us to assess the impact of liquid SLIT on public health. These results, also obtained with other allergen preparations, particularly in tablet form in French and German studies using data from health care databases, demonstrate the consistency of the data regarding the efficacy of SLIT.”
This article was translated from the Medscape French Edition. A version appeared on Medscape.com.
Beta-blocker gel shows promise for diabetic foot ulcers
say Indian researchers.
Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.
As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.
The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.
The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m2 and in those who weighed more than 80 kg (176 lb).
“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.
Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”
However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).
He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”
In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”
And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.
She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”
The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.
“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.
The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.
Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.
Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.
The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.
Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.
The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.
Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.
In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm2 and the average ulcer duration was 49.8 weeks.
The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.
Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).
The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.
In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).
Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).
Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.
The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
say Indian researchers.
Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.
As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.
The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.
The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m2 and in those who weighed more than 80 kg (176 lb).
“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.
Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”
However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).
He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”
In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”
And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.
She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”
The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.
“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.
The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.
Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.
Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.
The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.
Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.
The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.
Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.
In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm2 and the average ulcer duration was 49.8 weeks.
The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.
Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).
The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.
In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).
Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).
Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.
The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
say Indian researchers.
Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.
As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.
The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.
The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m2 and in those who weighed more than 80 kg (176 lb).
“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.
Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”
However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).
He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”
In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”
And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.
She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”
The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.
“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.
The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.
Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.
Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.
The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.
Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.
The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.
Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.
In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm2 and the average ulcer duration was 49.8 weeks.
The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.
Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).
The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.
In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).
Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).
Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.
The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
FDA approves new indication for avapritinib
Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.
The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.
The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.
The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).
Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.
“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.
A version of this article first appeared on Medscape.com.
Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.
Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.
The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.
The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.
The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).
Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.
“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.
A version of this article first appeared on Medscape.com.
Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.
Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.
The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.
The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.
The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).
Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.
“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.
A version of this article first appeared on Medscape.com.
Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.
FDA OKs new drug for Fabry disease
Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme alpha-galactosidase A (GLA), which leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, the heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems.
Elfabrio delivers a functional version of GLA. It’s given by intravenous infusion every 2 weeks.
Evidence for safety, tolerability, and efficacy of Elfabrio stems from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.
It has been studied in both ERT-naïve and ERT-experienced patients. In one head-to-head trial, Elfabrio was non-inferior in safety and efficacy to agalsidase beta (Fabrazyme, Sanofi Genzyme), the companies said in a press statement announcing approval.
“The totality of clinical data suggests that Elfabrio has the potential to be a long-lasting therapy,” Dror Bashan, president and CEO of Protalix, said in the statement.
Patients treated with Elfabrio have experienced hypersensitivity reactions, including anaphylaxis. In clinical trials, 20 (14%) patients treated with Elfabrio experienced hypersensitivity reactions; 4 patients (3%) experienced anaphylaxis reactions that occurred within 5-40 minutes of the start of the initial infusion.
Before administering Elfabrio, pretreatment with antihistamines, antipyretics, and/or corticosteroids should be considered, the label advises.
Patients and caregivers should be informed of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and instructed to seek medical care immediately if such symptoms occur.
A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials. Monitoring serum creatinine and urinary protein-to-creatinine ratio is advised. If glomerulonephritis is suspected, treatment should be stopped until a diagnostic evaluation can be conducted.
Full prescribing information is available online.
A version of this article first appeared on Medscape.com.
Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme alpha-galactosidase A (GLA), which leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, the heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems.
Elfabrio delivers a functional version of GLA. It’s given by intravenous infusion every 2 weeks.
Evidence for safety, tolerability, and efficacy of Elfabrio stems from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.
It has been studied in both ERT-naïve and ERT-experienced patients. In one head-to-head trial, Elfabrio was non-inferior in safety and efficacy to agalsidase beta (Fabrazyme, Sanofi Genzyme), the companies said in a press statement announcing approval.
“The totality of clinical data suggests that Elfabrio has the potential to be a long-lasting therapy,” Dror Bashan, president and CEO of Protalix, said in the statement.
Patients treated with Elfabrio have experienced hypersensitivity reactions, including anaphylaxis. In clinical trials, 20 (14%) patients treated with Elfabrio experienced hypersensitivity reactions; 4 patients (3%) experienced anaphylaxis reactions that occurred within 5-40 minutes of the start of the initial infusion.
Before administering Elfabrio, pretreatment with antihistamines, antipyretics, and/or corticosteroids should be considered, the label advises.
Patients and caregivers should be informed of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and instructed to seek medical care immediately if such symptoms occur.
A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials. Monitoring serum creatinine and urinary protein-to-creatinine ratio is advised. If glomerulonephritis is suspected, treatment should be stopped until a diagnostic evaluation can be conducted.
Full prescribing information is available online.
A version of this article first appeared on Medscape.com.
Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme alpha-galactosidase A (GLA), which leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, the heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems.
Elfabrio delivers a functional version of GLA. It’s given by intravenous infusion every 2 weeks.
Evidence for safety, tolerability, and efficacy of Elfabrio stems from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.
It has been studied in both ERT-naïve and ERT-experienced patients. In one head-to-head trial, Elfabrio was non-inferior in safety and efficacy to agalsidase beta (Fabrazyme, Sanofi Genzyme), the companies said in a press statement announcing approval.
“The totality of clinical data suggests that Elfabrio has the potential to be a long-lasting therapy,” Dror Bashan, president and CEO of Protalix, said in the statement.
Patients treated with Elfabrio have experienced hypersensitivity reactions, including anaphylaxis. In clinical trials, 20 (14%) patients treated with Elfabrio experienced hypersensitivity reactions; 4 patients (3%) experienced anaphylaxis reactions that occurred within 5-40 minutes of the start of the initial infusion.
Before administering Elfabrio, pretreatment with antihistamines, antipyretics, and/or corticosteroids should be considered, the label advises.
Patients and caregivers should be informed of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and instructed to seek medical care immediately if such symptoms occur.
A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials. Monitoring serum creatinine and urinary protein-to-creatinine ratio is advised. If glomerulonephritis is suspected, treatment should be stopped until a diagnostic evaluation can be conducted.
Full prescribing information is available online.
A version of this article first appeared on Medscape.com.
FDA approves first drug to treat Alzheimer’s agitation
(AD), making it the first FDA-approved drug for this indication.
“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” Tiffany Farchione, MD, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a news release.
