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PCPs Play a Key Role in Managing and Preventing the Atopic March in Children
Primary care physicians (PCPs) play a key role in treating young patients as they progress through the “atopic march” from atopic dermatitis through food allergy, asthma, and allergic rhinitis. They can also help prevent the process from starting.
“The PCP is usually the first clinician a family with concerns about atopic conditions sees, unless they first visit urgent care or an emergency department after an allergic reaction to food. Either way, families rely on their PCP for ongoing guidance,” said Terri F. Brown-Whitehorn, MD, attending physician in the Division of Allergy and Immunology at the Center for Pediatric Eosinophilic Disorders and the Integrative Health Program at Children’s Hospital of Philadelphia.
“The most important thing PCPs can do is know that the atopic march exists, how it progresses over time, and what signs and symptoms to look for,” she told this news organization.
The Atopic March
The atopic march describes the progression of allergic diseases in a child over time, with atopic dermatitis and food allergy in infancy tending to be followed by allergic rhinitis and asthma into later childhood and adulthood.
Although the pathophysiology of the inflammation that precedes atopic dermatitis is unclear, two main hypotheses have been proposed. The first suggests a primary immune dysfunction leads to immunoglobulin E (IgE) sensitization, allergic inflammation, and a secondary disturbance of the epithelial barrier; the second starts with a primary defect in the epithelial barrier that leads to secondary immunologic dysregulation and results in inflammation.
Genetics, infection, hygiene, extreme climate, food allergens, probiotics, aeroallergens, and tobacco smoke are thought to play roles in atopic dermatitis. An estimated 10%-12% of children and 1% of adults in the United States have been reported to have the condition, and the prevalence appears to be increasing. An estimated 85% of cases occur during the first year of life and 95% before the age of 5 years.
“Atopy often, though not always, runs in families, so PCPs should inquire about the history of atopic dermatitis, IgE-mediated food allergies, allergic rhinitis, and asthma in the patient’s siblings, parents, and grandparents,” Brown-Whitehorn said.
Key Educators
PCPs treat the full gamut of atopic conditions and are key educators on ways families can help mitigate their children’s atopic march or stop it before it begins, said Gerald Bell Lee, MD, an allergist and immunologist at Children’s Healthcare of Atlanta and an associate professor in the Division of Allergy and Immunology at Emory University School of Medicine, Atlanta.
“Most parents who bring their infants with eczema to the PCP assume their child ate something that caused their rash. But the relationship between atopic dermatitis, a type of eczema, and food allergy is more complicated,” he added.
Lee said PCPs should explain to their patients what atopic dermatitis is, how it starts and progresses, and how families can help prevent the condition by, for example, introducing allergenic foods to infants at around 4-6 months of age.
Atopic Dermatitis
PCPs should inform parents and other caregivers to wash their hands before moisturizing their child, take care not to contaminate the moisturizer, and bathe their child only when the child is dirty.
“Soap removes protective natural skin oils and increases moisture loss, and exposure to soap and bathing is a main contributor to eczema,” said Lee. “Dry skin loses its protective barrier, allowing outside agents to penetrate and be identified by the immune system.”
“According to one hypothesis, parents may eat food, not wash their hands afterwards, then moisturize their baby. This unhygienic practice spreads food proteins from the adult’s meal, and possibly from contaminants present in the moisturizer, all over the baby’s body,” he added.
Lee said he and his colleagues discourage overbathing babies to minimize the risk for skin injury that begins the atopic march: “New parents are inundated with infant skincare messaging and products. But we need to weigh societal pressures against practicality and ask, ‘Is the child’s skin actually dirty?’ ”
Atopic dermatitis tends to appear on the extensor surfaces, face, and scalp in infants and around arm and leg creases in toddlers and older children. Severe forms of the condition can be more widely distributed on the body, said Aarti P. Pandya, MD, medical director of the Food Allergy Center at Children’s Mercy Kansas City and clinical assistant professor of pediatrics at the University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
Avoid Triggers, Minimize Flares
Triggers of eczema are varied and common. To help minimize flares, PCPs can encourage caregivers to avoid products with fragrances or dyes, minimize the use of soaps, and completely rinse laundry detergent from clothing and household items. “Advise them to keep fingernails short and control dander, pollen, mold, household chemicals, and tobacco smoke, as well as the child’s stress and anxiety, which can also be a trigger,” Lee said.
“Skin infections from organisms such as staph, herpes, or coxsackie can also exacerbate symptoms,” Brown-Whitehorn added. “PCPs can educate caregivers to avoid all known triggers and give them an ‘action plan’ to carry out when skin flares.”
Food Allergies
Parents may be unaware food allergens can travel far beyond the plate, Lee said. Researchers vacuuming household bedding, carpets, furniture, and other surfaces have detected unnoticeably tiny quantities of allergenic food proteins in ordinary house dust. Touching this dust appears to provide the main exposure to those allergens.
“According to the dual exposure to allergen hypothesis, an infant’s tolerance to antigens occurs through high-dose exposure by mouth, and allergic sensitization occurs through low-dose exposure through the skin,” he said. “As young as four to six months of age, even before eating solid food, a child develops eczema, has a leaky skin barrier, comes in contact with food, and develops a food allergy.”
IgE-mediated food allergies can begin at any age. “Symptoms occur when a food is ingested and the patient develops symptoms including but not limited to urticaria, angioedema, pruritus, flushing, vomiting, diarrhea, coughing, wheezing, difficulty breathing, presyncope, or syncope,” Pandya noted.
In the case of eosinophilic esophagitis, which may also be part of the atopic march, infants and toddlers often have challenging-to-treat symptoms of reflux, while school-age children have reflux and abdominal pain, and adolescents and adults may experience difficulty swallowing and impactions of food or pills, Brown-Whitehorn said.
To differentiate between food allergy and contact dermatitis, Lee suggested providers ask, “ ’Is the rash hives? If yes, is the rash generalized or in a limited area?’ Then consider the statistical probabilities. Skin problems after milk, egg, wheat, soy, peanut, tree nut, fish, shellfish, or sesame are likely due to IgE-mediated food allergy, but after ketchup or strawberry are probably from skin contact.”
Allergic Rhinitis and Asthma
“For asthma, ask about frequency of night cough and symptoms with exercise, laughing, or crying. For allergic rhinitis, look for runny nose, itchy eyes, or sneezing,” Brown-Whitehorn said.
Testing and Monitoring
Assessing the extent of eczema with the Eczema Area and Severity Index or the SCORing Atopic Dermatitis index takes time but may be necessary to obtain insurance coverage for treatments such as biologics.
Avoid ordering IgE food panels, which can result in false positives that can lead to loss of tolerance and nutritional deficiencies; psychological harm from bullying, anxiety, and decreased quality of life; and higher food and healthcare costs, Pandya said.
Treatments
Caregivers may be wary about treatments, and all the three experts this news organization spoke with stressed the importance of educating caregivers about how treatments work and what to expect from them.
“Early and aggressive atopic dermatitis treatment could prevent sensitization to food or aeroallergens, which could help prevent additional atopic diseases, including those on the atopic march,” Pandya said. “Topical steroids are considered first line at any age. Topical phosphodiesterase inhibitors are approved at 3 months of age and above. Topical calcineurin inhibitors are approved at 2 years of age and above. Wet wrap therapy and bleach baths can be effective. Other options include biologic therapy, allergen immunotherapy, and UV therapy.”
“Epinephrine auto-injectors can counteract food reactions. For allergic rhinitis, non-sedating antihistamines, steroidal nasal sprays, and nasal antihistamines help. Asthma treatments include various inhaled medications,” Brown-Whitehorn added.
When to Refer to Specialists
Involving an allergist, dermatologist, pulmonologist, or ear nose throat specialist to the patient’s care team is advisable in more challenging cases.
If a child is younger than 3 months and has moderate to severe atopic dermatitis, an underlying immune defect may be to blame, so an allergy and immunology assessment is warranted, Brown-Whitehorn said. “An allergist can help any child who has recurrent coughing or wheezing avoid the emergency room or hospitalization.”
“In pediatrics, we always try to find the medication, regimen, and avoidance strategies that use the least treatment to provide the best care for each patient,” Brown-Whitehorn added. “Children eat, play, learn, and sleep, and every stage of the atopic march affects each of these activities. As clinicians, we need to be sure that we are helping children make the best of all these activities.”
Brown-Whitehorn reported financial relationships with DBV Technologies and Regeneron Pharmaceuticals. Lee reported financial relationships with Novartis. Pandya reported financial relationships with DBV Technologies, Thermo Fisher Scientific, and Sanofi.
A version of this article first appeared on Medscape.com.
Primary care physicians (PCPs) play a key role in treating young patients as they progress through the “atopic march” from atopic dermatitis through food allergy, asthma, and allergic rhinitis. They can also help prevent the process from starting.
“The PCP is usually the first clinician a family with concerns about atopic conditions sees, unless they first visit urgent care or an emergency department after an allergic reaction to food. Either way, families rely on their PCP for ongoing guidance,” said Terri F. Brown-Whitehorn, MD, attending physician in the Division of Allergy and Immunology at the Center for Pediatric Eosinophilic Disorders and the Integrative Health Program at Children’s Hospital of Philadelphia.
“The most important thing PCPs can do is know that the atopic march exists, how it progresses over time, and what signs and symptoms to look for,” she told this news organization.
The Atopic March
The atopic march describes the progression of allergic diseases in a child over time, with atopic dermatitis and food allergy in infancy tending to be followed by allergic rhinitis and asthma into later childhood and adulthood.
Although the pathophysiology of the inflammation that precedes atopic dermatitis is unclear, two main hypotheses have been proposed. The first suggests a primary immune dysfunction leads to immunoglobulin E (IgE) sensitization, allergic inflammation, and a secondary disturbance of the epithelial barrier; the second starts with a primary defect in the epithelial barrier that leads to secondary immunologic dysregulation and results in inflammation.
Genetics, infection, hygiene, extreme climate, food allergens, probiotics, aeroallergens, and tobacco smoke are thought to play roles in atopic dermatitis. An estimated 10%-12% of children and 1% of adults in the United States have been reported to have the condition, and the prevalence appears to be increasing. An estimated 85% of cases occur during the first year of life and 95% before the age of 5 years.
“Atopy often, though not always, runs in families, so PCPs should inquire about the history of atopic dermatitis, IgE-mediated food allergies, allergic rhinitis, and asthma in the patient’s siblings, parents, and grandparents,” Brown-Whitehorn said.
Key Educators
PCPs treat the full gamut of atopic conditions and are key educators on ways families can help mitigate their children’s atopic march or stop it before it begins, said Gerald Bell Lee, MD, an allergist and immunologist at Children’s Healthcare of Atlanta and an associate professor in the Division of Allergy and Immunology at Emory University School of Medicine, Atlanta.
“Most parents who bring their infants with eczema to the PCP assume their child ate something that caused their rash. But the relationship between atopic dermatitis, a type of eczema, and food allergy is more complicated,” he added.
Lee said PCPs should explain to their patients what atopic dermatitis is, how it starts and progresses, and how families can help prevent the condition by, for example, introducing allergenic foods to infants at around 4-6 months of age.
Atopic Dermatitis
PCPs should inform parents and other caregivers to wash their hands before moisturizing their child, take care not to contaminate the moisturizer, and bathe their child only when the child is dirty.
“Soap removes protective natural skin oils and increases moisture loss, and exposure to soap and bathing is a main contributor to eczema,” said Lee. “Dry skin loses its protective barrier, allowing outside agents to penetrate and be identified by the immune system.”
“According to one hypothesis, parents may eat food, not wash their hands afterwards, then moisturize their baby. This unhygienic practice spreads food proteins from the adult’s meal, and possibly from contaminants present in the moisturizer, all over the baby’s body,” he added.
Lee said he and his colleagues discourage overbathing babies to minimize the risk for skin injury that begins the atopic march: “New parents are inundated with infant skincare messaging and products. But we need to weigh societal pressures against practicality and ask, ‘Is the child’s skin actually dirty?’ ”
Atopic dermatitis tends to appear on the extensor surfaces, face, and scalp in infants and around arm and leg creases in toddlers and older children. Severe forms of the condition can be more widely distributed on the body, said Aarti P. Pandya, MD, medical director of the Food Allergy Center at Children’s Mercy Kansas City and clinical assistant professor of pediatrics at the University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
Avoid Triggers, Minimize Flares
Triggers of eczema are varied and common. To help minimize flares, PCPs can encourage caregivers to avoid products with fragrances or dyes, minimize the use of soaps, and completely rinse laundry detergent from clothing and household items. “Advise them to keep fingernails short and control dander, pollen, mold, household chemicals, and tobacco smoke, as well as the child’s stress and anxiety, which can also be a trigger,” Lee said.
“Skin infections from organisms such as staph, herpes, or coxsackie can also exacerbate symptoms,” Brown-Whitehorn added. “PCPs can educate caregivers to avoid all known triggers and give them an ‘action plan’ to carry out when skin flares.”
Food Allergies
Parents may be unaware food allergens can travel far beyond the plate, Lee said. Researchers vacuuming household bedding, carpets, furniture, and other surfaces have detected unnoticeably tiny quantities of allergenic food proteins in ordinary house dust. Touching this dust appears to provide the main exposure to those allergens.
“According to the dual exposure to allergen hypothesis, an infant’s tolerance to antigens occurs through high-dose exposure by mouth, and allergic sensitization occurs through low-dose exposure through the skin,” he said. “As young as four to six months of age, even before eating solid food, a child develops eczema, has a leaky skin barrier, comes in contact with food, and develops a food allergy.”
IgE-mediated food allergies can begin at any age. “Symptoms occur when a food is ingested and the patient develops symptoms including but not limited to urticaria, angioedema, pruritus, flushing, vomiting, diarrhea, coughing, wheezing, difficulty breathing, presyncope, or syncope,” Pandya noted.
In the case of eosinophilic esophagitis, which may also be part of the atopic march, infants and toddlers often have challenging-to-treat symptoms of reflux, while school-age children have reflux and abdominal pain, and adolescents and adults may experience difficulty swallowing and impactions of food or pills, Brown-Whitehorn said.
To differentiate between food allergy and contact dermatitis, Lee suggested providers ask, “ ’Is the rash hives? If yes, is the rash generalized or in a limited area?’ Then consider the statistical probabilities. Skin problems after milk, egg, wheat, soy, peanut, tree nut, fish, shellfish, or sesame are likely due to IgE-mediated food allergy, but after ketchup or strawberry are probably from skin contact.”
Allergic Rhinitis and Asthma
“For asthma, ask about frequency of night cough and symptoms with exercise, laughing, or crying. For allergic rhinitis, look for runny nose, itchy eyes, or sneezing,” Brown-Whitehorn said.
Testing and Monitoring
Assessing the extent of eczema with the Eczema Area and Severity Index or the SCORing Atopic Dermatitis index takes time but may be necessary to obtain insurance coverage for treatments such as biologics.
Avoid ordering IgE food panels, which can result in false positives that can lead to loss of tolerance and nutritional deficiencies; psychological harm from bullying, anxiety, and decreased quality of life; and higher food and healthcare costs, Pandya said.
Treatments
Caregivers may be wary about treatments, and all the three experts this news organization spoke with stressed the importance of educating caregivers about how treatments work and what to expect from them.
“Early and aggressive atopic dermatitis treatment could prevent sensitization to food or aeroallergens, which could help prevent additional atopic diseases, including those on the atopic march,” Pandya said. “Topical steroids are considered first line at any age. Topical phosphodiesterase inhibitors are approved at 3 months of age and above. Topical calcineurin inhibitors are approved at 2 years of age and above. Wet wrap therapy and bleach baths can be effective. Other options include biologic therapy, allergen immunotherapy, and UV therapy.”
“Epinephrine auto-injectors can counteract food reactions. For allergic rhinitis, non-sedating antihistamines, steroidal nasal sprays, and nasal antihistamines help. Asthma treatments include various inhaled medications,” Brown-Whitehorn added.
When to Refer to Specialists
Involving an allergist, dermatologist, pulmonologist, or ear nose throat specialist to the patient’s care team is advisable in more challenging cases.
If a child is younger than 3 months and has moderate to severe atopic dermatitis, an underlying immune defect may be to blame, so an allergy and immunology assessment is warranted, Brown-Whitehorn said. “An allergist can help any child who has recurrent coughing or wheezing avoid the emergency room or hospitalization.”
