User login
Reported COVID-19 symptoms by hospitalization status
Pregnancy can be ‘a vulnerable time’ for developing mental disorders
Pregnancy and the postpartum period are a “very vulnerable time for mental disorders,” according to Henry A. Nasrallah, MD.
“Those changes that are helping pregnancy can also have psychiatric and psychopathological implications,” Dr. Nasrallah said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
Numerous dramatic changes in physiology, immune functions, cognition, neuroplasticity, and behavior occur during pregnancy, noted Dr. Nasrallah of the University of Cincinnati. For example, the volume of the brain actually decreases during pregnancy, but brain size recovers over the 6 months after delivery. “Clearly, this is a transitional and a transient phenomenon,” he said. “The decrease in brain volume is associated with changes in brain metabolism and an increase in intracellular pH after delivery.”
But these changes can also carry risks for psychiatric disorders, Dr. Nasrallah explained. Changes in the hippocampus, which is “very plastic throughout adulthood,” have been linked to aging, cognition, pregnancy, and motherhood. “The hippocampus is the ‘Grand Central Station’ of memory in the brain, and the hippocampus is affected by neurodegenerative and psychiatric disorders, which disproportionately affect women,” he said at the meeting, presented by Global Academy for Medical Education.
Dr. Nasrallah said the hippocampus has particular susceptibility during pregnancy and in the postpartum period, or in women who have previously been pregnant.
Gender of the fetus can even affect the health of the mother, he added. In women who are pregnant with male fetuses, working memory and spatial ability are higher than in women who are pregnant with female fetuses, Dr. Nasrallah said. This is tied to higher numbers of proinflammatory cytokines present in male fetuses. In female fetuses, there are lower levels of interferon-gamma and interleukin (IL)-12 in the first trimester, and higher levels of IL-1 beta, tumor necrosis factor B, IL-5, and IL-10 in the second trimester.
In particular,
“Cytokine interleukin-10 and interleukin-6 are both increased during psychosis and during depression, so you can see the vulnerability for developing postpartum depression.” Some women “have other genes that make them susceptible for mood disorders, and the pregnancy can push them over the edge,” he said.
If women have bipolar disorder prior to delivery, “they have a very high risk of postpartum depression, possibly because of this immune dysregulation that serves the pregnancy, but unfortunately makes the woman vulnerable for postpartum psychiatric disorders,” Dr. Nasrallah said.
The effects of having children extend into middle age, Dr. Nasrallah said. Research has shown giving birth to more than one to two children can affect a woman’s risk for Alzheimer’s disease and risk for early-onset of the disease. Women who have three or fewer children later in life are also more likely to live longer, he said. In general, a longer reproductive period, duration of breastfeeding, and low number of pregnancies result in better cognition, while younger age at first pregnancy leads to worse cognition.
So-called pregnancy brain causes some cognitive functions to decline, and women may experience trouble concentrating and memory disturbance. “Other functions increase for the sake of the baby,” including a high reaction to threatening stimuli, absent-mindedness, motivation, reward, fear, executive functions, social cognition, salience, and attachment, Dr. Nasrallah said. In some cases, hormone-driven remodeling of the maternal brain can cause postpartum psychosis, which can reduce the anterior cingulate cortex, left parahippocampal gyrus volume, and left superior temporal gyrus volume.
Most changes in the brain, however, appear to be temporary, Dr. Nasrallah noted. Executive function improves 2-6 months after delivery, which includes goal and directed behavior, working memory, inhibitory function, and cognitive flexibility. In the postpartum period, “the gray matter increases in the first 3-4 months, especially in the brain areas that are involved in maternal behavior that includes amygdala, hypothalamus, and prefrontal cortex,” he added. “All of those changes correlate with positive maternal attachment, and so that makes it easier for the mother to bond with the baby.
“Don’t think of it as a negative,” he said. “The decline in brain volume is actually associated with better mothering and increased attachment between the mother and the baby, which is vital for survival of the baby.”
Global Academy and this news organization are owned by the same parent company. Dr. Nasrallah reports no relevant financial disclosures.
Pregnancy and the postpartum period are a “very vulnerable time for mental disorders,” according to Henry A. Nasrallah, MD.
“Those changes that are helping pregnancy can also have psychiatric and psychopathological implications,” Dr. Nasrallah said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
Numerous dramatic changes in physiology, immune functions, cognition, neuroplasticity, and behavior occur during pregnancy, noted Dr. Nasrallah of the University of Cincinnati. For example, the volume of the brain actually decreases during pregnancy, but brain size recovers over the 6 months after delivery. “Clearly, this is a transitional and a transient phenomenon,” he said. “The decrease in brain volume is associated with changes in brain metabolism and an increase in intracellular pH after delivery.”
But these changes can also carry risks for psychiatric disorders, Dr. Nasrallah explained. Changes in the hippocampus, which is “very plastic throughout adulthood,” have been linked to aging, cognition, pregnancy, and motherhood. “The hippocampus is the ‘Grand Central Station’ of memory in the brain, and the hippocampus is affected by neurodegenerative and psychiatric disorders, which disproportionately affect women,” he said at the meeting, presented by Global Academy for Medical Education.
Dr. Nasrallah said the hippocampus has particular susceptibility during pregnancy and in the postpartum period, or in women who have previously been pregnant.
Gender of the fetus can even affect the health of the mother, he added. In women who are pregnant with male fetuses, working memory and spatial ability are higher than in women who are pregnant with female fetuses, Dr. Nasrallah said. This is tied to higher numbers of proinflammatory cytokines present in male fetuses. In female fetuses, there are lower levels of interferon-gamma and interleukin (IL)-12 in the first trimester, and higher levels of IL-1 beta, tumor necrosis factor B, IL-5, and IL-10 in the second trimester.
In particular,
“Cytokine interleukin-10 and interleukin-6 are both increased during psychosis and during depression, so you can see the vulnerability for developing postpartum depression.” Some women “have other genes that make them susceptible for mood disorders, and the pregnancy can push them over the edge,” he said.
If women have bipolar disorder prior to delivery, “they have a very high risk of postpartum depression, possibly because of this immune dysregulation that serves the pregnancy, but unfortunately makes the woman vulnerable for postpartum psychiatric disorders,” Dr. Nasrallah said.
The effects of having children extend into middle age, Dr. Nasrallah said. Research has shown giving birth to more than one to two children can affect a woman’s risk for Alzheimer’s disease and risk for early-onset of the disease. Women who have three or fewer children later in life are also more likely to live longer, he said. In general, a longer reproductive period, duration of breastfeeding, and low number of pregnancies result in better cognition, while younger age at first pregnancy leads to worse cognition.
So-called pregnancy brain causes some cognitive functions to decline, and women may experience trouble concentrating and memory disturbance. “Other functions increase for the sake of the baby,” including a high reaction to threatening stimuli, absent-mindedness, motivation, reward, fear, executive functions, social cognition, salience, and attachment, Dr. Nasrallah said. In some cases, hormone-driven remodeling of the maternal brain can cause postpartum psychosis, which can reduce the anterior cingulate cortex, left parahippocampal gyrus volume, and left superior temporal gyrus volume.
Most changes in the brain, however, appear to be temporary, Dr. Nasrallah noted. Executive function improves 2-6 months after delivery, which includes goal and directed behavior, working memory, inhibitory function, and cognitive flexibility. In the postpartum period, “the gray matter increases in the first 3-4 months, especially in the brain areas that are involved in maternal behavior that includes amygdala, hypothalamus, and prefrontal cortex,” he added. “All of those changes correlate with positive maternal attachment, and so that makes it easier for the mother to bond with the baby.