Agitation can include symptoms that range from pacing or restlessness to verbal and physical aggression. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression,” Dr. Farchione said.
Brexpiprazole was approved by the FDA in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.
Approval of the supplemental application for brexpiprazole for agitation associated with AD dementia was based on results of two randomized, double-blind, placebo-controlled studies.
In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements in agitation symptoms, as shown by total Cohen-Mansfield Agitation Inventory (CMAI) score, compared with patients who received placebo.
The recommended starting dosage for the treatment of agitation associated with AD dementia is 0.5 mg once daily on days 1-7; it was increased to 1 mg once daily on days 8-14 and then to the recommended target dose of 2 mg once daily.
The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, depending on clinical response and tolerability.
The most common side effects of brexpiprazole in patients with agitation associated with AD dementia include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances.
The drug includes a boxed warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
The supplemental application for brexpiprazole for agitation had fast-track designation.
A version of this article first appeared on Medscape.com.
(AD), making it the first FDA-approved drug for this indication.
“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” Tiffany Farchione, MD, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a news release.
Agitation can include symptoms that range from pacing or restlessness to verbal and physical aggression. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression,” Dr. Farchione said.
Brexpiprazole was approved by the FDA in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.
Approval of the supplemental application for brexpiprazole for agitation associated with AD dementia was based on results of two randomized, double-blind, placebo-controlled studies.
In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements in agitation symptoms, as shown by total Cohen-Mansfield Agitation Inventory (CMAI) score, compared with patients who received placebo.
The recommended starting dosage for the treatment of agitation associated with AD dementia is 0.5 mg once daily on days 1-7; it was increased to 1 mg once daily on days 8-14 and then to the recommended target dose of 2 mg once daily.
The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, depending on clinical response and tolerability.
The most common side effects of brexpiprazole in patients with agitation associated with AD dementia include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances.
The drug includes a boxed warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
The supplemental application for brexpiprazole for agitation had fast-track designation.
A version of this article first appeared on Medscape.com.
(AD), making it the first FDA-approved drug for this indication.
“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” Tiffany Farchione, MD, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, said in a news release.
Agitation can include symptoms that range from pacing or restlessness to verbal and physical aggression. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression,” Dr. Farchione said.
Brexpiprazole was approved by the FDA in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.
Approval of the supplemental application for brexpiprazole for agitation associated with AD dementia was based on results of two randomized, double-blind, placebo-controlled studies.
In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements in agitation symptoms, as shown by total Cohen-Mansfield Agitation Inventory (CMAI) score, compared with patients who received placebo.
The recommended starting dosage for the treatment of agitation associated with AD dementia is 0.5 mg once daily on days 1-7; it was increased to 1 mg once daily on days 8-14 and then to the recommended target dose of 2 mg once daily.
The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, depending on clinical response and tolerability.
The most common side effects of brexpiprazole in patients with agitation associated with AD dementia include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances.
The drug includes a boxed warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
The supplemental application for brexpiprazole for agitation had fast-track designation.
A version of this article first appeared on Medscape.com.
Two phase 3 trials show benefits of dupilumab for prurigo nodularis
The results, which were published online in Nature Medicine, were the basis for the FDA approval of dupilumab (Dupixent) for adults with PN in September 2022, the first treatment approved for treating PN in the United States.
“These positive studies support the involvement of type 2 cytokines in driving PN disease pathogenesis and the targeting of the [interleukin]-4/IL-13 axis as a novel therapeutic paradigm for patients with PN,” wrote the researchers, who were led by principal investigator Gil Yosipovitch, MD, professor of dermatology at the University of Miami, Fla. Dupilumab, an IL-4 receptor alpha antagonist, blocks the shared receptor component (IL-4R alpha) for IL-4 and IL-13.
For the two phase 3 trials, which were called LIBERTY-PN PRIME and PRIME2 and were sponsored by Sanofi and Regeneron Pharmaceuticals, researchers randomized adults with PN with 20 or more nodules and severe itch uncontrolled with topical therapies 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, which was measured by the proportion of patients with a 4-point or greater reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included a reduction in the number of nodules to 5 or fewer at week 24.
PRIME and PRIME2 enrolled 151 and 160 patients, respectively. In PRIME, 60% of patients in the dupilumab arm achieved a 4-point or greater reduction in the WI-NRS at week 24, compared with 18.4% of patients in the placebo arm (P < .001). In PRIME2, 37.2% of patients in the dupilumab arm achieved a 4-point or greater reduction in the WI-NRS at week 12, compared with 22% of patients in the placebo arm (P = .022).
The researchers also reported that, from an initial baseline of 20 to greater than 100 nodules, 32.0% of dupilumab-treated patients in PRIME and 25.6% in PRIME2 showed a reduction to 5 nodules or fewer, which corresponded to a response of “clear” or “almost clear” skin at week 12, compared with 11.8% and 12.2% of placebo-treated patients, respectively. This treatment effect on skin lesions continued to improve after week 12, with 48% of dupilumab-treated patients in PRIME and 44.9% in PRIME2 having five nodules or fewer at week 24, compared with 18.4% and 15.9% of placebo-treated patients, respectively. Safety was consistent with the known dupilumab safety profile.
“Validation is the first success of this paper,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study. “While both the safety and efficacy of dupilumab in these two phase 3 programs is the meat of the matter, nuanced highlights for me include the rigid nature of the exclusion criteria to ensure a study population that truly has PN as a stand-alone disease, rather than a secondary finding as we once believed to be the entire story. I think it’s important for us to recognize that it’s not one or the other, rather there is both ‘primary’ prurigo nodularis, and then there is secondary prurigo nodularis associated with something else [a wide range of underlying medical conditions], just like we divide primary and secondary hyperhidrosis.”
Dr. Yosipovitch reported having competing interests with several pharmaceutical companies, including Regeneron and Sanofi. Dr. Friedman disclosed that he is a consultant to and a speaker for Regeneron.
The results, which were published online in Nature Medicine, were the basis for the FDA approval of dupilumab (Dupixent) for adults with PN in September 2022, the first treatment approved for treating PN in the United States.
“These positive studies support the involvement of type 2 cytokines in driving PN disease pathogenesis and the targeting of the [interleukin]-4/IL-13 axis as a novel therapeutic paradigm for patients with PN,” wrote the researchers, who were led by principal investigator Gil Yosipovitch, MD, professor of dermatology at the University of Miami, Fla. Dupilumab, an IL-4 receptor alpha antagonist, blocks the shared receptor component (IL-4R alpha) for IL-4 and IL-13.