“In pediatrics, we always try to find the medication, regimen, and avoidance strategies that use the least treatment to provide the best care for each patient,” Brown-Whitehorn added. “Children eat, play, learn, and sleep, and every stage of the atopic march affects each of these activities. As clinicians, we need to be sure that we are helping children make the best of all these activities.”
Brown-Whitehorn reported financial relationships with DBV Technologies and Regeneron Pharmaceuticals. Lee reported financial relationships with Novartis. Pandya reported financial relationships with DBV Technologies, Thermo Fisher Scientific, and Sanofi.
A version of this article first appeared on Medscape.com.
Primary care physicians (PCPs) play a key role in treating young patients as they progress through the “atopic march” from atopic dermatitis through food allergy, asthma, and allergic rhinitis. They can also help prevent the process from starting.
“The PCP is usually the first clinician a family with concerns about atopic conditions sees, unless they first visit urgent care or an emergency department after an allergic reaction to food. Either way, families rely on their PCP for ongoing guidance,” said Terri F. Brown-Whitehorn, MD, attending physician in the Division of Allergy and Immunology at the Center for Pediatric Eosinophilic Disorders and the Integrative Health Program at Children’s Hospital of Philadelphia.
“The most important thing PCPs can do is know that the atopic march exists, how it progresses over time, and what signs and symptoms to look for,” she told this news organization.
The Atopic March
The atopic march describes the progression of allergic diseases in a child over time, with atopic dermatitis and food allergy in infancy tending to be followed by allergic rhinitis and asthma into later childhood and adulthood.
Although the pathophysiology of the inflammation that precedes atopic dermatitis is unclear, two main hypotheses have been proposed. The first suggests a primary immune dysfunction leads to immunoglobulin E (IgE) sensitization, allergic inflammation, and a secondary disturbance of the epithelial barrier; the second starts with a primary defect in the epithelial barrier that leads to secondary immunologic dysregulation and results in inflammation.
Genetics, infection, hygiene, extreme climate, food allergens, probiotics, aeroallergens, and tobacco smoke are thought to play roles in atopic dermatitis. An estimated 10%-12% of children and 1% of adults in the United States have been reported to have the condition, and the prevalence appears to be increasing. An estimated 85% of cases occur during the first year of life and 95% before the age of 5 years.
“Atopy often, though not always, runs in families, so PCPs should inquire about the history of atopic dermatitis, IgE-mediated food allergies, allergic rhinitis, and asthma in the patient’s siblings, parents, and grandparents,” Brown-Whitehorn said.
Key Educators
PCPs treat the full gamut of atopic conditions and are key educators on ways families can help mitigate their children’s atopic march or stop it before it begins, said Gerald Bell Lee, MD, an allergist and immunologist at Children’s Healthcare of Atlanta and an associate professor in the Division of Allergy and Immunology at Emory University School of Medicine, Atlanta.
“Most parents who bring their infants with eczema to the PCP assume their child ate something that caused their rash. But the relationship between atopic dermatitis, a type of eczema, and food allergy is more complicated,” he added.
Lee said PCPs should explain to their patients what atopic dermatitis is, how it starts and progresses, and how families can help prevent the condition by, for example, introducing allergenic foods to infants at around 4-6 months of age.
Atopic Dermatitis
PCPs should inform parents and other caregivers to wash their hands before moisturizing their child, take care not to contaminate the moisturizer, and bathe their child only when the child is dirty.
“Soap removes protective natural skin oils and increases moisture loss, and exposure to soap and bathing is a main contributor to eczema,” said Lee. “Dry skin loses its protective barrier, allowing outside agents to penetrate and be identified by the immune system.”
“According to one hypothesis, parents may eat food, not wash their hands afterwards, then moisturize their baby. This unhygienic practice spreads food proteins from the adult’s meal, and possibly from contaminants present in the moisturizer, all over the baby’s body,” he added.
Lee said he and his colleagues discourage overbathing babies to minimize the risk for skin injury that begins the atopic march: “New parents are inundated with infant skincare messaging and products. But we need to weigh societal pressures against practicality and ask, ‘Is the child’s skin actually dirty?’ ”
Atopic dermatitis tends to appear on the extensor surfaces, face, and scalp in infants and around arm and leg creases in toddlers and older children. Severe forms of the condition can be more widely distributed on the body, said Aarti P. Pandya, MD, medical director of the Food Allergy Center at Children’s Mercy Kansas City and clinical assistant professor of pediatrics at the University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
Avoid Triggers, Minimize Flares
Triggers of eczema are varied and common. To help minimize flares, PCPs can encourage caregivers to avoid products with fragrances or dyes, minimize the use of soaps, and completely rinse laundry detergent from clothing and household items. “Advise them to keep fingernails short and control dander, pollen, mold, household chemicals, and tobacco smoke, as well as the child’s stress and anxiety, which can also be a trigger,” Lee said.
“Skin infections from organisms such as staph, herpes, or coxsackie can also exacerbate symptoms,” Brown-Whitehorn added. “PCPs can educate caregivers to avoid all known triggers and give them an ‘action plan’ to carry out when skin flares.”
Food Allergies
Parents may be unaware food allergens can travel far beyond the plate, Lee said. Researchers vacuuming household bedding, carpets, furniture, and other surfaces have detected unnoticeably tiny quantities of allergenic food proteins in ordinary house dust. Touching this dust appears to provide the main exposure to those allergens.
“According to the dual exposure to allergen hypothesis, an infant’s tolerance to antigens occurs through high-dose exposure by mouth, and allergic sensitization occurs through low-dose exposure through the skin,” he said. “As young as four to six months of age, even before eating solid food, a child develops eczema, has a leaky skin barrier, comes in contact with food, and develops a food allergy.”
IgE-mediated food allergies can begin at any age. “Symptoms occur when a food is ingested and the patient develops symptoms including but not limited to urticaria, angioedema, pruritus, flushing, vomiting, diarrhea, coughing, wheezing, difficulty breathing, presyncope, or syncope,” Pandya noted.
In the case of eosinophilic esophagitis, which may also be part of the atopic march, infants and toddlers often have challenging-to-treat symptoms of reflux, while school-age children have reflux and abdominal pain, and adolescents and adults may experience difficulty swallowing and impactions of food or pills, Brown-Whitehorn said.
To differentiate between food allergy and contact dermatitis, Lee suggested providers ask, “ ’Is the rash hives? If yes, is the rash generalized or in a limited area?’ Then consider the statistical probabilities. Skin problems after milk, egg, wheat, soy, peanut, tree nut, fish, shellfish, or sesame are likely due to IgE-mediated food allergy, but after ketchup or strawberry are probably from skin contact.”
Allergic Rhinitis and Asthma
“For asthma, ask about frequency of night cough and symptoms with exercise, laughing, or crying. For allergic rhinitis, look for runny nose, itchy eyes, or sneezing,” Brown-Whitehorn said.
Testing and Monitoring
Assessing the extent of eczema with the Eczema Area and Severity Index or the SCORing Atopic Dermatitis index takes time but may be necessary to obtain insurance coverage for treatments such as biologics.
Avoid ordering IgE food panels, which can result in false positives that can lead to loss of tolerance and nutritional deficiencies; psychological harm from bullying, anxiety, and decreased quality of life; and higher food and healthcare costs, Pandya said.
Treatments
Caregivers may be wary about treatments, and all the three experts this news organization spoke with stressed the importance of educating caregivers about how treatments work and what to expect from them.
“Early and aggressive atopic dermatitis treatment could prevent sensitization to food or aeroallergens, which could help prevent additional atopic diseases, including those on the atopic march,” Pandya said. “Topical steroids are considered first line at any age. Topical phosphodiesterase inhibitors are approved at 3 months of age and above. Topical calcineurin inhibitors are approved at 2 years of age and above. Wet wrap therapy and bleach baths can be effective. Other options include biologic therapy, allergen immunotherapy, and UV therapy.”
“Epinephrine auto-injectors can counteract food reactions. For allergic rhinitis, non-sedating antihistamines, steroidal nasal sprays, and nasal antihistamines help. Asthma treatments include various inhaled medications,” Brown-Whitehorn added.
When to Refer to Specialists
Involving an allergist, dermatologist, pulmonologist, or ear nose throat specialist to the patient’s care team is advisable in more challenging cases.
If a child is younger than 3 months and has moderate to severe atopic dermatitis, an underlying immune defect may be to blame, so an allergy and immunology assessment is warranted, Brown-Whitehorn said. “An allergist can help any child who has recurrent coughing or wheezing avoid the emergency room or hospitalization.”
“In pediatrics, we always try to find the medication, regimen, and avoidance strategies that use the least treatment to provide the best care for each patient,” Brown-Whitehorn added. “Children eat, play, learn, and sleep, and every stage of the atopic march affects each of these activities. As clinicians, we need to be sure that we are helping children make the best of all these activities.”
Brown-Whitehorn reported financial relationships with DBV Technologies and Regeneron Pharmaceuticals. Lee reported financial relationships with Novartis. Pandya reported financial relationships with DBV Technologies, Thermo Fisher Scientific, and Sanofi.
A version of this article first appeared on Medscape.com.
How ‘Oatzempic’ Stacks up to Ozempic
A so-called “oatzempic” diet has been bouncing around the internet posing as a cheap — and available — weight loss alternative to Ozempic.
Fans of the diet, made trendy by TikTok postings and a clever name, claim that an oat-based smoothie helps people quickly shed lots of weight. The smoothie is made by blending 1/2 cup of oats, 1 cup of water, a squeeze of lime, and maybe a dash of cinnamon or other flavoring agents, typically as the first meal of the day, often after fasting, followed by normal meals.
Despite the hype, the oatzempic drink is a far cry from Ozempic (semaglutide), the glucagon-like peptide 1 (GLP-1) medication the Food and Drug Administration has approved only for type 2 diabetes management but used off label for weight loss.
Nutritionists Answer Questions on Oatzempic
Caroline West Passerrello, EdD, RDN, LDN, an instructor and community coordinator in the School of Health and Rehabilitation Sciences at the University of Pittsburgh, Pennsylvania, and Emma Laing, PhD, RDN, LD, a clinical professor and director of dietetics in the College of Family and Consumer Sciences at the University of Georgia, Athens, talked about this fad in emails.
Can the ‘oatzempic’ diet help people lose weight?
Dr. Passerrello: Oats are particularly high in soluble fiber, and high-fiber foods can increase the natural production of GLPs. But studies are mixed on whether this happens when eating oats.
The high content of soluble beta-glucan fiber in oats and the appetite-suppressing citric acid in lime can potentially promote decreased appetite and increased satiety. But a bowl of oatmeal, though not as trendy, will probably produce the same results.
Is the oatzempic diet safe for people with type 2 diabetes?
Dr. Laing: This diet has the potential to cause harm. The diet and the drug are not similar in mechanism of action or strength of scientific evidence to support their role in diabetes and weight management. There is no evidence that this concoction provides the same outcomes as GLP-1 agonists. Rapid weight loss is unsustainable and can be harmful, and frequent spikes in blood sugar can harm adults and children with diabetes. So the oatzempic diet’s safety depends on the rate of weight loss and the effect on blood sugar. While it provides beta-glucan from oats and citric acid from lime juice, it is missing protein, healthy fats, and other vitamins and minerals that enhance the nutrient content and stabilize blood sugar.
Maintaining relatively consistent, normal-range blood glucose concentrations is key for managing diabetes and lowering the risks for other health complications. Carbohydrate sources consumed on their own can produce greater blood sugar fluctuations than when combined with proteins and fats, which slow carbohydrate digestion speed. So pairing oats with fruits, vegetables, healthy fats, and protein sources enhances the flavor, texture, and nutrient composition of the dish and can help slow the postprandial rise in blood glucose.
In the long term, any restrictive fad diet likely cannot be sustained and increases the risk for malnutrition, metabolic rate slowing to conserve energy, depression, social isolation, or eating disorder.
Additional considerations apply to children, with or without diabetes. Restrictive, extreme diets that promise quick results typically “work” by promoting body water and muscle mass losses. Such diets are not only contraindicated in children, who are undergoing rapid growth and development, but also unsustainable and can lead to physical and psychological problems that carry into adulthood.
What strategies and tactics can physicians use to effectively communicate with their patients about safe and effective diets?
Dr. Laing: Encourage patients to be skeptical of social media trends that seem too good to be true. Many [social media] creators lack the education or professional credentials to offer sound nutrition advice, and their posts could do harm. Explain that individual nutrition needs differ considerably based on age, activity patterns, health conditions, and medications, and one person’s way of eating or success is often not realistic for someone else.
Encourage open dialogue and provide nonjudgmental advice. If the taste of oatzempic intrigues patients, there is likely no harm in experimenting. Work on ensuring their meals are adequate in calories and contain sources of protein and healthy fats to prevent spikes in blood glucose. It’s crucial to communicate that weight loss doesn’t always equate with improved health.
Sharing information from the Academy of Nutrition and Dietetics and the American Diabetes Association can equip patients with tools they can implement under their clinician’s guidance. A provider’s greatest ally in diabetes care is a registered dietitian nutritionist (RDN) who is a Certified Diabetes Care and Education Specialist. RDNs will determine specific energy and nutrient needs and provide medical nutrition therapy such as carbohydrate counting, simplified meal plans, healthy food choices, exchange lists, and behavior strategies to help patients manage their diabetes. Many insurance plans cover these services.
What additional comments would you like to share with clinicians whose patients may ask them about the oatzempic diet?
Dr. Passerrello: What we do consistently matters. If your patient likes the taste of oatzempic in one meal a day, it’s a way to get more oats into their diet, if they focus their other meals on vegetables, fruits, whole grains, lean protein, and unsaturated fats.
Diets are out, and sustainable dietary patterns are in. Diets are one-size-fits-all, whereas a sustainable dietary pattern is individualized based on a person’s goals, medical history, taste preferences, budget, and lifestyle. Visit MyPlate.gov or work with an RDN [visit https://www.eatright.org/find-a-nutrition-expert to find nutritionists near your patients] to determine what a sustainable dietary pattern looks like.
What do clinicians need to know about claims on social media that a related drink — ‘ricezempic’ — aids weight loss?
Dr. Laing: Ricezempic promoters claim that drinking the beverage — typically made by soaking 1/2 cup of uncooked white rice in 1 cup of water and the juice from half a lime, then discarding the rice and drinking the liquid before breakfast — will lead to weight loss because the strained water provides a small dose of resistant starch, which is a source of prebiotics. Studies have shown that ingesting prebiotics may help lower blood cholesterol, improve blood glucose and insulin sensitivity, and benefit digestive function; however, more research is needed to determine specifics and if prebiotics are proven for weight loss.
Does ricezempic work?
Dr. Laing: There is no evidence that this concoction provides the same outcomes as GLP-1 agonists. The diet and the drug are not similar in mechanism of action or strength of scientific evidence to support their role in diabetes and weight management. Even if ricezempic provides a small amount of resistant starch and hydration from the rice water and citric acid from the lime juice, it is missing fiber, protein, healthy fats, and other vitamins and minerals that enhance the nutrient content of a meal or snack and stabilize blood sugar.
What advice do you have for clinicians whose patients with diabetes ask them about ricezempic?
Dr. Laing: I would not suggest that patients rely on ricezempic to support their health. There is no scientific evidence to show that people will lose weight in the short or long term by drinking ricezempic before a meal (or as a meal replacement).
If your patients are aiming to increase their intake of prebiotics, they are naturally found in various vegetables, fruits, whole grains, and seeds and in yogurt and high-fiber breads and cereals. A nutritious eating pattern that includes these foods is most beneficial for health.
A version of this article first appeared on Medscape.com.
A so-called “oatzempic” diet has been bouncing around the internet posing as a cheap — and available — weight loss alternative to Ozempic.
Fans of the diet, made trendy by TikTok postings and a clever name, claim that an oat-based smoothie helps people quickly shed lots of weight. The smoothie is made by blending 1/2 cup of oats, 1 cup of water, a squeeze of lime, and maybe a dash of cinnamon or other flavoring agents, typically as the first meal of the day, often after fasting, followed by normal meals.