“Don’t think of it as a negative,” he said. “The decline in brain volume is actually associated with better mothering and increased attachment between the mother and the baby, which is vital for survival of the baby.”
Global Academy and this news organization are owned by the same parent company. Dr. Nasrallah reports no relevant financial disclosures.
Pregnancy and the postpartum period are a “very vulnerable time for mental disorders,” according to Henry A. Nasrallah, MD.
“Those changes that are helping pregnancy can also have psychiatric and psychopathological implications,” Dr. Nasrallah said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
Numerous dramatic changes in physiology, immune functions, cognition, neuroplasticity, and behavior occur during pregnancy, noted Dr. Nasrallah of the University of Cincinnati. For example, the volume of the brain actually decreases during pregnancy, but brain size recovers over the 6 months after delivery. “Clearly, this is a transitional and a transient phenomenon,” he said. “The decrease in brain volume is associated with changes in brain metabolism and an increase in intracellular pH after delivery.”
But these changes can also carry risks for psychiatric disorders, Dr. Nasrallah explained. Changes in the hippocampus, which is “very plastic throughout adulthood,” have been linked to aging, cognition, pregnancy, and motherhood. “The hippocampus is the ‘Grand Central Station’ of memory in the brain, and the hippocampus is affected by neurodegenerative and psychiatric disorders, which disproportionately affect women,” he said at the meeting, presented by Global Academy for Medical Education.
Dr. Nasrallah said the hippocampus has particular susceptibility during pregnancy and in the postpartum period, or in women who have previously been pregnant.
Gender of the fetus can even affect the health of the mother, he added. In women who are pregnant with male fetuses, working memory and spatial ability are higher than in women who are pregnant with female fetuses, Dr. Nasrallah said. This is tied to higher numbers of proinflammatory cytokines present in male fetuses. In female fetuses, there are lower levels of interferon-gamma and interleukin (IL)-12 in the first trimester, and higher levels of IL-1 beta, tumor necrosis factor B, IL-5, and IL-10 in the second trimester.
In particular,
“Cytokine interleukin-10 and interleukin-6 are both increased during psychosis and during depression, so you can see the vulnerability for developing postpartum depression.” Some women “have other genes that make them susceptible for mood disorders, and the pregnancy can push them over the edge,” he said.
If women have bipolar disorder prior to delivery, “they have a very high risk of postpartum depression, possibly because of this immune dysregulation that serves the pregnancy, but unfortunately makes the woman vulnerable for postpartum psychiatric disorders,” Dr. Nasrallah said.
The effects of having children extend into middle age, Dr. Nasrallah said. Research has shown giving birth to more than one to two children can affect a woman’s risk for Alzheimer’s disease and risk for early-onset of the disease. Women who have three or fewer children later in life are also more likely to live longer, he said. In general, a longer reproductive period, duration of breastfeeding, and low number of pregnancies result in better cognition, while younger age at first pregnancy leads to worse cognition.
So-called pregnancy brain causes some cognitive functions to decline, and women may experience trouble concentrating and memory disturbance. “Other functions increase for the sake of the baby,” including a high reaction to threatening stimuli, absent-mindedness, motivation, reward, fear, executive functions, social cognition, salience, and attachment, Dr. Nasrallah said. In some cases, hormone-driven remodeling of the maternal brain can cause postpartum psychosis, which can reduce the anterior cingulate cortex, left parahippocampal gyrus volume, and left superior temporal gyrus volume.
Most changes in the brain, however, appear to be temporary, Dr. Nasrallah noted. Executive function improves 2-6 months after delivery, which includes goal and directed behavior, working memory, inhibitory function, and cognitive flexibility. In the postpartum period, “the gray matter increases in the first 3-4 months, especially in the brain areas that are involved in maternal behavior that includes amygdala, hypothalamus, and prefrontal cortex,” he added. “All of those changes correlate with positive maternal attachment, and so that makes it easier for the mother to bond with the baby.
“Don’t think of it as a negative,” he said. “The decline in brain volume is actually associated with better mothering and increased attachment between the mother and the baby, which is vital for survival of the baby.”
Global Academy and this news organization are owned by the same parent company. Dr. Nasrallah reports no relevant financial disclosures.
FROM FOCUS ON NEUROPSYCHIATRY 2020
Mapping melasma management
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
Melasma has such a high recurrence rate that, once the facial hyperpigmentation has been cleared, it’s best that treatment never entirely stops, Amit G. Pandya, MD, said at the virtual annual meeting of the American Academy of Dermatology.
He recommended alternating between a less-intensive maintenance therapy regimen in the winter months and an acute care regimen in the sunnier summer months. But . And that is largely a matter of location.
Location, location, location
Melasma has a distinctive symmetric bilateral distribution: “Melasma likes the central area of the forehead, whereas the lateral areas of the forehead are more involved in lichen planus pigmentosus. Melanoma likes the area above the eyebrow or under the eyebrow. However, it does not go below the superior orbital rim or above the inferior orbital rim,”said Dr. Pandya, a dermatologist at the Palo Alto Medical Foundation in Sunnyvale, Calif., who is also on the faculty at the University of Texas Southwestern Medical Center, Dallas.
Melasma is common on the bridge of the nose, but usually not along the nasolabial fold, where hyperpigmentation is much more likely to be due to seborrheic dermatitis or drug-induced hyperpigmentation. Melasma doesn’t affect the tip of the nose; that’s more likely a sign of sarcoidosis or drug-induced hyperpigmentation. Melasma is common on the zygomatic prominence, while acanthosis nigricans favors the concave area below the zygomatic prominence. And melasma stays above the mandible; pigmentation below the mandible is more suggestive of poikiloderma of Civatte. Lentigines are scattered broadly across sun-exposed areas of the face. They also tend to be less symmetrical than melasma, the dermatologist continued.
Acute treatment
Dr. Pandya’s acute treatment algorithm begins with topical 4% hydroquinone in patients who’ve never been on it before. A response to the drug, which blocks the tyrosine-to-melanin pathway, takes 4-6 weeks, with maximum effect not seen until 3-6 months or longer. Bluish-grey ochronosis is a rare side effect at the 4% concentration but becomes more common at higher concentrations or when the drug is used in combination therapy.
“Hydroquinone is a workhorse, the oldest and most effective depigmenting agent,” he said.
If the patient hasn’t responded positively by 3 months, Dr. Pandya moves on to daily use of the triple-drug combination of fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% known as Tri-Luma, a kinder, gentler descendant of the 45-year-old Kligman-Willis compounded formula comprised of 0.1% dexamethasone, 5% hydroquinone, and 0.1% tretinoin.
If Tri-Luma also proves ineffective, Dr. Pandya turns to oral tranexamic acid. This is off-label therapy for the drug, a plasmin inhibitor, which is approved for the treatment of menorrhagia. But oral tranexamic acid is widely used for treatment of melasma in East Asia, and Dr. Pandya and others have evaluated it in placebo-controlled clinical trials. His conclusion is that oral tranexamic acid appears to be safe and effective for treatment of melasma.
“The drug is not approved for melasma, it’s approved for menorrhagia, so every doctor has to decide how much risk they want to take. The evidence suggests 500 mg per day is a good dose,” he said.