For the two phase 3 trials, which were called LIBERTY-PN PRIME and PRIME2 and were sponsored by Sanofi and Regeneron Pharmaceuticals, researchers randomized adults with PN with 20 or more nodules and severe itch uncontrolled with topical therapies 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, which was measured by the proportion of patients with a 4-point or greater reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included a reduction in the number of nodules to 5 or fewer at week 24.
PRIME and PRIME2 enrolled 151 and 160 patients, respectively. In PRIME, 60% of patients in the dupilumab arm achieved a 4-point or greater reduction in the WI-NRS at week 24, compared with 18.4% of patients in the placebo arm (P < .001). In PRIME2, 37.2% of patients in the dupilumab arm achieved a 4-point or greater reduction in the WI-NRS at week 12, compared with 22% of patients in the placebo arm (P = .022).
The researchers also reported that, from an initial baseline of 20 to greater than 100 nodules, 32.0% of dupilumab-treated patients in PRIME and 25.6% in PRIME2 showed a reduction to 5 nodules or fewer, which corresponded to a response of “clear” or “almost clear” skin at week 12, compared with 11.8% and 12.2% of placebo-treated patients, respectively. This treatment effect on skin lesions continued to improve after week 12, with 48% of dupilumab-treated patients in PRIME and 44.9% in PRIME2 having five nodules or fewer at week 24, compared with 18.4% and 15.9% of placebo-treated patients, respectively. Safety was consistent with the known dupilumab safety profile.
“Validation is the first success of this paper,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study. “While both the safety and efficacy of dupilumab in these two phase 3 programs is the meat of the matter, nuanced highlights for me include the rigid nature of the exclusion criteria to ensure a study population that truly has PN as a stand-alone disease, rather than a secondary finding as we once believed to be the entire story. I think it’s important for us to recognize that it’s not one or the other, rather there is both ‘primary’ prurigo nodularis, and then there is secondary prurigo nodularis associated with something else [a wide range of underlying medical conditions], just like we divide primary and secondary hyperhidrosis.”
Dr. Yosipovitch reported having competing interests with several pharmaceutical companies, including Regeneron and Sanofi. Dr. Friedman disclosed that he is a consultant to and a speaker for Regeneron.
The results, which were published online in Nature Medicine, were the basis for the FDA approval of dupilumab (Dupixent) for adults with PN in September 2022, the first treatment approved for treating PN in the United States.
“These positive studies support the involvement of type 2 cytokines in driving PN disease pathogenesis and the targeting of the [interleukin]-4/IL-13 axis as a novel therapeutic paradigm for patients with PN,” wrote the researchers, who were led by principal investigator Gil Yosipovitch, MD, professor of dermatology at the University of Miami, Fla. Dupilumab, an IL-4 receptor alpha antagonist, blocks the shared receptor component (IL-4R alpha) for IL-4 and IL-13.
For the two phase 3 trials, which were called LIBERTY-PN PRIME and PRIME2 and were sponsored by Sanofi and Regeneron Pharmaceuticals, researchers randomized adults with PN with 20 or more nodules and severe itch uncontrolled with topical therapies 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, which was measured by the proportion of patients with a 4-point or greater reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included a reduction in the number of nodules to 5 or fewer at week 24.
PRIME and PRIME2 enrolled 151 and 160 patients, respectively. In PRIME, 60% of patients in the dupilumab arm achieved a 4-point or greater reduction in the WI-NRS at week 24, compared with 18.4% of patients in the placebo arm (P < .001). In PRIME2, 37.2% of patients in the dupilumab arm achieved a 4-point or greater reduction in the WI-NRS at week 12, compared with 22% of patients in the placebo arm (P = .022).
The researchers also reported that, from an initial baseline of 20 to greater than 100 nodules, 32.0% of dupilumab-treated patients in PRIME and 25.6% in PRIME2 showed a reduction to 5 nodules or fewer, which corresponded to a response of “clear” or “almost clear” skin at week 12, compared with 11.8% and 12.2% of placebo-treated patients, respectively. This treatment effect on skin lesions continued to improve after week 12, with 48% of dupilumab-treated patients in PRIME and 44.9% in PRIME2 having five nodules or fewer at week 24, compared with 18.4% and 15.9% of placebo-treated patients, respectively. Safety was consistent with the known dupilumab safety profile.
“Validation is the first success of this paper,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study. “While both the safety and efficacy of dupilumab in these two phase 3 programs is the meat of the matter, nuanced highlights for me include the rigid nature of the exclusion criteria to ensure a study population that truly has PN as a stand-alone disease, rather than a secondary finding as we once believed to be the entire story. I think it’s important for us to recognize that it’s not one or the other, rather there is both ‘primary’ prurigo nodularis, and then there is secondary prurigo nodularis associated with something else [a wide range of underlying medical conditions], just like we divide primary and secondary hyperhidrosis.”
Dr. Yosipovitch reported having competing interests with several pharmaceutical companies, including Regeneron and Sanofi. Dr. Friedman disclosed that he is a consultant to and a speaker for Regeneron.
FROM NATURE MEDICINE
FDA expands use of dapagliflozin to broader range of HF
– including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).
The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the United States for adults with heart failure with reduced ejection fraction (HFrEF).
The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left ventricular function.
In the trial, which included more than 6,200 patients, dapagliflozin led to a statistically significant and clinically meaningful early reduction in the primary composite endpoint of cardiovascular (CV) death or worsening HF for patients with HFmrEF or HFpEFF.
In addition, results of a pooled analysis of the DAPA-HF and DELIVER phase 3 trials showed a consistent benefit from dapagliflozin treatment in significantly reducing the combined endpoint of CV death or HF hospitalization across the range of LVEF.
The European Commission expanded the indication for dapagliflozin (Forxiga) to include HF across the full spectrum of LVEF in February.
The SGLT2 inhibitor is also approved for use by patients with chronic kidney disease. It was first approved in 2014 to improve glycemic control for patients with diabetes mellitus.
A version of this article first appeared on Medscape.com.
– including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).
The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the United States for adults with heart failure with reduced ejection fraction (HFrEF).
The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left ventricular function.