Despite the hype, the oatzempic drink is a far cry from Ozempic (semaglutide), the glucagon-like peptide 1 (GLP-1) medication the Food and Drug Administration has approved only for type 2 diabetes management but used off label for weight loss.
Nutritionists Answer Questions on Oatzempic
Caroline West Passerrello, EdD, RDN, LDN, an instructor and community coordinator in the School of Health and Rehabilitation Sciences at the University of Pittsburgh, Pennsylvania, and Emma Laing, PhD, RDN, LD, a clinical professor and director of dietetics in the College of Family and Consumer Sciences at the University of Georgia, Athens, talked about this fad in emails.
Can the ‘oatzempic’ diet help people lose weight?
Dr. Passerrello: Oats are particularly high in soluble fiber, and high-fiber foods can increase the natural production of GLPs. But studies are mixed on whether this happens when eating oats.
The high content of soluble beta-glucan fiber in oats and the appetite-suppressing citric acid in lime can potentially promote decreased appetite and increased satiety. But a bowl of oatmeal, though not as trendy, will probably produce the same results.
Is the oatzempic diet safe for people with type 2 diabetes?
Dr. Laing: This diet has the potential to cause harm. The diet and the drug are not similar in mechanism of action or strength of scientific evidence to support their role in diabetes and weight management. There is no evidence that this concoction provides the same outcomes as GLP-1 agonists. Rapid weight loss is unsustainable and can be harmful, and frequent spikes in blood sugar can harm adults and children with diabetes. So the oatzempic diet’s safety depends on the rate of weight loss and the effect on blood sugar. While it provides beta-glucan from oats and citric acid from lime juice, it is missing protein, healthy fats, and other vitamins and minerals that enhance the nutrient content and stabilize blood sugar.
Maintaining relatively consistent, normal-range blood glucose concentrations is key for managing diabetes and lowering the risks for other health complications. Carbohydrate sources consumed on their own can produce greater blood sugar fluctuations than when combined with proteins and fats, which slow carbohydrate digestion speed. So pairing oats with fruits, vegetables, healthy fats, and protein sources enhances the flavor, texture, and nutrient composition of the dish and can help slow the postprandial rise in blood glucose.
In the long term, any restrictive fad diet likely cannot be sustained and increases the risk for malnutrition, metabolic rate slowing to conserve energy, depression, social isolation, or eating disorder.
Additional considerations apply to children, with or without diabetes. Restrictive, extreme diets that promise quick results typically “work” by promoting body water and muscle mass losses. Such diets are not only contraindicated in children, who are undergoing rapid growth and development, but also unsustainable and can lead to physical and psychological problems that carry into adulthood.
What strategies and tactics can physicians use to effectively communicate with their patients about safe and effective diets?
Dr. Laing: Encourage patients to be skeptical of social media trends that seem too good to be true. Many [social media] creators lack the education or professional credentials to offer sound nutrition advice, and their posts could do harm. Explain that individual nutrition needs differ considerably based on age, activity patterns, health conditions, and medications, and one person’s way of eating or success is often not realistic for someone else.
Encourage open dialogue and provide nonjudgmental advice. If the taste of oatzempic intrigues patients, there is likely no harm in experimenting. Work on ensuring their meals are adequate in calories and contain sources of protein and healthy fats to prevent spikes in blood glucose. It’s crucial to communicate that weight loss doesn’t always equate with improved health.
Sharing information from the Academy of Nutrition and Dietetics and the American Diabetes Association can equip patients with tools they can implement under their clinician’s guidance. A provider’s greatest ally in diabetes care is a registered dietitian nutritionist (RDN) who is a Certified Diabetes Care and Education Specialist. RDNs will determine specific energy and nutrient needs and provide medical nutrition therapy such as carbohydrate counting, simplified meal plans, healthy food choices, exchange lists, and behavior strategies to help patients manage their diabetes. Many insurance plans cover these services.
What additional comments would you like to share with clinicians whose patients may ask them about the oatzempic diet?
Dr. Passerrello: What we do consistently matters. If your patient likes the taste of oatzempic in one meal a day, it’s a way to get more oats into their diet, if they focus their other meals on vegetables, fruits, whole grains, lean protein, and unsaturated fats.
Diets are out, and sustainable dietary patterns are in. Diets are one-size-fits-all, whereas a sustainable dietary pattern is individualized based on a person’s goals, medical history, taste preferences, budget, and lifestyle. Visit MyPlate.gov or work with an RDN [visit https://www.eatright.org/find-a-nutrition-expert to find nutritionists near your patients] to determine what a sustainable dietary pattern looks like.
What do clinicians need to know about claims on social media that a related drink — ‘ricezempic’ — aids weight loss?
Dr. Laing: Ricezempic promoters claim that drinking the beverage — typically made by soaking 1/2 cup of uncooked white rice in 1 cup of water and the juice from half a lime, then discarding the rice and drinking the liquid before breakfast — will lead to weight loss because the strained water provides a small dose of resistant starch, which is a source of prebiotics. Studies have shown that ingesting prebiotics may help lower blood cholesterol, improve blood glucose and insulin sensitivity, and benefit digestive function; however, more research is needed to determine specifics and if prebiotics are proven for weight loss.
Does ricezempic work?
Dr. Laing: There is no evidence that this concoction provides the same outcomes as GLP-1 agonists. The diet and the drug are not similar in mechanism of action or strength of scientific evidence to support their role in diabetes and weight management. Even if ricezempic provides a small amount of resistant starch and hydration from the rice water and citric acid from the lime juice, it is missing fiber, protein, healthy fats, and other vitamins and minerals that enhance the nutrient content of a meal or snack and stabilize blood sugar.
What advice do you have for clinicians whose patients with diabetes ask them about ricezempic?
Dr. Laing: I would not suggest that patients rely on ricezempic to support their health. There is no scientific evidence to show that people will lose weight in the short or long term by drinking ricezempic before a meal (or as a meal replacement).
If your patients are aiming to increase their intake of prebiotics, they are naturally found in various vegetables, fruits, whole grains, and seeds and in yogurt and high-fiber breads and cereals. A nutritious eating pattern that includes these foods is most beneficial for health.
A version of this article first appeared on Medscape.com.
A so-called “oatzempic” diet has been bouncing around the internet posing as a cheap — and available — weight loss alternative to Ozempic.
Fans of the diet, made trendy by TikTok postings and a clever name, claim that an oat-based smoothie helps people quickly shed lots of weight. The smoothie is made by blending 1/2 cup of oats, 1 cup of water, a squeeze of lime, and maybe a dash of cinnamon or other flavoring agents, typically as the first meal of the day, often after fasting, followed by normal meals.
Despite the hype, the oatzempic drink is a far cry from Ozempic (semaglutide), the glucagon-like peptide 1 (GLP-1) medication the Food and Drug Administration has approved only for type 2 diabetes management but used off label for weight loss.
Nutritionists Answer Questions on Oatzempic
Caroline West Passerrello, EdD, RDN, LDN, an instructor and community coordinator in the School of Health and Rehabilitation Sciences at the University of Pittsburgh, Pennsylvania, and Emma Laing, PhD, RDN, LD, a clinical professor and director of dietetics in the College of Family and Consumer Sciences at the University of Georgia, Athens, talked about this fad in emails.
Can the ‘oatzempic’ diet help people lose weight?
Dr. Passerrello: Oats are particularly high in soluble fiber, and high-fiber foods can increase the natural production of GLPs. But studies are mixed on whether this happens when eating oats.
The high content of soluble beta-glucan fiber in oats and the appetite-suppressing citric acid in lime can potentially promote decreased appetite and increased satiety. But a bowl of oatmeal, though not as trendy, will probably produce the same results.
Is the oatzempic diet safe for people with type 2 diabetes?
Dr. Laing: This diet has the potential to cause harm. The diet and the drug are not similar in mechanism of action or strength of scientific evidence to support their role in diabetes and weight management. There is no evidence that this concoction provides the same outcomes as GLP-1 agonists. Rapid weight loss is unsustainable and can be harmful, and frequent spikes in blood sugar can harm adults and children with diabetes. So the oatzempic diet’s safety depends on the rate of weight loss and the effect on blood sugar. While it provides beta-glucan from oats and citric acid from lime juice, it is missing protein, healthy fats, and other vitamins and minerals that enhance the nutrient content and stabilize blood sugar.
Maintaining relatively consistent, normal-range blood glucose concentrations is key for managing diabetes and lowering the risks for other health complications. Carbohydrate sources consumed on their own can produce greater blood sugar fluctuations than when combined with proteins and fats, which slow carbohydrate digestion speed. So pairing oats with fruits, vegetables, healthy fats, and protein sources enhances the flavor, texture, and nutrient composition of the dish and can help slow the postprandial rise in blood glucose.
In the long term, any restrictive fad diet likely cannot be sustained and increases the risk for malnutrition, metabolic rate slowing to conserve energy, depression, social isolation, or eating disorder.
Additional considerations apply to children, with or without diabetes. Restrictive, extreme diets that promise quick results typically “work” by promoting body water and muscle mass losses. Such diets are not only contraindicated in children, who are undergoing rapid growth and development, but also unsustainable and can lead to physical and psychological problems that carry into adulthood.
What strategies and tactics can physicians use to effectively communicate with their patients about safe and effective diets?
Dr. Laing: Encourage patients to be skeptical of social media trends that seem too good to be true. Many [social media] creators lack the education or professional credentials to offer sound nutrition advice, and their posts could do harm. Explain that individual nutrition needs differ considerably based on age, activity patterns, health conditions, and medications, and one person’s way of eating or success is often not realistic for someone else.
Encourage open dialogue and provide nonjudgmental advice. If the taste of oatzempic intrigues patients, there is likely no harm in experimenting. Work on ensuring their meals are adequate in calories and contain sources of protein and healthy fats to prevent spikes in blood glucose. It’s crucial to communicate that weight loss doesn’t always equate with improved health.
Sharing information from the Academy of Nutrition and Dietetics and the American Diabetes Association can equip patients with tools they can implement under their clinician’s guidance. A provider’s greatest ally in diabetes care is a registered dietitian nutritionist (RDN) who is a Certified Diabetes Care and Education Specialist. RDNs will determine specific energy and nutrient needs and provide medical nutrition therapy such as carbohydrate counting, simplified meal plans, healthy food choices, exchange lists, and behavior strategies to help patients manage their diabetes. Many insurance plans cover these services.
What additional comments would you like to share with clinicians whose patients may ask them about the oatzempic diet?
Dr. Passerrello: What we do consistently matters. If your patient likes the taste of oatzempic in one meal a day, it’s a way to get more oats into their diet, if they focus their other meals on vegetables, fruits, whole grains, lean protein, and unsaturated fats.
Diets are out, and sustainable dietary patterns are in. Diets are one-size-fits-all, whereas a sustainable dietary pattern is individualized based on a person’s goals, medical history, taste preferences, budget, and lifestyle. Visit MyPlate.gov or work with an RDN [visit https://www.eatright.org/find-a-nutrition-expert to find nutritionists near your patients] to determine what a sustainable dietary pattern looks like.
What do clinicians need to know about claims on social media that a related drink — ‘ricezempic’ — aids weight loss?
Dr. Laing: Ricezempic promoters claim that drinking the beverage — typically made by soaking 1/2 cup of uncooked white rice in 1 cup of water and the juice from half a lime, then discarding the rice and drinking the liquid before breakfast — will lead to weight loss because the strained water provides a small dose of resistant starch, which is a source of prebiotics. Studies have shown that ingesting prebiotics may help lower blood cholesterol, improve blood glucose and insulin sensitivity, and benefit digestive function; however, more research is needed to determine specifics and if prebiotics are proven for weight loss.
Does ricezempic work?
Dr. Laing: There is no evidence that this concoction provides the same outcomes as GLP-1 agonists. The diet and the drug are not similar in mechanism of action or strength of scientific evidence to support their role in diabetes and weight management. Even if ricezempic provides a small amount of resistant starch and hydration from the rice water and citric acid from the lime juice, it is missing fiber, protein, healthy fats, and other vitamins and minerals that enhance the nutrient content of a meal or snack and stabilize blood sugar.
What advice do you have for clinicians whose patients with diabetes ask them about ricezempic?
Dr. Laing: I would not suggest that patients rely on ricezempic to support their health. There is no scientific evidence to show that people will lose weight in the short or long term by drinking ricezempic before a meal (or as a meal replacement).
If your patients are aiming to increase their intake of prebiotics, they are naturally found in various vegetables, fruits, whole grains, and seeds and in yogurt and high-fiber breads and cereals. A nutritious eating pattern that includes these foods is most beneficial for health.
A version of this article first appeared on Medscape.com.
FDA Withdraws Melflufen Approval, but EMA Still Allows Its Use
But the European Medicines Agency (EMA) still authorizes the drug’s manufacturer Oncopeptides AB to market the drug, also called Pepaxti, in Europe, Iceland, Lichtenstein, Norway, and the United Kingdom.
Amol Akhade, MBBS, who describes himself as a senior consultant medical and hemato oncologist–bone marrow transplant physician on LinkedIn, raised questions about the inconsistencies between the FDA and EMA’s opinions about these drugs. Dr. Akhad, of Suyog Cancer Clinics in India, posted via the following handle @SuyogCancer on X (Twitter):
“How can one drug and one trial data [have] two diagonally different outcomes from two different drug approval agencies?
Melphalan Flufenamide is finally completely withdrawn by @US_FDA
But approval by @EMA_News stays.
How can be one drug be harmful across one side of Atlantic Ocean and becomes safe and useful on the other side of Atlantic Ocean?
Modern day miracle?”
EMA: Pepaxti’s Benefits Exceed Its Risks
The EMA, which could not be reached for comment regarding why the agency was still allowing patients to use the drug, said the following about Pepaxti on its website:
“The European Medicines Agency decided that Pepaxti’s benefits are greater than its risks and it can be authorised for use in the EU. The Agency noted the unmet medical need for patients with multiple myeloma who no longer improve with the available therapies. Despite some limitations in the studies, the results were considered clinically relevant, with the exception of the subgroup of patients who had an autologous stem cell transplant and whose disease progressed within three years of transplantation.
Regarding safety, although side effects, including severe effects, were seen with treatment involving Pepaxti, these were considered acceptable and manageable,” the agency wrote.
“Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Pepaxti have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Pepaxti are continuously monitored. Suspected side effects reported with Pepaxti are carefully evaluated and any necessary action taken to protect patients,” according to the EMA.
The FDA’s final decision, issued on February 23, 2024, follows its warning in 2021 that meflufen plus dexamethasone exposed patients with multiple myeloma to increased risk for death, and its call for withdrawal of the drug in 2022.
“The grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use,” Peter Marks, MD, PhD, Director of the FDA Center for Biologics Evaluation and Research, wrote in the final decision document.
Oncopeptides AB: Drug ‘Caters to a Large Unmet Need’
David Augustsson, Director of Corporate Affairs, Oncopeptides AB, explained in an interview why he thinks the EMA and FDA’s actions regarding the drug differ from each other.
“The European Medicines Agency had the opinion that the OCEAN study met its primary endpoint by demonstrating superior progression-free survival and it agreed that the potential detriment of overall survival was limited to patients progressing less than 36 months after an autologous stem cell transplant,” he said.“The FDA was not willing to acknowledge the observed clinically relevant differences across patient subgroups in the OCEAN study as confirmed.”
Mr. Augustsson added that this decision will deprive US patients of access to “a drug we believe caters to a large unmet need among elderly multiple myeloma patients with few treatment options left.”
“While we remain confident that we have science on our side we are of course disappointed in the decision [to remove Pepaxto from the US market],” Oncopeptides AB CEO Sofia Heigis said in a statement. “At the same time this is no change to our plans and we will continue to focus all our attention on the commercialization in Europe, progression of our pipeline and rest of world opportunities.”
FDA 'Took Swift Action' to Ensure Users of Pepaxto Were Informed of Risks
In February 2021, the FDA used the Accelerated Approval Program to enable certain patients with multiple myeloma to be treated with the peptide conjugated alkylating drug melflufen plus dexamethasone. Under the program, Oncopeptides was required to conduct the phase III randomized, controlled OCEAN clinical trial.
OCEAN enrolled 495 patients with relapsed/refractory multiple myeloma who had 2 to 4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy. Participants in the multinational study received either melflufen plus dexamethasone or pomalidomide plus dexamethasone until disease progression, unacceptable toxicity, or lack of benefit.
