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When sweaty palms are more than just sweaty palms
ORLANDO – When you extend your hand to a new patient, and he reflexively wipes his palm before shaking hands, be alert. It’s possible you’re seeing primary hyperhidrosis, a condition that’s both more common and more disabling than once thought.
“Looking at the biology of sweating, normally, it’s a good thing – we need it to survive. However, hyperhidrosis is too much of a good thing – it’s an excess of what is needed for normal biology,” said Adam Friedman, MD, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.
Recent data, he pointed out, show that hyperhidrosis is more prevalent than previously thought – about 4.8% of individuals may have the condition, with about half having axillary hyperhidrosis. Symptoms peak in early adulthood, with adults aged 18-54 most affected. “These are the prime working years,” he said.
About 2% of teens are affected, and many adults report that symptoms began before they were 12 years old. Hand hyperhidrosis is a factor for computer and electronic device work, sports, and even handling paper and pencils, noted Dr. Friedman, professor of dermatology at George Washington University, Washington.
“Does it affect quality of life? Yes. We have data to support the impact. The adverse impact is actually greater than that of eczema and psoriasis,” he said, adding that patients won’t always bring up their concerns about sweating. “Often, it’s the patient who apologizes for having sweaty palms or who sticks to the paper on the exam table. It’s worth asking these patients if they are bothered by excessive sweating.”
Is it hyperhidrosis?
A 2016 paper defined hyperhidrosis as “a condition that involves chronic excessive sweating of the underarms, hands, feet, face, groin, or other bodily areas, which is much more than what is normal, and occurs regardless of temperature, exercise, or situation, and may have an impact on quality of life” (Arch Dermatol Res. 2016 Dec;308[10]:743-9). The amount of sweating can be four to five times that seen in healthy controls.
Other clues that excess sweating might be hyperhidrosis? General hyperhidrosis is a secondary syndrome that can be caused by a variety of conditions including endocrine and metabolic disorders and malignancies. Drugs and toxins can also cause generalized excessive sweating.
Focal hyperhidrosis can be primary idiopathic disease; some neuropathies and certain spinal diseases and spinal cord injury can also cause focal hyperhidrosis, though not usually in the axillary/palmar/plantar distribution seen in primary hyperhidrosis.
Before settling on primary hyperhidrosis, the history and exam should also account for other possibilities in the differential: social anxiety disorder, eccrine nevus, gustatory sweating, Frey syndrome, and impaired evaporation could all account for excess sweating, which is also a postsurgical phenomenon for some patients.
Diagnostic criteria call for “focal, visible, excessive sweating” persisting for at least 6 months with no apparent cause. Additionally, patients must have at least two of the additional following criteria: sweating that is bilateral and symmetric, occurs at least once weekly, impairs daily activities, and starts before age 25 years, as well as a positive family history of hyperhidrosis and cessation of sweating during sleep.
The last point is critical, Dr. Friedman said. “If you sweat a lot at night, it’s not hyperhidrosis!”
Though gravimetric evaluation is used in hyperhidrosis research, the history and exam are really where the diagnosis is made in practice, he noted. The Hyperhidrosis Disease Severity Scale is a brief, useful clinical tool that asks patients to peg the extent to which their sweating interferes with daily life.
Topical treatments to try
Topical antiperspirants and other topical agents are a logical place to start and may be required as part of step therapy by insurers. Many patients will already have tried clinical strength over-the-counter antiperspirants containing aluminum zirconium trichlorohydrex, but these products rate low in patient satisfaction among those with primary hyperhidrosis.
Prescription aluminum salts can be compounded to various strengths, with 10%-20% concentration appropriate for axillae and 30%-40% a good strength for palms and soles, according to Dr. Friedman. All of these agents work by precipitating out solids that form a shallow plug in sweat ducts, slowing the flow of perspiration.
Pearls for topical treatment include the need for the product to be on the skin for 6-8 hours overnight. “Remember hyperhidrosis patients do not sweat at night,” so this is the time when the occlusive plugs can form. Then residue can be washed off in the morning, and patients can apply a deodorant. “I remind my patients that antiperspirants are for sweating, and deodorants are for odor,” said Dr. Friedman. These products can damage fabric, and they can be irritating, a problem addressed with low-potency topical steroids.
Topical regimens don’t need to be adjusted for pediatric patients, said Dr. Friedman.
Iontophoresis has been around since the 1950s, is effective, has few side effects, and is considered first-line treatment for severe palmar and plantar hyperhidrosis. But he said there’s one big rub: time. To be effective, patients need 20-30 minutes of application of 15-20 milliamperes of current 3-4 times weekly, not a schedule that works for most patients or practitioners, Dr. Friedman noted.
A treatment recently approved by the Food and Drug Administration for primary axillary hyperhidrosis is a topical anticholinergic, glycopyrronium tosylate, applied with wipes impregnated with glycopyrronium solution. This product significantly outperformed placebo in two clinical trials, with up to 64% of users meeting the primary endpoint of improving by at least 4 points on the Axillary Sweating Daily Diary (ASDD) scale. This product significantly outperformed placebo in two clinical trials, with 53% and 66% of users meeting the primary endpoint, improvement of at least 4 points from baseline in the weekly mean ASDD Item #2. It was approved in those aged 9 years and older.
“You can use this in kids, but you need to educate the kid and the parent or adult,” he said. “This is the last thing you do before bed, after brushing your teeth and after washing your face.”
Patients should apply one swipe to the clean skin of each underarm, and then wash their hands thoroughly. Clinical trials saw a greater proportion of off-target effects such as dry eyes and mouth and mydriasis in the active arm; unilateral mydriasis was more common than bilateral, underscoring the importance of hand washing as this was probably secondary transfer from hands to face during sleep, said Dr. Friedman. Patients can expect results in 2-3 weeks, and doses can be held as needed for anticholinergic side effects.
Systemic choices are limited
There are no FDA-approved systemic agents for hyperhidrosis, and the literature holds only case reports or small series, Dr. Friedman pointed out.
Though systemic treatment may be more effective in generalized hyperhidrosis and for patients with dysautonomia-associated hyperhidrosis, glycopyrrolate is a logical choice if a systemic anticholinergic is desired. A starting dose of 1 mg twice daily can be titrated for effect to about 6 mg daily. Though off-target effects may be a dose-limiting factor, glycopyrrolate is not very lipid soluble, so it penetrates the blood-brain barrier relatively poorly, he said.
Oxybutynin is available in many forms, including a slow-release tablet that permits once-daily dosing. Starting at 5-10 mg daily is a good idea, but dosing may need to be increased to as high as 20 mg daily to be effective. However, patients will often experience “major side effects” with oxybutynin, including significant xerostomia, constipation, blurred vision, and difficulty urinating.
For children, small studies have seen improvement with glycopyrrolate at an average dose of about 2 mg/day. Oxybutynin, which has been extensively studied in the pediatric population, was also effective, but central nervous system adverse events were common.
For some, beta-adrenergic blockade can be an extremely valuable tool, said Dr. Friedman. When sweating is linked to social phobia or performance anxiety, 10-20 mg of atenolol about an hour before the performance or public appearance can make a big difference. Bradycardia, atrioventricular block, and asthma are all contraindications, and the usual precautions should be taken with a host of other comorbidities, he noted.
It’s a good idea to check resting blood pressure and heart rate and take body mass into consideration, and adjust the dose downward appropriately. A key pearl: “Have them do a test run at home, to make sure they don’t keel over on the podium!” said Dr. Friedman.
Botulinum toxin tips and tricks
Botulinum toxin can be very effective and works directly by blocking acetylcholine release at the junction of the sympathetic sudomotor neuron and the sweat gland.
Before treatment, make sure the patient prepares correctly by abstaining from over-the-counter deodorants or antiperspirants, and resting without exertion or drinking hot beverages for about 30 minutes before the procedure.
To ascertain the follicular outline of the area to be injected, the iodine starch test can be used: Paint the axilla with iodine, allow it to dry, and then dust corn starch over the area. The follicular outline is mapped by the purple-blue reaction of the starch and iodine in the presence of moisture from perspiration, Dr. Friedman said.
Applying topical analgesia 30 minutes prior to the procedure helps with patient discomfort with axillary injections. When it comes time to inject, a shallow approach with the bevel side up works well, with a goal of blanketing the field identified by the iodine starch test with small aliquots of toxin placed 1-2 centimeters apart, said Dr. Friedman. However, for patients who might have tattoos that extend to the axillary area, “Avoid the ink!”
Patients will start to see improvement within 2-4 days, and although the literature says a toxin treatment can last 6-9 months, Dr. Friedman said he sees patients coming back in 4-5 months.
Obtaining botulinum toxin can be done in one of two ways: the “buy and bill” approach has the dermatologist purchasing the medication, using CPT 64650 and J code J0585 – “Remember the units!” said Dr. Friedman, because reimbursement will be based on the volume of toxin purchased.. This route may be cheaper for the patient because it avoids a medication copay. The physician obtains preauthorization for both the medication and procedure with this strategy.
The other route is to have the provider prescribe botulinum toxin and the patient purchase it at a regular or specialty pharmacy. In this case, the pharmacist obtains precertification for the medication, but the physician still needs to be precertified – and bill – for the injection procedure itself. This scenario is less risky for the physician but may trigger two separate copays for the patient.
Botulinum toxin can be effective for up to 90% of patients, but at a cost: Without insurance reimbursement, treatments can cost in the neighborhood of $1,500.
A good resource for patients and clinicians is the International Hyperhidrosis Society’s website (sweathelp.org), said Dr. Friedman.
Dr. Friedman disclosed relationships with multiple pharmaceutical and cosmetic companies, including Dermira, which markets topical glycopyrronium tosylate as Qbrexza.
ORLANDO – When you extend your hand to a new patient, and he reflexively wipes his palm before shaking hands, be alert. It’s possible you’re seeing primary hyperhidrosis, a condition that’s both more common and more disabling than once thought.
“Looking at the biology of sweating, normally, it’s a good thing – we need it to survive. However, hyperhidrosis is too much of a good thing – it’s an excess of what is needed for normal biology,” said Adam Friedman, MD, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.
Recent data, he pointed out, show that hyperhidrosis is more prevalent than previously thought – about 4.8% of individuals may have the condition, with about half having axillary hyperhidrosis. Symptoms peak in early adulthood, with adults aged 18-54 most affected. “These are the prime working years,” he said.
About 2% of teens are affected, and many adults report that symptoms began before they were 12 years old. Hand hyperhidrosis is a factor for computer and electronic device work, sports, and even handling paper and pencils, noted Dr. Friedman, professor of dermatology at George Washington University, Washington.
“Does it affect quality of life? Yes. We have data to support the impact. The adverse impact is actually greater than that of eczema and psoriasis,” he said, adding that patients won’t always bring up their concerns about sweating. “Often, it’s the patient who apologizes for having sweaty palms or who sticks to the paper on the exam table. It’s worth asking these patients if they are bothered by excessive sweating.”
Is it hyperhidrosis?
A 2016 paper defined hyperhidrosis as “a condition that involves chronic excessive sweating of the underarms, hands, feet, face, groin, or other bodily areas, which is much more than what is normal, and occurs regardless of temperature, exercise, or situation, and may have an impact on quality of life” (Arch Dermatol Res. 2016 Dec;308[10]:743-9). The amount of sweating can be four to five times that seen in healthy controls.
Other clues that excess sweating might be hyperhidrosis? General hyperhidrosis is a secondary syndrome that can be caused by a variety of conditions including endocrine and metabolic disorders and malignancies. Drugs and toxins can also cause generalized excessive sweating.
Focal hyperhidrosis can be primary idiopathic disease; some neuropathies and certain spinal diseases and spinal cord injury can also cause focal hyperhidrosis, though not usually in the axillary/palmar/plantar distribution seen in primary hyperhidrosis.
Before settling on primary hyperhidrosis, the history and exam should also account for other possibilities in the differential: social anxiety disorder, eccrine nevus, gustatory sweating, Frey syndrome, and impaired evaporation could all account for excess sweating, which is also a postsurgical phenomenon for some patients.
Diagnostic criteria call for “focal, visible, excessive sweating” persisting for at least 6 months with no apparent cause. Additionally, patients must have at least two of the additional following criteria: sweating that is bilateral and symmetric, occurs at least once weekly, impairs daily activities, and starts before age 25 years, as well as a positive family history of hyperhidrosis and cessation of sweating during sleep.
The last point is critical, Dr. Friedman said. “If you sweat a lot at night, it’s not hyperhidrosis!”
Though gravimetric evaluation is used in hyperhidrosis research, the history and exam are really where the diagnosis is made in practice, he noted. The Hyperhidrosis Disease Severity Scale is a brief, useful clinical tool that asks patients to peg the extent to which their sweating interferes with daily life.
Topical treatments to try
Topical antiperspirants and other topical agents are a logical place to start and may be required as part of step therapy by insurers. Many patients will already have tried clinical strength over-the-counter antiperspirants containing aluminum zirconium trichlorohydrex, but these products rate low in patient satisfaction among those with primary hyperhidrosis.
Prescription aluminum salts can be compounded to various strengths, with 10%-20% concentration appropriate for axillae and 30%-40% a good strength for palms and soles, according to Dr. Friedman. All of these agents work by precipitating out solids that form a shallow plug in sweat ducts, slowing the flow of perspiration.
Pearls for topical treatment include the need for the product to be on the skin for 6-8 hours overnight. “Remember hyperhidrosis patients do not sweat at night,” so this is the time when the occlusive plugs can form. Then residue can be washed off in the morning, and patients can apply a deodorant. “I remind my patients that antiperspirants are for sweating, and deodorants are for odor,” said Dr. Friedman. These products can damage fabric, and they can be irritating, a problem addressed with low-potency topical steroids.
Topical regimens don’t need to be adjusted for pediatric patients, said Dr. Friedman.
Iontophoresis has been around since the 1950s, is effective, has few side effects, and is considered first-line treatment for severe palmar and plantar hyperhidrosis. But he said there’s one big rub: time. To be effective, patients need 20-30 minutes of application of 15-20 milliamperes of current 3-4 times weekly, not a schedule that works for most patients or practitioners, Dr. Friedman noted.
A treatment recently approved by the Food and Drug Administration for primary axillary hyperhidrosis is a topical anticholinergic, glycopyrronium tosylate, applied with wipes impregnated with glycopyrronium solution. This product significantly outperformed placebo in two clinical trials, with up to 64% of users meeting the primary endpoint of improving by at least 4 points on the Axillary Sweating Daily Diary (ASDD) scale. This product significantly outperformed placebo in two clinical trials, with 53% and 66% of users meeting the primary endpoint, improvement of at least 4 points from baseline in the weekly mean ASDD Item #2. It was approved in those aged 9 years and older.
“You can use this in kids, but you need to educate the kid and the parent or adult,” he said. “This is the last thing you do before bed, after brushing your teeth and after washing your face.”
Patients should apply one swipe to the clean skin of each underarm, and then wash their hands thoroughly. Clinical trials saw a greater proportion of off-target effects such as dry eyes and mouth and mydriasis in the active arm; unilateral mydriasis was more common than bilateral, underscoring the importance of hand washing as this was probably secondary transfer from hands to face during sleep, said Dr. Friedman. Patients can expect results in 2-3 weeks, and doses can be held as needed for anticholinergic side effects.
Systemic choices are limited
There are no FDA-approved systemic agents for hyperhidrosis, and the literature holds only case reports or small series, Dr. Friedman pointed out.
Though systemic treatment may be more effective in generalized hyperhidrosis and for patients with dysautonomia-associated hyperhidrosis, glycopyrrolate is a logical choice if a systemic anticholinergic is desired. A starting dose of 1 mg twice daily can be titrated for effect to about 6 mg daily. Though off-target effects may be a dose-limiting factor, glycopyrrolate is not very lipid soluble, so it penetrates the blood-brain barrier relatively poorly, he said.
Oxybutynin is available in many forms, including a slow-release tablet that permits once-daily dosing. Starting at 5-10 mg daily is a good idea, but dosing may need to be increased to as high as 20 mg daily to be effective. However, patients will often experience “major side effects” with oxybutynin, including significant xerostomia, constipation, blurred vision, and difficulty urinating.
For children, small studies have seen improvement with glycopyrrolate at an average dose of about 2 mg/day. Oxybutynin, which has been extensively studied in the pediatric population, was also effective, but central nervous system adverse events were common.
For some, beta-adrenergic blockade can be an extremely valuable tool, said Dr. Friedman. When sweating is linked to social phobia or performance anxiety, 10-20 mg of atenolol about an hour before the performance or public appearance can make a big difference. Bradycardia, atrioventricular block, and asthma are all contraindications, and the usual precautions should be taken with a host of other comorbidities, he noted.
It’s a good idea to check resting blood pressure and heart rate and take body mass into consideration, and adjust the dose downward appropriately. A key pearl: “Have them do a test run at home, to make sure they don’t keel over on the podium!” said Dr. Friedman.
Botulinum toxin tips and tricks
Botulinum toxin can be very effective and works directly by blocking acetylcholine release at the junction of the sympathetic sudomotor neuron and the sweat gland.
Before treatment, make sure the patient prepares correctly by abstaining from over-the-counter deodorants or antiperspirants, and resting without exertion or drinking hot beverages for about 30 minutes before the procedure.
To ascertain the follicular outline of the area to be injected, the iodine starch test can be used: Paint the axilla with iodine, allow it to dry, and then dust corn starch over the area. The follicular outline is mapped by the purple-blue reaction of the starch and iodine in the presence of moisture from perspiration, Dr. Friedman said.
Applying topical analgesia 30 minutes prior to the procedure helps with patient discomfort with axillary injections. When it comes time to inject, a shallow approach with the bevel side up works well, with a goal of blanketing the field identified by the iodine starch test with small aliquots of toxin placed 1-2 centimeters apart, said Dr. Friedman. However, for patients who might have tattoos that extend to the axillary area, “Avoid the ink!”
Patients will start to see improvement within 2-4 days, and although the literature says a toxin treatment can last 6-9 months, Dr. Friedman said he sees patients coming back in 4-5 months.
Obtaining botulinum toxin can be done in one of two ways: the “buy and bill” approach has the dermatologist purchasing the medication, using CPT 64650 and J code J0585 – “Remember the units!” said Dr. Friedman, because reimbursement will be based on the volume of toxin purchased.. This route may be cheaper for the patient because it avoids a medication copay. The physician obtains preauthorization for both the medication and procedure with this strategy.
The other route is to have the provider prescribe botulinum toxin and the patient purchase it at a regular or specialty pharmacy. In this case, the pharmacist obtains precertification for the medication, but the physician still needs to be precertified – and bill – for the injection procedure itself. This scenario is less risky for the physician but may trigger two separate copays for the patient.
Botulinum toxin can be effective for up to 90% of patients, but at a cost: Without insurance reimbursement, treatments can cost in the neighborhood of $1,500.
A good resource for patients and clinicians is the International Hyperhidrosis Society’s website (sweathelp.org), said Dr. Friedman.
Dr. Friedman disclosed relationships with multiple pharmaceutical and cosmetic companies, including Dermira, which markets topical glycopyrronium tosylate as Qbrexza.
ORLANDO – When you extend your hand to a new patient, and he reflexively wipes his palm before shaking hands, be alert. It’s possible you’re seeing primary hyperhidrosis, a condition that’s both more common and more disabling than once thought.
“Looking at the biology of sweating, normally, it’s a good thing – we need it to survive. However, hyperhidrosis is too much of a good thing – it’s an excess of what is needed for normal biology,” said Adam Friedman, MD, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.
Recent data, he pointed out, show that hyperhidrosis is more prevalent than previously thought – about 4.8% of individuals may have the condition, with about half having axillary hyperhidrosis. Symptoms peak in early adulthood, with adults aged 18-54 most affected. “These are the prime working years,” he said.
About 2% of teens are affected, and many adults report that symptoms began before they were 12 years old. Hand hyperhidrosis is a factor for computer and electronic device work, sports, and even handling paper and pencils, noted Dr. Friedman, professor of dermatology at George Washington University, Washington.
“Does it affect quality of life? Yes. We have data to support the impact. The adverse impact is actually greater than that of eczema and psoriasis,” he said, adding that patients won’t always bring up their concerns about sweating. “Often, it’s the patient who apologizes for having sweaty palms or who sticks to the paper on the exam table. It’s worth asking these patients if they are bothered by excessive sweating.”
Is it hyperhidrosis?
A 2016 paper defined hyperhidrosis as “a condition that involves chronic excessive sweating of the underarms, hands, feet, face, groin, or other bodily areas, which is much more than what is normal, and occurs regardless of temperature, exercise, or situation, and may have an impact on quality of life” (Arch Dermatol Res. 2016 Dec;308[10]:743-9). The amount of sweating can be four to five times that seen in healthy controls.
Other clues that excess sweating might be hyperhidrosis? General hyperhidrosis is a secondary syndrome that can be caused by a variety of conditions including endocrine and metabolic disorders and malignancies. Drugs and toxins can also cause generalized excessive sweating.
Focal hyperhidrosis can be primary idiopathic disease; some neuropathies and certain spinal diseases and spinal cord injury can also cause focal hyperhidrosis, though not usually in the axillary/palmar/plantar distribution seen in primary hyperhidrosis.