In the trial, which included more than 6,200 patients, dapagliflozin led to a statistically significant and clinically meaningful early reduction in the primary composite endpoint of cardiovascular (CV) death or worsening HF for patients with HFmrEF or HFpEFF.
In addition, results of a pooled analysis of the DAPA-HF and DELIVER phase 3 trials showed a consistent benefit from dapagliflozin treatment in significantly reducing the combined endpoint of CV death or HF hospitalization across the range of LVEF.
The European Commission expanded the indication for dapagliflozin (Forxiga) to include HF across the full spectrum of LVEF in February.
The SGLT2 inhibitor is also approved for use by patients with chronic kidney disease. It was first approved in 2014 to improve glycemic control for patients with diabetes mellitus.
A version of this article first appeared on Medscape.com.
– including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).
The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the United States for adults with heart failure with reduced ejection fraction (HFrEF).
The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left ventricular function.
In the trial, which included more than 6,200 patients, dapagliflozin led to a statistically significant and clinically meaningful early reduction in the primary composite endpoint of cardiovascular (CV) death or worsening HF for patients with HFmrEF or HFpEFF.
In addition, results of a pooled analysis of the DAPA-HF and DELIVER phase 3 trials showed a consistent benefit from dapagliflozin treatment in significantly reducing the combined endpoint of CV death or HF hospitalization across the range of LVEF.
The European Commission expanded the indication for dapagliflozin (Forxiga) to include HF across the full spectrum of LVEF in February.
The SGLT2 inhibitor is also approved for use by patients with chronic kidney disease. It was first approved in 2014 to improve glycemic control for patients with diabetes mellitus.
A version of this article first appeared on Medscape.com.
Medications that scare me
An 85-year-old woman is brought to the emergency department after a syncopal episode. Her caregivers report a similar episode 2 weeks ago, but she recovered so quickly they did not seek evaluation for her.
Medications: Omeprazole 20 mg, pravastatin 40 mg, citalopram 10 mg, albuterol, donepezil 10 mg, isosorbide mononitrate 60 mg, and calcium. On exam, blood pressure is 100/60 mm Hg, pulse 55. ECG indicates bradycardia with normal intervals. What drug most likely caused her syncope?
A. Citalopram
B. Pravastatin
C. Donepezil
D. Isosorbide
E. Calcium
This woman’s syncope is likely caused by donepezil. Citalopram can lengthen the QT interval, especially in elderly patients, but the normal intervals on ECG eliminate this possibility. Donepezil can cause bradycardia, which can contribute to syncope.
Hernandez and colleagues evaluated a cohort of veterans with dementia over an 8-year period.1 They found that there was a 1.4-fold increased risk of bradycardia in patients with dementia treated with an acetylcholine inhibitor (compared with that in patients who were not taking these medications) and that there was a dose-dependent increase in risk for patients on donepezil.
Park-Wyllie et al. found in a study of 1.4 million older adults a greater than twofold risk of hospitalization for bradycardia in patients treated with a cholinesterase inhibitor.2 Gill and colleagues performed a population-based cohort study of 19,803 elderly patients with dementia who were prescribed cholinesterase inhibitors, and compared them to age-matched controls.3 They found increased hospital visits for syncope in people receiving cholinesterase inhibitors (hazard ratio, 1.76; 95% confidence interval, 1.57-1.98). Other syncope-related events were also more common in people receiving cholinesterase inhibitors, compared with controls: hospital visits for bradycardia (HR, 1.69; 95% CI, 1.32-2.15), permanent pacemaker insertion (HR, 1.49; 95% CI, 1.12-2.00), and hip fracture (HR, 1.18; (95% CI, 1.04-1.34).
Nausea, vomiting, and weight loss are much more common than the rarer side effects of bradycardia and syncope. The frequency of gastroenterological side effects is up to 25%. Cholinesterase inhibitors have modest effects on cognitive function with a high number needed to treat (NNT) of 10, and an NNT as high as 100 for global function. The number needed to harm (NNH) is 4, when gastrointestinal symptoms are added in.4 Another important, problematic side effect of cholinesterase inhibitors is urinary incontinence. This often leads to patients receiving medications, to combat this side effect, that may worsen cognitive function.
Another commonly used medication that scares me in certain circumstances is trimethoprim-sulfamethoxazole. My main concern is when it is used in patients who are elderly, have chronic kidney disease, or are taking other medications that can cause hyperkalemia (ACEIs, ARBs, potassium-sparing diuretics including spironolactone). Hyperkalemia is a real concern in these patient populations. Trimethoprim reduces renal potassium excretion through the competitive inhibition of sodium channels in the distal nephron, in a manner similar to the potassium-sparing diuretic amiloride. Hospitalizations for hyperkalemia are more common in patients who take ACEIs and ARBs and are prescribed trimethoprim-sulfamethoxazole, compared with other antibiotics.5
Sudden cardiac death is also more common in patients who are taking ACEIs or ARBs and receive trimethoprim-sulfamethoxazole.6 Trimethoprim-sulfamethoxazole also has a powerful interaction with warfarin, both displacing warfarin from albumin and inhibiting its metabolism. It raises the INR (international normalized ratio) in warfarin-treated patients much greater than do other antibiotics.7
Pearls
- Think carefully about the use of cholinesterase inhibitors because of the unfavorable NNH vs. NNT.
- Use caution prescribing trimethoprim for patients who are elderly, especially if they are on an ACEI, an ARB, or spironolactone, and in patients with chronic kidney disease.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Hernandez RK et al. J Am Geriatr Soc. 2009;57:1997-2003.
2. Park-Wyllie LY et al. PLoS Med. 2009;6:e1000157.
3. Gill SS et al. Arch Intern Med 2009;169:867-73.
4. Peters KR. J Am Geriatr Soc. 2013 Jul;61(7):1170-4.
5. Antoniou TN et al. Arch Intern Med. 2010;170(12):1045-9.
6. Fralick M et al. BMJ. 2014 Oct 30;349:g6196.
7. Glasheen JJ et al. J Gen Intern Med. 2005 Jul;20(7):653-6.
An 85-year-old woman is brought to the emergency department after a syncopal episode. Her caregivers report a similar episode 2 weeks ago, but she recovered so quickly they did not seek evaluation for her.
Medications: Omeprazole 20 mg, pravastatin 40 mg, citalopram 10 mg, albuterol, donepezil 10 mg, isosorbide mononitrate 60 mg, and calcium. On exam, blood pressure is 100/60 mm Hg, pulse 55. ECG indicates bradycardia with normal intervals. What drug most likely caused her syncope?