In July 2021, the FDA issued an alert that the study results showed increased risk for death in participants treated with melflufen. In October that year, at FDA request, Oncopeptides removed the drug from the US market but continued to provide it to patients already receiving it. In December 2022, the FDA requested that the company withdraw melflufen’s US marketing authorization.
Responding to questions about the timing of the FDA’s most recent decision about Pepaxto and how the decision will affect patient care in the US, the FDA emailed the following statement to this news organization:
“Since the OCEAN trial results for Pepaxto in 2021, the FDA has responded to safety concerns about Pepaxto by issuing a CDER Alert, communicating concerns to Oncopeptides, holding an Oncologic Drugs Advisory Committee meeting in September 2022, and issuing a letter of notice to Oncopeptides in July 2023, proposing to withdraw Pepaxto (NDA 214383). After receiving the notice, Oncopeptides appealed the withdrawal in August 2023. A meeting was held with the Commissioner’s designee, Dr. Peter Marks, Oncopeptides, and others from FDA in October 2023. Dr. Marks reviewed the record and considered the arguments made on appeal and issued a final decision on February 23, 2024. Prior to reaching a decision, the FDA took swift action to ensure those receiving Pepaxto in the post-confirmatory clinical trial were informed of the risks and that no new patients were enrolled in the trial. We also note that it is our understanding that Pepaxto has not been marketed in the U.S. since October 22, 2021.”
“This is the first time FDA has used the amended procedures for withdrawal of accelerated approval that were enacted in 2023, as part of the Food and Drug Omnibus Report Act of 2022 (FDORA),” the agency wrote in a Feb 23 statement. The agency will also remove melflufen from the Approved Drug Products with Therapeutic Equivalence Evaluations, also called the Orange Book.
But the European Medicines Agency (EMA) still authorizes the drug’s manufacturer Oncopeptides AB to market the drug, also called Pepaxti, in Europe, Iceland, Lichtenstein, Norway, and the United Kingdom.
Amol Akhade, MBBS, who describes himself as a senior consultant medical and hemato oncologist–bone marrow transplant physician on LinkedIn, raised questions about the inconsistencies between the FDA and EMA’s opinions about these drugs. Dr. Akhad, of Suyog Cancer Clinics in India, posted via the following handle @SuyogCancer on X (Twitter):
“How can one drug and one trial data [have] two diagonally different outcomes from two different drug approval agencies?
Melphalan Flufenamide is finally completely withdrawn by @US_FDA
But approval by @EMA_News stays.
How can be one drug be harmful across one side of Atlantic Ocean and becomes safe and useful on the other side of Atlantic Ocean?
Modern day miracle?”
EMA: Pepaxti’s Benefits Exceed Its Risks
The EMA, which could not be reached for comment regarding why the agency was still allowing patients to use the drug, said the following about Pepaxti on its website:
“The European Medicines Agency decided that Pepaxti’s benefits are greater than its risks and it can be authorised for use in the EU. The Agency noted the unmet medical need for patients with multiple myeloma who no longer improve with the available therapies. Despite some limitations in the studies, the results were considered clinically relevant, with the exception of the subgroup of patients who had an autologous stem cell transplant and whose disease progressed within three years of transplantation.
Regarding safety, although side effects, including severe effects, were seen with treatment involving Pepaxti, these were considered acceptable and manageable,” the agency wrote.
“Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Pepaxti have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Pepaxti are continuously monitored. Suspected side effects reported with Pepaxti are carefully evaluated and any necessary action taken to protect patients,” according to the EMA.
The FDA’s final decision, issued on February 23, 2024, follows its warning in 2021 that meflufen plus dexamethasone exposed patients with multiple myeloma to increased risk for death, and its call for withdrawal of the drug in 2022.
“The grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use,” Peter Marks, MD, PhD, Director of the FDA Center for Biologics Evaluation and Research, wrote in the final decision document.
Oncopeptides AB: Drug ‘Caters to a Large Unmet Need’
David Augustsson, Director of Corporate Affairs, Oncopeptides AB, explained in an interview why he thinks the EMA and FDA’s actions regarding the drug differ from each other.
“The European Medicines Agency had the opinion that the OCEAN study met its primary endpoint by demonstrating superior progression-free survival and it agreed that the potential detriment of overall survival was limited to patients progressing less than 36 months after an autologous stem cell transplant,” he said.“The FDA was not willing to acknowledge the observed clinically relevant differences across patient subgroups in the OCEAN study as confirmed.”
Mr. Augustsson added that this decision will deprive US patients of access to “a drug we believe caters to a large unmet need among elderly multiple myeloma patients with few treatment options left.”
“While we remain confident that we have science on our side we are of course disappointed in the decision [to remove Pepaxto from the US market],” Oncopeptides AB CEO Sofia Heigis said in a statement. “At the same time this is no change to our plans and we will continue to focus all our attention on the commercialization in Europe, progression of our pipeline and rest of world opportunities.”
FDA 'Took Swift Action' to Ensure Users of Pepaxto Were Informed of Risks
In February 2021, the FDA used the Accelerated Approval Program to enable certain patients with multiple myeloma to be treated with the peptide conjugated alkylating drug melflufen plus dexamethasone. Under the program, Oncopeptides was required to conduct the phase III randomized, controlled OCEAN clinical trial.
OCEAN enrolled 495 patients with relapsed/refractory multiple myeloma who had 2 to 4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy. Participants in the multinational study received either melflufen plus dexamethasone or pomalidomide plus dexamethasone until disease progression, unacceptable toxicity, or lack of benefit.
In July 2021, the FDA issued an alert that the study results showed increased risk for death in participants treated with melflufen. In October that year, at FDA request, Oncopeptides removed the drug from the US market but continued to provide it to patients already receiving it. In December 2022, the FDA requested that the company withdraw melflufen’s US marketing authorization.
Responding to questions about the timing of the FDA’s most recent decision about Pepaxto and how the decision will affect patient care in the US, the FDA emailed the following statement to this news organization:
“Since the OCEAN trial results for Pepaxto in 2021, the FDA has responded to safety concerns about Pepaxto by issuing a CDER Alert, communicating concerns to Oncopeptides, holding an Oncologic Drugs Advisory Committee meeting in September 2022, and issuing a letter of notice to Oncopeptides in July 2023, proposing to withdraw Pepaxto (NDA 214383). After receiving the notice, Oncopeptides appealed the withdrawal in August 2023. A meeting was held with the Commissioner’s designee, Dr. Peter Marks, Oncopeptides, and others from FDA in October 2023. Dr. Marks reviewed the record and considered the arguments made on appeal and issued a final decision on February 23, 2024. Prior to reaching a decision, the FDA took swift action to ensure those receiving Pepaxto in the post-confirmatory clinical trial were informed of the risks and that no new patients were enrolled in the trial. We also note that it is our understanding that Pepaxto has not been marketed in the U.S. since October 22, 2021.”
“This is the first time FDA has used the amended procedures for withdrawal of accelerated approval that were enacted in 2023, as part of the Food and Drug Omnibus Report Act of 2022 (FDORA),” the agency wrote in a Feb 23 statement. The agency will also remove melflufen from the Approved Drug Products with Therapeutic Equivalence Evaluations, also called the Orange Book.
But the European Medicines Agency (EMA) still authorizes the drug’s manufacturer Oncopeptides AB to market the drug, also called Pepaxti, in Europe, Iceland, Lichtenstein, Norway, and the United Kingdom.
Amol Akhade, MBBS, who describes himself as a senior consultant medical and hemato oncologist–bone marrow transplant physician on LinkedIn, raised questions about the inconsistencies between the FDA and EMA’s opinions about these drugs. Dr. Akhad, of Suyog Cancer Clinics in India, posted via the following handle @SuyogCancer on X (Twitter):
“How can one drug and one trial data [have] two diagonally different outcomes from two different drug approval agencies?
Melphalan Flufenamide is finally completely withdrawn by @US_FDA
But approval by @EMA_News stays.
How can be one drug be harmful across one side of Atlantic Ocean and becomes safe and useful on the other side of Atlantic Ocean?
Modern day miracle?”
EMA: Pepaxti’s Benefits Exceed Its Risks
The EMA, which could not be reached for comment regarding why the agency was still allowing patients to use the drug, said the following about Pepaxti on its website:
“The European Medicines Agency decided that Pepaxti’s benefits are greater than its risks and it can be authorised for use in the EU. The Agency noted the unmet medical need for patients with multiple myeloma who no longer improve with the available therapies. Despite some limitations in the studies, the results were considered clinically relevant, with the exception of the subgroup of patients who had an autologous stem cell transplant and whose disease progressed within three years of transplantation.
Regarding safety, although side effects, including severe effects, were seen with treatment involving Pepaxti, these were considered acceptable and manageable,” the agency wrote.
“Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Pepaxti have been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Pepaxti are continuously monitored. Suspected side effects reported with Pepaxti are carefully evaluated and any necessary action taken to protect patients,” according to the EMA.
The FDA’s final decision, issued on February 23, 2024, follows its warning in 2021 that meflufen plus dexamethasone exposed patients with multiple myeloma to increased risk for death, and its call for withdrawal of the drug in 2022.
“The grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use,” Peter Marks, MD, PhD, Director of the FDA Center for Biologics Evaluation and Research, wrote in the final decision document.
Oncopeptides AB: Drug ‘Caters to a Large Unmet Need’
David Augustsson, Director of Corporate Affairs, Oncopeptides AB, explained in an interview why he thinks the EMA and FDA’s actions regarding the drug differ from each other.
“The European Medicines Agency had the opinion that the OCEAN study met its primary endpoint by demonstrating superior progression-free survival and it agreed that the potential detriment of overall survival was limited to patients progressing less than 36 months after an autologous stem cell transplant,” he said.“The FDA was not willing to acknowledge the observed clinically relevant differences across patient subgroups in the OCEAN study as confirmed.”
Mr. Augustsson added that this decision will deprive US patients of access to “a drug we believe caters to a large unmet need among elderly multiple myeloma patients with few treatment options left.”
“While we remain confident that we have science on our side we are of course disappointed in the decision [to remove Pepaxto from the US market],” Oncopeptides AB CEO Sofia Heigis said in a statement. “At the same time this is no change to our plans and we will continue to focus all our attention on the commercialization in Europe, progression of our pipeline and rest of world opportunities.”
FDA 'Took Swift Action' to Ensure Users of Pepaxto Were Informed of Risks
In February 2021, the FDA used the Accelerated Approval Program to enable certain patients with multiple myeloma to be treated with the peptide conjugated alkylating drug melflufen plus dexamethasone. Under the program, Oncopeptides was required to conduct the phase III randomized, controlled OCEAN clinical trial.
OCEAN enrolled 495 patients with relapsed/refractory multiple myeloma who had 2 to 4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy. Participants in the multinational study received either melflufen plus dexamethasone or pomalidomide plus dexamethasone until disease progression, unacceptable toxicity, or lack of benefit.
In July 2021, the FDA issued an alert that the study results showed increased risk for death in participants treated with melflufen. In October that year, at FDA request, Oncopeptides removed the drug from the US market but continued to provide it to patients already receiving it. In December 2022, the FDA requested that the company withdraw melflufen’s US marketing authorization.
Responding to questions about the timing of the FDA’s most recent decision about Pepaxto and how the decision will affect patient care in the US, the FDA emailed the following statement to this news organization:
“Since the OCEAN trial results for Pepaxto in 2021, the FDA has responded to safety concerns about Pepaxto by issuing a CDER Alert, communicating concerns to Oncopeptides, holding an Oncologic Drugs Advisory Committee meeting in September 2022, and issuing a letter of notice to Oncopeptides in July 2023, proposing to withdraw Pepaxto (NDA 214383). After receiving the notice, Oncopeptides appealed the withdrawal in August 2023. A meeting was held with the Commissioner’s designee, Dr. Peter Marks, Oncopeptides, and others from FDA in October 2023. Dr. Marks reviewed the record and considered the arguments made on appeal and issued a final decision on February 23, 2024. Prior to reaching a decision, the FDA took swift action to ensure those receiving Pepaxto in the post-confirmatory clinical trial were informed of the risks and that no new patients were enrolled in the trial. We also note that it is our understanding that Pepaxto has not been marketed in the U.S. since October 22, 2021.”
“This is the first time FDA has used the amended procedures for withdrawal of accelerated approval that were enacted in 2023, as part of the Food and Drug Omnibus Report Act of 2022 (FDORA),” the agency wrote in a Feb 23 statement. The agency will also remove melflufen from the Approved Drug Products with Therapeutic Equivalence Evaluations, also called the Orange Book.
Dupilumab Improves AD Affecting the Hands, Feet
TOPLINE:
compared with placebo.
METHODOLOGY:
- The multinational phase 3 LIBERTY-AD-HAFT trial of adults and adolescents with moderate to severe chronic atopic dermatitis (AD) of the hands, feet, or both included 67 participants at 48 sites randomized to dupilumab monotherapy and 66 to placebo.
- The primary endpoint was the proportion of patients scoring 0 or 1 on Hand and Foot Investigator’s Global Assessment (HF-IGA) at week 16.
- Secondary endpoints were severity and extent of signs, symptom intensity (itch and pain), sleep, and quality of life.
TAKEAWAY:
- At week 16, 27 patients receiving dupilumab vs 11 receiving placebo achieved an HF-IGA score of 0 or 1 (40.3% vs 16.7%; P = .003).
- At week 16, 35 participants receiving dupilumab vs nine receiving placebo improved at least four points in the weekly average of daily HF-Peak Pruritus Numeric Rating Scale (52.2% vs 13.6%; P < .0001).
- At week 16, Quality of Life Hand Eczema Questionnaire results improved in the dupilumab group compared with controls (P < .0001), and weekly average of daily Sleep Numeric Rating Scale results improved in the dupilumab group compared with controls (P < .05).
- The safety profile was similar to the known profile in adults and adolescents with moderate to severe AD.
IN PRACTICE:
The results of the study “support dupilumab” as an “efficacious systemic therapy for moderate to severe H/F AD,” the authors wrote.
SOURCE:
The study, led by Eric L. Simpson, MD, MCR, professor of dermatology at the Oregon Health & Science University in Portland, was published on January 29, 2024, in the Journal of the American Academy of Dermatology.
LIMITATIONS:
The short duration of the study and the large proportion of patients with positive patch tests (31 of 133) suggested that some participants may have had concurrent AD and allergic contact dermatitis, so the effect of dupilumab on those patients needs further evaluation.
DISCLOSURES:
The study was sponsored by Sanofi and Regeneron. All but one author had financial relationships with Sanofi, Regeneron, or both. Several authors were employees of, and may hold stocks or stock options in, Sanofi or Regeneron.
TOPLINE:
compared with placebo.
METHODOLOGY:
- The multinational phase 3 LIBERTY-AD-HAFT trial of adults and adolescents with moderate to severe chronic atopic dermatitis (AD) of the hands, feet, or both included 67 participants at 48 sites randomized to dupilumab monotherapy and 66 to placebo.
- The primary endpoint was the proportion of patients scoring 0 or 1 on Hand and Foot Investigator’s Global Assessment (HF-IGA) at week 16.
- Secondary endpoints were severity and extent of signs, symptom intensity (itch and pain), sleep, and quality of life.
TAKEAWAY:
- At week 16, 27 patients receiving dupilumab vs 11 receiving placebo achieved an HF-IGA score of 0 or 1 (40.3% vs 16.7%; P = .003).
- At week 16, 35 participants receiving dupilumab vs nine receiving placebo improved at least four points in the weekly average of daily HF-Peak Pruritus Numeric Rating Scale (52.2% vs 13.6%; P < .0001).
- At week 16, Quality of Life Hand Eczema Questionnaire results improved in the dupilumab group compared with controls (P < .0001), and weekly average of daily Sleep Numeric Rating Scale results improved in the dupilumab group compared with controls (P < .05).
- The safety profile was similar to the known profile in adults and adolescents with moderate to severe AD.
IN PRACTICE:
The results of the study “support dupilumab” as an “efficacious systemic therapy for moderate to severe H/F AD,” the authors wrote.
SOURCE:
The study, led by Eric L. Simpson, MD, MCR, professor of dermatology at the Oregon Health & Science University in Portland, was published on January 29, 2024, in the Journal of the American Academy of Dermatology.