Before settling on primary hyperhidrosis, the history and exam should also account for other possibilities in the differential: social anxiety disorder, eccrine nevus, gustatory sweating, Frey syndrome, and impaired evaporation could all account for excess sweating, which is also a postsurgical phenomenon for some patients.
Diagnostic criteria call for “focal, visible, excessive sweating” persisting for at least 6 months with no apparent cause. Additionally, patients must have at least two of the additional following criteria: sweating that is bilateral and symmetric, occurs at least once weekly, impairs daily activities, and starts before age 25 years, as well as a positive family history of hyperhidrosis and cessation of sweating during sleep.
The last point is critical, Dr. Friedman said. “If you sweat a lot at night, it’s not hyperhidrosis!”
Though gravimetric evaluation is used in hyperhidrosis research, the history and exam are really where the diagnosis is made in practice, he noted. The Hyperhidrosis Disease Severity Scale is a brief, useful clinical tool that asks patients to peg the extent to which their sweating interferes with daily life.
Topical treatments to try
Topical antiperspirants and other topical agents are a logical place to start and may be required as part of step therapy by insurers. Many patients will already have tried clinical strength over-the-counter antiperspirants containing aluminum zirconium trichlorohydrex, but these products rate low in patient satisfaction among those with primary hyperhidrosis.
Prescription aluminum salts can be compounded to various strengths, with 10%-20% concentration appropriate for axillae and 30%-40% a good strength for palms and soles, according to Dr. Friedman. All of these agents work by precipitating out solids that form a shallow plug in sweat ducts, slowing the flow of perspiration.
Pearls for topical treatment include the need for the product to be on the skin for 6-8 hours overnight. “Remember hyperhidrosis patients do not sweat at night,” so this is the time when the occlusive plugs can form. Then residue can be washed off in the morning, and patients can apply a deodorant. “I remind my patients that antiperspirants are for sweating, and deodorants are for odor,” said Dr. Friedman. These products can damage fabric, and they can be irritating, a problem addressed with low-potency topical steroids.
Topical regimens don’t need to be adjusted for pediatric patients, said Dr. Friedman.
Iontophoresis has been around since the 1950s, is effective, has few side effects, and is considered first-line treatment for severe palmar and plantar hyperhidrosis. But he said there’s one big rub: time. To be effective, patients need 20-30 minutes of application of 15-20 milliamperes of current 3-4 times weekly, not a schedule that works for most patients or practitioners, Dr. Friedman noted.
A treatment recently approved by the Food and Drug Administration for primary axillary hyperhidrosis is a topical anticholinergic, glycopyrronium tosylate, applied with wipes impregnated with glycopyrronium solution. This product significantly outperformed placebo in two clinical trials, with up to 64% of users meeting the primary endpoint of improving by at least 4 points on the Axillary Sweating Daily Diary (ASDD) scale. This product significantly outperformed placebo in two clinical trials, with 53% and 66% of users meeting the primary endpoint, improvement of at least 4 points from baseline in the weekly mean ASDD Item #2. It was approved in those aged 9 years and older.
“You can use this in kids, but you need to educate the kid and the parent or adult,” he said. “This is the last thing you do before bed, after brushing your teeth and after washing your face.”
Patients should apply one swipe to the clean skin of each underarm, and then wash their hands thoroughly. Clinical trials saw a greater proportion of off-target effects such as dry eyes and mouth and mydriasis in the active arm; unilateral mydriasis was more common than bilateral, underscoring the importance of hand washing as this was probably secondary transfer from hands to face during sleep, said Dr. Friedman. Patients can expect results in 2-3 weeks, and doses can be held as needed for anticholinergic side effects.
Systemic choices are limited
There are no FDA-approved systemic agents for hyperhidrosis, and the literature holds only case reports or small series, Dr. Friedman pointed out.
Though systemic treatment may be more effective in generalized hyperhidrosis and for patients with dysautonomia-associated hyperhidrosis, glycopyrrolate is a logical choice if a systemic anticholinergic is desired. A starting dose of 1 mg twice daily can be titrated for effect to about 6 mg daily. Though off-target effects may be a dose-limiting factor, glycopyrrolate is not very lipid soluble, so it penetrates the blood-brain barrier relatively poorly, he said.
Oxybutynin is available in many forms, including a slow-release tablet that permits once-daily dosing. Starting at 5-10 mg daily is a good idea, but dosing may need to be increased to as high as 20 mg daily to be effective. However, patients will often experience “major side effects” with oxybutynin, including significant xerostomia, constipation, blurred vision, and difficulty urinating.
For children, small studies have seen improvement with glycopyrrolate at an average dose of about 2 mg/day. Oxybutynin, which has been extensively studied in the pediatric population, was also effective, but central nervous system adverse events were common.
For some, beta-adrenergic blockade can be an extremely valuable tool, said Dr. Friedman. When sweating is linked to social phobia or performance anxiety, 10-20 mg of atenolol about an hour before the performance or public appearance can make a big difference. Bradycardia, atrioventricular block, and asthma are all contraindications, and the usual precautions should be taken with a host of other comorbidities, he noted.
It’s a good idea to check resting blood pressure and heart rate and take body mass into consideration, and adjust the dose downward appropriately. A key pearl: “Have them do a test run at home, to make sure they don’t keel over on the podium!” said Dr. Friedman.
Botulinum toxin tips and tricks
Botulinum toxin can be very effective and works directly by blocking acetylcholine release at the junction of the sympathetic sudomotor neuron and the sweat gland.
Before treatment, make sure the patient prepares correctly by abstaining from over-the-counter deodorants or antiperspirants, and resting without exertion or drinking hot beverages for about 30 minutes before the procedure.
To ascertain the follicular outline of the area to be injected, the iodine starch test can be used: Paint the axilla with iodine, allow it to dry, and then dust corn starch over the area. The follicular outline is mapped by the purple-blue reaction of the starch and iodine in the presence of moisture from perspiration, Dr. Friedman said.
Applying topical analgesia 30 minutes prior to the procedure helps with patient discomfort with axillary injections. When it comes time to inject, a shallow approach with the bevel side up works well, with a goal of blanketing the field identified by the iodine starch test with small aliquots of toxin placed 1-2 centimeters apart, said Dr. Friedman. However, for patients who might have tattoos that extend to the axillary area, “Avoid the ink!”
Patients will start to see improvement within 2-4 days, and although the literature says a toxin treatment can last 6-9 months, Dr. Friedman said he sees patients coming back in 4-5 months.
Obtaining botulinum toxin can be done in one of two ways: the “buy and bill” approach has the dermatologist purchasing the medication, using CPT 64650 and J code J0585 – “Remember the units!” said Dr. Friedman, because reimbursement will be based on the volume of toxin purchased.. This route may be cheaper for the patient because it avoids a medication copay. The physician obtains preauthorization for both the medication and procedure with this strategy.
The other route is to have the provider prescribe botulinum toxin and the patient purchase it at a regular or specialty pharmacy. In this case, the pharmacist obtains precertification for the medication, but the physician still needs to be precertified – and bill – for the injection procedure itself. This scenario is less risky for the physician but may trigger two separate copays for the patient.
Botulinum toxin can be effective for up to 90% of patients, but at a cost: Without insurance reimbursement, treatments can cost in the neighborhood of $1,500.
A good resource for patients and clinicians is the International Hyperhidrosis Society’s website (sweathelp.org), said Dr. Friedman.
Dr. Friedman disclosed relationships with multiple pharmaceutical and cosmetic companies, including Dermira, which markets topical glycopyrronium tosylate as Qbrexza.
EXPERT ANALYSIS FROM ODAC 2019
Fine-tuning the male aesthetic consultation includes consideration of gender-specific wrinkle pattern
ORLANDO – The , a dermatologist in private practice in Arlington, Va. And he may not even be sure what he’s looking for.
However, he probably knows what he doesn’t like about his appearance. When men are questioned, the three areas they are most concerned about is their hairline, their eyes, and their jawline, said Dr. Keaney, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.
It’s important to evaluate men differently, not just for anatomic differences from women, but also for behavioral and psychological factors unique to men as aesthetic patients, he noted.
Anatomic differences are significant and fundamentally shape treatment decisions, Dr. Keaney said. Broadly speaking, “the male face is traditionally more square, with a prominent supraorbital ridge.” Rather than emphasizing breadth across the cheeks, as in rejuvenation for women, a strong, youthful male face will have a square jaw, appropriate width across the cheeks, and a strong brow line with an arch that is flatter than what women seek.
Male cosmetic goals can be complicated by the fact that men “age poorly” and tend to look older than their stated age, he continued, referring to a study that found that men appear about one-third year older than their age, and women about a half year younger. A higher rate of smoking and excess ultraviolet light exposure among men may contribute to this discrepancy, he said.
Overall, men see steady atrophy of facial soft tissue throughout adulthood, in contrast to women who see a more rapid decline that starts at menopause. This makes sense in the context of the slow drop in circulating testosterone that men see beginning at about age 30, at which time men can expect a decrease of about 1% per year, he noted.
A common opener from men, said Dr. Keaney, is “’I look tired.’ When I hear that, I’m thinking about the eyes.” Men are more likely to develop tear troughs and a sunken appearance because of their larger orbital cavities and smaller orbital fat pads, so periocular fillers are often a treatment tool to consider.
Around mens’ eyes, “it’s not just the presence, but the pattern of wrinkles that guides treatment,” he noted. At the lateral canthi, both at rest and with maximum smile, the predominant wrinkle pattern in crows’ feet is the lower fan. The cheek elevator musculature, including the zygomaticus major, are more involved in animation around the eyes with smiling, which is important because reaching for botulinum toxin alone is probably not going to give the patient his desired effect, he added.
Other differences in the male wrinkle pattern can be found on the brow. The “U” contraction pattern between the brows is more common in men than women, at least partly because men have greater involvement of the procerus muscle, Dr. Keaney said.
Taking all of this into account, caution is the watchword when using botulinum toxin for the glabellar and brow region. “Beware of eyebrow ptosis: avoid the frontalis in patients with eyebrow ptosis,” he said. Treating the corrugators can also be an unwise move, since toxin can diffuse to the inferior fibers of the frontalis muscle, he added.
For men with jawline concerns, consider a combination approach, Dr. Keaney said. The lower face and neck can be rejuvenated by a redraping solution, such as skin tightening with high frequency ultrasound or radiofrequency ablation.
Sometimes, a clean, tight sweep of jawline can be restored with dermal fillers to the lower face, along with a noninvasive fat reduction approach, said Dr. Keaney.
Knowing men’s unique anatomy and aging patterns is only half the battle, though. “How you communicate with men and evaluate them has to take into account that you might be seeing a sweaty, nervous, treatment-naive patient,” at the initial consultation, said Dr. Keaney. “Do men care? Yes, but men display a different set of motivations.”
Plan for all of this to take time. “The initial consultation tends to be longer” for male patients, who are “less savvy” about cosmetic procedures than women, he pointed out.
A clear discussion of side effects is critical when discussing treatment options with men. “If they get a side effect, you’ll never see them again – and you won’t ever hear about it,” he added.
Though overall, women have been shown to be more sensitive to pain, in cosmetic procedures, “men are less tolerant of pain.” Plan for this, set reasonable expectations but be proactive about pain control, and still expect a need for some hand-holding, said Dr. Keaney.
“Men do not like surprises,” he added. Clearly define what expected side effects may be, what they’ll look like, and what downtime the patient should expect.
For Dr. Keaney’s part, he’s found that the best way to retain men in his cosmetic practice is to “start with a home run treatment to earn trust.” Men often appreciate a slow and steady approach to addressing concerns. “Make sure to connect the treatment plan to the primary cosmetic concern.”
Dr. Keaney reported that he has relationships with multiple pharmaceutical and cosmetic companies.
ORLANDO – The , a dermatologist in private practice in Arlington, Va. And he may not even be sure what he’s looking for.
However, he probably knows what he doesn’t like about his appearance. When men are questioned, the three areas they are most concerned about is their hairline, their eyes, and their jawline, said Dr. Keaney, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.
It’s important to evaluate men differently, not just for anatomic differences from women, but also for behavioral and psychological factors unique to men as aesthetic patients, he noted.
Anatomic differences are significant and fundamentally shape treatment decisions, Dr. Keaney said. Broadly speaking, “the male face is traditionally more square, with a prominent supraorbital ridge.” Rather than emphasizing breadth across the cheeks, as in rejuvenation for women, a strong, youthful male face will have a square jaw, appropriate width across the cheeks, and a strong brow line with an arch that is flatter than what women seek.
Male cosmetic goals can be complicated by the fact that men “age poorly” and tend to look older than their stated age, he continued, referring to a study that found that men appear about one-third year older than their age, and women about a half year younger. A higher rate of smoking and excess ultraviolet light exposure among men may contribute to this discrepancy, he said.
Overall, men see steady atrophy of facial soft tissue throughout adulthood, in contrast to women who see a more rapid decline that starts at menopause. This makes sense in the context of the slow drop in circulating testosterone that men see beginning at about age 30, at which time men can expect a decrease of about 1% per year, he noted.
A common opener from men, said Dr. Keaney, is “’I look tired.’ When I hear that, I’m thinking about the eyes.” Men are more likely to develop tear troughs and a sunken appearance because of their larger orbital cavities and smaller orbital fat pads, so periocular fillers are often a treatment tool to consider.
Around mens’ eyes, “it’s not just the presence, but the pattern of wrinkles that guides treatment,” he noted. At the lateral canthi, both at rest and with maximum smile, the predominant wrinkle pattern in crows’ feet is the lower fan. The cheek elevator musculature, including the zygomaticus major, are more involved in animation around the eyes with smiling, which is important because reaching for botulinum toxin alone is probably not going to give the patient his desired effect, he added.
Other differences in the male wrinkle pattern can be found on the brow. The “U” contraction pattern between the brows is more common in men than women, at least partly because men have greater involvement of the procerus muscle, Dr. Keaney said.
Taking all of this into account, caution is the watchword when using botulinum toxin for the glabellar and brow region. “Beware of eyebrow ptosis: avoid the frontalis in patients with eyebrow ptosis,” he said. Treating the corrugators can also be an unwise move, since toxin can diffuse to the inferior fibers of the frontalis muscle, he added.
For men with jawline concerns, consider a combination approach, Dr. Keaney said. The lower face and neck can be rejuvenated by a redraping solution, such as skin tightening with high frequency ultrasound or radiofrequency ablation.
Sometimes, a clean, tight sweep of jawline can be restored with dermal fillers to the lower face, along with a noninvasive fat reduction approach, said Dr. Keaney.
Knowing men’s unique anatomy and aging patterns is only half the battle, though. “How you communicate with men and evaluate them has to take into account that you might be seeing a sweaty, nervous, treatment-naive patient,” at the initial consultation, said Dr. Keaney. “Do men care? Yes, but men display a different set of motivations.”
Plan for all of this to take time. “The initial consultation tends to be longer” for male patients, who are “less savvy” about cosmetic procedures than women, he pointed out.
A clear discussion of side effects is critical when discussing treatment options with men. “If they get a side effect, you’ll never see them again – and you won’t ever hear about it,” he added.
Though overall, women have been shown to be more sensitive to pain, in cosmetic procedures, “men are less tolerant of pain.” Plan for this, set reasonable expectations but be proactive about pain control, and still expect a need for some hand-holding, said Dr. Keaney.
“Men do not like surprises,” he added. Clearly define what expected side effects may be, what they’ll look like, and what downtime the patient should expect.
For Dr. Keaney’s part, he’s found that the best way to retain men in his cosmetic practice is to “start with a home run treatment to earn trust.” Men often appreciate a slow and steady approach to addressing concerns. “Make sure to connect the treatment plan to the primary cosmetic concern.”
Dr. Keaney reported that he has relationships with multiple pharmaceutical and cosmetic companies.
ORLANDO – The , a dermatologist in private practice in Arlington, Va. And he may not even be sure what he’s looking for.
However, he probably knows what he doesn’t like about his appearance. When men are questioned, the three areas they are most concerned about is their hairline, their eyes, and their jawline, said Dr. Keaney, speaking at the Orlando Dermatology Aesthetic and Clinical Conference.
It’s important to evaluate men differently, not just for anatomic differences from women, but also for behavioral and psychological factors unique to men as aesthetic patients, he noted.
Anatomic differences are significant and fundamentally shape treatment decisions, Dr. Keaney said. Broadly speaking, “the male face is traditionally more square, with a prominent supraorbital ridge.” Rather than emphasizing breadth across the cheeks, as in rejuvenation for women, a strong, youthful male face will have a square jaw, appropriate width across the cheeks, and a strong brow line with an arch that is flatter than what women seek.
Male cosmetic goals can be complicated by the fact that men “age poorly” and tend to look older than their stated age, he continued, referring to a study that found that men appear about one-third year older than their age, and women about a half year younger. A higher rate of smoking and excess ultraviolet light exposure among men may contribute to this discrepancy, he said.
Overall, men see steady atrophy of facial soft tissue throughout adulthood, in contrast to women who see a more rapid decline that starts at menopause. This makes sense in the context of the slow drop in circulating testosterone that men see beginning at about age 30, at which time men can expect a decrease of about 1% per year, he noted.
A common opener from men, said Dr. Keaney, is “’I look tired.’ When I hear that, I’m thinking about the eyes.” Men are more likely to develop tear troughs and a sunken appearance because of their larger orbital cavities and smaller orbital fat pads, so periocular fillers are often a treatment tool to consider.
Around mens’ eyes, “it’s not just the presence, but the pattern of wrinkles that guides treatment,” he noted. At the lateral canthi, both at rest and with maximum smile, the predominant wrinkle pattern in crows’ feet is the lower fan. The cheek elevator musculature, including the zygomaticus major, are more involved in animation around the eyes with smiling, which is important because reaching for botulinum toxin alone is probably not going to give the patient his desired effect, he added.
Other differences in the male wrinkle pattern can be found on the brow. The “U” contraction pattern between the brows is more common in men than women, at least partly because men have greater involvement of the procerus muscle, Dr. Keaney said.
Taking all of this into account, caution is the watchword when using botulinum toxin for the glabellar and brow region. “Beware of eyebrow ptosis: avoid the frontalis in patients with eyebrow ptosis,” he said. Treating the corrugators can also be an unwise move, since toxin can diffuse to the inferior fibers of the frontalis muscle, he added.
For men with jawline concerns, consider a combination approach, Dr. Keaney said. The lower face and neck can be rejuvenated by a redraping solution, such as skin tightening with high frequency ultrasound or radiofrequency ablation.
Sometimes, a clean, tight sweep of jawline can be restored with dermal fillers to the lower face, along with a noninvasive fat reduction approach, said Dr. Keaney.
Knowing men’s unique anatomy and aging patterns is only half the battle, though. “How you communicate with men and evaluate them has to take into account that you might be seeing a sweaty, nervous, treatment-naive patient,” at the initial consultation, said Dr. Keaney. “Do men care? Yes, but men display a different set of motivations.”
Plan for all of this to take time. “The initial consultation tends to be longer” for male patients, who are “less savvy” about cosmetic procedures than women, he pointed out.
A clear discussion of side effects is critical when discussing treatment options with men. “If they get a side effect, you’ll never see them again – and you won’t ever hear about it,” he added.
Though overall, women have been shown to be more sensitive to pain, in cosmetic procedures, “men are less tolerant of pain.” Plan for this, set reasonable expectations but be proactive about pain control, and still expect a need for some hand-holding, said Dr. Keaney.
“Men do not like surprises,” he added. Clearly define what expected side effects may be, what they’ll look like, and what downtime the patient should expect.
For Dr. Keaney’s part, he’s found that the best way to retain men in his cosmetic practice is to “start with a home run treatment to earn trust.” Men often appreciate a slow and steady approach to addressing concerns. “Make sure to connect the treatment plan to the primary cosmetic concern.”
Dr. Keaney reported that he has relationships with multiple pharmaceutical and cosmetic companies.
EXPERT ANALYSIS FROM ODAC 2019
Imaging, radiotherapy clarified in new PMBCL guidelines
Fertility preservation, imaging and radiotherapy guidelines, and best practices in relapse or salvage therapy for primary mediastinal B-cell lymphoma (PMBCL) are all highlighted in a new good practice paper from the British Society for Haematology.
Though PMBCL was previously thought of as a subtype of diffuse large B-cell lymphoma, “gene expression profiling data has shown it to be a separate clinicopathological entity with evidence of an overlap with classic Hodgkin lymphoma,” said Kate Cwynarski, MD, PhD, of University College London Hospitals NHS Foundation Trust in England, and her coauthors. The recommendations were published in the British Journal of Haematology.
PMBCL makes up 2%-4% of non-Hodgkin lymphomas, they said; a bulky anterior mediastinal mass is the usual initial presentation. PMBCL does not usually spread beyond the thoracic cavity.
Biopsy, which should be reviewed by a hematopathologist, is required for a histological diagnosis of PMBCL. A multidisciplinary team should review the clinical presentation, pathology, and management plan, according to the good practice paper authors. This was a strong recommendation backed by a high level of evidence.
In addition, patients should receive positron emission tomography–computed tomography (PET/CT) at diagnosis, before steroids are administered, if possible, as standard of care. Results from the PET/CT should be reported in accordance with international guidelines. These strong recommendations are backed by high-quality evidence.