A. Citalopram
B. Pravastatin
C. Donepezil
D. Isosorbide
E. Calcium
This woman’s syncope is likely caused by donepezil. Citalopram can lengthen the QT interval, especially in elderly patients, but the normal intervals on ECG eliminate this possibility. Donepezil can cause bradycardia, which can contribute to syncope.
Hernandez and colleagues evaluated a cohort of veterans with dementia over an 8-year period.1 They found that there was a 1.4-fold increased risk of bradycardia in patients with dementia treated with an acetylcholine inhibitor (compared with that in patients who were not taking these medications) and that there was a dose-dependent increase in risk for patients on donepezil.
Park-Wyllie et al. found in a study of 1.4 million older adults a greater than twofold risk of hospitalization for bradycardia in patients treated with a cholinesterase inhibitor.2 Gill and colleagues performed a population-based cohort study of 19,803 elderly patients with dementia who were prescribed cholinesterase inhibitors, and compared them to age-matched controls.3 They found increased hospital visits for syncope in people receiving cholinesterase inhibitors (hazard ratio, 1.76; 95% confidence interval, 1.57-1.98). Other syncope-related events were also more common in people receiving cholinesterase inhibitors, compared with controls: hospital visits for bradycardia (HR, 1.69; 95% CI, 1.32-2.15), permanent pacemaker insertion (HR, 1.49; 95% CI, 1.12-2.00), and hip fracture (HR, 1.18; (95% CI, 1.04-1.34).
Nausea, vomiting, and weight loss are much more common than the rarer side effects of bradycardia and syncope. The frequency of gastroenterological side effects is up to 25%. Cholinesterase inhibitors have modest effects on cognitive function with a high number needed to treat (NNT) of 10, and an NNT as high as 100 for global function. The number needed to harm (NNH) is 4, when gastrointestinal symptoms are added in.4 Another important, problematic side effect of cholinesterase inhibitors is urinary incontinence. This often leads to patients receiving medications, to combat this side effect, that may worsen cognitive function.
Another commonly used medication that scares me in certain circumstances is trimethoprim-sulfamethoxazole. My main concern is when it is used in patients who are elderly, have chronic kidney disease, or are taking other medications that can cause hyperkalemia (ACEIs, ARBs, potassium-sparing diuretics including spironolactone). Hyperkalemia is a real concern in these patient populations. Trimethoprim reduces renal potassium excretion through the competitive inhibition of sodium channels in the distal nephron, in a manner similar to the potassium-sparing diuretic amiloride. Hospitalizations for hyperkalemia are more common in patients who take ACEIs and ARBs and are prescribed trimethoprim-sulfamethoxazole, compared with other antibiotics.5
Sudden cardiac death is also more common in patients who are taking ACEIs or ARBs and receive trimethoprim-sulfamethoxazole.6 Trimethoprim-sulfamethoxazole also has a powerful interaction with warfarin, both displacing warfarin from albumin and inhibiting its metabolism. It raises the INR (international normalized ratio) in warfarin-treated patients much greater than do other antibiotics.7
Pearls
- Think carefully about the use of cholinesterase inhibitors because of the unfavorable NNH vs. NNT.
- Use caution prescribing trimethoprim for patients who are elderly, especially if they are on an ACEI, an ARB, or spironolactone, and in patients with chronic kidney disease.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Hernandez RK et al. J Am Geriatr Soc. 2009;57:1997-2003.
2. Park-Wyllie LY et al. PLoS Med. 2009;6:e1000157.
3. Gill SS et al. Arch Intern Med 2009;169:867-73.
4. Peters KR. J Am Geriatr Soc. 2013 Jul;61(7):1170-4.
5. Antoniou TN et al. Arch Intern Med. 2010;170(12):1045-9.
6. Fralick M et al. BMJ. 2014 Oct 30;349:g6196.
7. Glasheen JJ et al. J Gen Intern Med. 2005 Jul;20(7):653-6.
An 85-year-old woman is brought to the emergency department after a syncopal episode. Her caregivers report a similar episode 2 weeks ago, but she recovered so quickly they did not seek evaluation for her.
Medications: Omeprazole 20 mg, pravastatin 40 mg, citalopram 10 mg, albuterol, donepezil 10 mg, isosorbide mononitrate 60 mg, and calcium. On exam, blood pressure is 100/60 mm Hg, pulse 55. ECG indicates bradycardia with normal intervals. What drug most likely caused her syncope?
A. Citalopram
B. Pravastatin
C. Donepezil
D. Isosorbide
E. Calcium
This woman’s syncope is likely caused by donepezil. Citalopram can lengthen the QT interval, especially in elderly patients, but the normal intervals on ECG eliminate this possibility. Donepezil can cause bradycardia, which can contribute to syncope.
Hernandez and colleagues evaluated a cohort of veterans with dementia over an 8-year period.1 They found that there was a 1.4-fold increased risk of bradycardia in patients with dementia treated with an acetylcholine inhibitor (compared with that in patients who were not taking these medications) and that there was a dose-dependent increase in risk for patients on donepezil.
Park-Wyllie et al. found in a study of 1.4 million older adults a greater than twofold risk of hospitalization for bradycardia in patients treated with a cholinesterase inhibitor.2 Gill and colleagues performed a population-based cohort study of 19,803 elderly patients with dementia who were prescribed cholinesterase inhibitors, and compared them to age-matched controls.3 They found increased hospital visits for syncope in people receiving cholinesterase inhibitors (hazard ratio, 1.76; 95% confidence interval, 1.57-1.98). Other syncope-related events were also more common in people receiving cholinesterase inhibitors, compared with controls: hospital visits for bradycardia (HR, 1.69; 95% CI, 1.32-2.15), permanent pacemaker insertion (HR, 1.49; 95% CI, 1.12-2.00), and hip fracture (HR, 1.18; (95% CI, 1.04-1.34).
Nausea, vomiting, and weight loss are much more common than the rarer side effects of bradycardia and syncope. The frequency of gastroenterological side effects is up to 25%. Cholinesterase inhibitors have modest effects on cognitive function with a high number needed to treat (NNT) of 10, and an NNT as high as 100 for global function. The number needed to harm (NNH) is 4, when gastrointestinal symptoms are added in.4 Another important, problematic side effect of cholinesterase inhibitors is urinary incontinence. This often leads to patients receiving medications, to combat this side effect, that may worsen cognitive function.