The collective clinical trials experience with oral tranexamic acid for melasma shows a side effect profile consisting of mild GI upset, headache, and myalgia. While increased thromboembolic risk is a theoretic concern, it hasn’t been an issue in the published studies, which typically exclude patients with a history of thromboembolic disease from enrollment. Patient satisfaction with the oral agent is high, according to Dr. Pandya.
In one randomized, open-label, 40-patient study, oral tranexamic acid plus a triple-combination cream featuring fluocinolone 0.01%, hydroquinone 2%, and tretinoin 0.05%, applied once a day, was significantly more effective and faster-acting than the topical therapy alone. At 8 weeks, the dual-therapy group averaged an 88% improvement in the Melasma Activity and Severity Index (MASI) scores, compared with 55% with the topical therapy alone (Indian J Dermatol. Sep-Oct 2015;60[5]:520).
Cysteamine 5% cream, which is available over the counter as Cyspera but is pricey, showed promising efficacy in a 40-patient, randomized, double-blind trial (J Dermatolog Treat. 2018 Mar;29[2]:182-9). Dr. Pandya said he’s looking forward to seeing further studies.
Chemical peels can be used, but multiple treatment sessions using a superficial peeling agent are required, and even then “the efficacy is usually not profound,” according to Dr. Pandya. Together with two colleagues he recently published a comprehensive systematic review of 113 published studies of all treatments for melasma in nearly 7,000 patients (Am J Clin Dermatol. 2020 Apr;21(2):173-225).
Newer lasers with various pulse lengths, fluences, wave lengths, and treatment frequency show “some promise,” but there have also been published reports of hypopigmentation and rebound hyperpigmentation. The optimal laser regimen remains elusive, he said.
Maintenance therapy
Dr. Pandya usually switches from hydroquinone to a different topical tyrosinase inhibitor for maintenance therapy, such as kojic acid, arbutin, or azelaic acid, all available OTC in many formulations. Alternatively, he might drop down to 2% hydroquinone for the winter months. Another option is triple-combination cream applied two or three times per week. A topical formulation of tranexamic acid is available, but studies of this agent in patients with melasma have yielded mixed results.
“I don’t think topical tranexamic acid is going to harm the patient, but I don’t think the efficacy is as good as with oral tranexamic acid,” he said.
Slap that melasma in irons
A comprehensive melasma management plan requires year-round frequent daily application of a broad spectrum sunscreen. And since it’s now evident that visible-wavelength light can worsen melasma through mechanisms similar to UVA and UVB, which are long recognized as the major drivers of the hyperpigmentation disorder, serious consideration should be given to the use of a tinted broad-spectrum sunscreen or makeup containing more than 3% iron oxide, which blocks visible light. In contrast, zinc oxide does not, Dr. Pandya noted.
In one influential study, aminolevulinic acid was applied on the arms of 20 patients; two sunscreens were applied on areas where the ALA was applied, and on one area, no sunscreen was applied. The minimal phototoxic dose of visible blue light was doubled with application of a broad-spectrum sunscreen containing titanium dioxide, zinc oxide, and 0.2% iron oxide, compared with no sunscreen, but increased 21-fold using a sunscreen containing titanium dioxide, zinc oxide, and 3.2% iron oxide (Dermatol Surg. 2008 Nov;34[11]:1469-76).
Moreover, in a double-blind, randomized trial including 61 patients with melasma, all on background 4% hydroquinone, those assigned to a broad-spectrum sunscreen containing iron oxide had a 78% improvement in MASI scores at 8 weeks, compared with a 62% improvement with a broad-spectrum UV-only sunscreen. Both sunscreens had a sun protection factor of at least 50 (Photodermatol Photoimmunol Photomed. 2014 Feb;30[1]:35-42).
Numerous sunscreen and makeup products containing more than 3% iron oxide are available OTC in various tints. It’s a matter of finding a color that matches the patient’s skin.
Concern has been raised that exposure to the visible blue light emitted by computer screens and cell phones could worsen melasma. Dr. Pandya noted that reassurance on that score was recently provided by French investigators. They measured the intensity of visible light at the wavelengths emitted by computer screens and laptops and determined that it was 100- to 1,000-fold less than sunlight in the same spectrum. They also conducted a prospective, randomized, split-face trial in 12 melasma patients. One side of the face was exposed to the visible blue light at the same wavelengths emitted by device screens, but at far greater intensity. Blinded evaluators found no split-face difference in modified MASI scores.
“These results suggest that at a 20-cm distance, a maximized use of a high-intensity computer screen for 8 hours per day during a 5-day period does not worsen melasma lesions. Although it is very unlikely that similar exposure during a longer period would start to affect melasma lesions, such a possibility cannot be ruled out,” according to the investigators (J Am Acad Dermatol. 2019 Dec 27;S0190-9622(19)33324-9. doi: 10.1016/j.jaad.2019.12.047).
Dr. Pandya reported serving as a consultant to Incyte, Pfizer, Viela Bio, and Villaris.
FROM AAD 20
Large study finds no link between TCI use, skin cancer in patients with AD
The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.
“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.
In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.
The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.
Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.
Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.
“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.
In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.
“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.
Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.
“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.
The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.
Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”
“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”
Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”
In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”
Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.
These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”
This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.
SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.
The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.
“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.
In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.
The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.
Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.
Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.
“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.
In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.
“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.
Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.
“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.
The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.
Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”
“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”
Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”
In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”
Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.
These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”
This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.
SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.
The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.
“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.
In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.
The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.
Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.
Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.
“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.
In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.
“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.
Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.
“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.
The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.
Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”
“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”
Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”
In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”
Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.
These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”
This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.
SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.
FROM JAMA DERMATOLOGY
What if your patient is technology-challenged?
COVID-19 has forced health care organizations (HCOs) and medical practices to vastly speed up their adoption of technology for patient care. Patient portals and other tools enable visits for patients who have problems seeing physicians because of the pandemic or who prefer not to come to physician offices.
– in addition to being uncertain about the medical aspects of an exam or treatment.
When ordering groceries or sending a check drawn on the bank, using an app is simple, because the user fully understands the objective. But health care has several complicating factors, including changes to patient health status, multipart treatment plans, drug interactions, coordination with providers, and dealing with insurance coverage.
It can get even more complicated when you’re coordinating care with family members, caretakers, and other health care professionals. If technology is going to help you treat patients, the patient needs a clear and simple presentation of what he or she needs to do and know.
Can your patient actually use your tools and technology?
The design of your patient portal, your website, and a phone app will play a huge role in how easily your patient can interact with your practice. A poorly designed portal will undermine your efforts to engage patients and could even create problems for patient safety.
For most tools, more is not necessarily better: A long list of wonderful features and options could make it too complex or confusing for many patients.
Cluttered screens, tiny buttons, and links that are hard to see within large blocks of text make it hard for your patients to use tools or portals. Patients also find it confusing and difficult to understand long written explanations of medical issues or treatment steps that don’t focus on the patient’s individual status, even though these explanations may include important information.
Take a close look at the tools or screens you want your patients to use. At the same time, you’ll want to make sure that the workflow within your practice supports the technology. For example, your portal may have a button to immediately access a staff person on a screen, but that feature is helpful only if you have staff available to interact with the patient.
Similarly, having to click through four screens to access a telehealth visit will confuse your patients and increase telehealth no-shows. If your staff doesn’t respond to patient questions or data gathered by the technology, you may wind up with more phone calls from patients or a missed opportunity to help a patient avoid a problem.