If PET/CT is performed, then “a bone marrow biopsy is not considered essential,” said Dr. Cwynarski and her coauthors. However, if the findings would influence management, such as when there is extranodal disease that presents central nervous system opportunities, then bone marrow biopsy should be performed. It should also be performed when cytotoxic therapy was initiated before PET/CT could be done. This is a weak recommendation supported by moderate evidence.
Since patients with PMBCL are usually young adults at presentation, it’s important to consider fertility preservation in the face of chemotherapy. For males, semen preservation should be offered. Female patients may not be able to postpone treatment long enough to accomplish egg harvesting. The risk of infertility and premature ovarian failure will depend on the treatment regimen, so “the risks of each individual therapeutic regimen should be discussed with the patient,” Dr. Cwynarski and her colleagues said.
If a patient is diagnosed with PMBCL while pregnant, treatment should be managed in conjunction with high-risk obstetrics and anesthesia specialists. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been used in pregnancy, and immunotherapy without antimetabolites can be considered in the second and third trimesters, according to the good practice paper. These are strong fertility and pregnancy recommendations, backed by moderate to low-quality evidence.
If superior vena cava obstruction causes thrombosis, local standard of care for anticoagulation should be used, but therapy-induced thrombocytopenia should be taken into consideration.
There is a lack of prospective, randomized studies to guide treatment decisions in PMBCL, according to the paper. Still, adding rituximab improves both response rates and duration of remission, they noted.
The standard of care for treatment is six cycles of R-CHOP and involved site radiotherapy (ISRT). If the patient is being cared for at a site that can manage the complexities of dose adjustment and monitoring, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) without ISRT is an alternative, according to the good practice paper.
All patients should be offered clinical trial participation when feasible, a strong recommendation based on high-quality evidence.
To assess the response to therapy, R-CHOP and ISRT recipients not participating in a clinical trial should receive a PET-CT scan 2-3 months after treatment is completed, and DA-EPOCH-R patients should receive their scan 6 weeks after the end of therapy. For all patients, Deauville criteria should be used in reporting response scan results. These strong recommendations about posttherapy imaging are based on moderate-quality evidence.
The rate of relapse and refractory disease is relatively low at about 10%-30%, Dr. Cwynarski and her colleagues said. Relapse usually happens within the first year and is rare after 2 years; extranodal disease is common, but usually spares the central nervous system and bone marrow. The good practice paper authors strongly recommend, based on high-quality evidence, that biopsy and fluorodeoxyglucose-PET/CT should be performed with relapse.
Radiotherapy can be considered if the relapse is localized and the patient didn’t receive initial radiotherapy, a strong recommendation with moderate evidence to support it.
Salvage regimens for patients who have not previously achieved complete metabolic response lack a disease-specific evidence base, noted Dr. Cwynarski and her colleagues. Taking this into consideration, a PMBCL salvage regimen should be the same as that offered to patients with relapsed diffused large B-cell lymphoma. High-dose therapy and autologous stem cell transplantation is appropriate for responsive disease.
If radiotherapy had not been given previously, it should be considered either pre- or post transplant. This, along with the other salvage therapy guidance, is a weak recommendation, backed by moderate evidence.
For longer-term follow-up, asymptomatic patients should not have routine imaging, a strong recommendation with moderate evidence. “[P]atients who remain in remission may be considered for discharge back to primary care,” Dr. Cwynarski and her coauthors said, making a weak recommendation based on low-quality evidence. Patients and their primary care providers should know about the potential for such long-term complications as cardiac toxicities and second malignancies.
SOURCE: Cwynarski K et al. Br J Haematol. 2019 Jan 4. doi:10.1111/bjh.15731
Fertility preservation, imaging and radiotherapy guidelines, and best practices in relapse or salvage therapy for primary mediastinal B-cell lymphoma (PMBCL) are all highlighted in a new good practice paper from the British Society for Haematology.
Though PMBCL was previously thought of as a subtype of diffuse large B-cell lymphoma, “gene expression profiling data has shown it to be a separate clinicopathological entity with evidence of an overlap with classic Hodgkin lymphoma,” said Kate Cwynarski, MD, PhD, of University College London Hospitals NHS Foundation Trust in England, and her coauthors. The recommendations were published in the British Journal of Haematology.
PMBCL makes up 2%-4% of non-Hodgkin lymphomas, they said; a bulky anterior mediastinal mass is the usual initial presentation. PMBCL does not usually spread beyond the thoracic cavity.
Biopsy, which should be reviewed by a hematopathologist, is required for a histological diagnosis of PMBCL. A multidisciplinary team should review the clinical presentation, pathology, and management plan, according to the good practice paper authors. This was a strong recommendation backed by a high level of evidence.
In addition, patients should receive positron emission tomography–computed tomography (PET/CT) at diagnosis, before steroids are administered, if possible, as standard of care. Results from the PET/CT should be reported in accordance with international guidelines. These strong recommendations are backed by high-quality evidence.
If PET/CT is performed, then “a bone marrow biopsy is not considered essential,” said Dr. Cwynarski and her coauthors. However, if the findings would influence management, such as when there is extranodal disease that presents central nervous system opportunities, then bone marrow biopsy should be performed. It should also be performed when cytotoxic therapy was initiated before PET/CT could be done. This is a weak recommendation supported by moderate evidence.
Since patients with PMBCL are usually young adults at presentation, it’s important to consider fertility preservation in the face of chemotherapy. For males, semen preservation should be offered. Female patients may not be able to postpone treatment long enough to accomplish egg harvesting. The risk of infertility and premature ovarian failure will depend on the treatment regimen, so “the risks of each individual therapeutic regimen should be discussed with the patient,” Dr. Cwynarski and her colleagues said.
If a patient is diagnosed with PMBCL while pregnant, treatment should be managed in conjunction with high-risk obstetrics and anesthesia specialists. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been used in pregnancy, and immunotherapy without antimetabolites can be considered in the second and third trimesters, according to the good practice paper. These are strong fertility and pregnancy recommendations, backed by moderate to low-quality evidence.
If superior vena cava obstruction causes thrombosis, local standard of care for anticoagulation should be used, but therapy-induced thrombocytopenia should be taken into consideration.
There is a lack of prospective, randomized studies to guide treatment decisions in PMBCL, according to the paper. Still, adding rituximab improves both response rates and duration of remission, they noted.
The standard of care for treatment is six cycles of R-CHOP and involved site radiotherapy (ISRT). If the patient is being cared for at a site that can manage the complexities of dose adjustment and monitoring, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) without ISRT is an alternative, according to the good practice paper.
All patients should be offered clinical trial participation when feasible, a strong recommendation based on high-quality evidence.
To assess the response to therapy, R-CHOP and ISRT recipients not participating in a clinical trial should receive a PET-CT scan 2-3 months after treatment is completed, and DA-EPOCH-R patients should receive their scan 6 weeks after the end of therapy. For all patients, Deauville criteria should be used in reporting response scan results. These strong recommendations about posttherapy imaging are based on moderate-quality evidence.
The rate of relapse and refractory disease is relatively low at about 10%-30%, Dr. Cwynarski and her colleagues said. Relapse usually happens within the first year and is rare after 2 years; extranodal disease is common, but usually spares the central nervous system and bone marrow. The good practice paper authors strongly recommend, based on high-quality evidence, that biopsy and fluorodeoxyglucose-PET/CT should be performed with relapse.
Radiotherapy can be considered if the relapse is localized and the patient didn’t receive initial radiotherapy, a strong recommendation with moderate evidence to support it.
Salvage regimens for patients who have not previously achieved complete metabolic response lack a disease-specific evidence base, noted Dr. Cwynarski and her colleagues. Taking this into consideration, a PMBCL salvage regimen should be the same as that offered to patients with relapsed diffused large B-cell lymphoma. High-dose therapy and autologous stem cell transplantation is appropriate for responsive disease.
If radiotherapy had not been given previously, it should be considered either pre- or post transplant. This, along with the other salvage therapy guidance, is a weak recommendation, backed by moderate evidence.
For longer-term follow-up, asymptomatic patients should not have routine imaging, a strong recommendation with moderate evidence. “[P]atients who remain in remission may be considered for discharge back to primary care,” Dr. Cwynarski and her coauthors said, making a weak recommendation based on low-quality evidence. Patients and their primary care providers should know about the potential for such long-term complications as cardiac toxicities and second malignancies.
SOURCE: Cwynarski K et al. Br J Haematol. 2019 Jan 4. doi:10.1111/bjh.15731
Fertility preservation, imaging and radiotherapy guidelines, and best practices in relapse or salvage therapy for primary mediastinal B-cell lymphoma (PMBCL) are all highlighted in a new good practice paper from the British Society for Haematology.
Though PMBCL was previously thought of as a subtype of diffuse large B-cell lymphoma, “gene expression profiling data has shown it to be a separate clinicopathological entity with evidence of an overlap with classic Hodgkin lymphoma,” said Kate Cwynarski, MD, PhD, of University College London Hospitals NHS Foundation Trust in England, and her coauthors. The recommendations were published in the British Journal of Haematology.
PMBCL makes up 2%-4% of non-Hodgkin lymphomas, they said; a bulky anterior mediastinal mass is the usual initial presentation. PMBCL does not usually spread beyond the thoracic cavity.
Biopsy, which should be reviewed by a hematopathologist, is required for a histological diagnosis of PMBCL. A multidisciplinary team should review the clinical presentation, pathology, and management plan, according to the good practice paper authors. This was a strong recommendation backed by a high level of evidence.
In addition, patients should receive positron emission tomography–computed tomography (PET/CT) at diagnosis, before steroids are administered, if possible, as standard of care. Results from the PET/CT should be reported in accordance with international guidelines. These strong recommendations are backed by high-quality evidence.
If PET/CT is performed, then “a bone marrow biopsy is not considered essential,” said Dr. Cwynarski and her coauthors. However, if the findings would influence management, such as when there is extranodal disease that presents central nervous system opportunities, then bone marrow biopsy should be performed. It should also be performed when cytotoxic therapy was initiated before PET/CT could be done. This is a weak recommendation supported by moderate evidence.
Since patients with PMBCL are usually young adults at presentation, it’s important to consider fertility preservation in the face of chemotherapy. For males, semen preservation should be offered. Female patients may not be able to postpone treatment long enough to accomplish egg harvesting. The risk of infertility and premature ovarian failure will depend on the treatment regimen, so “the risks of each individual therapeutic regimen should be discussed with the patient,” Dr. Cwynarski and her colleagues said.
If a patient is diagnosed with PMBCL while pregnant, treatment should be managed in conjunction with high-risk obstetrics and anesthesia specialists. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been used in pregnancy, and immunotherapy without antimetabolites can be considered in the second and third trimesters, according to the good practice paper. These are strong fertility and pregnancy recommendations, backed by moderate to low-quality evidence.
If superior vena cava obstruction causes thrombosis, local standard of care for anticoagulation should be used, but therapy-induced thrombocytopenia should be taken into consideration.
There is a lack of prospective, randomized studies to guide treatment decisions in PMBCL, according to the paper. Still, adding rituximab improves both response rates and duration of remission, they noted.
The standard of care for treatment is six cycles of R-CHOP and involved site radiotherapy (ISRT). If the patient is being cared for at a site that can manage the complexities of dose adjustment and monitoring, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) without ISRT is an alternative, according to the good practice paper.
All patients should be offered clinical trial participation when feasible, a strong recommendation based on high-quality evidence.
To assess the response to therapy, R-CHOP and ISRT recipients not participating in a clinical trial should receive a PET-CT scan 2-3 months after treatment is completed, and DA-EPOCH-R patients should receive their scan 6 weeks after the end of therapy. For all patients, Deauville criteria should be used in reporting response scan results. These strong recommendations about posttherapy imaging are based on moderate-quality evidence.
The rate of relapse and refractory disease is relatively low at about 10%-30%, Dr. Cwynarski and her colleagues said. Relapse usually happens within the first year and is rare after 2 years; extranodal disease is common, but usually spares the central nervous system and bone marrow. The good practice paper authors strongly recommend, based on high-quality evidence, that biopsy and fluorodeoxyglucose-PET/CT should be performed with relapse.
Radiotherapy can be considered if the relapse is localized and the patient didn’t receive initial radiotherapy, a strong recommendation with moderate evidence to support it.
Salvage regimens for patients who have not previously achieved complete metabolic response lack a disease-specific evidence base, noted Dr. Cwynarski and her colleagues. Taking this into consideration, a PMBCL salvage regimen should be the same as that offered to patients with relapsed diffused large B-cell lymphoma. High-dose therapy and autologous stem cell transplantation is appropriate for responsive disease.
If radiotherapy had not been given previously, it should be considered either pre- or post transplant. This, along with the other salvage therapy guidance, is a weak recommendation, backed by moderate evidence.
For longer-term follow-up, asymptomatic patients should not have routine imaging, a strong recommendation with moderate evidence. “[P]atients who remain in remission may be considered for discharge back to primary care,” Dr. Cwynarski and her coauthors said, making a weak recommendation based on low-quality evidence. Patients and their primary care providers should know about the potential for such long-term complications as cardiac toxicities and second malignancies.
SOURCE: Cwynarski K et al. Br J Haematol. 2019 Jan 4. doi:10.1111/bjh.15731
FROM BRITISH JOURNAL OF HAEMATOLOGY
How not to miss the ‘invisible gorilla’: Visual intelligence in dermatology
CHICAGO – Medicine, perhaps uniquely among the highly skilled professions, requires the practitioner to use his or her senses on a daily basis. Dermatologists and dermatopathologists rely on visual skills – pattern recognition, gestalt or “gut” first impressions, and step-by-step deliberations – to care for their patients.
But, like all human cognitive processes, visual assessments are error prone. The same brains that can parse a field of blue and pink dots to discern melanoma on a slide are also capable of glaring errors of omission: All too often, the brain follows a cognitive path for the wrong reasons.
Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., became interested in the meta-cognition of her trade; that is, she sought to learn how to think about the thinking that’s needed to be a dermatologist or a dermatopathologist.
In a wide-ranging discussion at the summer meeting of the American Academy of Dermatology, Dr. Ko took attendees through The path led through lessons learned from cognitive science to the fine arts, to lessons learned from other visually oriented medical disciplines.
“Deliberate practice in dermatology is augmented by knowledge of specific cognitive principles that affect visual perception,” Dr. Ko said at the meeting. “This session will open your eyes to the world of visual intelligence that underlies expert dermatologic diagnosis.”
To begin with, what constitutes deliberate practice of dermatology or dermatopathology? Practically speaking, seeing many patients (or reading many slides) builds the base for true expertise, she noted. Physicians continue to hone their learning through independent reading, journal clubs, and meeting attendance, and seek opportunities for deliberate review of what’s still unknown, as in grand rounds – where, ideally, feedback is instantaneous.
Deliberate practice, though, should also include honing visual skills. “We find only the world we look for,” said Dr. Ko, quoting Henry David Thoreau. To sharpen the pattern recognition and keen observation that underpin dermatology and dermatopathology, she said, “We can train the brain.”
Radiology, another medical discipline that requires sustained visual attention, has a significant body of literature addressing common visually-related cognitive errors, she pointed out. In radiology, it’s been shown that deliberate observation of visual art can improve accuracy of reading films.
She observed that dermatologists and dermatopathologists need to think in color, so they may need to develop slightly different visual skills from radiologists who largely see a gray-scale world while they’re working.
Cognitive psychology also offers lessons. One seminal paper, “The invisible gorilla strikes again: Sustained inattentional blindness in expert observers,” issues a stern admonition: “[A] high level of expertise does not immunize individuals against inherent limitations of human attention imperception” (Psychol Sci. 2013 Sep;24[9]:1848-53). Inattentional blindness, Dr. Ko explained, occurs when “what we are focused on filters the world around us aggressively.” First author Trafton Drew, PhD, and his colleagues added: “Researchers should seek better understanding of these limits, so that medical and other man-made search tasks could be designed in ways that reduce the consequences of these limitations.”
How to overcome these limitations? “Concentrate on the camouflaged,” said Dr. Ko, taking a page – literally – from “Visual Intelligence: Sharpen Your Perception, Change Your Life” (Houghton Mifflin Harcourt, 2016), a book by Amy Herman, JD. Ms. Herman devised the mnemonic “COBRA” to identify several steps that can prevent cognitive error from visual observation:
- Concentrating on the camouflaged, for dermatologists, might mean just looking again and focusing on the less-obvious. But, Dr. Ko said, it might mean turning your attention elsewhere for a while, and then looking back at the area in question. Or the patient or slide – or even the examiner – might need repositioning, for a fresh perspective.
- Taking One thing at a time. For dermatologists and dermatopathologists, this means sorting out the who, what, when, and where of the problem at hand. “ ‘Who’ is always the patient,” said Dr. Ko. “But part of ‘who’ is also us; if we’re tired, it can affect things.” There are many ‘whats’ to consider about the presenting problem or the tissue sample: What is the configuration? The architecture? What is the morphology? What’s the color, or cell type? Are there secondary changes? Does the tissue fit into the general category of a benign, or a malignant, lesion? The examination should include a methodical search for clues as to the duration of the problem – Is it acute or chronic? Finally, the ‘where’ – distribution on the body, or of a specimen on a slide, should also be noted.
- Take a Break. This means resting the eye and the mind by turning attention elsewhere, or shifting to light conversation with the patient, or just stepping away from the microscope for a time.
- Realign your expectations. What might you have missed? Is the patient telling you something in the history? Is it possible this is an uncommon presentation of a common condition, rather than a “zebra”?
- Ask someone else to look with you. Sometimes there’s no substitute for another set of eyes, and another brain working on the problem.
A congruent perspective comes from Daniel Kahneman, PhD, a Nobel Prize–winning economist. In 2011, he published a work addressing meta-cognition, called “Thinking Fast and Slow.”
From Dr. Kahneman’s work, Dr. Ko says dermatologists can learn to recognize two complementary ways of thinking. The “fast” system engages multiple cognitive processes to create a gestalt, “gut” impression. “Slow” thinking, in Dr. Kahneman’s construct, is deliberative, methodical, and traditionally thought of as “logical.” However, it would be a mistake to think of these two systems as existing in opposition, or even as completely separate from each other. “It’s sort of just a linguistic tool for us to have something to call it,” she said.
A “fast” analysis will involve some key elements of visual assessment, said Dr. Ko. Figure-ground separation is a basic element of visual assessment and is vital for the work of the dermatopathologist. “Choosing the wrong ‘figure’ may lead to cognitive error,” she explained, citing work on visual perception among dermatopathologists that found that figure-ground separation errors account for a significant number of diagnostic errors.
Other contributors to “fast” thinking include one’s own experience, seeing just a part of the image, judging which elements are close to each other and similar, and noting color contrasts and gradations.
The “slow” assessment is where deliberate practice comes in, said Dr. Ko. Here, the physician goes further, “to check for pertinent positive and negative evidence” for the initial diagnosis. “Play devil’s advocate, and ask yourself why it couldn’t be something else,” she said.
Eve Lowenstein, MD, PhD, is a dermatologist who publishes about heuristics in dermatology. She and Dr. Ko have collaborated to create a forthcoming two-part continuing medical education article in the Journal of the American Academy of Dermatology (JAAD) about cognitive biases and errors in dermatology.
Dr. Lowenstein’s perspective, recently elucidated in two British Journal of Dermatology articles, acknowledges that while “ubiquitous cognitive and visual heuristics can enhance diagnostic speed, they also create pitfalls and thinking traps that introduce significant variation in the diagnostic process,” she and her coauthor Richard Sidlow, MD, of Staten Island (N.Y.) University Hospital, wrote in the abstract accompanying the first article (Br J Dermatol. 2018 Dec;179[6]:1263-9). The second article was published in the same issue (Br J Dermatol. 2018 Dec;179[6]:1270-6).
Heuristics are cognitive shortcuts used to speed decision-making that build on what’s already known, as in the “fast” thinking of Dr. Kahneman’s paradigm. Though heuristics are used in all sorts of professions with high cognitive loads, there’s a risk when physicians get too comfortable with the shortcuts. Speaking frankly in an interview, Dr. Lowenstein said, “intellectual presumptiveness or overconfidence, which is a natural human tendency, can result in oversights and missing information critical to making a correct diagnosis, and premature closure on the wrong diagnosis.”
Diagnostic error, Dr. Lowenstein pointed out, can also result from an “attitudinal overconfidence,” which can come from complacency – being satisfied with the status quo or a lack of intellectual curiosity – or arrogance, she said.
“Complacency is the opposite of what is needed in medicine: an attitude where one cannot know enough. The pursuit of knowledge goes on, ever vigilantly. The world changes; practitioners must keep up and cannot fall back on their knowledge,” she said.
This kind of attitudinal and cognitive humility, she said, is essential to practicing quality care in dermatology. Having practical strategies to improve diagnosis, especially in difficult cases, can make a big difference. For Dr. Lowenstein, one of these tactics is to keep an error diary. “It has been said that ‘the only way to safeguard against error is to embrace it,’ ” she said, quoting Kathryn Schulz in “Being Wrong.” “Unfortunately, we learn some of our most profound lessons from our errors.”