Another commonly used medication that scares me in certain circumstances is trimethoprim-sulfamethoxazole. My main concern is when it is used in patients who are elderly, have chronic kidney disease, or are taking other medications that can cause hyperkalemia (ACEIs, ARBs, potassium-sparing diuretics including spironolactone). Hyperkalemia is a real concern in these patient populations. Trimethoprim reduces renal potassium excretion through the competitive inhibition of sodium channels in the distal nephron, in a manner similar to the potassium-sparing diuretic amiloride. Hospitalizations for hyperkalemia are more common in patients who take ACEIs and ARBs and are prescribed trimethoprim-sulfamethoxazole, compared with other antibiotics.5
Sudden cardiac death is also more common in patients who are taking ACEIs or ARBs and receive trimethoprim-sulfamethoxazole.6 Trimethoprim-sulfamethoxazole also has a powerful interaction with warfarin, both displacing warfarin from albumin and inhibiting its metabolism. It raises the INR (international normalized ratio) in warfarin-treated patients much greater than do other antibiotics.7
Pearls
- Think carefully about the use of cholinesterase inhibitors because of the unfavorable NNH vs. NNT.
- Use caution prescribing trimethoprim for patients who are elderly, especially if they are on an ACEI, an ARB, or spironolactone, and in patients with chronic kidney disease.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Hernandez RK et al. J Am Geriatr Soc. 2009;57:1997-2003.
2. Park-Wyllie LY et al. PLoS Med. 2009;6:e1000157.
3. Gill SS et al. Arch Intern Med 2009;169:867-73.
4. Peters KR. J Am Geriatr Soc. 2013 Jul;61(7):1170-4.
5. Antoniou TN et al. Arch Intern Med. 2010;170(12):1045-9.
6. Fralick M et al. BMJ. 2014 Oct 30;349:g6196.
7. Glasheen JJ et al. J Gen Intern Med. 2005 Jul;20(7):653-6.
Phase 3 trial: Maribavir yields post-transplant benefits
Overall mortality in the 109 patients from these subcohorts from SOLSTICE was lower, compared with mortality reported for similar populations treated with conventional therapies used to treat relapsed or refractory (R/R) CMV, according to findings presented in April at the annual meeting of the European Society for Bone and Marrow Transplantation.
“These results, in addition to the superior efficacy in CMV clearance observed for maribavir in SOLSTICE provide supportive evidence of the potential for the long-term benefit of maribavir treatment for post-transplant CMV infection,” Ishan Hirji, of Takeda Development Center Americas, and colleagues reported during a poster session at the meeting.
A retrospective chart review of the 41 hematopoietic stem cell transplant (HSCT) patients and 68 solid organ transplant (SOT) patients randomized to receive maribavir showed an overall mortality rate of 15.6% at 52 weeks after initiation of treatment with the antiviral agent. Among the HSCT patients, 14 deaths occurred (34.1%), with 8 occurring during the study periods and 6 occurring during follow-up. Among the SOT patients, three deaths occurred (4.4%), all during follow-up chart review.
Causes of death included underlying disease relapse in four patients, infection other than CMV in six patients, and one case each of CMV-related factors, transplant-related factors, acute lymphoblastic leukemia, and septic shock. Causes of death in the SOT patients included one case each of CMV-related factors, anemia, and renal failure.
“No patients had new graft loss or retransplantation during the chart review period,” the investigators noted.
The findings are notable as CMV infection occurs in 30%-70% of HSCT recipients and 16%-56% of SOT recipients and can lead to complications, including transplant failure and death. Reported 1-year mortality rates following standard therapies for CMV range from 31% to 50%, they explained.
Patients in the SOLSTICE trial received 8 weeks of treatment and were followed for 12 additional weeks. CMV clearance at the end of treatment was 55.7% in the maribavir treatment arm versus 23.9% in a control group of patients treated with investigator choice of therapy. As reported by this news organization, the findings formed the basis for U.S. Food and Drug Administration approval of maribavir in November 2021.
The current analysis included a chart review period that started 1 day after the SOLSTICE trial period and continued for 32 additional weeks.
These long-term follow-up data confirm the benefits of maribavir for the treatment of post-transplant CMV, according to the investigators, and findings from a separate study reported at the ESBMT meeting underscore the importance of the durable benefits observed with maribavir treatment.
For that retrospective study, Maria Laura Fox, of Vall d’Hebron Institute of Oncology, Barcelona, and colleagues pooled de-identified data from 250 adult HSCT recipients with R/R CMV who were treated with agents other than maribavir at transplant centers in the United States or Europe. They aimed to “generate real-world evidence on the burden of CMV infection/disease in HSCT recipients who had refractory/resistant CMV or were intolerant to current treatments.”
Nearly 92% of patients received two or more therapies to treat CMV, and 92.2% discontinued treatment or had one or more therapy dose changes or discontinuation, and 42 patients failed to achieve clearance of the CMV index episode.
CMV recurred in 35.2% of patients, and graft failure occurred in 4% of patients, the investigators reported.
All-cause mortality was 56.0%, and mortality at 1 year after identification of R/R disease or treatment intolerance was 45.2%, they noted, adding that the study results “highlight the real-world complexities and high burden of CMV infection for HSCT recipients.”
“With available anti-CMV agents [excluding maribavir], a notable proportion of patients failed to achieve viremia clearance once developing RRI [resistant, refractory, or intolerant] CMV and/or experienced recurrence, and were at risk of adverse outcomes, including myelosuppression and mortality. There is a need for therapies that achieve and maintain CMV clearance with improved safety profiles,” they concluded.
Both studies were funded by Takeda Development Center Americas, the maker of Levtencity. Ms. Hirji is an employee of Takeda and reported stock ownership. Ms. Fox reported relationships with Sierra Oncology, GlaxoSmithKline, Bristol Myers Squibb, Novartis, and AbbVie.
Overall mortality in the 109 patients from these subcohorts from SOLSTICE was lower, compared with mortality reported for similar populations treated with conventional therapies used to treat relapsed or refractory (R/R) CMV, according to findings presented in April at the annual meeting of the European Society for Bone and Marrow Transplantation.
“These results, in addition to the superior efficacy in CMV clearance observed for maribavir in SOLSTICE provide supportive evidence of the potential for the long-term benefit of maribavir treatment for post-transplant CMV infection,” Ishan Hirji, of Takeda Development Center Americas, and colleagues reported during a poster session at the meeting.