Here are ways you can help patients use your technology and prevent confusion:
Create short, targeted help tools and videos. These can show how to use the patient tools and technology, and they can be customized for different patient groups. Instead of a long video that covers many topics, it’s better to have separate videos for each remote patient-monitoring device (as short as 1-4 minutes). For your help tools and videos:
- Create a video that addresses the key steps of your patient’s medical visit, such as how to complete each health assessment questionnaire, how to send a message to your office, how to request a prescription, and how to view the treatment plan.
- Consider making videos that give instructions for specific diseases and care. For example, a video explaining the use of a spirometer would include a step-by-step demonstration that encourages the patient to follow along. Similarly, a video on blood pressure cuffs would have clear instructions on how to properly place the cuff and how to use it.
- Develop separate videos for each medical device, showing how each is used. For example, create separate videos for blood pressure cuffs on the wrist and the bicep.
- Make access to the videos easy and obvious. For example, have a link to the blood pressure cuff video on the blood pressure screen, or have a short video about tracking physical activities available on the treatment plan screen.
- Offer additional informational videos that give patients general information about their disease and condition.
- Present patient stories and testimonials (after getting signed permission from the patients). These can help patients better understand the practical aspects of their treatment and how technological tools and portals can help them.
Make buttons legible and write text that is easy to read. Many patients have smartphones and iPads with small screens. Larger displays are easier to see and may be less intimidating. Your technology should include a smartphone-friendly interface as well as a tablet- or iPad-friendly interface. Prominently display the key information.
Include only important and relevant information. The more information and clutter shown, the less likely patients are to focus on the really important issues. For example, some patient portals list items on the treatment plan without highlighting the important items in comparison to the informative or future orders. Don’t include older information that confuses them.
Use consumer terminology. When you’re giving treatment plans and care options, make sure to use words that the patient will understand and that are similar to the words you’d use when educating any patient or when you or your staff are giving verbal instructions.
Engaging patients
The more your patient uses your tools or technology during their care, the more familiar they’ll be with it and the more adept they’ll become at using it. Using a portal once a year will not create familiarity with your tools or create a good working relationship.
Continuing exchanges of information and telehealth visits with patients increase patient familiarity and comfort with your technology.
Here are some ways to help patients become more comfortable with and familiar with your technology:
Use remote patient monitoring. Remote patient monitoring (RPM) involves gathering physiologic information, such as blood pressure, pulse oximetry measurements, and glucose levels, from patients on a periodic, even daily basis. Insurance companies pay for this service because it helps spot potential problems before they become more serious and more costly to treat.
Look into conditions you treat in which RPM would be helpful. Through RPM, patients could be sending information daily, and your health care organization (HCO) could be coordinating refinements to the patient’s treatment plan based on daily information and trends over time. For example, a decrease in pulse oximetry levels could trigger a telehealth visit with a patient.
Use a health assessment questionnaire to engage your patients and reinforce important patient activities. A sample health assessment questionnaire can be found at ARHQ.gov. You may have several different questionnaires based on patient problems and treatment strategies. The questionnaire should be as concise as possible and target issues that would help your HCO understand the current health status of the patient and frame the next steps in patient service.
The data you receive can be used to provide follow-up services or even provision supplies, durable medical equipment, and prescriptions. Many patients face challenges in getting prescriptions and supplies in addition to presenting for planned check-ups and physicals.
Hold disease-specific group meetings. Group meeting technology, such as Zoom, can be used to conduct group meetings and provide information to at-risk patients. During online group patient meetings, you can give advice and guidance that can help offset the flood of rumors and false information about health care in general as well as COVID-19.
Offer general health information and conduct surveys. A medical organization or practice can present useful information on wearing a mask, social distancing, and other COVID-19 issues as well as disease-specific guidance to help patients more effectively interact with the practice. You might find it useful to periodically conduct a survey to assess and highlight mitigation strategies for at-risk populations.
Send email and text messages. Your practice should have the option of sending the patient an email or text message with a link to the relevant information or for a telehealth visit. For example, 15 minutes before a scheduled telehealth visit, your technology may send a message reminding the patient of the visit. Text links are particularly helpful – over 90% of text messages are read within 30 minutes of receipt.
How to help technology-challenged patients
Helping patients who have trouble with technology can be expensive and time consuming. Staff may spend a lot of time trying to train or support a patient who is struggling with technology.
Realistically, not every patient will be able to engage through your technology and tools. Some may not have a computer, laptop, or smartphone in their home or a reliable connection to the Internet. Other patients may have trouble affording devices such as tablets or services. Also important, not all smartphones, tablets, and computers may work with your technology base. (For patients who don’t have or can’t afford compatible technology, some state and local initiatives provide such tools to underserved and rural patients in response to the COVID-19 pandemic.)
You may need to assess whether some patients are good candidates for using technology, based on their education, finances, or ability to follow instructions. For those who are not, stick with more frequent office visits and phone-based consultations.
If a patient is unable to use the available tools, document it in your patient record so that you or other clinicians can structure the patient’s treatment plan in accordance with the patient’s abilities.
Going forward, patients may prefer using COVID-19–driven telehealth services in their homes over making a trip to the clinic. If you can put in the effort to ensure that your technologies are relevant and are targeted to the appropriate patients, you’ll be able to provide better care during the COVID-19 pandemic, and the COVID-19–driven changes may become permanent.
Dr. Sterling has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
COVID-19 has forced health care organizations (HCOs) and medical practices to vastly speed up their adoption of technology for patient care. Patient portals and other tools enable visits for patients who have problems seeing physicians because of the pandemic or who prefer not to come to physician offices.
– in addition to being uncertain about the medical aspects of an exam or treatment.
When ordering groceries or sending a check drawn on the bank, using an app is simple, because the user fully understands the objective. But health care has several complicating factors, including changes to patient health status, multipart treatment plans, drug interactions, coordination with providers, and dealing with insurance coverage.
It can get even more complicated when you’re coordinating care with family members, caretakers, and other health care professionals. If technology is going to help you treat patients, the patient needs a clear and simple presentation of what he or she needs to do and know.
Can your patient actually use your tools and technology?
The design of your patient portal, your website, and a phone app will play a huge role in how easily your patient can interact with your practice. A poorly designed portal will undermine your efforts to engage patients and could even create problems for patient safety.
For most tools, more is not necessarily better: A long list of wonderful features and options could make it too complex or confusing for many patients.
Cluttered screens, tiny buttons, and links that are hard to see within large blocks of text make it hard for your patients to use tools or portals. Patients also find it confusing and difficult to understand long written explanations of medical issues or treatment steps that don’t focus on the patient’s individual status, even though these explanations may include important information.
Take a close look at the tools or screens you want your patients to use. At the same time, you’ll want to make sure that the workflow within your practice supports the technology. For example, your portal may have a button to immediately access a staff person on a screen, but that feature is helpful only if you have staff available to interact with the patient.
Similarly, having to click through four screens to access a telehealth visit will confuse your patients and increase telehealth no-shows. If your staff doesn’t respond to patient questions or data gathered by the technology, you may wind up with more phone calls from patients or a missed opportunity to help a patient avoid a problem.
Here are ways you can help patients use your technology and prevent confusion:
Create short, targeted help tools and videos. These can show how to use the patient tools and technology, and they can be customized for different patient groups. Instead of a long video that covers many topics, it’s better to have separate videos for each remote patient-monitoring device (as short as 1-4 minutes). For your help tools and videos:
- Create a video that addresses the key steps of your patient’s medical visit, such as how to complete each health assessment questionnaire, how to send a message to your office, how to request a prescription, and how to view the treatment plan.