By recording and tracking her own errors, not only is she able to see her own cognitive blind spots through meta-cognition – thinking about how we think – but she’s also able to share these lessons in her teaching. “Some of my best teaching tools for residents are from everything I have screwed up,” said Dr. Lowenstein, director of medical dermatology at the State University of New York Downstate Medical Center and Kings County Hospital, Brooklyn, N.Y.
Another useful tip is simply “to put what you see into words,” when the presentation is confusing or the diagnosis doesn’t quite fit, she added.
“Transforming signs and findings into semantics triggers a differential diagnosis, which is especially useful when we are diagnostically stumped. Studies have found that successful diagnosticians use twice as many semantic qualifiers as the physicians who were diagnostically incorrect.” This is especially significant in visual fields like dermatology, where a single word can paint a picture and rapidly focus a diagnostic search. “We often undervalue this function and relegate it to students starting out in the field,” Dr. Lowenstein said.
Cognitive shortcuts such as diagnostic heuristics all have blind spots, and diagnostic errors tend to fall in these blind spots, she added. “We tend to ignore them. In driving, we adapt to the use of rear and side view mirrors in order to drive safely. Similarly, in diagnostics, alternative views on the data can be very helpful. For example, when faced with difficult cases, take a time out to reanalyze the information without framing or context. Use systematic approaches, such as running down a papulosquamous differential diagnosis. Ask yourself: What can’t be explained in the picture? What doesn’t fit? Think in terms of probabilities – a rare presentation of a common disease is more likely than a rare disease,” she said.
Finally, asking for advice or second opinions from peers, whether by face-to-face discussion or via an online chat site, within the department or appealing to broader groups such as hospitalist dermatologist chat groups, can be helpful with difficult cases. Another strategy is simply to email an expert. Dr. Lowenstein said she’s had great success reaching out to authors of relevant papers by email. Most of her peers, she said, are interested in unusual cases and happy to help.
Dr. Ko has authored or coauthored books on the topics of visual recognition in dermatology and dermatopathology. They are “Dermatology: Visual Recognition and Case Reviews,” and “Dermatopathology: Diagnosis by First Impression.” Dr. Lowenstein reported that she has no conflicts of interest.
CHICAGO – Medicine, perhaps uniquely among the highly skilled professions, requires the practitioner to use his or her senses on a daily basis. Dermatologists and dermatopathologists rely on visual skills – pattern recognition, gestalt or “gut” first impressions, and step-by-step deliberations – to care for their patients.
But, like all human cognitive processes, visual assessments are error prone. The same brains that can parse a field of blue and pink dots to discern melanoma on a slide are also capable of glaring errors of omission: All too often, the brain follows a cognitive path for the wrong reasons.
Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., became interested in the meta-cognition of her trade; that is, she sought to learn how to think about the thinking that’s needed to be a dermatologist or a dermatopathologist.
In a wide-ranging discussion at the summer meeting of the American Academy of Dermatology, Dr. Ko took attendees through The path led through lessons learned from cognitive science to the fine arts, to lessons learned from other visually oriented medical disciplines.
“Deliberate practice in dermatology is augmented by knowledge of specific cognitive principles that affect visual perception,” Dr. Ko said at the meeting. “This session will open your eyes to the world of visual intelligence that underlies expert dermatologic diagnosis.”
To begin with, what constitutes deliberate practice of dermatology or dermatopathology? Practically speaking, seeing many patients (or reading many slides) builds the base for true expertise, she noted. Physicians continue to hone their learning through independent reading, journal clubs, and meeting attendance, and seek opportunities for deliberate review of what’s still unknown, as in grand rounds – where, ideally, feedback is instantaneous.
Deliberate practice, though, should also include honing visual skills. “We find only the world we look for,” said Dr. Ko, quoting Henry David Thoreau. To sharpen the pattern recognition and keen observation that underpin dermatology and dermatopathology, she said, “We can train the brain.”
Radiology, another medical discipline that requires sustained visual attention, has a significant body of literature addressing common visually-related cognitive errors, she pointed out. In radiology, it’s been shown that deliberate observation of visual art can improve accuracy of reading films.
She observed that dermatologists and dermatopathologists need to think in color, so they may need to develop slightly different visual skills from radiologists who largely see a gray-scale world while they’re working.
Cognitive psychology also offers lessons. One seminal paper, “The invisible gorilla strikes again: Sustained inattentional blindness in expert observers,” issues a stern admonition: “[A] high level of expertise does not immunize individuals against inherent limitations of human attention imperception” (Psychol Sci. 2013 Sep;24[9]:1848-53). Inattentional blindness, Dr. Ko explained, occurs when “what we are focused on filters the world around us aggressively.” First author Trafton Drew, PhD, and his colleagues added: “Researchers should seek better understanding of these limits, so that medical and other man-made search tasks could be designed in ways that reduce the consequences of these limitations.”
How to overcome these limitations? “Concentrate on the camouflaged,” said Dr. Ko, taking a page – literally – from “Visual Intelligence: Sharpen Your Perception, Change Your Life” (Houghton Mifflin Harcourt, 2016), a book by Amy Herman, JD. Ms. Herman devised the mnemonic “COBRA” to identify several steps that can prevent cognitive error from visual observation:
- Concentrating on the camouflaged, for dermatologists, might mean just looking again and focusing on the less-obvious. But, Dr. Ko said, it might mean turning your attention elsewhere for a while, and then looking back at the area in question. Or the patient or slide – or even the examiner – might need repositioning, for a fresh perspective.
- Taking One thing at a time. For dermatologists and dermatopathologists, this means sorting out the who, what, when, and where of the problem at hand. “ ‘Who’ is always the patient,” said Dr. Ko. “But part of ‘who’ is also us; if we’re tired, it can affect things.” There are many ‘whats’ to consider about the presenting problem or the tissue sample: What is the configuration? The architecture? What is the morphology? What’s the color, or cell type? Are there secondary changes? Does the tissue fit into the general category of a benign, or a malignant, lesion? The examination should include a methodical search for clues as to the duration of the problem – Is it acute or chronic? Finally, the ‘where’ – distribution on the body, or of a specimen on a slide, should also be noted.
- Take a Break. This means resting the eye and the mind by turning attention elsewhere, or shifting to light conversation with the patient, or just stepping away from the microscope for a time.
- Realign your expectations. What might you have missed? Is the patient telling you something in the history? Is it possible this is an uncommon presentation of a common condition, rather than a “zebra”?
- Ask someone else to look with you. Sometimes there’s no substitute for another set of eyes, and another brain working on the problem.
A congruent perspective comes from Daniel Kahneman, PhD, a Nobel Prize–winning economist. In 2011, he published a work addressing meta-cognition, called “Thinking Fast and Slow.”
From Dr. Kahneman’s work, Dr. Ko says dermatologists can learn to recognize two complementary ways of thinking. The “fast” system engages multiple cognitive processes to create a gestalt, “gut” impression. “Slow” thinking, in Dr. Kahneman’s construct, is deliberative, methodical, and traditionally thought of as “logical.” However, it would be a mistake to think of these two systems as existing in opposition, or even as completely separate from each other. “It’s sort of just a linguistic tool for us to have something to call it,” she said.
A “fast” analysis will involve some key elements of visual assessment, said Dr. Ko. Figure-ground separation is a basic element of visual assessment and is vital for the work of the dermatopathologist. “Choosing the wrong ‘figure’ may lead to cognitive error,” she explained, citing work on visual perception among dermatopathologists that found that figure-ground separation errors account for a significant number of diagnostic errors.
Other contributors to “fast” thinking include one’s own experience, seeing just a part of the image, judging which elements are close to each other and similar, and noting color contrasts and gradations.
The “slow” assessment is where deliberate practice comes in, said Dr. Ko. Here, the physician goes further, “to check for pertinent positive and negative evidence” for the initial diagnosis. “Play devil’s advocate, and ask yourself why it couldn’t be something else,” she said.
Eve Lowenstein, MD, PhD, is a dermatologist who publishes about heuristics in dermatology. She and Dr. Ko have collaborated to create a forthcoming two-part continuing medical education article in the Journal of the American Academy of Dermatology (JAAD) about cognitive biases and errors in dermatology.
Dr. Lowenstein’s perspective, recently elucidated in two British Journal of Dermatology articles, acknowledges that while “ubiquitous cognitive and visual heuristics can enhance diagnostic speed, they also create pitfalls and thinking traps that introduce significant variation in the diagnostic process,” she and her coauthor Richard Sidlow, MD, of Staten Island (N.Y.) University Hospital, wrote in the abstract accompanying the first article (Br J Dermatol. 2018 Dec;179[6]:1263-9). The second article was published in the same issue (Br J Dermatol. 2018 Dec;179[6]:1270-6).
Heuristics are cognitive shortcuts used to speed decision-making that build on what’s already known, as in the “fast” thinking of Dr. Kahneman’s paradigm. Though heuristics are used in all sorts of professions with high cognitive loads, there’s a risk when physicians get too comfortable with the shortcuts. Speaking frankly in an interview, Dr. Lowenstein said, “intellectual presumptiveness or overconfidence, which is a natural human tendency, can result in oversights and missing information critical to making a correct diagnosis, and premature closure on the wrong diagnosis.”
Diagnostic error, Dr. Lowenstein pointed out, can also result from an “attitudinal overconfidence,” which can come from complacency – being satisfied with the status quo or a lack of intellectual curiosity – or arrogance, she said.
“Complacency is the opposite of what is needed in medicine: an attitude where one cannot know enough. The pursuit of knowledge goes on, ever vigilantly. The world changes; practitioners must keep up and cannot fall back on their knowledge,” she said.
This kind of attitudinal and cognitive humility, she said, is essential to practicing quality care in dermatology. Having practical strategies to improve diagnosis, especially in difficult cases, can make a big difference. For Dr. Lowenstein, one of these tactics is to keep an error diary. “It has been said that ‘the only way to safeguard against error is to embrace it,’ ” she said, quoting Kathryn Schulz in “Being Wrong.” “Unfortunately, we learn some of our most profound lessons from our errors.”
By recording and tracking her own errors, not only is she able to see her own cognitive blind spots through meta-cognition – thinking about how we think – but she’s also able to share these lessons in her teaching. “Some of my best teaching tools for residents are from everything I have screwed up,” said Dr. Lowenstein, director of medical dermatology at the State University of New York Downstate Medical Center and Kings County Hospital, Brooklyn, N.Y.
Another useful tip is simply “to put what you see into words,” when the presentation is confusing or the diagnosis doesn’t quite fit, she added.
“Transforming signs and findings into semantics triggers a differential diagnosis, which is especially useful when we are diagnostically stumped. Studies have found that successful diagnosticians use twice as many semantic qualifiers as the physicians who were diagnostically incorrect.” This is especially significant in visual fields like dermatology, where a single word can paint a picture and rapidly focus a diagnostic search. “We often undervalue this function and relegate it to students starting out in the field,” Dr. Lowenstein said.
Cognitive shortcuts such as diagnostic heuristics all have blind spots, and diagnostic errors tend to fall in these blind spots, she added. “We tend to ignore them. In driving, we adapt to the use of rear and side view mirrors in order to drive safely. Similarly, in diagnostics, alternative views on the data can be very helpful. For example, when faced with difficult cases, take a time out to reanalyze the information without framing or context. Use systematic approaches, such as running down a papulosquamous differential diagnosis. Ask yourself: What can’t be explained in the picture? What doesn’t fit? Think in terms of probabilities – a rare presentation of a common disease is more likely than a rare disease,” she said.
Finally, asking for advice or second opinions from peers, whether by face-to-face discussion or via an online chat site, within the department or appealing to broader groups such as hospitalist dermatologist chat groups, can be helpful with difficult cases. Another strategy is simply to email an expert. Dr. Lowenstein said she’s had great success reaching out to authors of relevant papers by email. Most of her peers, she said, are interested in unusual cases and happy to help.
Dr. Ko has authored or coauthored books on the topics of visual recognition in dermatology and dermatopathology. They are “Dermatology: Visual Recognition and Case Reviews,” and “Dermatopathology: Diagnosis by First Impression.” Dr. Lowenstein reported that she has no conflicts of interest.
CHICAGO – Medicine, perhaps uniquely among the highly skilled professions, requires the practitioner to use his or her senses on a daily basis. Dermatologists and dermatopathologists rely on visual skills – pattern recognition, gestalt or “gut” first impressions, and step-by-step deliberations – to care for their patients.
But, like all human cognitive processes, visual assessments are error prone. The same brains that can parse a field of blue and pink dots to discern melanoma on a slide are also capable of glaring errors of omission: All too often, the brain follows a cognitive path for the wrong reasons.
Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., became interested in the meta-cognition of her trade; that is, she sought to learn how to think about the thinking that’s needed to be a dermatologist or a dermatopathologist.
In a wide-ranging discussion at the summer meeting of the American Academy of Dermatology, Dr. Ko took attendees through The path led through lessons learned from cognitive science to the fine arts, to lessons learned from other visually oriented medical disciplines.
“Deliberate practice in dermatology is augmented by knowledge of specific cognitive principles that affect visual perception,” Dr. Ko said at the meeting. “This session will open your eyes to the world of visual intelligence that underlies expert dermatologic diagnosis.”
To begin with, what constitutes deliberate practice of dermatology or dermatopathology? Practically speaking, seeing many patients (or reading many slides) builds the base for true expertise, she noted. Physicians continue to hone their learning through independent reading, journal clubs, and meeting attendance, and seek opportunities for deliberate review of what’s still unknown, as in grand rounds – where, ideally, feedback is instantaneous.
Deliberate practice, though, should also include honing visual skills. “We find only the world we look for,” said Dr. Ko, quoting Henry David Thoreau. To sharpen the pattern recognition and keen observation that underpin dermatology and dermatopathology, she said, “We can train the brain.”
Radiology, another medical discipline that requires sustained visual attention, has a significant body of literature addressing common visually-related cognitive errors, she pointed out. In radiology, it’s been shown that deliberate observation of visual art can improve accuracy of reading films.
She observed that dermatologists and dermatopathologists need to think in color, so they may need to develop slightly different visual skills from radiologists who largely see a gray-scale world while they’re working.
Cognitive psychology also offers lessons. One seminal paper, “The invisible gorilla strikes again: Sustained inattentional blindness in expert observers,” issues a stern admonition: “[A] high level of expertise does not immunize individuals against inherent limitations of human attention imperception” (Psychol Sci. 2013 Sep;24[9]:1848-53). Inattentional blindness, Dr. Ko explained, occurs when “what we are focused on filters the world around us aggressively.” First author Trafton Drew, PhD, and his colleagues added: “Researchers should seek better understanding of these limits, so that medical and other man-made search tasks could be designed in ways that reduce the consequences of these limitations.”
How to overcome these limitations? “Concentrate on the camouflaged,” said Dr. Ko, taking a page – literally – from “Visual Intelligence: Sharpen Your Perception, Change Your Life” (Houghton Mifflin Harcourt, 2016), a book by Amy Herman, JD. Ms. Herman devised the mnemonic “COBRA” to identify several steps that can prevent cognitive error from visual observation:
- Concentrating on the camouflaged, for dermatologists, might mean just looking again and focusing on the less-obvious. But, Dr. Ko said, it might mean turning your attention elsewhere for a while, and then looking back at the area in question. Or the patient or slide – or even the examiner – might need repositioning, for a fresh perspective.
- Taking One thing at a time. For dermatologists and dermatopathologists, this means sorting out the who, what, when, and where of the problem at hand. “ ‘Who’ is always the patient,” said Dr. Ko. “But part of ‘who’ is also us; if we’re tired, it can affect things.” There are many ‘whats’ to consider about the presenting problem or the tissue sample: What is the configuration? The architecture? What is the morphology? What’s the color, or cell type? Are there secondary changes? Does the tissue fit into the general category of a benign, or a malignant, lesion? The examination should include a methodical search for clues as to the duration of the problem – Is it acute or chronic? Finally, the ‘where’ – distribution on the body, or of a specimen on a slide, should also be noted.
- Take a Break. This means resting the eye and the mind by turning attention elsewhere, or shifting to light conversation with the patient, or just stepping away from the microscope for a time.
- Realign your expectations. What might you have missed? Is the patient telling you something in the history? Is it possible this is an uncommon presentation of a common condition, rather than a “zebra”?
- Ask someone else to look with you. Sometimes there’s no substitute for another set of eyes, and another brain working on the problem.
A congruent perspective comes from Daniel Kahneman, PhD, a Nobel Prize–winning economist. In 2011, he published a work addressing meta-cognition, called “Thinking Fast and Slow.”
From Dr. Kahneman’s work, Dr. Ko says dermatologists can learn to recognize two complementary ways of thinking. The “fast” system engages multiple cognitive processes to create a gestalt, “gut” impression. “Slow” thinking, in Dr. Kahneman’s construct, is deliberative, methodical, and traditionally thought of as “logical.” However, it would be a mistake to think of these two systems as existing in opposition, or even as completely separate from each other. “It’s sort of just a linguistic tool for us to have something to call it,” she said.
A “fast” analysis will involve some key elements of visual assessment, said Dr. Ko. Figure-ground separation is a basic element of visual assessment and is vital for the work of the dermatopathologist. “Choosing the wrong ‘figure’ may lead to cognitive error,” she explained, citing work on visual perception among dermatopathologists that found that figure-ground separation errors account for a significant number of diagnostic errors.
Other contributors to “fast” thinking include one’s own experience, seeing just a part of the image, judging which elements are close to each other and similar, and noting color contrasts and gradations.
The “slow” assessment is where deliberate practice comes in, said Dr. Ko. Here, the physician goes further, “to check for pertinent positive and negative evidence” for the initial diagnosis. “Play devil’s advocate, and ask yourself why it couldn’t be something else,” she said.
Eve Lowenstein, MD, PhD, is a dermatologist who publishes about heuristics in dermatology. She and Dr. Ko have collaborated to create a forthcoming two-part continuing medical education article in the Journal of the American Academy of Dermatology (JAAD) about cognitive biases and errors in dermatology.
Dr. Lowenstein’s perspective, recently elucidated in two British Journal of Dermatology articles, acknowledges that while “ubiquitous cognitive and visual heuristics can enhance diagnostic speed, they also create pitfalls and thinking traps that introduce significant variation in the diagnostic process,” she and her coauthor Richard Sidlow, MD, of Staten Island (N.Y.) University Hospital, wrote in the abstract accompanying the first article (Br J Dermatol. 2018 Dec;179[6]:1263-9). The second article was published in the same issue (Br J Dermatol. 2018 Dec;179[6]:1270-6).
Heuristics are cognitive shortcuts used to speed decision-making that build on what’s already known, as in the “fast” thinking of Dr. Kahneman’s paradigm. Though heuristics are used in all sorts of professions with high cognitive loads, there’s a risk when physicians get too comfortable with the shortcuts. Speaking frankly in an interview, Dr. Lowenstein said, “intellectual presumptiveness or overconfidence, which is a natural human tendency, can result in oversights and missing information critical to making a correct diagnosis, and premature closure on the wrong diagnosis.”
Diagnostic error, Dr. Lowenstein pointed out, can also result from an “attitudinal overconfidence,” which can come from complacency – being satisfied with the status quo or a lack of intellectual curiosity – or arrogance, she said.
“Complacency is the opposite of what is needed in medicine: an attitude where one cannot know enough. The pursuit of knowledge goes on, ever vigilantly. The world changes; practitioners must keep up and cannot fall back on their knowledge,” she said.
This kind of attitudinal and cognitive humility, she said, is essential to practicing quality care in dermatology. Having practical strategies to improve diagnosis, especially in difficult cases, can make a big difference. For Dr. Lowenstein, one of these tactics is to keep an error diary. “It has been said that ‘the only way to safeguard against error is to embrace it,’ ” she said, quoting Kathryn Schulz in “Being Wrong.” “Unfortunately, we learn some of our most profound lessons from our errors.”
By recording and tracking her own errors, not only is she able to see her own cognitive blind spots through meta-cognition – thinking about how we think – but she’s also able to share these lessons in her teaching. “Some of my best teaching tools for residents are from everything I have screwed up,” said Dr. Lowenstein, director of medical dermatology at the State University of New York Downstate Medical Center and Kings County Hospital, Brooklyn, N.Y.
Another useful tip is simply “to put what you see into words,” when the presentation is confusing or the diagnosis doesn’t quite fit, she added.
“Transforming signs and findings into semantics triggers a differential diagnosis, which is especially useful when we are diagnostically stumped. Studies have found that successful diagnosticians use twice as many semantic qualifiers as the physicians who were diagnostically incorrect.” This is especially significant in visual fields like dermatology, where a single word can paint a picture and rapidly focus a diagnostic search. “We often undervalue this function and relegate it to students starting out in the field,” Dr. Lowenstein said.
Cognitive shortcuts such as diagnostic heuristics all have blind spots, and diagnostic errors tend to fall in these blind spots, she added. “We tend to ignore them. In driving, we adapt to the use of rear and side view mirrors in order to drive safely. Similarly, in diagnostics, alternative views on the data can be very helpful. For example, when faced with difficult cases, take a time out to reanalyze the information without framing or context. Use systematic approaches, such as running down a papulosquamous differential diagnosis. Ask yourself: What can’t be explained in the picture? What doesn’t fit? Think in terms of probabilities – a rare presentation of a common disease is more likely than a rare disease,” she said.