A retrospective chart review of the 41 hematopoietic stem cell transplant (HSCT) patients and 68 solid organ transplant (SOT) patients randomized to receive maribavir showed an overall mortality rate of 15.6% at 52 weeks after initiation of treatment with the antiviral agent. Among the HSCT patients, 14 deaths occurred (34.1%), with 8 occurring during the study periods and 6 occurring during follow-up. Among the SOT patients, three deaths occurred (4.4%), all during follow-up chart review.
Causes of death included underlying disease relapse in four patients, infection other than CMV in six patients, and one case each of CMV-related factors, transplant-related factors, acute lymphoblastic leukemia, and septic shock. Causes of death in the SOT patients included one case each of CMV-related factors, anemia, and renal failure.
“No patients had new graft loss or retransplantation during the chart review period,” the investigators noted.
The findings are notable as CMV infection occurs in 30%-70% of HSCT recipients and 16%-56% of SOT recipients and can lead to complications, including transplant failure and death. Reported 1-year mortality rates following standard therapies for CMV range from 31% to 50%, they explained.
Patients in the SOLSTICE trial received 8 weeks of treatment and were followed for 12 additional weeks. CMV clearance at the end of treatment was 55.7% in the maribavir treatment arm versus 23.9% in a control group of patients treated with investigator choice of therapy. As reported by this news organization, the findings formed the basis for U.S. Food and Drug Administration approval of maribavir in November 2021.
The current analysis included a chart review period that started 1 day after the SOLSTICE trial period and continued for 32 additional weeks.
These long-term follow-up data confirm the benefits of maribavir for the treatment of post-transplant CMV, according to the investigators, and findings from a separate study reported at the ESBMT meeting underscore the importance of the durable benefits observed with maribavir treatment.
For that retrospective study, Maria Laura Fox, of Vall d’Hebron Institute of Oncology, Barcelona, and colleagues pooled de-identified data from 250 adult HSCT recipients with R/R CMV who were treated with agents other than maribavir at transplant centers in the United States or Europe. They aimed to “generate real-world evidence on the burden of CMV infection/disease in HSCT recipients who had refractory/resistant CMV or were intolerant to current treatments.”
Nearly 92% of patients received two or more therapies to treat CMV, and 92.2% discontinued treatment or had one or more therapy dose changes or discontinuation, and 42 patients failed to achieve clearance of the CMV index episode.
CMV recurred in 35.2% of patients, and graft failure occurred in 4% of patients, the investigators reported.
All-cause mortality was 56.0%, and mortality at 1 year after identification of R/R disease or treatment intolerance was 45.2%, they noted, adding that the study results “highlight the real-world complexities and high burden of CMV infection for HSCT recipients.”
“With available anti-CMV agents [excluding maribavir], a notable proportion of patients failed to achieve viremia clearance once developing RRI [resistant, refractory, or intolerant] CMV and/or experienced recurrence, and were at risk of adverse outcomes, including myelosuppression and mortality. There is a need for therapies that achieve and maintain CMV clearance with improved safety profiles,” they concluded.
Both studies were funded by Takeda Development Center Americas, the maker of Levtencity. Ms. Hirji is an employee of Takeda and reported stock ownership. Ms. Fox reported relationships with Sierra Oncology, GlaxoSmithKline, Bristol Myers Squibb, Novartis, and AbbVie.
Overall mortality in the 109 patients from these subcohorts from SOLSTICE was lower, compared with mortality reported for similar populations treated with conventional therapies used to treat relapsed or refractory (R/R) CMV, according to findings presented in April at the annual meeting of the European Society for Bone and Marrow Transplantation.
“These results, in addition to the superior efficacy in CMV clearance observed for maribavir in SOLSTICE provide supportive evidence of the potential for the long-term benefit of maribavir treatment for post-transplant CMV infection,” Ishan Hirji, of Takeda Development Center Americas, and colleagues reported during a poster session at the meeting.
A retrospective chart review of the 41 hematopoietic stem cell transplant (HSCT) patients and 68 solid organ transplant (SOT) patients randomized to receive maribavir showed an overall mortality rate of 15.6% at 52 weeks after initiation of treatment with the antiviral agent. Among the HSCT patients, 14 deaths occurred (34.1%), with 8 occurring during the study periods and 6 occurring during follow-up. Among the SOT patients, three deaths occurred (4.4%), all during follow-up chart review.
Causes of death included underlying disease relapse in four patients, infection other than CMV in six patients, and one case each of CMV-related factors, transplant-related factors, acute lymphoblastic leukemia, and septic shock. Causes of death in the SOT patients included one case each of CMV-related factors, anemia, and renal failure.
“No patients had new graft loss or retransplantation during the chart review period,” the investigators noted.
The findings are notable as CMV infection occurs in 30%-70% of HSCT recipients and 16%-56% of SOT recipients and can lead to complications, including transplant failure and death. Reported 1-year mortality rates following standard therapies for CMV range from 31% to 50%, they explained.
Patients in the SOLSTICE trial received 8 weeks of treatment and were followed for 12 additional weeks. CMV clearance at the end of treatment was 55.7% in the maribavir treatment arm versus 23.9% in a control group of patients treated with investigator choice of therapy. As reported by this news organization, the findings formed the basis for U.S. Food and Drug Administration approval of maribavir in November 2021.
The current analysis included a chart review period that started 1 day after the SOLSTICE trial period and continued for 32 additional weeks.
These long-term follow-up data confirm the benefits of maribavir for the treatment of post-transplant CMV, according to the investigators, and findings from a separate study reported at the ESBMT meeting underscore the importance of the durable benefits observed with maribavir treatment.
For that retrospective study, Maria Laura Fox, of Vall d’Hebron Institute of Oncology, Barcelona, and colleagues pooled de-identified data from 250 adult HSCT recipients with R/R CMV who were treated with agents other than maribavir at transplant centers in the United States or Europe. They aimed to “generate real-world evidence on the burden of CMV infection/disease in HSCT recipients who had refractory/resistant CMV or were intolerant to current treatments.”
Nearly 92% of patients received two or more therapies to treat CMV, and 92.2% discontinued treatment or had one or more therapy dose changes or discontinuation, and 42 patients failed to achieve clearance of the CMV index episode.