- Consider making videos that give instructions for specific diseases and care. For example, a video explaining the use of a spirometer would include a step-by-step demonstration that encourages the patient to follow along. Similarly, a video on blood pressure cuffs would have clear instructions on how to properly place the cuff and how to use it.
- Develop separate videos for each medical device, showing how each is used. For example, create separate videos for blood pressure cuffs on the wrist and the bicep.
- Make access to the videos easy and obvious. For example, have a link to the blood pressure cuff video on the blood pressure screen, or have a short video about tracking physical activities available on the treatment plan screen.
- Offer additional informational videos that give patients general information about their disease and condition.
- Present patient stories and testimonials (after getting signed permission from the patients). These can help patients better understand the practical aspects of their treatment and how technological tools and portals can help them.
Make buttons legible and write text that is easy to read. Many patients have smartphones and iPads with small screens. Larger displays are easier to see and may be less intimidating. Your technology should include a smartphone-friendly interface as well as a tablet- or iPad-friendly interface. Prominently display the key information.
Include only important and relevant information. The more information and clutter shown, the less likely patients are to focus on the really important issues. For example, some patient portals list items on the treatment plan without highlighting the important items in comparison to the informative or future orders. Don’t include older information that confuses them.
Use consumer terminology. When you’re giving treatment plans and care options, make sure to use words that the patient will understand and that are similar to the words you’d use when educating any patient or when you or your staff are giving verbal instructions.
Engaging patients
The more your patient uses your tools or technology during their care, the more familiar they’ll be with it and the more adept they’ll become at using it. Using a portal once a year will not create familiarity with your tools or create a good working relationship.
Continuing exchanges of information and telehealth visits with patients increase patient familiarity and comfort with your technology.
Here are some ways to help patients become more comfortable with and familiar with your technology:
Use remote patient monitoring. Remote patient monitoring (RPM) involves gathering physiologic information, such as blood pressure, pulse oximetry measurements, and glucose levels, from patients on a periodic, even daily basis. Insurance companies pay for this service because it helps spot potential problems before they become more serious and more costly to treat.
Look into conditions you treat in which RPM would be helpful. Through RPM, patients could be sending information daily, and your health care organization (HCO) could be coordinating refinements to the patient’s treatment plan based on daily information and trends over time. For example, a decrease in pulse oximetry levels could trigger a telehealth visit with a patient.
Use a health assessment questionnaire to engage your patients and reinforce important patient activities. A sample health assessment questionnaire can be found at ARHQ.gov. You may have several different questionnaires based on patient problems and treatment strategies. The questionnaire should be as concise as possible and target issues that would help your HCO understand the current health status of the patient and frame the next steps in patient service.
The data you receive can be used to provide follow-up services or even provision supplies, durable medical equipment, and prescriptions. Many patients face challenges in getting prescriptions and supplies in addition to presenting for planned check-ups and physicals.
Hold disease-specific group meetings. Group meeting technology, such as Zoom, can be used to conduct group meetings and provide information to at-risk patients. During online group patient meetings, you can give advice and guidance that can help offset the flood of rumors and false information about health care in general as well as COVID-19.
Offer general health information and conduct surveys. A medical organization or practice can present useful information on wearing a mask, social distancing, and other COVID-19 issues as well as disease-specific guidance to help patients more effectively interact with the practice. You might find it useful to periodically conduct a survey to assess and highlight mitigation strategies for at-risk populations.
Send email and text messages. Your practice should have the option of sending the patient an email or text message with a link to the relevant information or for a telehealth visit. For example, 15 minutes before a scheduled telehealth visit, your technology may send a message reminding the patient of the visit. Text links are particularly helpful – over 90% of text messages are read within 30 minutes of receipt.
How to help technology-challenged patients
Helping patients who have trouble with technology can be expensive and time consuming. Staff may spend a lot of time trying to train or support a patient who is struggling with technology.
Realistically, not every patient will be able to engage through your technology and tools. Some may not have a computer, laptop, or smartphone in their home or a reliable connection to the Internet. Other patients may have trouble affording devices such as tablets or services. Also important, not all smartphones, tablets, and computers may work with your technology base. (For patients who don’t have or can’t afford compatible technology, some state and local initiatives provide such tools to underserved and rural patients in response to the COVID-19 pandemic.)
You may need to assess whether some patients are good candidates for using technology, based on their education, finances, or ability to follow instructions. For those who are not, stick with more frequent office visits and phone-based consultations.
If a patient is unable to use the available tools, document it in your patient record so that you or other clinicians can structure the patient’s treatment plan in accordance with the patient’s abilities.
Going forward, patients may prefer using COVID-19–driven telehealth services in their homes over making a trip to the clinic. If you can put in the effort to ensure that your technologies are relevant and are targeted to the appropriate patients, you’ll be able to provide better care during the COVID-19 pandemic, and the COVID-19–driven changes may become permanent.
Dr. Sterling has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
COVID-19 has forced health care organizations (HCOs) and medical practices to vastly speed up their adoption of technology for patient care. Patient portals and other tools enable visits for patients who have problems seeing physicians because of the pandemic or who prefer not to come to physician offices.
– in addition to being uncertain about the medical aspects of an exam or treatment.
When ordering groceries or sending a check drawn on the bank, using an app is simple, because the user fully understands the objective. But health care has several complicating factors, including changes to patient health status, multipart treatment plans, drug interactions, coordination with providers, and dealing with insurance coverage.
It can get even more complicated when you’re coordinating care with family members, caretakers, and other health care professionals. If technology is going to help you treat patients, the patient needs a clear and simple presentation of what he or she needs to do and know.
Can your patient actually use your tools and technology?
The design of your patient portal, your website, and a phone app will play a huge role in how easily your patient can interact with your practice. A poorly designed portal will undermine your efforts to engage patients and could even create problems for patient safety.
For most tools, more is not necessarily better: A long list of wonderful features and options could make it too complex or confusing for many patients.
Cluttered screens, tiny buttons, and links that are hard to see within large blocks of text make it hard for your patients to use tools or portals. Patients also find it confusing and difficult to understand long written explanations of medical issues or treatment steps that don’t focus on the patient’s individual status, even though these explanations may include important information.
Take a close look at the tools or screens you want your patients to use. At the same time, you’ll want to make sure that the workflow within your practice supports the technology. For example, your portal may have a button to immediately access a staff person on a screen, but that feature is helpful only if you have staff available to interact with the patient.
Similarly, having to click through four screens to access a telehealth visit will confuse your patients and increase telehealth no-shows. If your staff doesn’t respond to patient questions or data gathered by the technology, you may wind up with more phone calls from patients or a missed opportunity to help a patient avoid a problem.
Here are ways you can help patients use your technology and prevent confusion:
Create short, targeted help tools and videos. These can show how to use the patient tools and technology, and they can be customized for different patient groups. Instead of a long video that covers many topics, it’s better to have separate videos for each remote patient-monitoring device (as short as 1-4 minutes). For your help tools and videos:
- Create a video that addresses the key steps of your patient’s medical visit, such as how to complete each health assessment questionnaire, how to send a message to your office, how to request a prescription, and how to view the treatment plan.
- Consider making videos that give instructions for specific diseases and care. For example, a video explaining the use of a spirometer would include a step-by-step demonstration that encourages the patient to follow along. Similarly, a video on blood pressure cuffs would have clear instructions on how to properly place the cuff and how to use it.