Finally, asking for advice or second opinions from peers, whether by face-to-face discussion or via an online chat site, within the department or appealing to broader groups such as hospitalist dermatologist chat groups, can be helpful with difficult cases. Another strategy is simply to email an expert. Dr. Lowenstein said she’s had great success reaching out to authors of relevant papers by email. Most of her peers, she said, are interested in unusual cases and happy to help.
Dr. Ko has authored or coauthored books on the topics of visual recognition in dermatology and dermatopathology. They are “Dermatology: Visual Recognition and Case Reviews,” and “Dermatopathology: Diagnosis by First Impression.” Dr. Lowenstein reported that she has no conflicts of interest.
EXPERT ANALYSIS FROM SUMMER AAD 2018
With RRMM and renal impairment, carfilzomib improves survival
Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.
In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.
Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.
The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.
In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.
For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).
Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).
The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.
Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).
“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.
Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.
Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.
However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.
The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”
These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.
The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.
SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.
Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.
In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.
Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.
The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.
In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.
For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).
Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).
The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.
Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).
“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.
Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.
Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.
However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.
The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”
These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.
The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.
SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.
Patients with renal failure and relapsed or refractory multiple myeloma fared better with the selective proteasome inhibitor carfilzomib, compared with bortezomib, according to a post hoc subgroup analysis of a large clinical trial.
In addition, patients who had a complete renal response had longer progression-free survival (PFS) and overall survival (OS), regardless of treatment group.
Many aspects of the disease state and treatment can contribute to renal failure in multiple myeloma, but cast nephropathy from precipitation of monoclonal light chains certainly contributes to persistent renal failure, Meletios Dimopoulos, MD, professor and chair of clinical therapeutics at the University of Athens, Greece, and his coauthors wrote in Blood.
The investigators wanted to see how individuals with varying levels of renal function fared in the ENDEAVOR trial, which compared carfilzomib (56 mg/m2) plus dexamethasone (Kd56) with bortezomib plus dexamethasone (Vd) for patients with relapsed or refractory multiple myeloma.
In an intent-to-treat population of 929 patients, 85 Kd56 and 99 Vd patients had creatinine clearance (CrCL) of at least 15 but less than 50 mL/min. Of patients with mild renal failure (CrCL of at least 50 but less than 80 mL/min), 186 were in the Kd56 and 177 in the Vd group. One hundred ninety-three patients receiving Kd56 and 189 Vd patients had CrCL of 80 mL/min or greater.
For ENDEAVOR patients with the lowest CrCL, median PFS was 14.9 months with Kd56 and 6.5 months with Vd (hazard ratio [HR], 0.49). For patients with intermediate CrCL, median PFS was 18.6 versus 9.4 months with Kd56 and Vd, respectively (HR, 0.48). For patients with the highest CrCL, PFS was not reached with Kd56; with Vd, median PFS was 12.2 months (HR, 0.60).
Patterns for OS mirrored the advantage seen with Kd56. Median OS was 42.1 versus 23.7 months for those with the worst renal function in the Kd56 arm and the Vd arm, respectively (HR, 0.66). Those with intermediate renal function saw median OS of 42.5 versus 32.8 months on Kd56 and Vd, respectively (HR, 0.83). Median OS for those with the highest CrCL was not reached on Kd56 and 42.3 months on Vd (HR, 0.75).
The investigators also tracked kidney function over the course of the study, with complete renal response defined as improvement of CrCL to at least 60 mL/min in any two consecutive study visits. By this yardstick, complete renal response was 15.3% for the Kd56 arm and 14.1% for those receiving Vd.
Looking across participants regardless of therapy, those with CrCL of at least 15 but less than 50 mL/min who also had complete renal response had longer PFS, compared with nonresponders (median 14.1 versus 9.4 months, HR, .805). OS also was longer in this group of patients (median 35.3 versus 29.7 months, HR, 0.91).
“Patients with complete renal response had superior overall outcomes compared with renal nonresponders across treatment groups ... highlighting the association between improved renal function and greater survival rates,” Dr. Dimopoulos and his colleagues wrote.
Kd56 therapy was associated with a higher number of grade 3 or higher adverse events, seen in 77.1%-87.1% of Kd56 patients and 65.9%-79.4% of Vd patients.
Renal failure, common in multiple myeloma, is associated with poor prognosis. Also, therapeutic options can be limited and dosing adjustments must often be made when patients have poor renal function, Dr. Dimopoulos and his coauthors noted.
However, previous studies showed that carfilzomib clearance, exposure, and overall pharmacokinetics were similar between multiple myeloma patients with and without renal impairment, including end-stage renal disease, the investigators wrote.
The subgroup analysis from ENDEAVOR suggested that “Kd56 may overcome the poor prognosis of baseline advanced renal impairment,” Dr. Dimopoulos and his colleagues wrote. “Furthermore, patients in the Kd56 arm had deeper responses compared with the Vd arm, regardless of baseline renal impairment.”
These data suggest that Kd56 should be considered a “standard of care” in patients with relapsed or refractory multiple myeloma, regardless of a patient’s baseline renal function.
The investigators reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and supported the study.
SOURCE: Dimopoulos M et al. Blood. 2019;133(2):147-55.
FROM BLOOD
Key clinical point:
Major finding: Median progression-free survival was better with carfilzomib for patients with relapsed/refractory multiple myeloma (hazard ratios, 0.48-0.60).
Study details: Post hoc subgroup analysis of open-label randomized controlled trial of 929 patients receiving either carfilzomib or bortezomib with dexamethasone for relapsed/refractory multiple myeloma.
Disclosures: The authors reported multiple financial relationships with pharmaceutical companies, including Amgen, which markets carfilzomib and sponsored the study.
Source: Dimopoulos M et al. Blood. 2019;133(2):147-55.
Platelet-rich plasma: Is your practice ready?
ORLANDO – Platelet-rich plasma offers much for patients and dermatologists: It’s low-risk, has a low cost of entry, and usefully augments other medications and procedures for androgenetic alopecia and facial rejuvenation.
But there’s work to be done in standardizing its use and really understanding where, when, and for whom platelet-rich plasma (PRP) will be best used, said Dierdre Hooper, MD, a dermatologist in private practice in New Orleans.
As far back as the 1970s, PRP was used as a transfusion product, with use expanding during the following decade. “It’s really the ‘everywhere’ product,’” said Dr. Hooper, speaking at the Aesthetic, Surgical, and Clinical Dermatology Conference (ODAC).
Over the course of the past four decades, PRP has been explored for musculoskeletal healing, in gynecology, urology, cardiac surgery, ophthalmology, and for plastic surgery. “Initial skepticism has given way as some evidence is building,” said Dr. Hooper.
PRP, considered a biologic product, is produced by centrifuging a donor venipuncture. Among the pros of using PRP in a clinical practice, said Dr. Hooper, is the fact that numerous clinical studies do show benefit. The risk is low, as is the cost, and downtime is brief. All of these contribute to attractiveness to patients, who also like the idea of an all-natural product with an autologous source.
But consensus is lacking about some key aspects of utilization, including the best mode of preparation and optimal treatment schedule. Outcomes can be unpredictable, making it tough to say how cost-effective the regimen will be for a particular patient. “The ‘cons’ just come down to no consensus,” said Dr. Hooper.
Some of the basic science makes a compelling case for PRP: Activated platelets have secretory granules. These modify the pericellular milieu through release of a variety of growth factors by secretory granules. “We all were taught back in the day that platelets adhere to promote clotting, but they do a lot more than that – when the platelet is activated, it releases growth factors,” said Dr. Hooper. “Big picture? Think: This is how we heal.”
After blood collection, the sample is centrifuged. The goal of centrifuging is to achieve a platelet concentration of 1 to 1.5 million platelets per mL, or four to six times the platelet concentration seen in whole blood. In practice, there are variations in the mode of preparation, and in an individual’s platelet level at the time of venipuncture, said Dr. Hooper, so it’s hard to know what the platelet “dose” is from PRP.
After centrifuging, the sample will be stratified into a bottom portion, consisting primarily of red blood cells, a middle portion that’s the PRP, and a top portion that is platelet-poor plasma. Dr. Hooper draws up and saves the platelet- poor plasma as well, since it probably also contains some growth factors. She’ll save that for application or injection after a PRP treatment for some patients.
Dermatology presents a host of uses for PRP. In addition to application after microneedling or resurfacing and injectable aesthetic uses, PRP can also be used to treat melasma, acne scarring, and androgenetic alopecia.
The strongest data for PRP currently are for androgenetic alopecia, said Dr. Hooper, because that’s where most of the work has been done to date. Growth factors in PRP can target the dermal papillae, shortening the anagen phase. “You will improve the anagen:telogen ratio and increase hair density and thickness,” she said.
“When you talk to your hair loss patients, there are drawbacks” with home therapy such as minoxidil and finasteride, said Dr. Hooper. “Compliance is an issue. I’m a firm believer in combination treatment for hair loss.” Studies have shown increased hair thickness and moderately decreased hair loss with PRP. Anecdotally, said Dr. Hooper, hair becomes coarser, feeling fuller and thicker; one study found that about a quarter of patients reported this effect.
Through experience, Dr. Hooper’s learned some pearls for using PRP for androgenetic alopecia. Her male patients appreciate the use of a chilling device to help with pain, especially since Dr. Hooper uses a triple-needle syringe to stamp the scalp as she injects the PRP. Depending on how her patients are tolerating the procedure, she’ll follow up by injecting some platelet-poor plasma as well.
An additional pearl? “Have your patients bring a baseball cap.” Between procedure preparation, some oozing of PRP, and bleeding from injection sites, men don’t leave as well-coiffed as when they entered, she said.
Dr. Hooper has patients return four times over the course of 6 months for androgenetic alopecia, with repeat treatments about every 6 months thereafter.
Several studies have looked at using intradermal PRP for facial rejuvenation, with largely positive results. “Once again, we see consistent efficacy with no side effects,” said Dr. Hooper. She will use PRP either intradermally or topically after microneedling or fractional ablative laser resurfacing.
If it’s being used topically, Dr. Hooper will simply wipe the PRP on after the resurfacing treatment. For microneedling, “As we finish one zone, we topically apply the PRP and move on,” she said, adding that she instructs the patient not to wash her face until bedtime.
“I like injectable delivery for PRP as well,” said Dr. Hooper. She will often use it for crepey skin under the eyes as an add-on to other treatments, she said.
Her patients report that one major upside of post-resurfacing PRP is that they feel they recover more quickly. “Less erythema and less recovery time – that’s something that’s always helpful,” said Dr. Hooper. She uses the same treatment schedule for rejuvenation as for alopecia.
Some studies have shown promise for injected PRP for striae, said Dr. Hooper. She has just begun using injected PRP for striae in her practice and is encouraged by early results she’s seeing. It’s easier for patients than using multiple at-home treatments: “I think it’s just an option, they can pop in 3 times over the next few months” for some added benefit, she said.
Scanning the audience, Dr. Hooper said, “I see a lot of younger faces out there. I would challenge you to do the studies” to build evidence-based protocols for PRP in dermatology, since lack of consensus still hinders both adoption and high-quality research.
Dr. Hooper reported multiple financial relationships with pharmaceutical and cosmetic companies.
SOURCE: Hooper, D. ODAC 2018.
ORLANDO – Platelet-rich plasma offers much for patients and dermatologists: It’s low-risk, has a low cost of entry, and usefully augments other medications and procedures for androgenetic alopecia and facial rejuvenation.
But there’s work to be done in standardizing its use and really understanding where, when, and for whom platelet-rich plasma (PRP) will be best used, said Dierdre Hooper, MD, a dermatologist in private practice in New Orleans.
As far back as the 1970s, PRP was used as a transfusion product, with use expanding during the following decade. “It’s really the ‘everywhere’ product,’” said Dr. Hooper, speaking at the Aesthetic, Surgical, and Clinical Dermatology Conference (ODAC).
Over the course of the past four decades, PRP has been explored for musculoskeletal healing, in gynecology, urology, cardiac surgery, ophthalmology, and for plastic surgery. “Initial skepticism has given way as some evidence is building,” said Dr. Hooper.
PRP, considered a biologic product, is produced by centrifuging a donor venipuncture. Among the pros of using PRP in a clinical practice, said Dr. Hooper, is the fact that numerous clinical studies do show benefit. The risk is low, as is the cost, and downtime is brief. All of these contribute to attractiveness to patients, who also like the idea of an all-natural product with an autologous source.
But consensus is lacking about some key aspects of utilization, including the best mode of preparation and optimal treatment schedule. Outcomes can be unpredictable, making it tough to say how cost-effective the regimen will be for a particular patient. “The ‘cons’ just come down to no consensus,” said Dr. Hooper.
Some of the basic science makes a compelling case for PRP: Activated platelets have secretory granules. These modify the pericellular milieu through release of a variety of growth factors by secretory granules. “We all were taught back in the day that platelets adhere to promote clotting, but they do a lot more than that – when the platelet is activated, it releases growth factors,” said Dr. Hooper. “Big picture? Think: This is how we heal.”
After blood collection, the sample is centrifuged. The goal of centrifuging is to achieve a platelet concentration of 1 to 1.5 million platelets per mL, or four to six times the platelet concentration seen in whole blood. In practice, there are variations in the mode of preparation, and in an individual’s platelet level at the time of venipuncture, said Dr. Hooper, so it’s hard to know what the platelet “dose” is from PRP.
After centrifuging, the sample will be stratified into a bottom portion, consisting primarily of red blood cells, a middle portion that’s the PRP, and a top portion that is platelet-poor plasma. Dr. Hooper draws up and saves the platelet- poor plasma as well, since it probably also contains some growth factors. She’ll save that for application or injection after a PRP treatment for some patients.
Dermatology presents a host of uses for PRP. In addition to application after microneedling or resurfacing and injectable aesthetic uses, PRP can also be used to treat melasma, acne scarring, and androgenetic alopecia.
The strongest data for PRP currently are for androgenetic alopecia, said Dr. Hooper, because that’s where most of the work has been done to date. Growth factors in PRP can target the dermal papillae, shortening the anagen phase. “You will improve the anagen:telogen ratio and increase hair density and thickness,” she said.
“When you talk to your hair loss patients, there are drawbacks” with home therapy such as minoxidil and finasteride, said Dr. Hooper. “Compliance is an issue. I’m a firm believer in combination treatment for hair loss.” Studies have shown increased hair thickness and moderately decreased hair loss with PRP. Anecdotally, said Dr. Hooper, hair becomes coarser, feeling fuller and thicker; one study found that about a quarter of patients reported this effect.
Through experience, Dr. Hooper’s learned some pearls for using PRP for androgenetic alopecia. Her male patients appreciate the use of a chilling device to help with pain, especially since Dr. Hooper uses a triple-needle syringe to stamp the scalp as she injects the PRP. Depending on how her patients are tolerating the procedure, she’ll follow up by injecting some platelet-poor plasma as well.
An additional pearl? “Have your patients bring a baseball cap.” Between procedure preparation, some oozing of PRP, and bleeding from injection sites, men don’t leave as well-coiffed as when they entered, she said.
Dr. Hooper has patients return four times over the course of 6 months for androgenetic alopecia, with repeat treatments about every 6 months thereafter.
Several studies have looked at using intradermal PRP for facial rejuvenation, with largely positive results. “Once again, we see consistent efficacy with no side effects,” said Dr. Hooper. She will use PRP either intradermally or topically after microneedling or fractional ablative laser resurfacing.
If it’s being used topically, Dr. Hooper will simply wipe the PRP on after the resurfacing treatment. For microneedling, “As we finish one zone, we topically apply the PRP and move on,” she said, adding that she instructs the patient not to wash her face until bedtime.
“I like injectable delivery for PRP as well,” said Dr. Hooper. She will often use it for crepey skin under the eyes as an add-on to other treatments, she said.
Her patients report that one major upside of post-resurfacing PRP is that they feel they recover more quickly. “Less erythema and less recovery time – that’s something that’s always helpful,” said Dr. Hooper. She uses the same treatment schedule for rejuvenation as for alopecia.
Some studies have shown promise for injected PRP for striae, said Dr. Hooper. She has just begun using injected PRP for striae in her practice and is encouraged by early results she’s seeing. It’s easier for patients than using multiple at-home treatments: “I think it’s just an option, they can pop in 3 times over the next few months” for some added benefit, she said.
Scanning the audience, Dr. Hooper said, “I see a lot of younger faces out there. I would challenge you to do the studies” to build evidence-based protocols for PRP in dermatology, since lack of consensus still hinders both adoption and high-quality research.
Dr. Hooper reported multiple financial relationships with pharmaceutical and cosmetic companies.
SOURCE: Hooper, D. ODAC 2018.
ORLANDO – Platelet-rich plasma offers much for patients and dermatologists: It’s low-risk, has a low cost of entry, and usefully augments other medications and procedures for androgenetic alopecia and facial rejuvenation.
But there’s work to be done in standardizing its use and really understanding where, when, and for whom platelet-rich plasma (PRP) will be best used, said Dierdre Hooper, MD, a dermatologist in private practice in New Orleans.
As far back as the 1970s, PRP was used as a transfusion product, with use expanding during the following decade. “It’s really the ‘everywhere’ product,’” said Dr. Hooper, speaking at the Aesthetic, Surgical, and Clinical Dermatology Conference (ODAC).
Over the course of the past four decades, PRP has been explored for musculoskeletal healing, in gynecology, urology, cardiac surgery, ophthalmology, and for plastic surgery. “Initial skepticism has given way as some evidence is building,” said Dr. Hooper.
PRP, considered a biologic product, is produced by centrifuging a donor venipuncture. Among the pros of using PRP in a clinical practice, said Dr. Hooper, is the fact that numerous clinical studies do show benefit. The risk is low, as is the cost, and downtime is brief. All of these contribute to attractiveness to patients, who also like the idea of an all-natural product with an autologous source.
But consensus is lacking about some key aspects of utilization, including the best mode of preparation and optimal treatment schedule. Outcomes can be unpredictable, making it tough to say how cost-effective the regimen will be for a particular patient. “The ‘cons’ just come down to no consensus,” said Dr. Hooper.
Some of the basic science makes a compelling case for PRP: Activated platelets have secretory granules. These modify the pericellular milieu through release of a variety of growth factors by secretory granules. “We all were taught back in the day that platelets adhere to promote clotting, but they do a lot more than that – when the platelet is activated, it releases growth factors,” said Dr. Hooper. “Big picture? Think: This is how we heal.”
After blood collection, the sample is centrifuged. The goal of centrifuging is to achieve a platelet concentration of 1 to 1.5 million platelets per mL, or four to six times the platelet concentration seen in whole blood. In practice, there are variations in the mode of preparation, and in an individual’s platelet level at the time of venipuncture, said Dr. Hooper, so it’s hard to know what the platelet “dose” is from PRP.
After centrifuging, the sample will be stratified into a bottom portion, consisting primarily of red blood cells, a middle portion that’s the PRP, and a top portion that is platelet-poor plasma. Dr. Hooper draws up and saves the platelet- poor plasma as well, since it probably also contains some growth factors. She’ll save that for application or injection after a PRP treatment for some patients.
Dermatology presents a host of uses for PRP. In addition to application after microneedling or resurfacing and injectable aesthetic uses, PRP can also be used to treat melasma, acne scarring, and androgenetic alopecia.
The strongest data for PRP currently are for androgenetic alopecia, said Dr. Hooper, because that’s where most of the work has been done to date. Growth factors in PRP can target the dermal papillae, shortening the anagen phase. “You will improve the anagen:telogen ratio and increase hair density and thickness,” she said.
“When you talk to your hair loss patients, there are drawbacks” with home therapy such as minoxidil and finasteride, said Dr. Hooper. “Compliance is an issue. I’m a firm believer in combination treatment for hair loss.” Studies have shown increased hair thickness and moderately decreased hair loss with PRP. Anecdotally, said Dr. Hooper, hair becomes coarser, feeling fuller and thicker; one study found that about a quarter of patients reported this effect.
Through experience, Dr. Hooper’s learned some pearls for using PRP for androgenetic alopecia. Her male patients appreciate the use of a chilling device to help with pain, especially since Dr. Hooper uses a triple-needle syringe to stamp the scalp as she injects the PRP. Depending on how her patients are tolerating the procedure, she’ll follow up by injecting some platelet-poor plasma as well.
An additional pearl? “Have your patients bring a baseball cap.” Between procedure preparation, some oozing of PRP, and bleeding from injection sites, men don’t leave as well-coiffed as when they entered, she said.
Dr. Hooper has patients return four times over the course of 6 months for androgenetic alopecia, with repeat treatments about every 6 months thereafter.
Several studies have looked at using intradermal PRP for facial rejuvenation, with largely positive results. “Once again, we see consistent efficacy with no side effects,” said Dr. Hooper. She will use PRP either intradermally or topically after microneedling or fractional ablative laser resurfacing.
If it’s being used topically, Dr. Hooper will simply wipe the PRP on after the resurfacing treatment. For microneedling, “As we finish one zone, we topically apply the PRP and move on,” she said, adding that she instructs the patient not to wash her face until bedtime.