CMV recurred in 35.2% of patients, and graft failure occurred in 4% of patients, the investigators reported.
All-cause mortality was 56.0%, and mortality at 1 year after identification of R/R disease or treatment intolerance was 45.2%, they noted, adding that the study results “highlight the real-world complexities and high burden of CMV infection for HSCT recipients.”
“With available anti-CMV agents [excluding maribavir], a notable proportion of patients failed to achieve viremia clearance once developing RRI [resistant, refractory, or intolerant] CMV and/or experienced recurrence, and were at risk of adverse outcomes, including myelosuppression and mortality. There is a need for therapies that achieve and maintain CMV clearance with improved safety profiles,” they concluded.
Both studies were funded by Takeda Development Center Americas, the maker of Levtencity. Ms. Hirji is an employee of Takeda and reported stock ownership. Ms. Fox reported relationships with Sierra Oncology, GlaxoSmithKline, Bristol Myers Squibb, Novartis, and AbbVie.
FROM ESBMT 2023
Teriflunomide delays MS symptoms in radiologically isolated syndrome
BOSTON – , according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.
“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
TERIS trial data
In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.
During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.
Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.
“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
Caution warranted when interpreting the findings
The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.
“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.
“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.
Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
Challenging the traditional definition of MS
The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.
“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”
“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.
“Gaining a more refined sense of who we should treat will require more work,” he said.
These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.
“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”
Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.
BOSTON – , according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.
“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
TERIS trial data
In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.
During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.
Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.
“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
Caution warranted when interpreting the findings
The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.
“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.
“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.
Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
Challenging the traditional definition of MS
The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.
“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”
“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.
“Gaining a more refined sense of who we should treat will require more work,” he said.
These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.
“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”
Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.
BOSTON – , according to a double-blind, phase 3 trial presented in the Emerging Science session of the 2023 annual meeting of the American Academy of Neurology.
“These data add to the evidence that early immunomodulation offers clinical benefit even in the presymptomatic phase of MS,” reported Christine Lebrun-Frenay, MD, PhD, head of inflammatory neurological disorders research unit, University of Nice, France. This is the second study to show a benefit from a disease-modifying therapy in asymptomatic RIS patients. The ARISE study, which was presented at the 2022 European Committee for Treatment and Research in MS and has now been published, compared 240 mg of twice-daily dimethyl fumarate with placebo. Dimethyl fumarate was associated with an 82% (hazard ratio, 0.18; P = .007) reduction in the risk of a first demyelinating event after 96 weeks of follow-up.
TERIS trial data
In the new study, called TERIS, the design and outcomes were similar to the ARISE study. Eighty-nine patients meeting standard criteria for RIS were randomized to 14 mg of once-daily teriflunomide or placebo. The majority (71%) were female, and the mean age was 39.8 years. At the time of RIS diagnosis, the mean age was 38 years. At study entry, standardized MRI studies were performed of the brain and spinal cord.
During 2 years of follow-up, 8 of 28 demyelinating events were observed in the active treatment group. The remaining 20 occurred in the placebo group. This translated to a 63% reduction (HR, 0.37; P = .018) in favor of teriflunomide. When graphed, the curves separated at about 6 months and then widened progressively over time.
Distinct from clinically isolated syndrome (CIS), which describes individuals who have a symptomatic episode consistent with a demyelinating event, RIS is based primarily on an MRI that shows lesions highly suggestive of MS. Neither confirms the MS diagnosis, but both are associated with a high likelihood of eventually meeting MS diagnostic criteria. The ARISE and TERIS studies now support therapy to delay demyelinating events.
“With more and more people having brain scans for various reasons, such as headache or head trauma, more of these cases are being discovered,” Dr. Lebrun-Frenay said.
Caution warranted when interpreting the findings
The data support the theory that treatment should begin early in patients with a high likelihood of developing symptomatic MS on the basis of brain lesions. It is logical to assume that preventing damage to the myelin will reduce or delay permanent symptoms and permanent neurologic impairment, but Dr. Lebrun-Frenay suggested that the available data from ARISE and TERIS are not practice changing even though both were multicenter double-blind trials.
“More data from larger groups of patients are needed to confirm the findings,” she said. She expressed concern about not adhering to strict criteria to diagnosis RIS.
“It is important that medical professionals are cautious,” she said, citing the risk of misdiagnosis of pathology of MRI that leads to treatment of patients with a low risk of developing symptomatic MS.
Teriflunomide and dimethyl fumarate, which have long been available as first-line therapies in relapsing-remitting MS, are generally well tolerated. In the TERIS and ARISE studies, mild or moderate events occurred more commonly in the active treatment than the placebo arms, but there were no serious adverse events. However, both can produce more serious adverse events, which, in the case of teriflunomide, include liver toxicity leading to injury and liver failure.
Challenging the traditional definition of MS
The author of the ARISE study, Darin T. Okuda, MD, a professor of neurology at the UT Southwestern Medical Center, Dallas, indicated that his study, now reinforced by the TERIS study, challenges the definition of MS.
“Both ARISE and TERIS demonstrated a significant reduction in seminal clinical event rates related to inflammatory demyelination,” Dr. Okuda said in an interview. They provide evidence that patients are at high risk of the demyelinating events that characterize MS. Given the potential difficulty for accessing therapies of benefit, “how we define multiple sclerosis is highly important.”
“Individuals of younger age with abnormal spinal cord MRI studies along with other paraclinical features related to risk for a first event may be the most ideal group to treat,” he said. However, he agreed with Dr. Lebrun-Frenay that it is not yet clear which RIS patients are the most appropriate candidates.
“Gaining a more refined sense of who we should treat will require more work,” he said.
These data are likely to change the orientation toward RIS, according to Melina Hosseiny, MD, department of radiology, University of California, Los Angeles, Medical Center. She noted that the relationship between RIS and increased risk of MS has long been recognized, and the risk increases with specific features on imaging.
“Studies have shown that spinal cord lesions are associated with a greater than 50% chance of converting to MS,” said Dr. Hosseiny, who was the lead author of a review article on RIS. “Identifying such imaging findings can help identify patients who may benefit from disease-modifying medications.”
Dr. Lebrun-Frenay reports no potential conflicts of interest. Dr. Okuda has financial relationships with Alexion, Biogen, Celgene, EMD Serono, Genzyme, TG Therapeutics, and VielaBio. Dr. Hosseiny reports no potential conflicts of interest.
AT AAN 2023