- Develop separate videos for each medical device, showing how each is used. For example, create separate videos for blood pressure cuffs on the wrist and the bicep.
- Make access to the videos easy and obvious. For example, have a link to the blood pressure cuff video on the blood pressure screen, or have a short video about tracking physical activities available on the treatment plan screen.
- Offer additional informational videos that give patients general information about their disease and condition.
- Present patient stories and testimonials (after getting signed permission from the patients). These can help patients better understand the practical aspects of their treatment and how technological tools and portals can help them.
Make buttons legible and write text that is easy to read. Many patients have smartphones and iPads with small screens. Larger displays are easier to see and may be less intimidating. Your technology should include a smartphone-friendly interface as well as a tablet- or iPad-friendly interface. Prominently display the key information.
Include only important and relevant information. The more information and clutter shown, the less likely patients are to focus on the really important issues. For example, some patient portals list items on the treatment plan without highlighting the important items in comparison to the informative or future orders. Don’t include older information that confuses them.
Use consumer terminology. When you’re giving treatment plans and care options, make sure to use words that the patient will understand and that are similar to the words you’d use when educating any patient or when you or your staff are giving verbal instructions.
Engaging patients
The more your patient uses your tools or technology during their care, the more familiar they’ll be with it and the more adept they’ll become at using it. Using a portal once a year will not create familiarity with your tools or create a good working relationship.
Continuing exchanges of information and telehealth visits with patients increase patient familiarity and comfort with your technology.
Here are some ways to help patients become more comfortable with and familiar with your technology:
Use remote patient monitoring. Remote patient monitoring (RPM) involves gathering physiologic information, such as blood pressure, pulse oximetry measurements, and glucose levels, from patients on a periodic, even daily basis. Insurance companies pay for this service because it helps spot potential problems before they become more serious and more costly to treat.
Look into conditions you treat in which RPM would be helpful. Through RPM, patients could be sending information daily, and your health care organization (HCO) could be coordinating refinements to the patient’s treatment plan based on daily information and trends over time. For example, a decrease in pulse oximetry levels could trigger a telehealth visit with a patient.
Use a health assessment questionnaire to engage your patients and reinforce important patient activities. A sample health assessment questionnaire can be found at ARHQ.gov. You may have several different questionnaires based on patient problems and treatment strategies. The questionnaire should be as concise as possible and target issues that would help your HCO understand the current health status of the patient and frame the next steps in patient service.
The data you receive can be used to provide follow-up services or even provision supplies, durable medical equipment, and prescriptions. Many patients face challenges in getting prescriptions and supplies in addition to presenting for planned check-ups and physicals.
Hold disease-specific group meetings. Group meeting technology, such as Zoom, can be used to conduct group meetings and provide information to at-risk patients. During online group patient meetings, you can give advice and guidance that can help offset the flood of rumors and false information about health care in general as well as COVID-19.
Offer general health information and conduct surveys. A medical organization or practice can present useful information on wearing a mask, social distancing, and other COVID-19 issues as well as disease-specific guidance to help patients more effectively interact with the practice. You might find it useful to periodically conduct a survey to assess and highlight mitigation strategies for at-risk populations.
Send email and text messages. Your practice should have the option of sending the patient an email or text message with a link to the relevant information or for a telehealth visit. For example, 15 minutes before a scheduled telehealth visit, your technology may send a message reminding the patient of the visit. Text links are particularly helpful – over 90% of text messages are read within 30 minutes of receipt.
How to help technology-challenged patients
Helping patients who have trouble with technology can be expensive and time consuming. Staff may spend a lot of time trying to train or support a patient who is struggling with technology.
Realistically, not every patient will be able to engage through your technology and tools. Some may not have a computer, laptop, or smartphone in their home or a reliable connection to the Internet. Other patients may have trouble affording devices such as tablets or services. Also important, not all smartphones, tablets, and computers may work with your technology base. (For patients who don’t have or can’t afford compatible technology, some state and local initiatives provide such tools to underserved and rural patients in response to the COVID-19 pandemic.)
You may need to assess whether some patients are good candidates for using technology, based on their education, finances, or ability to follow instructions. For those who are not, stick with more frequent office visits and phone-based consultations.
If a patient is unable to use the available tools, document it in your patient record so that you or other clinicians can structure the patient’s treatment plan in accordance with the patient’s abilities.
Going forward, patients may prefer using COVID-19–driven telehealth services in their homes over making a trip to the clinic. If you can put in the effort to ensure that your technologies are relevant and are targeted to the appropriate patients, you’ll be able to provide better care during the COVID-19 pandemic, and the COVID-19–driven changes may become permanent.
Dr. Sterling has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Early psychosis: No need for antipsychotics to recover?
Two new studies highlight the importance of early intervention in first-episode psychosis (FEP).
In the first study, Australian investigators conclude that, for some FEP patients, early psychosocial interventions may fend off the need for immediate treatment with antipsychotic medications.
In the second study, UK researchers show that long duration of untreated psychosis (DUP) is linked to a significantly reduced treatment response.
For both studies, the findings highlight the importance of rapid access to a comprehensive range of treatments in the first weeks after FEP onset.
“In a select group of people with first-episode psychosis, we found there was no difference in symptoms and functioning between those who had antipsychotic medication and those who didn’t,” lead author Shona M. Francey, PhD, clinical psychologist at Orygen, the National Center of Excellence in Youth Mental Health, Parkville, Australia, told Medscape Medical News.
“These findings supported our idea that, in the early phases of psychosis, with close monitoring and good psychosocial intervention, antipsychotic medication can be delayed,” Francey said.
The Australian study was published in Schizophrenia Bulletin Open. The British study was published in Lancet Psychiatry.
Adverse effects
Francey and colleagues note that, in comparison with standard treatment, early interventions produce superior outcomes for patients with psychosis. Although there are a variety of treatment options, low-dose second-generation antipsychotics typically play a central role.
However, atypical antipsychotics have rapid metabolic side effects, including weight gain and altered glucose metabolism, that increase the risk for cardiovascular disease and premature mortality. Importantly, such adverse effects are amplified among patients with FEP, who tend to be younger and treatment naive.
On the other hand, a growing body of evidence shows the benefit of nonpharmacologic interventions for patients with FEP, the investigators note. In addition, clinical staging models appear to support the use of less aggressive treatment early in the disease course.
“We have been working in early intervention for psychosis for a number of years and have found it’s possible to intervene early with young people and either prevent the onset of psychosis or ameliorate its impact,” said Francey.
“Since we can see some improvement in people in the prepsychotic phase, we wanted to know if we can also see some benefit without medication after the onset of what we would call full-threshold psychosis,” she added.
Staged Treatment and Acceptability Guidelines in Early Psychosis (STAGES) was a 6-month, triple-blind, randomized controlled noninferiority study that included 90 participants between the ages of 15 and 25 years who had FEP.
To maximize safety, patients were required to have low levels of suicidality and aggression, a DUP of less than 6 months, and to be living in stable accommodation with social support.
Participants were randomly assigned to two groups – one in which patients underwent intensive psychosocial therapy and received low-dose antipsychotic medication (n = 44), and one in which patients underwent intensive psychosocial therapy and were given placebo (n = 46).
Depending on the timing of study enrollment, those in the medication group received risperidone 1 mg or paliperidone 3 mg.
that is strongly focused on therapeutic engagement.
CBCM delivers formulation-driven cognitive-behavioral therapy and psychoeducation within a therapeutic case management framework, Francey said.