LIMITATIONS:
The short duration of the study and the large proportion of patients with positive patch tests (31 of 133) suggested that some participants may have had concurrent AD and allergic contact dermatitis, so the effect of dupilumab on those patients needs further evaluation.
DISCLOSURES:
The study was sponsored by Sanofi and Regeneron. All but one author had financial relationships with Sanofi, Regeneron, or both. Several authors were employees of, and may hold stocks or stock options in, Sanofi or Regeneron.
TOPLINE:
compared with placebo.
METHODOLOGY:
- The multinational phase 3 LIBERTY-AD-HAFT trial of adults and adolescents with moderate to severe chronic atopic dermatitis (AD) of the hands, feet, or both included 67 participants at 48 sites randomized to dupilumab monotherapy and 66 to placebo.
- The primary endpoint was the proportion of patients scoring 0 or 1 on Hand and Foot Investigator’s Global Assessment (HF-IGA) at week 16.
- Secondary endpoints were severity and extent of signs, symptom intensity (itch and pain), sleep, and quality of life.
TAKEAWAY:
- At week 16, 27 patients receiving dupilumab vs 11 receiving placebo achieved an HF-IGA score of 0 or 1 (40.3% vs 16.7%; P = .003).
- At week 16, 35 participants receiving dupilumab vs nine receiving placebo improved at least four points in the weekly average of daily HF-Peak Pruritus Numeric Rating Scale (52.2% vs 13.6%; P < .0001).
- At week 16, Quality of Life Hand Eczema Questionnaire results improved in the dupilumab group compared with controls (P < .0001), and weekly average of daily Sleep Numeric Rating Scale results improved in the dupilumab group compared with controls (P < .05).
- The safety profile was similar to the known profile in adults and adolescents with moderate to severe AD.
IN PRACTICE:
The results of the study “support dupilumab” as an “efficacious systemic therapy for moderate to severe H/F AD,” the authors wrote.
SOURCE:
The study, led by Eric L. Simpson, MD, MCR, professor of dermatology at the Oregon Health & Science University in Portland, was published on January 29, 2024, in the Journal of the American Academy of Dermatology.
LIMITATIONS:
The short duration of the study and the large proportion of patients with positive patch tests (31 of 133) suggested that some participants may have had concurrent AD and allergic contact dermatitis, so the effect of dupilumab on those patients needs further evaluation.
DISCLOSURES:
The study was sponsored by Sanofi and Regeneron. All but one author had financial relationships with Sanofi, Regeneron, or both. Several authors were employees of, and may hold stocks or stock options in, Sanofi or Regeneron.
Combined rituximab and omalizumab promising for refractory bullous pemphigoid
who do not respond to rituximab alone, results of a case series suggest.
Bullous pemphigoid (BP) is a rare, chronic, inflammatory, blistering disease that mainly occurs in people in their 50s through their 70s. BP has high morbidity and mortality, especially in people with comorbidities common to the elderly, yet no Food and Drug Administration–approved therapies for BP exist, Stephanie T. Le, MD, a dermatologist in the department of dermatology of the University of California, Davis, told this publication.
“BP is typically thought of as an IgG-mediated disease, but many BP patients also have elevated levels of total circulating IgE levels, which has been linked to hallmarks of bullous pemphigoid, including blisters,” Dr. Le said. “These findings suggest that ideal BP treatments, such as rituximab and omalizumab, should target both IgG and IgE.”
In a study published in JAMA Dermatology, Dr. Le and her coauthors analyzed the electronic medical record data of adult patients with BP who were treated with combined rituximab and omalizumab at UC Davis between 2015 and 2022. The 10 patients who met their selection criteria averaged 62 years of age. Most were female, and most were non-Hispanic White. All had severe BP, with an initial mean BP Disease Area index score of 170, and all applied whole-body topical corticosteroid for treatment.
All participants received 1000 mg intravenous rituximab on days 0 and 15. In addition to rituximab, seven patients received subcutaneous high-dose omalizumab (300 mg every 2 weeks); and three patients received low-dose omalizumab (300 mg every 4 weeks or 150 mg every 2 weeks).
After a mean of 2.1 months, all patients in the high-dose omalizumab-plus-rituximab group had achieved complete remission. By contrast, all patients in the low-dose omalizumab-plus-rituximab group improved after a mean of 13 months, and none achieved complete remission.
At 3 months, all study participants were rated as being very much improved. All four patients in the high-dose omalizumab group who tapered omalizumab dosage or frequency had flare-ups within 1-3 months that resolved when they restarted the medication. Among patients who achieved complete remission, 4 of 7 required rituximab redosing between 6 and 16 months later. Rituximab alone did not achieve remission: Three patients needed to add high-dose omalizumab. All reported adverse effects were mild.
Alternatives to Corticosteroids Are Needed
For BP, “with no FDA-approved therapies available, corticosteroids remain first line for acute flares. However, prolonged corticosteroid use is associated with multiple adverse effects, including increased susceptibility to infection, osteoporosis, and diabetes mellitus,” Dr. Le pointed out. “Patients with BP who are treated with high-dose corticosteroids have significantly increased mortality and have very poor 1-year survival.
“Rituximab and omalizumab dual therapy offers another potential treatment option for severe or treatment-refractory BP,” she added. “We are hopeful that other physicians will adopt this therapy.”
The authors acknowledged limitations of the study, including its retrospective design, small sample size, lack of standardized intervals between rituximab and omalizumab, and variation in concurrent therapies, and they recommended further related research.
No conflicts of interest were reported. No funding details were provided.
who do not respond to rituximab alone, results of a case series suggest.
Bullous pemphigoid (BP) is a rare, chronic, inflammatory, blistering disease that mainly occurs in people in their 50s through their 70s. BP has high morbidity and mortality, especially in people with comorbidities common to the elderly, yet no Food and Drug Administration–approved therapies for BP exist, Stephanie T. Le, MD, a dermatologist in the department of dermatology of the University of California, Davis, told this publication.
“BP is typically thought of as an IgG-mediated disease, but many BP patients also have elevated levels of total circulating IgE levels, which has been linked to hallmarks of bullous pemphigoid, including blisters,” Dr. Le said. “These findings suggest that ideal BP treatments, such as rituximab and omalizumab, should target both IgG and IgE.”
In a study published in JAMA Dermatology, Dr. Le and her coauthors analyzed the electronic medical record data of adult patients with BP who were treated with combined rituximab and omalizumab at UC Davis between 2015 and 2022. The 10 patients who met their selection criteria averaged 62 years of age. Most were female, and most were non-Hispanic White. All had severe BP, with an initial mean BP Disease Area index score of 170, and all applied whole-body topical corticosteroid for treatment.
All participants received 1000 mg intravenous rituximab on days 0 and 15. In addition to rituximab, seven patients received subcutaneous high-dose omalizumab (300 mg every 2 weeks); and three patients received low-dose omalizumab (300 mg every 4 weeks or 150 mg every 2 weeks).
After a mean of 2.1 months, all patients in the high-dose omalizumab-plus-rituximab group had achieved complete remission. By contrast, all patients in the low-dose omalizumab-plus-rituximab group improved after a mean of 13 months, and none achieved complete remission.
At 3 months, all study participants were rated as being very much improved. All four patients in the high-dose omalizumab group who tapered omalizumab dosage or frequency had flare-ups within 1-3 months that resolved when they restarted the medication. Among patients who achieved complete remission, 4 of 7 required rituximab redosing between 6 and 16 months later. Rituximab alone did not achieve remission: Three patients needed to add high-dose omalizumab. All reported adverse effects were mild.
Alternatives to Corticosteroids Are Needed
For BP, “with no FDA-approved therapies available, corticosteroids remain first line for acute flares. However, prolonged corticosteroid use is associated with multiple adverse effects, including increased susceptibility to infection, osteoporosis, and diabetes mellitus,” Dr. Le pointed out. “Patients with BP who are treated with high-dose corticosteroids have significantly increased mortality and have very poor 1-year survival.
“Rituximab and omalizumab dual therapy offers another potential treatment option for severe or treatment-refractory BP,” she added. “We are hopeful that other physicians will adopt this therapy.”
The authors acknowledged limitations of the study, including its retrospective design, small sample size, lack of standardized intervals between rituximab and omalizumab, and variation in concurrent therapies, and they recommended further related research.
No conflicts of interest were reported. No funding details were provided.
who do not respond to rituximab alone, results of a case series suggest.
Bullous pemphigoid (BP) is a rare, chronic, inflammatory, blistering disease that mainly occurs in people in their 50s through their 70s. BP has high morbidity and mortality, especially in people with comorbidities common to the elderly, yet no Food and Drug Administration–approved therapies for BP exist, Stephanie T. Le, MD, a dermatologist in the department of dermatology of the University of California, Davis, told this publication.
“BP is typically thought of as an IgG-mediated disease, but many BP patients also have elevated levels of total circulating IgE levels, which has been linked to hallmarks of bullous pemphigoid, including blisters,” Dr. Le said. “These findings suggest that ideal BP treatments, such as rituximab and omalizumab, should target both IgG and IgE.”
In a study published in JAMA Dermatology, Dr. Le and her coauthors analyzed the electronic medical record data of adult patients with BP who were treated with combined rituximab and omalizumab at UC Davis between 2015 and 2022. The 10 patients who met their selection criteria averaged 62 years of age. Most were female, and most were non-Hispanic White. All had severe BP, with an initial mean BP Disease Area index score of 170, and all applied whole-body topical corticosteroid for treatment.
All participants received 1000 mg intravenous rituximab on days 0 and 15. In addition to rituximab, seven patients received subcutaneous high-dose omalizumab (300 mg every 2 weeks); and three patients received low-dose omalizumab (300 mg every 4 weeks or 150 mg every 2 weeks).
After a mean of 2.1 months, all patients in the high-dose omalizumab-plus-rituximab group had achieved complete remission. By contrast, all patients in the low-dose omalizumab-plus-rituximab group improved after a mean of 13 months, and none achieved complete remission.
At 3 months, all study participants were rated as being very much improved. All four patients in the high-dose omalizumab group who tapered omalizumab dosage or frequency had flare-ups within 1-3 months that resolved when they restarted the medication. Among patients who achieved complete remission, 4 of 7 required rituximab redosing between 6 and 16 months later. Rituximab alone did not achieve remission: Three patients needed to add high-dose omalizumab. All reported adverse effects were mild.
Alternatives to Corticosteroids Are Needed
For BP, “with no FDA-approved therapies available, corticosteroids remain first line for acute flares. However, prolonged corticosteroid use is associated with multiple adverse effects, including increased susceptibility to infection, osteoporosis, and diabetes mellitus,” Dr. Le pointed out. “Patients with BP who are treated with high-dose corticosteroids have significantly increased mortality and have very poor 1-year survival.
“Rituximab and omalizumab dual therapy offers another potential treatment option for severe or treatment-refractory BP,” she added. “We are hopeful that other physicians will adopt this therapy.”
The authors acknowledged limitations of the study, including its retrospective design, small sample size, lack of standardized intervals between rituximab and omalizumab, and variation in concurrent therapies, and they recommended further related research.
No conflicts of interest were reported. No funding details were provided.
FROM JAMA DERMATOLOGY
Meet the newest acronym in primary care: CKM
The advisory, published recently in Circulation introduces the concept of CKM health and reevaluates the relationships between obesity, diabetes, kidney disease, and cardiovascular disease (CVD).
“This approach not only raises awareness, it also empowers PCPs to diagnose and treat these conditions more holistically,” Salim Hayek, MD, associate professor of cardiovascular disease and internal medicine, and medical director of the Frankel Cardiovascular Center Clinics at the University of Michigan in Ann Arbor, said in an interview.
New CKM Staging, Testing, and Care Strategies
The advisory introduces a new scoring system that ranges from stage 0 (patients with no risk factors for CKM) through stage 4 (patients with clinical CVD in CKM syndrome). Each stage requires specific management strategies and may include screening starting at age 30 years for diabetes, hypertension, and heart failure.
“Stage 0 CKM is usually found in young people, and CKM risk factors and scores typically increase as people age,” said Sean M. Drake, MD, a primary care physician at Henry Ford Health in Sterling Heights, Michigan.
Dr. Drake advised PCPs to encourage patients who are at stage 0 to maintain ideal cardiovascular health and to monitor those at risk of progressing through the stages.
While PCPs already perform many of the tests the advisory recommends, the conditions overlap and an abnormality in one system should prompt more testing for other conditions. Additional tests, such as urine albumin-creatinine ratio, and more frequent glomerular filtration rate and lipid profile are advised, according to Dr. Drake.
“There also appears to be a role for additional cardiac testing, including echocardiograms and coronary CT scans, and for liver fibrosis screening,” Dr. Drake said. “Medications such as SGLT2 inhibitors, GLP-1 receptor agonists, and ACE inhibitors, beyond current routine use, are emphasized.”
To better characterize body composition and help diagnose metabolic syndrome, the advisory also recommends measuring waist circumference, which is not routine practice, noted Joshua J. Joseph, MD, MPH, an associate professor of endocrinology, diabetes, and metabolism at The Ohio State University Wexner Medical Center in Columbus, and a co-author of the advisory.
Recognizing the interconnected nature of cardiac, kidney, and metabolic diseases encourages a shift in mindset for clinicians, according to Neha Pagidipati, MD, MPH, a cardiologist at Duke Health in Durham, North Carolina.
“We have often been trained to focus on the specific problem in front of us,” Dr. Pagidipati said. “We need to be hyper-aware that many patients we see are at risk for multiple CKM entities. We need to be proactive about screening for and treating these when appropriate.”
The advisory emphasizes the need for CKM coordinators to support teams of clinicians from primary care, cardiology, endocrinology, nephrology, nursing, and pharmacy, as well as social workers, care navigators, or community health workers, Dr. Joseph said.
“The advisory repositions the PCP at the forefront of CKM care coordination, marking a departure from the traditional model where subspecialists primarily manage complications,” Dr. Hayek added.
Changes to Payment
The new recommendations are consistent with current management guidelines for obesity, hypertriglyceridemia, hypertension, type 2 diabetes, and chronic kidney disease.
“The advisory provides integrated algorithms for cardiovascular prevention and management, with specific therapeutic guidance tied to CKM stages, bringing together the current evidence for best practices from the various guidelines and filling gaps in a unified approach,” Dr. Joseph said.
In addition, the advisory draws attention to the care of younger patients, who may be at increased risk for cardiovascular disease due to lifestyle factors, according to Nishant Shah, MD, assistant professor of medicine at Duke.
“It considers barriers to care that prevent people from optimizing their cardiovascular health,” Dr. Shah said.
Although the advisory does not specify proposed payment changes to support the new care model, the move towards value-based care may require billing practices that accommodate integrated care as well as more frequent and more specialized testing, Dr. Hayek said.
“The advisory is an empowering tool for PCPs, underscoring their critical role in healthcare,” Dr. Hayek said. “It encourages PCPs to advocate for integrated care within their practices and to consider workflow adjustments that enhance the identification and initiation of preventive care for at-risk patients.”
Funding information was not provided.
Dr. Joseph reports no relevant financial involvements; several advisory co-authors report financial involvements with pharmaceutical companies. Dr. Pagidipati reports relevant financial involvement with pharmaceutical companies. Dr. Hayek, Dr. Drake, and Dr. Shah report no relevant financial involvements. Dr. Joseph is an author of the advisory. Dr. Pagidipati, Dr. Hayek, Dr. Drake, and Dr. Shah were not involved in the writing of the advisory.
A version of this article appeared on Medscape.com.
The advisory, published recently in Circulation introduces the concept of CKM health and reevaluates the relationships between obesity, diabetes, kidney disease, and cardiovascular disease (CVD).
“This approach not only raises awareness, it also empowers PCPs to diagnose and treat these conditions more holistically,” Salim Hayek, MD, associate professor of cardiovascular disease and internal medicine, and medical director of the Frankel Cardiovascular Center Clinics at the University of Michigan in Ann Arbor, said in an interview.
New CKM Staging, Testing, and Care Strategies
The advisory introduces a new scoring system that ranges from stage 0 (patients with no risk factors for CKM) through stage 4 (patients with clinical CVD in CKM syndrome). Each stage requires specific management strategies and may include screening starting at age 30 years for diabetes, hypertension, and heart failure.