“I like injectable delivery for PRP as well,” said Dr. Hooper. She will often use it for crepey skin under the eyes as an add-on to other treatments, she said.
Her patients report that one major upside of post-resurfacing PRP is that they feel they recover more quickly. “Less erythema and less recovery time – that’s something that’s always helpful,” said Dr. Hooper. She uses the same treatment schedule for rejuvenation as for alopecia.
Some studies have shown promise for injected PRP for striae, said Dr. Hooper. She has just begun using injected PRP for striae in her practice and is encouraged by early results she’s seeing. It’s easier for patients than using multiple at-home treatments: “I think it’s just an option, they can pop in 3 times over the next few months” for some added benefit, she said.
Scanning the audience, Dr. Hooper said, “I see a lot of younger faces out there. I would challenge you to do the studies” to build evidence-based protocols for PRP in dermatology, since lack of consensus still hinders both adoption and high-quality research.
Dr. Hooper reported multiple financial relationships with pharmaceutical and cosmetic companies.
SOURCE: Hooper, D. ODAC 2018.
EXPERT ANALYSIS FROM ODAC 2019
Bidirectional relationship found between depression, vitiligo
Vitiligo and major depressive disorder have a bidirectional relationship, according to a new study that examined data from a cohort of more than 6 million people.
“Ultimately, this suggests that mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo, which in turn can increase the risk of MDD, especially in younger patients,” wrote Isabelle Vallerand, PhD, and her colleagues. The report is in the Journal of the American Academy of Dermatology.
Dr. Vallerand and her colleagues found that patients with major depressive disorder (MDD, n = 405,397) had a 64% increased risk of vitiligo, compared with a referent cohort (n = 5,739,048; 95% confidence interval, 1.43-1.87; P less than .0001). Conversely, patients who had vitiligo also were at an increased risk of MDD. Patients who were younger than 30 years old at diagnosis (n = 7,104) had a hazard ratio of 1.31 for MDD (P less than .0001), compared with 1.22 for patients aged 30 years and older (P = .001).
Individuals who took antidepressants, whether or not they also had an MDD diagnosis, had a decreased risk for vitiligo.
Though it’s known that vitiligo increases the risk of MDD, less clarity has been in the literature about whether the converse also might be true. “The question of whether vitiligo onset can be precipitated by MDD has received less attention, despite the notion that patients often ask their dermatologists if stress or depression may have contributed to their disease,” wrote Dr. Vallerand, an epidemiologist and medical student at the University of Calgary, Alberta, and her colleagues.
There is a biologic plausibility for a bidirectional relationship, said Dr. Vallerand and her colleagues, since depression can boost systemic inflammation, and the risk for autoimmune disease such as vitiligo can be increased by proinflammatory states.
Access to a large dataset gave Dr. Vallerand and her collaborators the numbers to look at the relationship between vitiligo and MDD in the context of potential confounders, and to correct for those in their statistical analysis. Using medical records from The Health Improvement Network (THIN) database in the United Kingdom, the investigators conducted two independent population-based cohort studies. Each looked at risk in one direction of the MDD-vitiligo association.
The first analysis looked at MDD as a risk factor for vitiligo, following all patients with an incident diagnostic code for MDD. Patients without the MDD diagnosis code were the referent cohort. Patients in each cohort were followed until they reached the outcome of interest – a diagnosis of vitiligo – or were censored. Patients who had a vitiligo diagnosis before receiving an MDD diagnosis were not included.
The second analysis examined whether vitiligo was a risk factor for MDD, with a similar design that used nonvitiligo patients as the referent cohort. This analysis followed all patients until a diagnosis of MDD was recorded, or patients were censored. Again, patients with MDD diagnoses that came before the vitiligo diagnosis were excluded.
For the analysis of risk of vitiligo, the investigators looked at the effects of multiple covariates, including age, sex, alcohol use and smoking status, socioeconomic status, medical comorbidities, and whether patients were taking antidepressants. The covariates included in the analysis of risk of MDD were age, sex, medical comorbidities, and type of vitiligo treatment.
After the researchers determined unadjusted hazard ratios, each covariate was removed one at a time to see where there were substantial changes to the HR. Two additional models, one unadjusted and one that fully adjusted for all covariates, also were built.
The sensitivity analyses showed “an overall protective effect of antidepressants among both cohorts,” wrote Dr. Vallerand and her colleagues. The incidence rate of vitiligo among patients with MDD using antidepressants was 19.7 per 100,000 person-years, compared with 27.5 among MDD patients not using antidepressants (P = .0053).
“Similarly, those in the referent cohort who used antidepressants had about half the risk of vitiligo,” compared with the nonusers in the referent group, the investigators said. Serotonin also is present in the skin, and neurons and melanocytes share embryonic ectodermal origins, Dr. Vallerand and her colleagues said. Though the exact mechanisms are not known, in the THIN cohorts, they noted.
Though younger patients with vitiligo were at higher risk for MDD than were those aged 30 years and older, the overall cohort of individuals with vitiligo still had an unadjusted elevated risk for MDD, compared with the referent cohort (HR 1.27; 95% confidence interval, 1.16-1.40; P less than .0001).
“Unexpectedly, the magnitude of the reciprocal association was highest with MDD being a risk factor for vitiligo,” wrote Dr. Vallerand and her colleagues. “This highlights the notion that mental health may have a greater impact on the body, specifically with dermatologic manifestations, than previously thought.”
Some misclassification of both conditions is likely in such a large dataset, the investigators acknowledged. Also, subclinical depression was not evaluated, and there was no way to track the severity of either depression or vitiligo, they noted. Still, the big data approach “renders this one of the largest studies on psychodermatology to date,” said Dr. Vallerand and her colleagues, and the independent bidirectional analyses support causality.
Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRX, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.
SOURCE: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.
Vitiligo and major depressive disorder have a bidirectional relationship, according to a new study that examined data from a cohort of more than 6 million people.
“Ultimately, this suggests that mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo, which in turn can increase the risk of MDD, especially in younger patients,” wrote Isabelle Vallerand, PhD, and her colleagues. The report is in the Journal of the American Academy of Dermatology.
Dr. Vallerand and her colleagues found that patients with major depressive disorder (MDD, n = 405,397) had a 64% increased risk of vitiligo, compared with a referent cohort (n = 5,739,048; 95% confidence interval, 1.43-1.87; P less than .0001). Conversely, patients who had vitiligo also were at an increased risk of MDD. Patients who were younger than 30 years old at diagnosis (n = 7,104) had a hazard ratio of 1.31 for MDD (P less than .0001), compared with 1.22 for patients aged 30 years and older (P = .001).
Individuals who took antidepressants, whether or not they also had an MDD diagnosis, had a decreased risk for vitiligo.
Though it’s known that vitiligo increases the risk of MDD, less clarity has been in the literature about whether the converse also might be true. “The question of whether vitiligo onset can be precipitated by MDD has received less attention, despite the notion that patients often ask their dermatologists if stress or depression may have contributed to their disease,” wrote Dr. Vallerand, an epidemiologist and medical student at the University of Calgary, Alberta, and her colleagues.
There is a biologic plausibility for a bidirectional relationship, said Dr. Vallerand and her colleagues, since depression can boost systemic inflammation, and the risk for autoimmune disease such as vitiligo can be increased by proinflammatory states.
Access to a large dataset gave Dr. Vallerand and her collaborators the numbers to look at the relationship between vitiligo and MDD in the context of potential confounders, and to correct for those in their statistical analysis. Using medical records from The Health Improvement Network (THIN) database in the United Kingdom, the investigators conducted two independent population-based cohort studies. Each looked at risk in one direction of the MDD-vitiligo association.
The first analysis looked at MDD as a risk factor for vitiligo, following all patients with an incident diagnostic code for MDD. Patients without the MDD diagnosis code were the referent cohort. Patients in each cohort were followed until they reached the outcome of interest – a diagnosis of vitiligo – or were censored. Patients who had a vitiligo diagnosis before receiving an MDD diagnosis were not included.
The second analysis examined whether vitiligo was a risk factor for MDD, with a similar design that used nonvitiligo patients as the referent cohort. This analysis followed all patients until a diagnosis of MDD was recorded, or patients were censored. Again, patients with MDD diagnoses that came before the vitiligo diagnosis were excluded.
For the analysis of risk of vitiligo, the investigators looked at the effects of multiple covariates, including age, sex, alcohol use and smoking status, socioeconomic status, medical comorbidities, and whether patients were taking antidepressants. The covariates included in the analysis of risk of MDD were age, sex, medical comorbidities, and type of vitiligo treatment.
After the researchers determined unadjusted hazard ratios, each covariate was removed one at a time to see where there were substantial changes to the HR. Two additional models, one unadjusted and one that fully adjusted for all covariates, also were built.
The sensitivity analyses showed “an overall protective effect of antidepressants among both cohorts,” wrote Dr. Vallerand and her colleagues. The incidence rate of vitiligo among patients with MDD using antidepressants was 19.7 per 100,000 person-years, compared with 27.5 among MDD patients not using antidepressants (P = .0053).
“Similarly, those in the referent cohort who used antidepressants had about half the risk of vitiligo,” compared with the nonusers in the referent group, the investigators said. Serotonin also is present in the skin, and neurons and melanocytes share embryonic ectodermal origins, Dr. Vallerand and her colleagues said. Though the exact mechanisms are not known, in the THIN cohorts, they noted.
Though younger patients with vitiligo were at higher risk for MDD than were those aged 30 years and older, the overall cohort of individuals with vitiligo still had an unadjusted elevated risk for MDD, compared with the referent cohort (HR 1.27; 95% confidence interval, 1.16-1.40; P less than .0001).
“Unexpectedly, the magnitude of the reciprocal association was highest with MDD being a risk factor for vitiligo,” wrote Dr. Vallerand and her colleagues. “This highlights the notion that mental health may have a greater impact on the body, specifically with dermatologic manifestations, than previously thought.”
Some misclassification of both conditions is likely in such a large dataset, the investigators acknowledged. Also, subclinical depression was not evaluated, and there was no way to track the severity of either depression or vitiligo, they noted. Still, the big data approach “renders this one of the largest studies on psychodermatology to date,” said Dr. Vallerand and her colleagues, and the independent bidirectional analyses support causality.
Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRX, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.
SOURCE: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.
Vitiligo and major depressive disorder have a bidirectional relationship, according to a new study that examined data from a cohort of more than 6 million people.
“Ultimately, this suggests that mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo, which in turn can increase the risk of MDD, especially in younger patients,” wrote Isabelle Vallerand, PhD, and her colleagues. The report is in the Journal of the American Academy of Dermatology.
Dr. Vallerand and her colleagues found that patients with major depressive disorder (MDD, n = 405,397) had a 64% increased risk of vitiligo, compared with a referent cohort (n = 5,739,048; 95% confidence interval, 1.43-1.87; P less than .0001). Conversely, patients who had vitiligo also were at an increased risk of MDD. Patients who were younger than 30 years old at diagnosis (n = 7,104) had a hazard ratio of 1.31 for MDD (P less than .0001), compared with 1.22 for patients aged 30 years and older (P = .001).
Individuals who took antidepressants, whether or not they also had an MDD diagnosis, had a decreased risk for vitiligo.
Though it’s known that vitiligo increases the risk of MDD, less clarity has been in the literature about whether the converse also might be true. “The question of whether vitiligo onset can be precipitated by MDD has received less attention, despite the notion that patients often ask their dermatologists if stress or depression may have contributed to their disease,” wrote Dr. Vallerand, an epidemiologist and medical student at the University of Calgary, Alberta, and her colleagues.
There is a biologic plausibility for a bidirectional relationship, said Dr. Vallerand and her colleagues, since depression can boost systemic inflammation, and the risk for autoimmune disease such as vitiligo can be increased by proinflammatory states.
Access to a large dataset gave Dr. Vallerand and her collaborators the numbers to look at the relationship between vitiligo and MDD in the context of potential confounders, and to correct for those in their statistical analysis. Using medical records from The Health Improvement Network (THIN) database in the United Kingdom, the investigators conducted two independent population-based cohort studies. Each looked at risk in one direction of the MDD-vitiligo association.
The first analysis looked at MDD as a risk factor for vitiligo, following all patients with an incident diagnostic code for MDD. Patients without the MDD diagnosis code were the referent cohort. Patients in each cohort were followed until they reached the outcome of interest – a diagnosis of vitiligo – or were censored. Patients who had a vitiligo diagnosis before receiving an MDD diagnosis were not included.
The second analysis examined whether vitiligo was a risk factor for MDD, with a similar design that used nonvitiligo patients as the referent cohort. This analysis followed all patients until a diagnosis of MDD was recorded, or patients were censored. Again, patients with MDD diagnoses that came before the vitiligo diagnosis were excluded.
For the analysis of risk of vitiligo, the investigators looked at the effects of multiple covariates, including age, sex, alcohol use and smoking status, socioeconomic status, medical comorbidities, and whether patients were taking antidepressants. The covariates included in the analysis of risk of MDD were age, sex, medical comorbidities, and type of vitiligo treatment.
After the researchers determined unadjusted hazard ratios, each covariate was removed one at a time to see where there were substantial changes to the HR. Two additional models, one unadjusted and one that fully adjusted for all covariates, also were built.
The sensitivity analyses showed “an overall protective effect of antidepressants among both cohorts,” wrote Dr. Vallerand and her colleagues. The incidence rate of vitiligo among patients with MDD using antidepressants was 19.7 per 100,000 person-years, compared with 27.5 among MDD patients not using antidepressants (P = .0053).
“Similarly, those in the referent cohort who used antidepressants had about half the risk of vitiligo,” compared with the nonusers in the referent group, the investigators said. Serotonin also is present in the skin, and neurons and melanocytes share embryonic ectodermal origins, Dr. Vallerand and her colleagues said. Though the exact mechanisms are not known, in the THIN cohorts, they noted.
Though younger patients with vitiligo were at higher risk for MDD than were those aged 30 years and older, the overall cohort of individuals with vitiligo still had an unadjusted elevated risk for MDD, compared with the referent cohort (HR 1.27; 95% confidence interval, 1.16-1.40; P less than .0001).
“Unexpectedly, the magnitude of the reciprocal association was highest with MDD being a risk factor for vitiligo,” wrote Dr. Vallerand and her colleagues. “This highlights the notion that mental health may have a greater impact on the body, specifically with dermatologic manifestations, than previously thought.”
Some misclassification of both conditions is likely in such a large dataset, the investigators acknowledged. Also, subclinical depression was not evaluated, and there was no way to track the severity of either depression or vitiligo, they noted. Still, the big data approach “renders this one of the largest studies on psychodermatology to date,” said Dr. Vallerand and her colleagues, and the independent bidirectional analyses support causality.
Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRX, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.
SOURCE: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.
FROM JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Key clinical point: The findings suggest that “mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo.”
Major finding: Patients with major depressive disorder had a 64% increased risk of vitiligo.
Study details: Retrospective records review of 405,397 patients with MDD and 5,738,048 patients in a referent cohort.
Disclosures: Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRx, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.
Source: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.
FDA committee votes yes on romosozumab for osteoporosis
In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member Sundeep Khosla, MD, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab (Prolia) for another 12 months. This study, dubbed Trial 337, followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, Trial 142, was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.
Hip fractures were less common among those given romosozumab, and bone mineral density increased significantly as well.
Vertebral fractures were reduced by 36% in the romosozumab group relative to the alendronate group, and clinical fractures by 27% (P less than .001 for both).
Overall, the number of adverse events for the more than 7,500 patients in the safety population was similar between those receiving romosozumab and either placebo or alendronate, said Scott Wasserman, MD, vice president of global development for Amgen.
However, in Trial 142, which included patients who were slightly older and on more cardiovascular medications at baseline than in Trial 337, MACE – defined as cardiovascular death, MI, and stroke – occurred more frequently among those taking romosozumab, driven primarily by increased cardiac and cerebral ischemic events occurring within the first 12 months of beginning the study drug. At 12 months, the romosozumab arm saw 41 instances of MACE, compared with 22 in the alendronate arm to produce the HR of 1.87 (2.0% vs. 1.1%).
With regard to the imbalance in MACE seen in Trial 142, both the FDA and presenters for the sponsor entertained the notion that alendronate may have been somewhat protective for cardiovascular events. Although there is some biologic plausibility for a cardioprotective event for bisphosphonates, alendronate is highly specific for bone activity and the preponderance of previous studies have not shown such cardioprotection, the FDA, sponsors, and committee members all agreed.
Marc Sabatine, MD, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Harvard Medical School, Boston, was available to answer questions on behalf of the study’s sponsor. He noted at several points during the meeting just how few total cardiovascular events were seen overall in the romosozumab trial. The overall small numbers, he said, made it very difficult to distinguish whether the smaller number of MACE seen in the alendronate arm of Trial 142 were a true safety signal or just “a play of chance.”
Almost all the committee’s questioning and discussion centered on this potential increased cardiovascular risk. Amgen, in discussion with the FDA, had agreed to a black box warning designed to wave off prescribing romosozumab to those at increased risk for cardiovascular disease, focusing on those with a history of MI or stroke.
Additionally, the sponsor proposed a postmarketing real-world observational study to track incidence of MACE in those receiving romosozumab, comparing them with those receiving standard of care for osteoporosis.
Several committee members pointed out a problem with the proposed safety mitigation scheme: By conducting a postmarketing observational study for a drug that has a black-box warning to exclude those at high risk for MACE, the chance of detecting an actual cardiovascular safety problem plummets. “This is the textbook example of when observational studies struggle or are virtually guaranteed to fail,” noted Tobias Gerhard, PhD, a pharmacoepidemiologist at Rutgers University, New Brunswick, N.J.
On the other hand, noted several committee members, pausing to conduct a premarketing randomized, controlled trial would keep a beneficial drug away from a population in need. A postmarketing randomized, controlled trial, even a simple trial, still presents challenges, some of the committee acknowledged. Dr. Khosla voiced the opinion that “A randomized, controlled trial is virtually impossible.”
The committee, which was charged with discussing, but not voting on, what additional data should be obtained – and when – to sort out the cardiovascular safety question, was approximately evenly divided in the matter of whether an observational or registry-based trial, or a controlled trial, would be the best path forward.
Committee member Robert A. Adler, MD, put a realistic frame around the debate. “As an endocrinologist, I deal with nuances every day. I really think the kind of clinician who is going to be using this drug is used to dealing with benefits and risks and trying to tailor treatment to a given patient,” said Dr. Adler, professor of internal medicine and epidemiology at Virginia Commonwealth University, Richmond.
In its proposed indication, Amgen defined the population of menopausal women at high risk of fracture as those with a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Romosozumab would be given as a once-monthly subcutaneous injection of 210 mg for a period of 12 months, to be followed by antiresorptive therapy.
Most of the participants in the clinical trials resided outside the United States, primarily because of the difficulty of recruiting clinical trial participants in the United States, Amgen officials said during their presentation. However, neither the time to the first positively adjudicated MACE nor bone mineral density responses at month 12 differed significantly across the various geographic regions where clinical trial sites were located, said Rachel Wagman, MD, the executive medical director of global clinical development for Amgen. Still, several committee members called for postmarketing data to focus on U.S. patients.
Romosozumab was approved for marketing in Japan on Jan. 8, 2019; approval is also being sought in Europe .
The FDA usually follows the recommendations of its advisory panels.
In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member Sundeep Khosla, MD, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab (Prolia) for another 12 months. This study, dubbed Trial 337, followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, Trial 142, was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.
Hip fractures were less common among those given romosozumab, and bone mineral density increased significantly as well.
Vertebral fractures were reduced by 36% in the romosozumab group relative to the alendronate group, and clinical fractures by 27% (P less than .001 for both).
Overall, the number of adverse events for the more than 7,500 patients in the safety population was similar between those receiving romosozumab and either placebo or alendronate, said Scott Wasserman, MD, vice president of global development for Amgen.
However, in Trial 142, which included patients who were slightly older and on more cardiovascular medications at baseline than in Trial 337, MACE – defined as cardiovascular death, MI, and stroke – occurred more frequently among those taking romosozumab, driven primarily by increased cardiac and cerebral ischemic events occurring within the first 12 months of beginning the study drug. At 12 months, the romosozumab arm saw 41 instances of MACE, compared with 22 in the alendronate arm to produce the HR of 1.87 (2.0% vs. 1.1%).
With regard to the imbalance in MACE seen in Trial 142, both the FDA and presenters for the sponsor entertained the notion that alendronate may have been somewhat protective for cardiovascular events. Although there is some biologic plausibility for a cardioprotective event for bisphosphonates, alendronate is highly specific for bone activity and the preponderance of previous studies have not shown such cardioprotection, the FDA, sponsors, and committee members all agreed.
Marc Sabatine, MD, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Harvard Medical School, Boston, was available to answer questions on behalf of the study’s sponsor. He noted at several points during the meeting just how few total cardiovascular events were seen overall in the romosozumab trial. The overall small numbers, he said, made it very difficult to distinguish whether the smaller number of MACE seen in the alendronate arm of Trial 142 were a true safety signal or just “a play of chance.”
Almost all the committee’s questioning and discussion centered on this potential increased cardiovascular risk. Amgen, in discussion with the FDA, had agreed to a black box warning designed to wave off prescribing romosozumab to those at increased risk for cardiovascular disease, focusing on those with a history of MI or stroke.