The primary outcome was level of functioning at 6, 12, and 24 months, as measured by the Social and Occupational Functioning Scale (SOFAS). The primary prespecified endpoint was outcome at 6 months. A noninferiority margin of 10.5 on the SOFAS was used as the smallest value representing a clinically important effect.
Other assessment tools included the BPRS-4 to test for positive psychotic symptoms, the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety.
At baseline, the two treatment groups were comparable with respect to all measures of functioning and psychopathology.
The study’s discontinuation rate was high. At 6 months, only 16 patients in the psychosocial group had completed therapy, compared with 11 in the antipsychotic group.
At this point, the two groups were comparable in terms of psychopathology and functioning ratings. Both groups had lower symptoms, higher functioning scores, and higher Quality of Life Scale (QLS) scores than at baseline.
SOFAS scores were not significantly different between the groups at this time point. The mean score was 61.7 ± 16.8 in the psychosocial group and 61.5 ± 13.4 in the medication group.
The researchers note that, because the upper limit of the confidence interval (CI) was less than the study’s a priori inferiority margin of 10.5, psychosocial therapy was not inferior to medication at the 6-month assessment point.
Antipsychotics: Use with caution
Although between-group differences in SOFAS scores were not significant at 12 and 24 months, noninferiority of psychosocial therapy alone could not be confirmed because the CIs included the inferiority margin at each time point.
The two groups were statistically comparable at 6 months with respect to all other measures of psychopathology and the QLS. Similar results were found at 12 and 24 months.
The lone exception was with SANS at 12 months, on which patients in the placebo group had significantly higher negative symptom scores than the patients in the medication group.
There were no significant differences between study groups with respect to the number of adverse events.
Francey noted that the findings are important because they suggest that some young people with early-stage FEP and short DUP may be able to achieve symptom remission and function better without antipsychotic medication, provided they receive psychological interventions and comprehensive case management.
This challenges conventional wisdom that antipsychotic medications should be used for all patients who experience psychosis, she added.
However, managing FEP with psychosocial interventions should only be considered when it is safe to do so, Francey noted. In addition, the benefits of psychosocial interventions in these patients are less clear at 12 and 24 months.
Given these caveats, she noted that antipsychotics still play an important role in the treatment of these patients.
“I think there is definitely a place for medications. But I think they should be used cautiously, and you need a good, strong relationship between your treating team and your [patient] to work out what is needed and when it’s needed,” said Francey.
In addition, “when we do use medications, we should use the smallest possible dose that we can and also incorporate psychological support. I think that’s a really important part of it as well,” she said.
Timing matters
In the Lancet Psychiatry study, the researchers note that prolonged DUP is associated with worse outcomes, including increased symptoms, diminished social functioning, and poorer quality of life. The mechanism by which delayed treatment causes more harm remains unclear.
It is possible that symptoms simply accumulate over time, thereby worsening presentation. Another possibility is that continued psychosis after an initial critical period may cause long-term harm, they write.
They hypothesize that untreated psychosis can cause general treatment resistance by exacerbating underlying disease processes and that such damage progresses faster in the early stages of illness and then slows over time.
In addition, socially disruptive symptoms that are evident prior to FEP presentation may have a confounding effect, thereby leading to earlier presentation.
The investigators used data from two longitudinal cohort studies – the National Evaluation of Development of Early Intervention Network (NEDEN) study and the Outlook study.
In the NEDEN trial, 290 of 901 FEP patients (32%) were assessed within 3 weeks of presentation. In Outlook, 69 of 332 patients (21%) were assessed within 3 weeks of presentation.
In both studies, patients were examined at baseline, 6 months, and 12 months using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, the Mania Rating Scale, the Insight Scale, and SOFAS. The latter two measures were used only at baseline and 12-month follow-up. Logistic regression analyses were used to determine the association between DUP and outcomes.
In the NEDEN study, 751 patients were assessed at 6 months, and 719 were assessed at 12 months. In the Outlook study, 238 and 220 were assessed at the same two time points, respectively.
Results showed a curvilinear relationship between DUP and symptom severity. Longer DUP was predictive of reduced treatment response. However, patient response worsened more slowly as DUP lengthened.
For example, increasing DUP by ten times was predictive of less improvement in PANSS total score by 7.34 (95% CI, 5.76 – 8.92; P < .0001) in NEDEN and by 3.85 (95% CI, 1.69 – 600; P =. 0005) in Outlook. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN.
The findings seem to support that the potential harm incurred by delaying treatment among patients with FEP is greatest in the early weeks of psychosis and then levels off, the investigators note.
Given these insights, mental health professionals might consider focusing their efforts on the early detection and treatment of patients for whom DUP is short.
Similarly, because DUP was directly associated with all symptoms, early access to comprehensive treatment “might be preferable to early delivery of particular treatments with particular effects (eg, dopamine antagonists),” they write.
“A pragmatic call”
Commenting on the British study in an accompanying editorial, Lena K. Palaniyappan, MD, University of Western Ontario, London, Canada, and Rajeev Krishnadas, MD, University of Glasgow, Scotland, write that any illness left untreated can become more challenging to treat, including psychosis.
“This should make early intervention in psychosis a pragmatic call with no prima facie argument against it,” they write. A reduction in DUP “underpins the rationale behind early detection and intervention in psychosis.”
The editorialists note that the relationship between DUP and successful treatment in early psychosis “strengthens the argument for more proactive early assessment and intervention to shorten treatment delay.
“As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis,” they write.
Francey also recognizes the value of early intervention in FEP. However, she noted that comprehensive psychosocial therapy might well prove effective enough to stave off antipsychotic therapy in a certain subset of patients.
“For some people, antipsychotics may never need to be introduced,” she said. “Some people recover from their first episode of psychosis and don’t go on to have any more, while others have an episodic illness,” she said.
If another episode develops and the symptoms come back, further psychosocial interventions could then be tried “or you might want to move on” to psychotic medication “because trying to get people better and functioning as well as they can is our primary aim,” Francey said.
The STAGES study was supported by the Australian National Health and Medical Research Council. The British study was funded by the UK Department of Health, the National Institute of Health Research, and the Medical Research Council. Francey and Krishnadas have reported no relevant financial relationships. Palaniyappan has received grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and the Canadian Psychiatric Association.
This article first appeared on Medscape.com.
Two new studies highlight the importance of early intervention in first-episode psychosis (FEP).
In the first study, Australian investigators conclude that, for some FEP patients, early psychosocial interventions may fend off the need for immediate treatment with antipsychotic medications.
In the second study, UK researchers show that long duration of untreated psychosis (DUP) is linked to a significantly reduced treatment response.
For both studies, the findings highlight the importance of rapid access to a comprehensive range of treatments in the first weeks after FEP onset.
“In a select group of people with first-episode psychosis, we found there was no difference in symptoms and functioning between those who had antipsychotic medication and those who didn’t,” lead author Shona M. Francey, PhD, clinical psychologist at Orygen, the National Center of Excellence in Youth Mental Health, Parkville, Australia, told Medscape Medical News.
“These findings supported our idea that, in the early phases of psychosis, with close monitoring and good psychosocial intervention, antipsychotic medication can be delayed,” Francey said.
The Australian study was published in Schizophrenia Bulletin Open. The British study was published in Lancet Psychiatry.
Adverse effects
Francey and colleagues note that, in comparison with standard treatment, early interventions produce superior outcomes for patients with psychosis. Although there are a variety of treatment options, low-dose second-generation antipsychotics typically play a central role.