“Stage 0 CKM is usually found in young people, and CKM risk factors and scores typically increase as people age,” said Sean M. Drake, MD, a primary care physician at Henry Ford Health in Sterling Heights, Michigan.
Dr. Drake advised PCPs to encourage patients who are at stage 0 to maintain ideal cardiovascular health and to monitor those at risk of progressing through the stages.
While PCPs already perform many of the tests the advisory recommends, the conditions overlap and an abnormality in one system should prompt more testing for other conditions. Additional tests, such as urine albumin-creatinine ratio, and more frequent glomerular filtration rate and lipid profile are advised, according to Dr. Drake.
“There also appears to be a role for additional cardiac testing, including echocardiograms and coronary CT scans, and for liver fibrosis screening,” Dr. Drake said. “Medications such as SGLT2 inhibitors, GLP-1 receptor agonists, and ACE inhibitors, beyond current routine use, are emphasized.”
To better characterize body composition and help diagnose metabolic syndrome, the advisory also recommends measuring waist circumference, which is not routine practice, noted Joshua J. Joseph, MD, MPH, an associate professor of endocrinology, diabetes, and metabolism at The Ohio State University Wexner Medical Center in Columbus, and a co-author of the advisory.
Recognizing the interconnected nature of cardiac, kidney, and metabolic diseases encourages a shift in mindset for clinicians, according to Neha Pagidipati, MD, MPH, a cardiologist at Duke Health in Durham, North Carolina.
“We have often been trained to focus on the specific problem in front of us,” Dr. Pagidipati said. “We need to be hyper-aware that many patients we see are at risk for multiple CKM entities. We need to be proactive about screening for and treating these when appropriate.”
The advisory emphasizes the need for CKM coordinators to support teams of clinicians from primary care, cardiology, endocrinology, nephrology, nursing, and pharmacy, as well as social workers, care navigators, or community health workers, Dr. Joseph said.
“The advisory repositions the PCP at the forefront of CKM care coordination, marking a departure from the traditional model where subspecialists primarily manage complications,” Dr. Hayek added.
Changes to Payment
The new recommendations are consistent with current management guidelines for obesity, hypertriglyceridemia, hypertension, type 2 diabetes, and chronic kidney disease.
“The advisory provides integrated algorithms for cardiovascular prevention and management, with specific therapeutic guidance tied to CKM stages, bringing together the current evidence for best practices from the various guidelines and filling gaps in a unified approach,” Dr. Joseph said.
In addition, the advisory draws attention to the care of younger patients, who may be at increased risk for cardiovascular disease due to lifestyle factors, according to Nishant Shah, MD, assistant professor of medicine at Duke.
“It considers barriers to care that prevent people from optimizing their cardiovascular health,” Dr. Shah said.
Although the advisory does not specify proposed payment changes to support the new care model, the move towards value-based care may require billing practices that accommodate integrated care as well as more frequent and more specialized testing, Dr. Hayek said.
“The advisory is an empowering tool for PCPs, underscoring their critical role in healthcare,” Dr. Hayek said. “It encourages PCPs to advocate for integrated care within their practices and to consider workflow adjustments that enhance the identification and initiation of preventive care for at-risk patients.”
Funding information was not provided.
Dr. Joseph reports no relevant financial involvements; several advisory co-authors report financial involvements with pharmaceutical companies. Dr. Pagidipati reports relevant financial involvement with pharmaceutical companies. Dr. Hayek, Dr. Drake, and Dr. Shah report no relevant financial involvements. Dr. Joseph is an author of the advisory. Dr. Pagidipati, Dr. Hayek, Dr. Drake, and Dr. Shah were not involved in the writing of the advisory.
A version of this article appeared on Medscape.com.
The advisory, published recently in Circulation introduces the concept of CKM health and reevaluates the relationships between obesity, diabetes, kidney disease, and cardiovascular disease (CVD).
“This approach not only raises awareness, it also empowers PCPs to diagnose and treat these conditions more holistically,” Salim Hayek, MD, associate professor of cardiovascular disease and internal medicine, and medical director of the Frankel Cardiovascular Center Clinics at the University of Michigan in Ann Arbor, said in an interview.
New CKM Staging, Testing, and Care Strategies
The advisory introduces a new scoring system that ranges from stage 0 (patients with no risk factors for CKM) through stage 4 (patients with clinical CVD in CKM syndrome). Each stage requires specific management strategies and may include screening starting at age 30 years for diabetes, hypertension, and heart failure.
“Stage 0 CKM is usually found in young people, and CKM risk factors and scores typically increase as people age,” said Sean M. Drake, MD, a primary care physician at Henry Ford Health in Sterling Heights, Michigan.
Dr. Drake advised PCPs to encourage patients who are at stage 0 to maintain ideal cardiovascular health and to monitor those at risk of progressing through the stages.
While PCPs already perform many of the tests the advisory recommends, the conditions overlap and an abnormality in one system should prompt more testing for other conditions. Additional tests, such as urine albumin-creatinine ratio, and more frequent glomerular filtration rate and lipid profile are advised, according to Dr. Drake.
“There also appears to be a role for additional cardiac testing, including echocardiograms and coronary CT scans, and for liver fibrosis screening,” Dr. Drake said. “Medications such as SGLT2 inhibitors, GLP-1 receptor agonists, and ACE inhibitors, beyond current routine use, are emphasized.”
To better characterize body composition and help diagnose metabolic syndrome, the advisory also recommends measuring waist circumference, which is not routine practice, noted Joshua J. Joseph, MD, MPH, an associate professor of endocrinology, diabetes, and metabolism at The Ohio State University Wexner Medical Center in Columbus, and a co-author of the advisory.
Recognizing the interconnected nature of cardiac, kidney, and metabolic diseases encourages a shift in mindset for clinicians, according to Neha Pagidipati, MD, MPH, a cardiologist at Duke Health in Durham, North Carolina.
“We have often been trained to focus on the specific problem in front of us,” Dr. Pagidipati said. “We need to be hyper-aware that many patients we see are at risk for multiple CKM entities. We need to be proactive about screening for and treating these when appropriate.”
The advisory emphasizes the need for CKM coordinators to support teams of clinicians from primary care, cardiology, endocrinology, nephrology, nursing, and pharmacy, as well as social workers, care navigators, or community health workers, Dr. Joseph said.
“The advisory repositions the PCP at the forefront of CKM care coordination, marking a departure from the traditional model where subspecialists primarily manage complications,” Dr. Hayek added.
Changes to Payment
The new recommendations are consistent with current management guidelines for obesity, hypertriglyceridemia, hypertension, type 2 diabetes, and chronic kidney disease.
“The advisory provides integrated algorithms for cardiovascular prevention and management, with specific therapeutic guidance tied to CKM stages, bringing together the current evidence for best practices from the various guidelines and filling gaps in a unified approach,” Dr. Joseph said.
In addition, the advisory draws attention to the care of younger patients, who may be at increased risk for cardiovascular disease due to lifestyle factors, according to Nishant Shah, MD, assistant professor of medicine at Duke.
“It considers barriers to care that prevent people from optimizing their cardiovascular health,” Dr. Shah said.
Although the advisory does not specify proposed payment changes to support the new care model, the move towards value-based care may require billing practices that accommodate integrated care as well as more frequent and more specialized testing, Dr. Hayek said.
“The advisory is an empowering tool for PCPs, underscoring their critical role in healthcare,” Dr. Hayek said. “It encourages PCPs to advocate for integrated care within their practices and to consider workflow adjustments that enhance the identification and initiation of preventive care for at-risk patients.”
Funding information was not provided.
Dr. Joseph reports no relevant financial involvements; several advisory co-authors report financial involvements with pharmaceutical companies. Dr. Pagidipati reports relevant financial involvement with pharmaceutical companies. Dr. Hayek, Dr. Drake, and Dr. Shah report no relevant financial involvements. Dr. Joseph is an author of the advisory. Dr. Pagidipati, Dr. Hayek, Dr. Drake, and Dr. Shah were not involved in the writing of the advisory.
A version of this article appeared on Medscape.com.
FROM CIRCULATION
Postmenopausal testosterone for low libido only, doctors say
Your patients may see ads claiming that testosterone replacement therapy (TRT) offers postmenopausal women health benefits beyond restored sex drive: that TRT can improve their mood, energy, and thinking and give them stronger bones and bigger muscles.
How accurate are these claims? According to six experts who talked with this news organization, not very.
“Right now in this country and around the world, testosterone’s only use in postmenopausal women is for libido,” said Adrian Sandra Dobs, MD, MHS, professor of medicine and director of the Johns Hopkins Clinical Research Network at Johns Hopkins Medicine, Baltimore.
“Treating postmenopausal women with testosterone is a rarity. Some physicians and some wellness centers make their money out of prescribing estrogen and testosterone to women in patches, gels, creams, capsules, pellets, and other forms. she added by phone.
“One has to be very careful about using testosterone in women,” Dr. Dobs cautioned. “There’s a lot of hype out there.”
Low testosterone in women has not been well studied, and no testosterone treatments for this condition have been approved by the U.S. Food and Drug Administration. Providers need to adjust male treatment data to their female patients, who require significantly lower doses than males. Contraindications and long-term side effects are poorly understood, said Mary Rosser, MD, PhD, assistant professor of women’s health and director of integrated women’s health at Columbia University Irving Medical Center, New York.
“Despite this preponderance of scientific evidence and recommendations, the myths about testosterone die hard, including that it improves women’s muscle function, endurance, and well-being,” Dr. Rosser said.
“Websites that use compounded products or pellets are not FDA-regulated; therefore, they have no responsibility to prove their claims. They can entice women into using this stuff with all kinds of promises about ‘hormone balancing’ and other meaningless terms. The Endocrine Society statement reviewed the clinical studies on testosterone for various indications surrounding physical endurance, well-being, and mental health – and the studies do not support its use,” Dr. Rosser added.
According to the Australasian Menopause Society, women’s blood testosterone levels tend to peak in their 20s, slowly decline to around 25% of peak levels at menopause, then rise again in later years.
Susan Davis, PhD, and her colleagues at Monash University, Melbourne, found in a study that TRT in postmenopausal women may improve sexual well-being and that side effects include acne and increased hair growth. But they found no benefits for cognition, bone mineral density, body composition, muscle strength, or psychological well-being, and they note that more data are needed on long-term safety.
Postmenopausal testosterone recommended for libido only
“Hypoactive sexual desire disorder (HSDD) is really the only indication for postmenopausal testosterone use,” Nanette F. Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine, Aurora, noted by email. “In clinical studies using androgen gel containing testosterone, testosterone treatment has resulted in a mean of one more satisfying sexual encounter per month. Consensus statements issued by the Endocrine Society, The International Menopause Society, and the North American Menopause Society have come to similar conclusions: The only indication for androgen therapy for women is HSDD,” added Santoro, an author of the Endocrine Society statement.
“Sexual health and the sense of well-being are very much related,” Sandra Ann Carson, MD, professor of obstetrics and gynecology at Yale Medicine, New Haven, Conn., said by phone. “So we give testosterone to increase sexual desire. Testosterone is not a treatment for decreased sense of well-being alone. Women who lose their sense of well-being due to depression or other factors need to have a mental health evaluation, not testosterone.”
“Because no female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly,” Dr. Rosser said. “The recommendation is for considering use of compounded testosterone for hypoactive sexual desire only; it is against use for overall health and wellness.”
“The real mischief occurs when women are exposed to doses that are supraphysiologic,” Dr. Rosser cautioned. “At high doses that approach and sometimes exceed men’s levels of testosterone, women can have deepening of the voice, adverse changes in cholesterol, and even breast atrophy. This can occur with bioidentical compounded testosterone and with testosterone pellets. The National Academies of Science, Engineering, and Medicine recommend unequivocally that such preparations not be used.”
Not all postmenopausal women should take TRT, said Meredith McClure, MD, assistant professor in the department of obstetrics and gynecology of UT Southwestern Medical School, Dallas, because it has only been shown in trials to help with HSDD.
She advised clinicians to avoid prescribing testosterone to patients who “can’t take estrogen, including if [they] have hormone-sensitive cancer, blood clot risk, liver disease, heart attack, stroke, or undiagnosed genital bleeding.”
TRT for non-libido issues may sometimes be appropriate
“Perhaps women with hip fracture or cancer cachexia could benefit from testosterone to build muscle mass,” said Dr. Dobbs, who is involved in an ongoing study of testosterone treatment in women with hip fracture. “But as yet, we have no proof that testosterone helps.”
In rare cases, Stanley G. Korenman, MD, a reproductive endocrinologist and associate dean for ethics at UCLA Health, treats postmenopausal patients with TRT for reasons other than low libido. “I have a very specialized practice in reproductive endocrinology and internal medicine and am one of very few people in the country who do this kind of management,” he said in an interview. “If my postmenopausal patients have low testosterone and lack energy, I’m willing to give them low doses. If they feel more energetic, we continue, but if they don’t, we stop. I don’t think there’s any risk whatsoever at the low level I prescribe.
“I prescribe standard gel that comes in a squirt bottle, and I suggest they take half a squirt every other day – about one-eighth of a male dose – on the sole of the foot, where hair does not grow.
“I would not prescribe testosterone for bone health. We have bisphosphonates and other much better treatments for that. And I would not prescribe it to someone who is seriously emotionally disturbed or seriously depressed. This is not a treatment for depression.”
“Postmenopausal testosterone is not ‘the latest greatest thing,’ but being very low risk, it’s worth trying once in a while, in the appropriate patient, at the right dose,” Dr. Korenman advised. He cautioned people to “avoid the longevity salespeople who sell all sorts of things in all sorts of doses to try to keep us alive forever.”
All contributors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Your patients may see ads claiming that testosterone replacement therapy (TRT) offers postmenopausal women health benefits beyond restored sex drive: that TRT can improve their mood, energy, and thinking and give them stronger bones and bigger muscles.
How accurate are these claims? According to six experts who talked with this news organization, not very.
“Right now in this country and around the world, testosterone’s only use in postmenopausal women is for libido,” said Adrian Sandra Dobs, MD, MHS, professor of medicine and director of the Johns Hopkins Clinical Research Network at Johns Hopkins Medicine, Baltimore.
“Treating postmenopausal women with testosterone is a rarity. Some physicians and some wellness centers make their money out of prescribing estrogen and testosterone to women in patches, gels, creams, capsules, pellets, and other forms. she added by phone.
“One has to be very careful about using testosterone in women,” Dr. Dobs cautioned. “There’s a lot of hype out there.”
Low testosterone in women has not been well studied, and no testosterone treatments for this condition have been approved by the U.S. Food and Drug Administration. Providers need to adjust male treatment data to their female patients, who require significantly lower doses than males. Contraindications and long-term side effects are poorly understood, said Mary Rosser, MD, PhD, assistant professor of women’s health and director of integrated women’s health at Columbia University Irving Medical Center, New York.
“Despite this preponderance of scientific evidence and recommendations, the myths about testosterone die hard, including that it improves women’s muscle function, endurance, and well-being,” Dr. Rosser said.
“Websites that use compounded products or pellets are not FDA-regulated; therefore, they have no responsibility to prove their claims. They can entice women into using this stuff with all kinds of promises about ‘hormone balancing’ and other meaningless terms. The Endocrine Society statement reviewed the clinical studies on testosterone for various indications surrounding physical endurance, well-being, and mental health – and the studies do not support its use,” Dr. Rosser added.
According to the Australasian Menopause Society, women’s blood testosterone levels tend to peak in their 20s, slowly decline to around 25% of peak levels at menopause, then rise again in later years.
Susan Davis, PhD, and her colleagues at Monash University, Melbourne, found in a study that TRT in postmenopausal women may improve sexual well-being and that side effects include acne and increased hair growth. But they found no benefits for cognition, bone mineral density, body composition, muscle strength, or psychological well-being, and they note that more data are needed on long-term safety.
Postmenopausal testosterone recommended for libido only
“Hypoactive sexual desire disorder (HSDD) is really the only indication for postmenopausal testosterone use,” Nanette F. Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine, Aurora, noted by email. “In clinical studies using androgen gel containing testosterone, testosterone treatment has resulted in a mean of one more satisfying sexual encounter per month. Consensus statements issued by the Endocrine Society, The International Menopause Society, and the North American Menopause Society have come to similar conclusions: The only indication for androgen therapy for women is HSDD,” added Santoro, an author of the Endocrine Society statement.