Additionally, the sponsor proposed a postmarketing real-world observational study to track incidence of MACE in those receiving romosozumab, comparing them with those receiving standard of care for osteoporosis.
Several committee members pointed out a problem with the proposed safety mitigation scheme: By conducting a postmarketing observational study for a drug that has a black-box warning to exclude those at high risk for MACE, the chance of detecting an actual cardiovascular safety problem plummets. “This is the textbook example of when observational studies struggle or are virtually guaranteed to fail,” noted Tobias Gerhard, PhD, a pharmacoepidemiologist at Rutgers University, New Brunswick, N.J.
On the other hand, noted several committee members, pausing to conduct a premarketing randomized, controlled trial would keep a beneficial drug away from a population in need. A postmarketing randomized, controlled trial, even a simple trial, still presents challenges, some of the committee acknowledged. Dr. Khosla voiced the opinion that “A randomized, controlled trial is virtually impossible.”
The committee, which was charged with discussing, but not voting on, what additional data should be obtained – and when – to sort out the cardiovascular safety question, was approximately evenly divided in the matter of whether an observational or registry-based trial, or a controlled trial, would be the best path forward.
Committee member Robert A. Adler, MD, put a realistic frame around the debate. “As an endocrinologist, I deal with nuances every day. I really think the kind of clinician who is going to be using this drug is used to dealing with benefits and risks and trying to tailor treatment to a given patient,” said Dr. Adler, professor of internal medicine and epidemiology at Virginia Commonwealth University, Richmond.
In its proposed indication, Amgen defined the population of menopausal women at high risk of fracture as those with a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Romosozumab would be given as a once-monthly subcutaneous injection of 210 mg for a period of 12 months, to be followed by antiresorptive therapy.
Most of the participants in the clinical trials resided outside the United States, primarily because of the difficulty of recruiting clinical trial participants in the United States, Amgen officials said during their presentation. However, neither the time to the first positively adjudicated MACE nor bone mineral density responses at month 12 differed significantly across the various geographic regions where clinical trial sites were located, said Rachel Wagman, MD, the executive medical director of global clinical development for Amgen. Still, several committee members called for postmarketing data to focus on U.S. patients.
Romosozumab was approved for marketing in Japan on Jan. 8, 2019; approval is also being sought in Europe .
The FDA usually follows the recommendations of its advisory panels.
In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member Sundeep Khosla, MD, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab (Prolia) for another 12 months. This study, dubbed Trial 337, followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, Trial 142, was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.
Hip fractures were less common among those given romosozumab, and bone mineral density increased significantly as well.
Vertebral fractures were reduced by 36% in the romosozumab group relative to the alendronate group, and clinical fractures by 27% (P less than .001 for both).
Overall, the number of adverse events for the more than 7,500 patients in the safety population was similar between those receiving romosozumab and either placebo or alendronate, said Scott Wasserman, MD, vice president of global development for Amgen.
However, in Trial 142, which included patients who were slightly older and on more cardiovascular medications at baseline than in Trial 337, MACE – defined as cardiovascular death, MI, and stroke – occurred more frequently among those taking romosozumab, driven primarily by increased cardiac and cerebral ischemic events occurring within the first 12 months of beginning the study drug. At 12 months, the romosozumab arm saw 41 instances of MACE, compared with 22 in the alendronate arm to produce the HR of 1.87 (2.0% vs. 1.1%).
With regard to the imbalance in MACE seen in Trial 142, both the FDA and presenters for the sponsor entertained the notion that alendronate may have been somewhat protective for cardiovascular events. Although there is some biologic plausibility for a cardioprotective event for bisphosphonates, alendronate is highly specific for bone activity and the preponderance of previous studies have not shown such cardioprotection, the FDA, sponsors, and committee members all agreed.
Marc Sabatine, MD, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Harvard Medical School, Boston, was available to answer questions on behalf of the study’s sponsor. He noted at several points during the meeting just how few total cardiovascular events were seen overall in the romosozumab trial. The overall small numbers, he said, made it very difficult to distinguish whether the smaller number of MACE seen in the alendronate arm of Trial 142 were a true safety signal or just “a play of chance.”
Almost all the committee’s questioning and discussion centered on this potential increased cardiovascular risk. Amgen, in discussion with the FDA, had agreed to a black box warning designed to wave off prescribing romosozumab to those at increased risk for cardiovascular disease, focusing on those with a history of MI or stroke.
Additionally, the sponsor proposed a postmarketing real-world observational study to track incidence of MACE in those receiving romosozumab, comparing them with those receiving standard of care for osteoporosis.
Several committee members pointed out a problem with the proposed safety mitigation scheme: By conducting a postmarketing observational study for a drug that has a black-box warning to exclude those at high risk for MACE, the chance of detecting an actual cardiovascular safety problem plummets. “This is the textbook example of when observational studies struggle or are virtually guaranteed to fail,” noted Tobias Gerhard, PhD, a pharmacoepidemiologist at Rutgers University, New Brunswick, N.J.
On the other hand, noted several committee members, pausing to conduct a premarketing randomized, controlled trial would keep a beneficial drug away from a population in need. A postmarketing randomized, controlled trial, even a simple trial, still presents challenges, some of the committee acknowledged. Dr. Khosla voiced the opinion that “A randomized, controlled trial is virtually impossible.”
The committee, which was charged with discussing, but not voting on, what additional data should be obtained – and when – to sort out the cardiovascular safety question, was approximately evenly divided in the matter of whether an observational or registry-based trial, or a controlled trial, would be the best path forward.
Committee member Robert A. Adler, MD, put a realistic frame around the debate. “As an endocrinologist, I deal with nuances every day. I really think the kind of clinician who is going to be using this drug is used to dealing with benefits and risks and trying to tailor treatment to a given patient,” said Dr. Adler, professor of internal medicine and epidemiology at Virginia Commonwealth University, Richmond.
In its proposed indication, Amgen defined the population of menopausal women at high risk of fracture as those with a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Romosozumab would be given as a once-monthly subcutaneous injection of 210 mg for a period of 12 months, to be followed by antiresorptive therapy.
Most of the participants in the clinical trials resided outside the United States, primarily because of the difficulty of recruiting clinical trial participants in the United States, Amgen officials said during their presentation. However, neither the time to the first positively adjudicated MACE nor bone mineral density responses at month 12 differed significantly across the various geographic regions where clinical trial sites were located, said Rachel Wagman, MD, the executive medical director of global clinical development for Amgen. Still, several committee members called for postmarketing data to focus on U.S. patients.
Romosozumab was approved for marketing in Japan on Jan. 8, 2019; approval is also being sought in Europe .
The FDA usually follows the recommendations of its advisory panels.
SMFM and ACOG team up for interpregnancy care guidance
A new consensus statement places renewed focus on maternal interpregnancy care, with a goal of extending care past the postpartum period to provide a wellness-maximizing continuum of care.
The document, developed by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (SMFM), recognizes that pregnancy is part of the lifelong continuum of health and wellness. Although not all women will go on to have another pregnancy, the concept of interpregnancy care recognizes that ob.gyns. have a vital role that extends past the postpartum period.
“This is a shift in what we used to think was our job. We used to think that our job ended when the baby came out,” said the first author of the obstetric care consensus statement, Judette Marie Louis, MD, an ob.gyn. faculty member at the University of South Florida, Tampa, and a SMFM board member. “For too long, our focus was just the baby; we need to tell women, ‘You’re important too,’ ” she said in an interview.
“The interpregnancy period is an opportunity to address these complications of medical issues that have developed during pregnancy, to assess a woman’s mental and physical well-being, and to optimize her health along her life course,” Dr. Louis and her coauthors wrote in Obstetrics & Gynecology.
Conceptually, the opportunity for interpregnancy care arises after any pregnancy, no matter the outcome, and is part of the continuum of care for women of reproductive age. For women who do not intend a future pregnancy, well-woman care is the focus, while women who currently intend to become pregnant again receive interpregnancy care. Women may move from one arm of the continuum to the other if their intentions change or if they become pregnant, explained Dr. Louis and her coauthors.
Birth spacing
The new consensus document includes an emphasis on long-term health outcomes as well as maternal and neonatal outcomes in future pregnancies. Although the evidence is of no more than moderate quality, women should be advised to have an interpregnancy interval of at least 6 months and offered counseling about family planning before delivery. Risks and benefits of an interpregnancy interval of less than 18 months should be reviewed as well.
For women with a history of preterm birth and those who have had a prior cesarean delivery and desire a subsequent trial of labor, birth spacing is particularly important, noted Dr. Louis and her colleagues. There is higher-risk evidence for uterine rupture after cesarean delivery if delivery-to-delivery intervals are 18-24 months or less.
Recommendations regarding the length of the interpregnancy interval generally should not be affected by a history of prior infertility.
Other recommendations
High-quality evidence supports breast feeding’s salutary effects on maternal and child health, so women should receive anticipatory support and guidance to enable breastfeeding, according to the document.
In accordance with other guidelines, the document recommends that all women be screened for depression post partum and as part of well-woman care in the interpregnancy interval. Procedures for effective diagnosis, treatment, and follow-up should accompany the screening.
Best practices dictate that women are asked about alcohol, prescription, and nonprescription drug use as a routine matter. High-quality evidence supports offering smoking cessation support to women who smoke and giving specific advice about nutrition and physical activity that’s based on “proven behavioral techniques.”
Evidence is of moderate quality that women should be encouraged to reach their prepregnancy weight by a year after delivery, with the ultimate goal of having a body mass index of 18.5-24.9.
High-quality evidence backs encouragement to engage in safe sex practices, with care providers also advised to facilitate partner screening and treatment for STIs.
Screening for STIs should follow guidance put forward by the Centers for Disease Control and Prevention and should be offered to women at high risk for STIs; those with a history of STI should have a careful history taken to determine risks for current or repeat infections, wrote Dr. Louis and her coauthors. These strong recommendations have high-quality evidence behind them.
The consensus statement recommends screening women for intimate partner violence, with moderate-quality evidence to support the recommendation. Patient navigators, expert medical interpretation, and other health educators can be offered to women with health literacy or language and communication challenges, but the evidence backing the recommendation is of low quality.
A subset of the interpregnancy care recommendations gives additional guidance regarding women with a history of high-risk pregnancy. All women planning pregnancy – or who could become pregnant – should take 500 mcg of folic acid daily beginning 1 month before fertilization and continuing through the 12th week of pregnancy. Folic acid supplementation for women who have had children with neural tube defects should begin at least 3 months before fertilization and continue through 12 weeks of pregnancy, at a dose of 400 mg.
All prescription and nonprescription medications, as well as potential environmental teratogens, should be reviewed before a repeat pregnancy. This, as well as the folic acid recommendations, are strong recommendations backed by high-quality evidence.
When appropriate, genetic counseling should be offered to women who have had prior pregnancies with genetic disorders or congenital anomalies. Asymptomatic genitourinary infections should not be treated in women with a history of preterm birth during the interpregnancy interval. These are strong recommendations, but are backed by low to moderate quality evidence, wrote Dr. Louis and her colleagues.
Another section of the consensus document specifically addresses specific health conditions, including diabetes, gestational diabetes, gestational and chronic hypertension, and preeclampsia, as well as mental health disorders and overweight or obesity.
For each, Dr. Louis and her coauthors recommend counseling that reviews complications and risk for future disease; for example, not only does prior preeclampsia increase risk for that complication in future pregnancies, risk for later cardiovascular disease is also doubled. The document outlines recommended interpregnancy testing, management considerations and medications of concern for health care providers caring for women with these conditions, and condition-specific goals.
Of the association between gestational diabetes, hypertension, and preeclampsia with later disease, Dr. Louis said in the interview, “We don’t know. ... It may be that pregnancy accelerates these diseases. We do know that normal changes in pregnancy stress your body, and that preeclampsia damages your vessels. Pregnancy can give you a warning, but we don’t have enough information to predict the outcome” in later life. “We do know there is some advice we can give: stop smoking and maintain a normal body weight.”
Other conditions such as HIV, renal disease, epilepsy, autoimmune and thyroid disease, and thrombophilias and antiphospholipid antibody syndrome are also addressed in this section of the consensus document.
Specific attention also is given to psychosocial risks, such as socioeconomic disadvantages and being a member of a racial or ethnic minority. Social determinants of health are complex, said Dr. Louis, but socioeconomic and racial stressors can include the added burden of caring for loved ones with constrained resources. Additionally, there can be access issues: Women can get emergent care by presenting to the ED but receiving continued primary and specialty care can be much more of a challenge.
Regarding racism, Dr. Louis said, “We all come into caring for these women with certain ideas.” For example, it’s not enough to say of a patient, “She’s noncompliant. You need to ask why.” When the “why” question is asked, then you may discover, “there’s something you can help the patient with,” she said. “We need to ask why, and then take steps to help our patients.”
Document building
The working group for the consensus document felt it was important to include nonphysicians who care for women, Dr. Louis said, so drafts were reviewed by and input received from the American College of Nurse-Midwives and the National Association of Nurse Practitioners in Women’s Health. Both groups endorsed the document.
The collaborative process of putting drafts together and then reviewing and revising the document was a big part of the reason it took 2 years to produce the interpregnancy care consensus statement. “It was the equivalent of two full gestations with a short interpregnancy interval!” said Dr. Louis, laughing. But seeking input from all stakeholders strengthened the final product.
Dr. Louis reported no conflicts of interest and no outside sources of funding were reported.
SOURCE: Louis JM et al. Obstet Gynecol. 2019;133:e51-72.
A new consensus statement places renewed focus on maternal interpregnancy care, with a goal of extending care past the postpartum period to provide a wellness-maximizing continuum of care.
The document, developed by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (SMFM), recognizes that pregnancy is part of the lifelong continuum of health and wellness. Although not all women will go on to have another pregnancy, the concept of interpregnancy care recognizes that ob.gyns. have a vital role that extends past the postpartum period.
“This is a shift in what we used to think was our job. We used to think that our job ended when the baby came out,” said the first author of the obstetric care consensus statement, Judette Marie Louis, MD, an ob.gyn. faculty member at the University of South Florida, Tampa, and a SMFM board member. “For too long, our focus was just the baby; we need to tell women, ‘You’re important too,’ ” she said in an interview.
“The interpregnancy period is an opportunity to address these complications of medical issues that have developed during pregnancy, to assess a woman’s mental and physical well-being, and to optimize her health along her life course,” Dr. Louis and her coauthors wrote in Obstetrics & Gynecology.
Conceptually, the opportunity for interpregnancy care arises after any pregnancy, no matter the outcome, and is part of the continuum of care for women of reproductive age. For women who do not intend a future pregnancy, well-woman care is the focus, while women who currently intend to become pregnant again receive interpregnancy care. Women may move from one arm of the continuum to the other if their intentions change or if they become pregnant, explained Dr. Louis and her coauthors.
Birth spacing
The new consensus document includes an emphasis on long-term health outcomes as well as maternal and neonatal outcomes in future pregnancies. Although the evidence is of no more than moderate quality, women should be advised to have an interpregnancy interval of at least 6 months and offered counseling about family planning before delivery. Risks and benefits of an interpregnancy interval of less than 18 months should be reviewed as well.
For women with a history of preterm birth and those who have had a prior cesarean delivery and desire a subsequent trial of labor, birth spacing is particularly important, noted Dr. Louis and her colleagues. There is higher-risk evidence for uterine rupture after cesarean delivery if delivery-to-delivery intervals are 18-24 months or less.
Recommendations regarding the length of the interpregnancy interval generally should not be affected by a history of prior infertility.
Other recommendations
High-quality evidence supports breast feeding’s salutary effects on maternal and child health, so women should receive anticipatory support and guidance to enable breastfeeding, according to the document.
In accordance with other guidelines, the document recommends that all women be screened for depression post partum and as part of well-woman care in the interpregnancy interval. Procedures for effective diagnosis, treatment, and follow-up should accompany the screening.
Best practices dictate that women are asked about alcohol, prescription, and nonprescription drug use as a routine matter. High-quality evidence supports offering smoking cessation support to women who smoke and giving specific advice about nutrition and physical activity that’s based on “proven behavioral techniques.”
Evidence is of moderate quality that women should be encouraged to reach their prepregnancy weight by a year after delivery, with the ultimate goal of having a body mass index of 18.5-24.9.
High-quality evidence backs encouragement to engage in safe sex practices, with care providers also advised to facilitate partner screening and treatment for STIs.
Screening for STIs should follow guidance put forward by the Centers for Disease Control and Prevention and should be offered to women at high risk for STIs; those with a history of STI should have a careful history taken to determine risks for current or repeat infections, wrote Dr. Louis and her coauthors. These strong recommendations have high-quality evidence behind them.
The consensus statement recommends screening women for intimate partner violence, with moderate-quality evidence to support the recommendation. Patient navigators, expert medical interpretation, and other health educators can be offered to women with health literacy or language and communication challenges, but the evidence backing the recommendation is of low quality.
A subset of the interpregnancy care recommendations gives additional guidance regarding women with a history of high-risk pregnancy. All women planning pregnancy – or who could become pregnant – should take 500 mcg of folic acid daily beginning 1 month before fertilization and continuing through the 12th week of pregnancy. Folic acid supplementation for women who have had children with neural tube defects should begin at least 3 months before fertilization and continue through 12 weeks of pregnancy, at a dose of 400 mg.
All prescription and nonprescription medications, as well as potential environmental teratogens, should be reviewed before a repeat pregnancy. This, as well as the folic acid recommendations, are strong recommendations backed by high-quality evidence.
When appropriate, genetic counseling should be offered to women who have had prior pregnancies with genetic disorders or congenital anomalies. Asymptomatic genitourinary infections should not be treated in women with a history of preterm birth during the interpregnancy interval. These are strong recommendations, but are backed by low to moderate quality evidence, wrote Dr. Louis and her colleagues.
Another section of the consensus document specifically addresses specific health conditions, including diabetes, gestational diabetes, gestational and chronic hypertension, and preeclampsia, as well as mental health disorders and overweight or obesity.
For each, Dr. Louis and her coauthors recommend counseling that reviews complications and risk for future disease; for example, not only does prior preeclampsia increase risk for that complication in future pregnancies, risk for later cardiovascular disease is also doubled. The document outlines recommended interpregnancy testing, management considerations and medications of concern for health care providers caring for women with these conditions, and condition-specific goals.
Of the association between gestational diabetes, hypertension, and preeclampsia with later disease, Dr. Louis said in the interview, “We don’t know. ... It may be that pregnancy accelerates these diseases. We do know that normal changes in pregnancy stress your body, and that preeclampsia damages your vessels. Pregnancy can give you a warning, but we don’t have enough information to predict the outcome” in later life. “We do know there is some advice we can give: stop smoking and maintain a normal body weight.”
Other conditions such as HIV, renal disease, epilepsy, autoimmune and thyroid disease, and thrombophilias and antiphospholipid antibody syndrome are also addressed in this section of the consensus document.
Specific attention also is given to psychosocial risks, such as socioeconomic disadvantages and being a member of a racial or ethnic minority. Social determinants of health are complex, said Dr. Louis, but socioeconomic and racial stressors can include the added burden of caring for loved ones with constrained resources. Additionally, there can be access issues: Women can get emergent care by presenting to the ED but receiving continued primary and specialty care can be much more of a challenge.
Regarding racism, Dr. Louis said, “We all come into caring for these women with certain ideas.” For example, it’s not enough to say of a patient, “She’s noncompliant. You need to ask why.” When the “why” question is asked, then you may discover, “there’s something you can help the patient with,” she said. “We need to ask why, and then take steps to help our patients.”
Document building
The working group for the consensus document felt it was important to include nonphysicians who care for women, Dr. Louis said, so drafts were reviewed by and input received from the American College of Nurse-Midwives and the National Association of Nurse Practitioners in Women’s Health. Both groups endorsed the document.
The collaborative process of putting drafts together and then reviewing and revising the document was a big part of the reason it took 2 years to produce the interpregnancy care consensus statement. “It was the equivalent of two full gestations with a short interpregnancy interval!” said Dr. Louis, laughing. But seeking input from all stakeholders strengthened the final product.
Dr. Louis reported no conflicts of interest and no outside sources of funding were reported.
SOURCE: Louis JM et al. Obstet Gynecol. 2019;133:e51-72.
A new consensus statement places renewed focus on maternal interpregnancy care, with a goal of extending care past the postpartum period to provide a wellness-maximizing continuum of care.
The document, developed by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine (SMFM), recognizes that pregnancy is part of the lifelong continuum of health and wellness. Although not all women will go on to have another pregnancy, the concept of interpregnancy care recognizes that ob.gyns. have a vital role that extends past the postpartum period.
“This is a shift in what we used to think was our job. We used to think that our job ended when the baby came out,” said the first author of the obstetric care consensus statement, Judette Marie Louis, MD, an ob.gyn. faculty member at the University of South Florida, Tampa, and a SMFM board member. “For too long, our focus was just the baby; we need to tell women, ‘You’re important too,’ ” she said in an interview.