“Sexual health and the sense of well-being are very much related,” Sandra Ann Carson, MD, professor of obstetrics and gynecology at Yale Medicine, New Haven, Conn., said by phone. “So we give testosterone to increase sexual desire. Testosterone is not a treatment for decreased sense of well-being alone. Women who lose their sense of well-being due to depression or other factors need to have a mental health evaluation, not testosterone.”
“Because no female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly,” Dr. Rosser said. “The recommendation is for considering use of compounded testosterone for hypoactive sexual desire only; it is against use for overall health and wellness.”
“The real mischief occurs when women are exposed to doses that are supraphysiologic,” Dr. Rosser cautioned. “At high doses that approach and sometimes exceed men’s levels of testosterone, women can have deepening of the voice, adverse changes in cholesterol, and even breast atrophy. This can occur with bioidentical compounded testosterone and with testosterone pellets. The National Academies of Science, Engineering, and Medicine recommend unequivocally that such preparations not be used.”
Not all postmenopausal women should take TRT, said Meredith McClure, MD, assistant professor in the department of obstetrics and gynecology of UT Southwestern Medical School, Dallas, because it has only been shown in trials to help with HSDD.
She advised clinicians to avoid prescribing testosterone to patients who “can’t take estrogen, including if [they] have hormone-sensitive cancer, blood clot risk, liver disease, heart attack, stroke, or undiagnosed genital bleeding.”
TRT for non-libido issues may sometimes be appropriate
“Perhaps women with hip fracture or cancer cachexia could benefit from testosterone to build muscle mass,” said Dr. Dobbs, who is involved in an ongoing study of testosterone treatment in women with hip fracture. “But as yet, we have no proof that testosterone helps.”
In rare cases, Stanley G. Korenman, MD, a reproductive endocrinologist and associate dean for ethics at UCLA Health, treats postmenopausal patients with TRT for reasons other than low libido. “I have a very specialized practice in reproductive endocrinology and internal medicine and am one of very few people in the country who do this kind of management,” he said in an interview. “If my postmenopausal patients have low testosterone and lack energy, I’m willing to give them low doses. If they feel more energetic, we continue, but if they don’t, we stop. I don’t think there’s any risk whatsoever at the low level I prescribe.
“I prescribe standard gel that comes in a squirt bottle, and I suggest they take half a squirt every other day – about one-eighth of a male dose – on the sole of the foot, where hair does not grow.
“I would not prescribe testosterone for bone health. We have bisphosphonates and other much better treatments for that. And I would not prescribe it to someone who is seriously emotionally disturbed or seriously depressed. This is not a treatment for depression.”
“Postmenopausal testosterone is not ‘the latest greatest thing,’ but being very low risk, it’s worth trying once in a while, in the appropriate patient, at the right dose,” Dr. Korenman advised. He cautioned people to “avoid the longevity salespeople who sell all sorts of things in all sorts of doses to try to keep us alive forever.”
All contributors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Your patients may see ads claiming that testosterone replacement therapy (TRT) offers postmenopausal women health benefits beyond restored sex drive: that TRT can improve their mood, energy, and thinking and give them stronger bones and bigger muscles.
How accurate are these claims? According to six experts who talked with this news organization, not very.
“Right now in this country and around the world, testosterone’s only use in postmenopausal women is for libido,” said Adrian Sandra Dobs, MD, MHS, professor of medicine and director of the Johns Hopkins Clinical Research Network at Johns Hopkins Medicine, Baltimore.
“Treating postmenopausal women with testosterone is a rarity. Some physicians and some wellness centers make their money out of prescribing estrogen and testosterone to women in patches, gels, creams, capsules, pellets, and other forms. she added by phone.
“One has to be very careful about using testosterone in women,” Dr. Dobs cautioned. “There’s a lot of hype out there.”
Low testosterone in women has not been well studied, and no testosterone treatments for this condition have been approved by the U.S. Food and Drug Administration. Providers need to adjust male treatment data to their female patients, who require significantly lower doses than males. Contraindications and long-term side effects are poorly understood, said Mary Rosser, MD, PhD, assistant professor of women’s health and director of integrated women’s health at Columbia University Irving Medical Center, New York.
“Despite this preponderance of scientific evidence and recommendations, the myths about testosterone die hard, including that it improves women’s muscle function, endurance, and well-being,” Dr. Rosser said.
“Websites that use compounded products or pellets are not FDA-regulated; therefore, they have no responsibility to prove their claims. They can entice women into using this stuff with all kinds of promises about ‘hormone balancing’ and other meaningless terms. The Endocrine Society statement reviewed the clinical studies on testosterone for various indications surrounding physical endurance, well-being, and mental health – and the studies do not support its use,” Dr. Rosser added.
According to the Australasian Menopause Society, women’s blood testosterone levels tend to peak in their 20s, slowly decline to around 25% of peak levels at menopause, then rise again in later years.
Susan Davis, PhD, and her colleagues at Monash University, Melbourne, found in a study that TRT in postmenopausal women may improve sexual well-being and that side effects include acne and increased hair growth. But they found no benefits for cognition, bone mineral density, body composition, muscle strength, or psychological well-being, and they note that more data are needed on long-term safety.
Postmenopausal testosterone recommended for libido only
“Hypoactive sexual desire disorder (HSDD) is really the only indication for postmenopausal testosterone use,” Nanette F. Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine, Aurora, noted by email. “In clinical studies using androgen gel containing testosterone, testosterone treatment has resulted in a mean of one more satisfying sexual encounter per month. Consensus statements issued by the Endocrine Society, The International Menopause Society, and the North American Menopause Society have come to similar conclusions: The only indication for androgen therapy for women is HSDD,” added Santoro, an author of the Endocrine Society statement.
“Sexual health and the sense of well-being are very much related,” Sandra Ann Carson, MD, professor of obstetrics and gynecology at Yale Medicine, New Haven, Conn., said by phone. “So we give testosterone to increase sexual desire. Testosterone is not a treatment for decreased sense of well-being alone. Women who lose their sense of well-being due to depression or other factors need to have a mental health evaluation, not testosterone.”
“Because no female product is presently approved by a national regulatory body, male formulations can be judiciously used in female doses and blood testosterone concentrations must be monitored regularly,” Dr. Rosser said. “The recommendation is for considering use of compounded testosterone for hypoactive sexual desire only; it is against use for overall health and wellness.”
“The real mischief occurs when women are exposed to doses that are supraphysiologic,” Dr. Rosser cautioned. “At high doses that approach and sometimes exceed men’s levels of testosterone, women can have deepening of the voice, adverse changes in cholesterol, and even breast atrophy. This can occur with bioidentical compounded testosterone and with testosterone pellets. The National Academies of Science, Engineering, and Medicine recommend unequivocally that such preparations not be used.”
Not all postmenopausal women should take TRT, said Meredith McClure, MD, assistant professor in the department of obstetrics and gynecology of UT Southwestern Medical School, Dallas, because it has only been shown in trials to help with HSDD.
She advised clinicians to avoid prescribing testosterone to patients who “can’t take estrogen, including if [they] have hormone-sensitive cancer, blood clot risk, liver disease, heart attack, stroke, or undiagnosed genital bleeding.”
TRT for non-libido issues may sometimes be appropriate
“Perhaps women with hip fracture or cancer cachexia could benefit from testosterone to build muscle mass,” said Dr. Dobbs, who is involved in an ongoing study of testosterone treatment in women with hip fracture. “But as yet, we have no proof that testosterone helps.”
In rare cases, Stanley G. Korenman, MD, a reproductive endocrinologist and associate dean for ethics at UCLA Health, treats postmenopausal patients with TRT for reasons other than low libido. “I have a very specialized practice in reproductive endocrinology and internal medicine and am one of very few people in the country who do this kind of management,” he said in an interview. “If my postmenopausal patients have low testosterone and lack energy, I’m willing to give them low doses. If they feel more energetic, we continue, but if they don’t, we stop. I don’t think there’s any risk whatsoever at the low level I prescribe.
“I prescribe standard gel that comes in a squirt bottle, and I suggest they take half a squirt every other day – about one-eighth of a male dose – on the sole of the foot, where hair does not grow.
“I would not prescribe testosterone for bone health. We have bisphosphonates and other much better treatments for that. And I would not prescribe it to someone who is seriously emotionally disturbed or seriously depressed. This is not a treatment for depression.”
“Postmenopausal testosterone is not ‘the latest greatest thing,’ but being very low risk, it’s worth trying once in a while, in the appropriate patient, at the right dose,” Dr. Korenman advised. He cautioned people to “avoid the longevity salespeople who sell all sorts of things in all sorts of doses to try to keep us alive forever.”
All contributors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Advances in testing and therapeutics are improving the lives of patients with Fabry disease
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care.
“An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care.
“An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care.
“An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Study finds inflammatory bowel disease risk higher in children, adults with atopic dermatitis
The published recently in JAMA Dermatology.
The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.
“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.
“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”
The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.
“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.
UK general practice cohort
AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.
To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.
The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.
In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
AD severity linked with IBD risk
The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.
Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.
AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).
Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.
Robust data with cautionary note
“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”
However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.
Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.
But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”
For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.
“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.
“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”
The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”
Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.
“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”
The authors recommend future related studies in more diverse populations.
Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
The published recently in JAMA Dermatology.
The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.
“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.
“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”
The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.
“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.
UK general practice cohort
AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.
To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.
The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.
In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
AD severity linked with IBD risk
The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.
Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.
AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).
Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.
Robust data with cautionary note
“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”
However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.
Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.
But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”
For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.
“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.
“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”
The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”
Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.
“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”
The authors recommend future related studies in more diverse populations.
Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
The published recently in JAMA Dermatology.
The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.
“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.
“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”
The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.
“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.
UK general practice cohort
AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.
To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.
The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.
In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
AD severity linked with IBD risk
The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.
Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.
AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).
Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.
Robust data with cautionary note
“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”
However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.
Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.
But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”
For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.
“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.
“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”
The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”
Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.
“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”
The authors recommend future related studies in more diverse populations.
Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
FROM JAMA DERMATOLOGY
Primary care clinicians should spearhead HIV prevention
HIV continues to be a significant public health concern in the United States, with an estimated 1.2 million people currently living with the virus and more than 30,000 new diagnoses in 2020 alone.
Primary care clinicians can help decrease rates of HIV infection by prescribing pre-exposure prophylaxis to people who are sexually active.
But many do not.
“In medical school, we don’t spend much time discussing sexuality, sexual behavior, sexually transmitted infections, and such, so providers may feel uncomfortable asking what kind of sex their patient is having and with whom, whether they use a condom, and other basics,” said Matthew M. Hamill, MBChB, PhD, MPH, a specialist in sexually transmitted diseases at Johns Hopkins Medicine, Baltimore.
PrEP (pre-exposure prophylaxis) is an antiviral medication that cuts the risk of contracting HIV through sex by around 99% when taken as prescribed, according to the Centers for Disease Control and Prevention.
“Many people who would benefit from PrEP are not receiving this highly effective medication,” said John B. Wong, MD, a primary care internist and professor of medicine at Tufts University, Boston. The gap is particularly acute among Black, Hispanic, and Latino people, who are significantly more likely to be diagnosed with HIV but are much less likely than Whites to receive PrEP, he said.
Dr. Wong, a member of the U.S. Preventive Services Task Force, helped write the group’s new PrEP recommendations. Published in August, the guidelines call for clinicians to prescribe the drugs to adolescents and adults who do not have HIV but are at an increased risk for infection.
“Primary care physicians are ideally positioned to prescribe PrEP for their patients because they have longitudinal relationships: They get to know their patients, and hopefully their patients feel comfortable talking with them about their sexual health,” said Brandon Pollak, MD, a primary care physician and HIV specialist at the Ohio State University College of Medicine, Columbus.
Dr. Pollak, who was not involved with the USPSTF recommendations, cares for patients who are heterosexual and living with HIV.
Clinicians should consider PrEP for all patients who have sex with someone who has HIV, do not use condoms, or have had a sexually transmitted infection within the previous 6 months. Men who have sex with men, transgender women who have sex with men, people who inject illicit drugs or engage in transactional sex, and Black, Hispanic, and Latino individuals also are at increased risk for the infection.
“The vast majority of patients on PrEP in any form sail through with no problems; they have regular lab work and can follow up in person or by telemedicine,” Dr. Hamill said. “They tend to be young, fit people without complicated medical histories, and the medications are very well-tolerated, particularly if people expect some short-term side effects.”
What you need to know when prescribing PrEP
Prescribing PrEP is similar in complexity to prescribing hypertension or diabetes medications, Dr. Hamill said.
Because taking the medications while already infected with the virus can lead to the emergence of drug-resistant HIV, patients must have a negative HIV test before starting PrEP. In addition, the USPSTF recommends testing for other sexually transmitted infections and for pregnancy, if appropriate. The task force also recommends conducting kidney function and hepatitis B tests, and a lipid profile before starting specific types of PrEP.
HIV screening is also recommended at 3-month intervals.
“Providers may order labs done at 3- to 4-month intervals but only see patients in clinic once or twice per year, depending on patient needs and risk behaviors,” said Jill S. Blumenthal, MD, associate professor of medicine at UC San Diego Health.
Clinicians should consider medication adherence and whether a patient is likely to take a pill once a day or could benefit from receiving an injection every 2 months. Patients may experience side effects such as diarrhea or headache with oral PrEP or soreness at the injection site. In rare cases, some of the drugs may cause kidney toxicity or bone mineral loss, according to Dr. Hamill.
Three similarly effective forms of PrEP approved by the U.S. Food and Drug Administration enable clinicians to tailor the medications to the specific needs and preferences of each patient. Truvada (emtricitabine and tenofovir disoproxil fumarate) and Descovy (emtricitabine and tenofovir alafenamide) are both daily tablets, although the latter is not advised for people assigned female sex at birth who have receptive vaginal sex. Apretude (cabotegravir), an injectable agent, is not recommended for people who inject illegal drugs.
Patients with renal or bone disease are not good candidates for Truvada.
“Truvada can decrease bone density, so for someone with osteoporosis, you might choose Descovy or Apretude,” Dr. Pollak said. “For someone with chronic kidney disease, consider Descovy or Apretude. “If a patient has hepatitis B, Truvada or Descovy are appropriate, because hepatitis B is treatable.”
Patients taking an injectable PrEP may need more attention, because the concentration of the medication in the body decreases slowly and may linger for many months at low levels that don’t prevent HIV, according to Dr. Hamill. Someone who acquires HIV during that “tail” period might develop resistance to PrEP.
New research also showed that Descovy users were at elevated risk of developing hypertension and statin initiation, especially among those over age 40 years.
Primary care physicians may want to consult with renal specialists about medication safety in patients with severe kidney disease or with rheumatologists or endocrinologists about metabolic bone disease concerns, Dr. Hamill said.
Meanwhile, if a person begins a monogamous relationship and their risk for HIV drops, “it’s fine to stop taking PrEP tablets,” Dr. Pollak said. “I would still recommend routine HIV screening every 6 or 12 months or however often, depending on other risk factors.”
Caring for these patients entails ensuring labs are completed, monitoring adherence, ordering refills, and scheduling regular follow-up visits.
“For the vast majority of patients, the primary care physician is perfectly equipped for their care through the entire PrEP journey, from discussion and initiation to provision of PrEP,” and most cases do not require specialist care, Dr. Hamill said.
However, “if PrEP fails, which is exceedingly rare, primary care physicians should refer patients immediately, preferably with a warm handoff, for linkage to HIV care,” Dr. Blumenthal said.
Talking about PrEP opens the door to conversations with patients about sexual health and broader health issues, Dr. Hamill said. Although these may not come naturally to primary care clinicians, training is available. The National Network of STD Clinical Prevention Training Centers, funded by the CDC, trains providers on how to overcome their anxiety and have open, inclusive conversations about sexuality and sexual behaviors with transgender and gender-diverse, nonbinary people.
“People worry about saying the wrong thing, about causing offense,” Dr. Hamill said. “But once you get comfortable discussing sexuality, you may open conversations around other health issues.”
Barriers for patients
The task force identified several barriers to PrEP access for patients because of lack of trusting relationships with health care, the effects of structural racism on health disparities, and persistent biases within the health care system.
Racial and ethnic disparities in HIV incidence persist, with 42% of new diagnoses occurring among Black people, 27% among Hispanic or Latino people, and 26% among White people in 2020.
Rates of PrEP usage for a year or longer are also low. Sometimes the patient no longer needs PrEP, but barriers often involve the costs of taking time off from work and arranging transportation to clinic visits.
Although nearly all insurance plans and state Medicaid programs cover PrEP, if a patient does not have coverage, the drugs and required tests and office visits can be expensive.
“One of the biggest barriers for all providers is navigating our complicated health system and drug assistance programs,” said Mehri S. McKellar, MD, associate professor of medicine at Duke University School of Medicine, Durham, N.C.
But lower-cost FDA-approved generic emtricitabine/tenofovir disoproxil fumarate is now available, and clinicians can direct patients to programs that help provide the medications at low or no cost.
“Providing PrEP care is straightforward, beneficial, and satisfying,” Dr. Hamill said. “You help people protect themselves from a life-changing diagnosis, and the health system doesn’t need to pay the cost of treating HIV. Everyone wins.”
Dr. Hamill, Dr. McKellar, Dr. Pollak, and Dr. Wong have reported no relevant financial relationships. Dr. Blumenthal has reported a financial relationship with Gilead Sciences.
A version of this article appeared on Medscape.com.
HIV continues to be a significant public health concern in the United States, with an estimated 1.2 million people currently living with the virus and more than 30,000 new diagnoses in 2020 alone.
Primary care clinicians can help decrease rates of HIV infection by prescribing pre-exposure prophylaxis to people who are sexually active.
But many do not.
“In medical school, we don’t spend much time discussing sexuality, sexual behavior, sexually transmitted infections, and such, so providers may feel uncomfortable asking what kind of sex their patient is having and with whom, whether they use a condom, and other basics,” said Matthew M. Hamill, MBChB, PhD, MPH, a specialist in sexually transmitted diseases at Johns Hopkins Medicine, Baltimore.
PrEP (pre-exposure prophylaxis) is an antiviral medication that cuts the risk of contracting HIV through sex by around 99% when taken as prescribed, according to the Centers for Disease Control and Prevention.
“Many people who would benefit from PrEP are not receiving this highly effective medication,” said John B. Wong, MD, a primary care internist and professor of medicine at Tufts University, Boston. The gap is particularly acute among Black, Hispanic, and Latino people, who are significantly more likely to be diagnosed with HIV but are much less likely than Whites to receive PrEP, he said.
Dr. Wong, a member of the U.S. Preventive Services Task Force, helped write the group’s new PrEP recommendations. Published in August, the guidelines call for clinicians to prescribe the drugs to adolescents and adults who do not have HIV but are at an increased risk for infection.
“Primary care physicians are ideally positioned to prescribe PrEP for their patients because they have longitudinal relationships: They get to know their patients, and hopefully their patients feel comfortable talking with them about their sexual health,” said Brandon Pollak, MD, a primary care physician and HIV specialist at the Ohio State University College of Medicine, Columbus.
Dr. Pollak, who was not involved with the USPSTF recommendations, cares for patients who are heterosexual and living with HIV.
Clinicians should consider PrEP for all patients who have sex with someone who has HIV, do not use condoms, or have had a sexually transmitted infection within the previous 6 months. Men who have sex with men, transgender women who have sex with men, people who inject illicit drugs or engage in transactional sex, and Black, Hispanic, and Latino individuals also are at increased risk for the infection.
“The vast majority of patients on PrEP in any form sail through with no problems; they have regular lab work and can follow up in person or by telemedicine,” Dr. Hamill said. “They tend to be young, fit people without complicated medical histories, and the medications are very well-tolerated, particularly if people expect some short-term side effects.”
What you need to know when prescribing PrEP
Prescribing PrEP is similar in complexity to prescribing hypertension or diabetes medications, Dr. Hamill said.
Because taking the medications while already infected with the virus can lead to the emergence of drug-resistant HIV, patients must have a negative HIV test before starting PrEP. In addition, the USPSTF recommends testing for other sexually transmitted infections and for pregnancy, if appropriate. The task force also recommends conducting kidney function and hepatitis B tests, and a lipid profile before starting specific types of PrEP.
HIV screening is also recommended at 3-month intervals.
“Providers may order labs done at 3- to 4-month intervals but only see patients in clinic once or twice per year, depending on patient needs and risk behaviors,” said Jill S. Blumenthal, MD, associate professor of medicine at UC San Diego Health.
Clinicians should consider medication adherence and whether a patient is likely to take a pill once a day or could benefit from receiving an injection every 2 months. Patients may experience side effects such as diarrhea or headache with oral PrEP or soreness at the injection site. In rare cases, some of the drugs may cause kidney toxicity or bone mineral loss, according to Dr. Hamill.
Three similarly effective forms of PrEP approved by the U.S. Food and Drug Administration enable clinicians to tailor the medications to the specific needs and preferences of each patient. Truvada (emtricitabine and tenofovir disoproxil fumarate) and Descovy (emtricitabine and tenofovir alafenamide) are both daily tablets, although the latter is not advised for people assigned female sex at birth who have receptive vaginal sex. Apretude (cabotegravir), an injectable agent, is not recommended for people who inject illegal drugs.
Patients with renal or bone disease are not good candidates for Truvada.
“Truvada can decrease bone density, so for someone with osteoporosis, you might choose Descovy or Apretude,” Dr. Pollak said. “For someone with chronic kidney disease, consider Descovy or Apretude. “If a patient has hepatitis B, Truvada or Descovy are appropriate, because hepatitis B is treatable.”
Patients taking an injectable PrEP may need more attention, because the concentration of the medication in the body decreases slowly and may linger for many months at low levels that don’t prevent HIV, according to Dr. Hamill. Someone who acquires HIV during that “tail” period might develop resistance to PrEP.
New research also showed that Descovy users were at elevated risk of developing hypertension and statin initiation, especially among those over age 40 years.
Primary care physicians may want to consult with renal specialists about medication safety in patients with severe kidney disease or with rheumatologists or endocrinologists about metabolic bone disease concerns, Dr. Hamill said.
Meanwhile, if a person begins a monogamous relationship and their risk for HIV drops, “it’s fine to stop taking PrEP tablets,” Dr. Pollak said. “I would still recommend routine HIV screening every 6 or 12 months or however often, depending on other risk factors.”
Caring for these patients entails ensuring labs are completed, monitoring adherence, ordering refills, and scheduling regular follow-up visits.
“For the vast majority of patients, the primary care physician is perfectly equipped for their care through the entire PrEP journey, from discussion and initiation to provision of PrEP,” and most cases do not require specialist care, Dr. Hamill said.
However, “if PrEP fails, which is exceedingly rare, primary care physicians should refer patients immediately, preferably with a warm handoff, for linkage to HIV care,” Dr. Blumenthal said.
Talking about PrEP opens the door to conversations with patients about sexual health and broader health issues, Dr. Hamill said. Although these may not come naturally to primary care clinicians, training is available. The National Network of STD Clinical Prevention Training Centers, funded by the CDC, trains providers on how to overcome their anxiety and have open, inclusive conversations about sexuality and sexual behaviors with transgender and gender-diverse, nonbinary people.
“People worry about saying the wrong thing, about causing offense,” Dr. Hamill said. “But once you get comfortable discussing sexuality, you may open conversations around other health issues.”
Barriers for patients
The task force identified several barriers to PrEP access for patients because of lack of trusting relationships with health care, the effects of structural racism on health disparities, and persistent biases within the health care system.
Racial and ethnic disparities in HIV incidence persist, with 42% of new diagnoses occurring among Black people, 27% among Hispanic or Latino people, and 26% among White people in 2020.
Rates of PrEP usage for a year or longer are also low. Sometimes the patient no longer needs PrEP, but barriers often involve the costs of taking time off from work and arranging transportation to clinic visits.
Although nearly all insurance plans and state Medicaid programs cover PrEP, if a patient does not have coverage, the drugs and required tests and office visits can be expensive.
“One of the biggest barriers for all providers is navigating our complicated health system and drug assistance programs,” said Mehri S. McKellar, MD, associate professor of medicine at Duke University School of Medicine, Durham, N.C.
But lower-cost FDA-approved generic emtricitabine/tenofovir disoproxil fumarate is now available, and clinicians can direct patients to programs that help provide the medications at low or no cost.
“Providing PrEP care is straightforward, beneficial, and satisfying,” Dr. Hamill said. “You help people protect themselves from a life-changing diagnosis, and the health system doesn’t need to pay the cost of treating HIV. Everyone wins.”
Dr. Hamill, Dr. McKellar, Dr. Pollak, and Dr. Wong have reported no relevant financial relationships. Dr. Blumenthal has reported a financial relationship with Gilead Sciences.
A version of this article appeared on Medscape.com.
HIV continues to be a significant public health concern in the United States, with an estimated 1.2 million people currently living with the virus and more than 30,000 new diagnoses in 2020 alone.
Primary care clinicians can help decrease rates of HIV infection by prescribing pre-exposure prophylaxis to people who are sexually active.
But many do not.
“In medical school, we don’t spend much time discussing sexuality, sexual behavior, sexually transmitted infections, and such, so providers may feel uncomfortable asking what kind of sex their patient is having and with whom, whether they use a condom, and other basics,” said Matthew M. Hamill, MBChB, PhD, MPH, a specialist in sexually transmitted diseases at Johns Hopkins Medicine, Baltimore.
PrEP (pre-exposure prophylaxis) is an antiviral medication that cuts the risk of contracting HIV through sex by around 99% when taken as prescribed, according to the Centers for Disease Control and Prevention.
“Many people who would benefit from PrEP are not receiving this highly effective medication,” said John B. Wong, MD, a primary care internist and professor of medicine at Tufts University, Boston. The gap is particularly acute among Black, Hispanic, and Latino people, who are significantly more likely to be diagnosed with HIV but are much less likely than Whites to receive PrEP, he said.
Dr. Wong, a member of the U.S. Preventive Services Task Force, helped write the group’s new PrEP recommendations. Published in August, the guidelines call for clinicians to prescribe the drugs to adolescents and adults who do not have HIV but are at an increased risk for infection.
“Primary care physicians are ideally positioned to prescribe PrEP for their patients because they have longitudinal relationships: They get to know their patients, and hopefully their patients feel comfortable talking with them about their sexual health,” said Brandon Pollak, MD, a primary care physician and HIV specialist at the Ohio State University College of Medicine, Columbus.
Dr. Pollak, who was not involved with the USPSTF recommendations, cares for patients who are heterosexual and living with HIV.
Clinicians should consider PrEP for all patients who have sex with someone who has HIV, do not use condoms, or have had a sexually transmitted infection within the previous 6 months. Men who have sex with men, transgender women who have sex with men, people who inject illicit drugs or engage in transactional sex, and Black, Hispanic, and Latino individuals also are at increased risk for the infection.
“The vast majority of patients on PrEP in any form sail through with no problems; they have regular lab work and can follow up in person or by telemedicine,” Dr. Hamill said. “They tend to be young, fit people without complicated medical histories, and the medications are very well-tolerated, particularly if people expect some short-term side effects.”
What you need to know when prescribing PrEP
Prescribing PrEP is similar in complexity to prescribing hypertension or diabetes medications, Dr. Hamill said.
Because taking the medications while already infected with the virus can lead to the emergence of drug-resistant HIV, patients must have a negative HIV test before starting PrEP. In addition, the USPSTF recommends testing for other sexually transmitted infections and for pregnancy, if appropriate. The task force also recommends conducting kidney function and hepatitis B tests, and a lipid profile before starting specific types of PrEP.
HIV screening is also recommended at 3-month intervals.
“Providers may order labs done at 3- to 4-month intervals but only see patients in clinic once or twice per year, depending on patient needs and risk behaviors,” said Jill S. Blumenthal, MD, associate professor of medicine at UC San Diego Health.
Clinicians should consider medication adherence and whether a patient is likely to take a pill once a day or could benefit from receiving an injection every 2 months. Patients may experience side effects such as diarrhea or headache with oral PrEP or soreness at the injection site. In rare cases, some of the drugs may cause kidney toxicity or bone mineral loss, according to Dr. Hamill.
Three similarly effective forms of PrEP approved by the U.S. Food and Drug Administration enable clinicians to tailor the medications to the specific needs and preferences of each patient. Truvada (emtricitabine and tenofovir disoproxil fumarate) and Descovy (emtricitabine and tenofovir alafenamide) are both daily tablets, although the latter is not advised for people assigned female sex at birth who have receptive vaginal sex. Apretude (cabotegravir), an injectable agent, is not recommended for people who inject illegal drugs.
Patients with renal or bone disease are not good candidates for Truvada.
“Truvada can decrease bone density, so for someone with osteoporosis, you might choose Descovy or Apretude,” Dr. Pollak said. “For someone with chronic kidney disease, consider Descovy or Apretude. “If a patient has hepatitis B, Truvada or Descovy are appropriate, because hepatitis B is treatable.”
Patients taking an injectable PrEP may need more attention, because the concentration of the medication in the body decreases slowly and may linger for many months at low levels that don’t prevent HIV, according to Dr. Hamill. Someone who acquires HIV during that “tail” period might develop resistance to PrEP.
New research also showed that Descovy users were at elevated risk of developing hypertension and statin initiation, especially among those over age 40 years.
Primary care physicians may want to consult with renal specialists about medication safety in patients with severe kidney disease or with rheumatologists or endocrinologists about metabolic bone disease concerns, Dr. Hamill said.
Meanwhile, if a person begins a monogamous relationship and their risk for HIV drops, “it’s fine to stop taking PrEP tablets,” Dr. Pollak said. “I would still recommend routine HIV screening every 6 or 12 months or however often, depending on other risk factors.”
Caring for these patients entails ensuring labs are completed, monitoring adherence, ordering refills, and scheduling regular follow-up visits.
“For the vast majority of patients, the primary care physician is perfectly equipped for their care through the entire PrEP journey, from discussion and initiation to provision of PrEP,” and most cases do not require specialist care, Dr. Hamill said.
However, “if PrEP fails, which is exceedingly rare, primary care physicians should refer patients immediately, preferably with a warm handoff, for linkage to HIV care,” Dr. Blumenthal said.
Talking about PrEP opens the door to conversations with patients about sexual health and broader health issues, Dr. Hamill said. Although these may not come naturally to primary care clinicians, training is available. The National Network of STD Clinical Prevention Training Centers, funded by the CDC, trains providers on how to overcome their anxiety and have open, inclusive conversations about sexuality and sexual behaviors with transgender and gender-diverse, nonbinary people.
“People worry about saying the wrong thing, about causing offense,” Dr. Hamill said. “But once you get comfortable discussing sexuality, you may open conversations around other health issues.”
Barriers for patients
The task force identified several barriers to PrEP access for patients because of lack of trusting relationships with health care, the effects of structural racism on health disparities, and persistent biases within the health care system.
Racial and ethnic disparities in HIV incidence persist, with 42% of new diagnoses occurring among Black people, 27% among Hispanic or Latino people, and 26% among White people in 2020.
Rates of PrEP usage for a year or longer are also low. Sometimes the patient no longer needs PrEP, but barriers often involve the costs of taking time off from work and arranging transportation to clinic visits.
Although nearly all insurance plans and state Medicaid programs cover PrEP, if a patient does not have coverage, the drugs and required tests and office visits can be expensive.
“One of the biggest barriers for all providers is navigating our complicated health system and drug assistance programs,” said Mehri S. McKellar, MD, associate professor of medicine at Duke University School of Medicine, Durham, N.C.
But lower-cost FDA-approved generic emtricitabine/tenofovir disoproxil fumarate is now available, and clinicians can direct patients to programs that help provide the medications at low or no cost.
“Providing PrEP care is straightforward, beneficial, and satisfying,” Dr. Hamill said. “You help people protect themselves from a life-changing diagnosis, and the health system doesn’t need to pay the cost of treating HIV. Everyone wins.”
Dr. Hamill, Dr. McKellar, Dr. Pollak, and Dr. Wong have reported no relevant financial relationships. Dr. Blumenthal has reported a financial relationship with Gilead Sciences.
A version of this article appeared on Medscape.com.