“The interpregnancy period is an opportunity to address these complications of medical issues that have developed during pregnancy, to assess a woman’s mental and physical well-being, and to optimize her health along her life course,” Dr. Louis and her coauthors wrote in Obstetrics & Gynecology.
Conceptually, the opportunity for interpregnancy care arises after any pregnancy, no matter the outcome, and is part of the continuum of care for women of reproductive age. For women who do not intend a future pregnancy, well-woman care is the focus, while women who currently intend to become pregnant again receive interpregnancy care. Women may move from one arm of the continuum to the other if their intentions change or if they become pregnant, explained Dr. Louis and her coauthors.
Birth spacing
The new consensus document includes an emphasis on long-term health outcomes as well as maternal and neonatal outcomes in future pregnancies. Although the evidence is of no more than moderate quality, women should be advised to have an interpregnancy interval of at least 6 months and offered counseling about family planning before delivery. Risks and benefits of an interpregnancy interval of less than 18 months should be reviewed as well.
For women with a history of preterm birth and those who have had a prior cesarean delivery and desire a subsequent trial of labor, birth spacing is particularly important, noted Dr. Louis and her colleagues. There is higher-risk evidence for uterine rupture after cesarean delivery if delivery-to-delivery intervals are 18-24 months or less.
Recommendations regarding the length of the interpregnancy interval generally should not be affected by a history of prior infertility.
Other recommendations
High-quality evidence supports breast feeding’s salutary effects on maternal and child health, so women should receive anticipatory support and guidance to enable breastfeeding, according to the document.
In accordance with other guidelines, the document recommends that all women be screened for depression post partum and as part of well-woman care in the interpregnancy interval. Procedures for effective diagnosis, treatment, and follow-up should accompany the screening.
Best practices dictate that women are asked about alcohol, prescription, and nonprescription drug use as a routine matter. High-quality evidence supports offering smoking cessation support to women who smoke and giving specific advice about nutrition and physical activity that’s based on “proven behavioral techniques.”
Evidence is of moderate quality that women should be encouraged to reach their prepregnancy weight by a year after delivery, with the ultimate goal of having a body mass index of 18.5-24.9.
High-quality evidence backs encouragement to engage in safe sex practices, with care providers also advised to facilitate partner screening and treatment for STIs.
Screening for STIs should follow guidance put forward by the Centers for Disease Control and Prevention and should be offered to women at high risk for STIs; those with a history of STI should have a careful history taken to determine risks for current or repeat infections, wrote Dr. Louis and her coauthors. These strong recommendations have high-quality evidence behind them.
The consensus statement recommends screening women for intimate partner violence, with moderate-quality evidence to support the recommendation. Patient navigators, expert medical interpretation, and other health educators can be offered to women with health literacy or language and communication challenges, but the evidence backing the recommendation is of low quality.
A subset of the interpregnancy care recommendations gives additional guidance regarding women with a history of high-risk pregnancy. All women planning pregnancy – or who could become pregnant – should take 500 mcg of folic acid daily beginning 1 month before fertilization and continuing through the 12th week of pregnancy. Folic acid supplementation for women who have had children with neural tube defects should begin at least 3 months before fertilization and continue through 12 weeks of pregnancy, at a dose of 400 mg.
All prescription and nonprescription medications, as well as potential environmental teratogens, should be reviewed before a repeat pregnancy. This, as well as the folic acid recommendations, are strong recommendations backed by high-quality evidence.
When appropriate, genetic counseling should be offered to women who have had prior pregnancies with genetic disorders or congenital anomalies. Asymptomatic genitourinary infections should not be treated in women with a history of preterm birth during the interpregnancy interval. These are strong recommendations, but are backed by low to moderate quality evidence, wrote Dr. Louis and her colleagues.
Another section of the consensus document specifically addresses specific health conditions, including diabetes, gestational diabetes, gestational and chronic hypertension, and preeclampsia, as well as mental health disorders and overweight or obesity.
For each, Dr. Louis and her coauthors recommend counseling that reviews complications and risk for future disease; for example, not only does prior preeclampsia increase risk for that complication in future pregnancies, risk for later cardiovascular disease is also doubled. The document outlines recommended interpregnancy testing, management considerations and medications of concern for health care providers caring for women with these conditions, and condition-specific goals.
Of the association between gestational diabetes, hypertension, and preeclampsia with later disease, Dr. Louis said in the interview, “We don’t know. ... It may be that pregnancy accelerates these diseases. We do know that normal changes in pregnancy stress your body, and that preeclampsia damages your vessels. Pregnancy can give you a warning, but we don’t have enough information to predict the outcome” in later life. “We do know there is some advice we can give: stop smoking and maintain a normal body weight.”
Other conditions such as HIV, renal disease, epilepsy, autoimmune and thyroid disease, and thrombophilias and antiphospholipid antibody syndrome are also addressed in this section of the consensus document.
Specific attention also is given to psychosocial risks, such as socioeconomic disadvantages and being a member of a racial or ethnic minority. Social determinants of health are complex, said Dr. Louis, but socioeconomic and racial stressors can include the added burden of caring for loved ones with constrained resources. Additionally, there can be access issues: Women can get emergent care by presenting to the ED but receiving continued primary and specialty care can be much more of a challenge.
Regarding racism, Dr. Louis said, “We all come into caring for these women with certain ideas.” For example, it’s not enough to say of a patient, “She’s noncompliant. You need to ask why.” When the “why” question is asked, then you may discover, “there’s something you can help the patient with,” she said. “We need to ask why, and then take steps to help our patients.”
Document building
The working group for the consensus document felt it was important to include nonphysicians who care for women, Dr. Louis said, so drafts were reviewed by and input received from the American College of Nurse-Midwives and the National Association of Nurse Practitioners in Women’s Health. Both groups endorsed the document.
The collaborative process of putting drafts together and then reviewing and revising the document was a big part of the reason it took 2 years to produce the interpregnancy care consensus statement. “It was the equivalent of two full gestations with a short interpregnancy interval!” said Dr. Louis, laughing. But seeking input from all stakeholders strengthened the final product.
Dr. Louis reported no conflicts of interest and no outside sources of funding were reported.
SOURCE: Louis JM et al. Obstet Gynecol. 2019;133:e51-72.
FROM OBSTETRICS & GYNECOLOGY
Soy didn’t up all-cause mortality in breast cancer survivors
A cohort of Chinese women who are breast cancer survivors had no increased mortality from soy intake, according to a new study.
The work adds to the existing body of evidence that women with breast cancer, or risk for breast cancer, don’t need to modify their soy intake to mitigate risk, said the study’s first author, Suzanne C. Ho, PhD.
Speaking at the annual meeting of the North American Menopause Society, Dr. Ho noted that the combination of increasing breast cancer incidence and improved outcome has resulted in larger numbers of breast cancer survivors in Hong Kong, where she is professor emerita at the Chinese University of Hong Kong.
The prospective, ongoing study examines the association between soy intake pre- and postdiagnosis and total mortality for Chinese women who are breast cancer survivors. Dr. Ho said that she and her colleagues hypothesized that they would not see higher mortality among women who had higher soy intake – and this was the case.
Of 1,497 breast cancer survivors drawn from two facilities in Hong Kong, those who consumed higher quantities of dietary soy did not have increased risk of all-cause mortality, compared with those in the lowest tertile of soy consumption.
There are theoretical underpinnings for thinking that soy could be a player in cancer risk, but the biochemistry and epidemiology behind the studies are complicated. Estrogen plays a role in human breast cancer, and many modern breast cancer treatments actually dampen endogenous estrogens.
However, epidemiologic data have shown that consumption of soy-based foods – which contain phytoestrogens, primarily in the form of isoflavones – is inversely associated with developing breast cancer.
This is all part of why soy-based foods have been thought of as a mixed bag with regard to breast cancer: Soy isoflavones are, said Dr. Ho, “Natural estrogen receptor modulators that possess both estrogenlike and antiestrogenic properties.”
Other chemicals contained in soy may fight cancer, with effects that are antioxidative and strengthen immune response. Soy constituents also inhibit DNA topoisomerase I and II, proteases, tyrosine kinases, and inositol phosphate, effects that can slow tumor growth. Still, one soy isoflavone, genistein, actually can promote growth of estrogen-dependent tumors in rats, said Dr. Ho
Dr. Ho and her colleagues enrolled Hong Kong residents for the study of mortality among breast cancer survivors. Participants were included if they were Chinese, female, aged 24-77 years, and had their first primary breast cancer histologically confirmed within 12 months of entering the study. Cancer had to be graded below stage III.
Using a 109-item validated food questionnaire, investigators gathered information about participants’ soy intake and general diet for the year prior to breast cancer diagnosis. Other patient characteristics, relevant prognostic information from medical records, and anthropometric data were collected at baseline, and repeated at 18, 36, and 60 months.
The primary outcome measure – all-cause mortality during the follow-up period – was tracked for a mean 50.9 months, with a 78% retention rate for study participants, said Dr. Ho. In total, 96 patients died during follow-up, making up 5.9% of the premenopausal and 7% of the postmenopausal participants.
Statistical analysis corrected for potential confounders, including patient and disease characteristics and treatment modalities, as well as overall energy consumption.
Patients were evenly divided into tertiles of soy isoflavone intake, with cutpoints of 3.77 mg/1,000 kcal and 10.05 mg/1,000 kcal for the lower limit of the two higher tertiles. For the highest tertile, though, mean isoflavone intake was actually 20.87 mg/1,000 kcal.
Patient, disease, and treatment characteristics did not differ significantly among the tertiles.
An adjusted statistical analysis looked at pre- and postmenopausal women separately by tertile of soy isoflavone consumption, setting the hazard ratio for all-cause mortality at 1.00 for women in the lowest tertile of soy consumption.
For premenopausal women in the middle tertile, the HR was 0.45 (95% confidence interval, 0.20-1.00), and 0.86 for those in the highest tertile (95% CI, 0.43-1.72); 782 participants, in all, were premenopausal.
For the 715 postmenopausal women, the HR for those in the middle tertile of soy consumption was 0.94 (95% CI, 0.43-2.05), and 1.11 in the highest (95% CI, 0.54-2.29).
Taking all pre- and postmenopausal participants together, those in the middle tertile of soy isoflavone intake had an all-cause mortality HR of 0.63 (95% CI, 0.37-1.09). For the highest tertile of the full cohort, the HR was 0.95 (95% CI, 0.58-1.55).
Confidence intervals were wide in these findings, but Dr. Ho noted that “moderate soy food intake might be associated with better survival.”
“Prediagnosis soy intake did not increase the risk of all-cause mortality in breast cancer survivors,” said Dr. Ho, findings she called “consistent with the literature that soy consumption does not adversely effect breast cancer survival.”
The study is ongoing, she explained, and “longer follow-up will provide further evidence on the effect of pre- and postdiagnosis soy intake on breast cancer outcomes.”
The study had a homogeneous population of southern Chinese women, with fairly good retention and robust statistical adjustment for confounders. However, it wasn’t possible to assess bioavailability of isoflavones and their metabolites, which can vary according to individual microbiota. Also, researchers did not track whether patients used traditional Chinese medicine.
The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
SOURCE: Ho S et al. NAMS 2018, Abstract S-23.
A cohort of Chinese women who are breast cancer survivors had no increased mortality from soy intake, according to a new study.
The work adds to the existing body of evidence that women with breast cancer, or risk for breast cancer, don’t need to modify their soy intake to mitigate risk, said the study’s first author, Suzanne C. Ho, PhD.
Speaking at the annual meeting of the North American Menopause Society, Dr. Ho noted that the combination of increasing breast cancer incidence and improved outcome has resulted in larger numbers of breast cancer survivors in Hong Kong, where she is professor emerita at the Chinese University of Hong Kong.
The prospective, ongoing study examines the association between soy intake pre- and postdiagnosis and total mortality for Chinese women who are breast cancer survivors. Dr. Ho said that she and her colleagues hypothesized that they would not see higher mortality among women who had higher soy intake – and this was the case.
Of 1,497 breast cancer survivors drawn from two facilities in Hong Kong, those who consumed higher quantities of dietary soy did not have increased risk of all-cause mortality, compared with those in the lowest tertile of soy consumption.
There are theoretical underpinnings for thinking that soy could be a player in cancer risk, but the biochemistry and epidemiology behind the studies are complicated. Estrogen plays a role in human breast cancer, and many modern breast cancer treatments actually dampen endogenous estrogens.
However, epidemiologic data have shown that consumption of soy-based foods – which contain phytoestrogens, primarily in the form of isoflavones – is inversely associated with developing breast cancer.
This is all part of why soy-based foods have been thought of as a mixed bag with regard to breast cancer: Soy isoflavones are, said Dr. Ho, “Natural estrogen receptor modulators that possess both estrogenlike and antiestrogenic properties.”
Other chemicals contained in soy may fight cancer, with effects that are antioxidative and strengthen immune response. Soy constituents also inhibit DNA topoisomerase I and II, proteases, tyrosine kinases, and inositol phosphate, effects that can slow tumor growth. Still, one soy isoflavone, genistein, actually can promote growth of estrogen-dependent tumors in rats, said Dr. Ho
Dr. Ho and her colleagues enrolled Hong Kong residents for the study of mortality among breast cancer survivors. Participants were included if they were Chinese, female, aged 24-77 years, and had their first primary breast cancer histologically confirmed within 12 months of entering the study. Cancer had to be graded below stage III.
Using a 109-item validated food questionnaire, investigators gathered information about participants’ soy intake and general diet for the year prior to breast cancer diagnosis. Other patient characteristics, relevant prognostic information from medical records, and anthropometric data were collected at baseline, and repeated at 18, 36, and 60 months.
The primary outcome measure – all-cause mortality during the follow-up period – was tracked for a mean 50.9 months, with a 78% retention rate for study participants, said Dr. Ho. In total, 96 patients died during follow-up, making up 5.9% of the premenopausal and 7% of the postmenopausal participants.
Statistical analysis corrected for potential confounders, including patient and disease characteristics and treatment modalities, as well as overall energy consumption.
Patients were evenly divided into tertiles of soy isoflavone intake, with cutpoints of 3.77 mg/1,000 kcal and 10.05 mg/1,000 kcal for the lower limit of the two higher tertiles. For the highest tertile, though, mean isoflavone intake was actually 20.87 mg/1,000 kcal.
Patient, disease, and treatment characteristics did not differ significantly among the tertiles.
An adjusted statistical analysis looked at pre- and postmenopausal women separately by tertile of soy isoflavone consumption, setting the hazard ratio for all-cause mortality at 1.00 for women in the lowest tertile of soy consumption.
For premenopausal women in the middle tertile, the HR was 0.45 (95% confidence interval, 0.20-1.00), and 0.86 for those in the highest tertile (95% CI, 0.43-1.72); 782 participants, in all, were premenopausal.
For the 715 postmenopausal women, the HR for those in the middle tertile of soy consumption was 0.94 (95% CI, 0.43-2.05), and 1.11 in the highest (95% CI, 0.54-2.29).
Taking all pre- and postmenopausal participants together, those in the middle tertile of soy isoflavone intake had an all-cause mortality HR of 0.63 (95% CI, 0.37-1.09). For the highest tertile of the full cohort, the HR was 0.95 (95% CI, 0.58-1.55).
Confidence intervals were wide in these findings, but Dr. Ho noted that “moderate soy food intake might be associated with better survival.”
“Prediagnosis soy intake did not increase the risk of all-cause mortality in breast cancer survivors,” said Dr. Ho, findings she called “consistent with the literature that soy consumption does not adversely effect breast cancer survival.”
The study is ongoing, she explained, and “longer follow-up will provide further evidence on the effect of pre- and postdiagnosis soy intake on breast cancer outcomes.”
The study had a homogeneous population of southern Chinese women, with fairly good retention and robust statistical adjustment for confounders. However, it wasn’t possible to assess bioavailability of isoflavones and their metabolites, which can vary according to individual microbiota. Also, researchers did not track whether patients used traditional Chinese medicine.
The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
SOURCE: Ho S et al. NAMS 2018, Abstract S-23.
A cohort of Chinese women who are breast cancer survivors had no increased mortality from soy intake, according to a new study.
The work adds to the existing body of evidence that women with breast cancer, or risk for breast cancer, don’t need to modify their soy intake to mitigate risk, said the study’s first author, Suzanne C. Ho, PhD.
Speaking at the annual meeting of the North American Menopause Society, Dr. Ho noted that the combination of increasing breast cancer incidence and improved outcome has resulted in larger numbers of breast cancer survivors in Hong Kong, where she is professor emerita at the Chinese University of Hong Kong.
The prospective, ongoing study examines the association between soy intake pre- and postdiagnosis and total mortality for Chinese women who are breast cancer survivors. Dr. Ho said that she and her colleagues hypothesized that they would not see higher mortality among women who had higher soy intake – and this was the case.
Of 1,497 breast cancer survivors drawn from two facilities in Hong Kong, those who consumed higher quantities of dietary soy did not have increased risk of all-cause mortality, compared with those in the lowest tertile of soy consumption.
There are theoretical underpinnings for thinking that soy could be a player in cancer risk, but the biochemistry and epidemiology behind the studies are complicated. Estrogen plays a role in human breast cancer, and many modern breast cancer treatments actually dampen endogenous estrogens.
However, epidemiologic data have shown that consumption of soy-based foods – which contain phytoestrogens, primarily in the form of isoflavones – is inversely associated with developing breast cancer.
This is all part of why soy-based foods have been thought of as a mixed bag with regard to breast cancer: Soy isoflavones are, said Dr. Ho, “Natural estrogen receptor modulators that possess both estrogenlike and antiestrogenic properties.”
Other chemicals contained in soy may fight cancer, with effects that are antioxidative and strengthen immune response. Soy constituents also inhibit DNA topoisomerase I and II, proteases, tyrosine kinases, and inositol phosphate, effects that can slow tumor growth. Still, one soy isoflavone, genistein, actually can promote growth of estrogen-dependent tumors in rats, said Dr. Ho
Dr. Ho and her colleagues enrolled Hong Kong residents for the study of mortality among breast cancer survivors. Participants were included if they were Chinese, female, aged 24-77 years, and had their first primary breast cancer histologically confirmed within 12 months of entering the study. Cancer had to be graded below stage III.
Using a 109-item validated food questionnaire, investigators gathered information about participants’ soy intake and general diet for the year prior to breast cancer diagnosis. Other patient characteristics, relevant prognostic information from medical records, and anthropometric data were collected at baseline, and repeated at 18, 36, and 60 months.
The primary outcome measure – all-cause mortality during the follow-up period – was tracked for a mean 50.9 months, with a 78% retention rate for study participants, said Dr. Ho. In total, 96 patients died during follow-up, making up 5.9% of the premenopausal and 7% of the postmenopausal participants.
Statistical analysis corrected for potential confounders, including patient and disease characteristics and treatment modalities, as well as overall energy consumption.
Patients were evenly divided into tertiles of soy isoflavone intake, with cutpoints of 3.77 mg/1,000 kcal and 10.05 mg/1,000 kcal for the lower limit of the two higher tertiles. For the highest tertile, though, mean isoflavone intake was actually 20.87 mg/1,000 kcal.
Patient, disease, and treatment characteristics did not differ significantly among the tertiles.
An adjusted statistical analysis looked at pre- and postmenopausal women separately by tertile of soy isoflavone consumption, setting the hazard ratio for all-cause mortality at 1.00 for women in the lowest tertile of soy consumption.
For premenopausal women in the middle tertile, the HR was 0.45 (95% confidence interval, 0.20-1.00), and 0.86 for those in the highest tertile (95% CI, 0.43-1.72); 782 participants, in all, were premenopausal.
For the 715 postmenopausal women, the HR for those in the middle tertile of soy consumption was 0.94 (95% CI, 0.43-2.05), and 1.11 in the highest (95% CI, 0.54-2.29).
Taking all pre- and postmenopausal participants together, those in the middle tertile of soy isoflavone intake had an all-cause mortality HR of 0.63 (95% CI, 0.37-1.09). For the highest tertile of the full cohort, the HR was 0.95 (95% CI, 0.58-1.55).
Confidence intervals were wide in these findings, but Dr. Ho noted that “moderate soy food intake might be associated with better survival.”
“Prediagnosis soy intake did not increase the risk of all-cause mortality in breast cancer survivors,” said Dr. Ho, findings she called “consistent with the literature that soy consumption does not adversely effect breast cancer survival.”
The study is ongoing, she explained, and “longer follow-up will provide further evidence on the effect of pre- and postdiagnosis soy intake on breast cancer outcomes.”
The study had a homogeneous population of southern Chinese women, with fairly good retention and robust statistical adjustment for confounders. However, it wasn’t possible to assess bioavailability of isoflavones and their metabolites, which can vary according to individual microbiota. Also, researchers did not track whether patients used traditional Chinese medicine.
The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
SOURCE: Ho S et al. NAMS 2018, Abstract S-23.
REPORTING FROM NAMS 2018
Key clinical point: Soy consumption did not increase mortality risk in breast cancer survivors.
Major finding: The hazard ratios for all-cause mortality were 0.63 and 0.95 for the two highest tertiles of soy consumption.
Study details: An ongoing prospective cohort study of 1,497 female breast cancer survivors in Hong Kong.
Disclosures: The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
Source: Ho S et al. NAMS 2018, Abstract S-23.