However, atypical antipsychotics have rapid metabolic side effects, including weight gain and altered glucose metabolism, that increase the risk for cardiovascular disease and premature mortality. Importantly, such adverse effects are amplified among patients with FEP, who tend to be younger and treatment naive.
On the other hand, a growing body of evidence shows the benefit of nonpharmacologic interventions for patients with FEP, the investigators note. In addition, clinical staging models appear to support the use of less aggressive treatment early in the disease course.
“We have been working in early intervention for psychosis for a number of years and have found it’s possible to intervene early with young people and either prevent the onset of psychosis or ameliorate its impact,” said Francey.
“Since we can see some improvement in people in the prepsychotic phase, we wanted to know if we can also see some benefit without medication after the onset of what we would call full-threshold psychosis,” she added.
Staged Treatment and Acceptability Guidelines in Early Psychosis (STAGES) was a 6-month, triple-blind, randomized controlled noninferiority study that included 90 participants between the ages of 15 and 25 years who had FEP.
To maximize safety, patients were required to have low levels of suicidality and aggression, a DUP of less than 6 months, and to be living in stable accommodation with social support.
Participants were randomly assigned to two groups – one in which patients underwent intensive psychosocial therapy and received low-dose antipsychotic medication (n = 44), and one in which patients underwent intensive psychosocial therapy and were given placebo (n = 46).
Depending on the timing of study enrollment, those in the medication group received risperidone 1 mg or paliperidone 3 mg.
that is strongly focused on therapeutic engagement.
CBCM delivers formulation-driven cognitive-behavioral therapy and psychoeducation within a therapeutic case management framework, Francey said.
The primary outcome was level of functioning at 6, 12, and 24 months, as measured by the Social and Occupational Functioning Scale (SOFAS). The primary prespecified endpoint was outcome at 6 months. A noninferiority margin of 10.5 on the SOFAS was used as the smallest value representing a clinically important effect.
Other assessment tools included the BPRS-4 to test for positive psychotic symptoms, the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety.
At baseline, the two treatment groups were comparable with respect to all measures of functioning and psychopathology.
The study’s discontinuation rate was high. At 6 months, only 16 patients in the psychosocial group had completed therapy, compared with 11 in the antipsychotic group.
At this point, the two groups were comparable in terms of psychopathology and functioning ratings. Both groups had lower symptoms, higher functioning scores, and higher Quality of Life Scale (QLS) scores than at baseline.
SOFAS scores were not significantly different between the groups at this time point. The mean score was 61.7 ± 16.8 in the psychosocial group and 61.5 ± 13.4 in the medication group.
The researchers note that, because the upper limit of the confidence interval (CI) was less than the study’s a priori inferiority margin of 10.5, psychosocial therapy was not inferior to medication at the 6-month assessment point.
Antipsychotics: Use with caution
Although between-group differences in SOFAS scores were not significant at 12 and 24 months, noninferiority of psychosocial therapy alone could not be confirmed because the CIs included the inferiority margin at each time point.
The two groups were statistically comparable at 6 months with respect to all other measures of psychopathology and the QLS. Similar results were found at 12 and 24 months.
The lone exception was with SANS at 12 months, on which patients in the placebo group had significantly higher negative symptom scores than the patients in the medication group.
There were no significant differences between study groups with respect to the number of adverse events.
Francey noted that the findings are important because they suggest that some young people with early-stage FEP and short DUP may be able to achieve symptom remission and function better without antipsychotic medication, provided they receive psychological interventions and comprehensive case management.
This challenges conventional wisdom that antipsychotic medications should be used for all patients who experience psychosis, she added.
However, managing FEP with psychosocial interventions should only be considered when it is safe to do so, Francey noted. In addition, the benefits of psychosocial interventions in these patients are less clear at 12 and 24 months.
Given these caveats, she noted that antipsychotics still play an important role in the treatment of these patients.
“I think there is definitely a place for medications. But I think they should be used cautiously, and you need a good, strong relationship between your treating team and your [patient] to work out what is needed and when it’s needed,” said Francey.
In addition, “when we do use medications, we should use the smallest possible dose that we can and also incorporate psychological support. I think that’s a really important part of it as well,” she said.
Timing matters
In the Lancet Psychiatry study, the researchers note that prolonged DUP is associated with worse outcomes, including increased symptoms, diminished social functioning, and poorer quality of life. The mechanism by which delayed treatment causes more harm remains unclear.
It is possible that symptoms simply accumulate over time, thereby worsening presentation. Another possibility is that continued psychosis after an initial critical period may cause long-term harm, they write.
They hypothesize that untreated psychosis can cause general treatment resistance by exacerbating underlying disease processes and that such damage progresses faster in the early stages of illness and then slows over time.
In addition, socially disruptive symptoms that are evident prior to FEP presentation may have a confounding effect, thereby leading to earlier presentation.
The investigators used data from two longitudinal cohort studies – the National Evaluation of Development of Early Intervention Network (NEDEN) study and the Outlook study.
In the NEDEN trial, 290 of 901 FEP patients (32%) were assessed within 3 weeks of presentation. In Outlook, 69 of 332 patients (21%) were assessed within 3 weeks of presentation.
In both studies, patients were examined at baseline, 6 months, and 12 months using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, the Mania Rating Scale, the Insight Scale, and SOFAS. The latter two measures were used only at baseline and 12-month follow-up. Logistic regression analyses were used to determine the association between DUP and outcomes.
In the NEDEN study, 751 patients were assessed at 6 months, and 719 were assessed at 12 months. In the Outlook study, 238 and 220 were assessed at the same two time points, respectively.
Results showed a curvilinear relationship between DUP and symptom severity. Longer DUP was predictive of reduced treatment response. However, patient response worsened more slowly as DUP lengthened.
For example, increasing DUP by ten times was predictive of less improvement in PANSS total score by 7.34 (95% CI, 5.76 – 8.92; P < .0001) in NEDEN and by 3.85 (95% CI, 1.69 – 600; P =. 0005) in Outlook. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN.
The findings seem to support that the potential harm incurred by delaying treatment among patients with FEP is greatest in the early weeks of psychosis and then levels off, the investigators note.
Given these insights, mental health professionals might consider focusing their efforts on the early detection and treatment of patients for whom DUP is short.
Similarly, because DUP was directly associated with all symptoms, early access to comprehensive treatment “might be preferable to early delivery of particular treatments with particular effects (eg, dopamine antagonists),” they write.
“A pragmatic call”
Commenting on the British study in an accompanying editorial, Lena K. Palaniyappan, MD, University of Western Ontario, London, Canada, and Rajeev Krishnadas, MD, University of Glasgow, Scotland, write that any illness left untreated can become more challenging to treat, including psychosis.
“This should make early intervention in psychosis a pragmatic call with no prima facie argument against it,” they write. A reduction in DUP “underpins the rationale behind early detection and intervention in psychosis.”
The editorialists note that the relationship between DUP and successful treatment in early psychosis “strengthens the argument for more proactive early assessment and intervention to shorten treatment delay.
“As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis,” they write.
Francey also recognizes the value of early intervention in FEP. However, she noted that comprehensive psychosocial therapy might well prove effective enough to stave off antipsychotic therapy in a certain subset of patients.
“For some people, antipsychotics may never need to be introduced,” she said. “Some people recover from their first episode of psychosis and don’t go on to have any more, while others have an episodic illness,” she said.
If another episode develops and the symptoms come back, further psychosocial interventions could then be tried “or you might want to move on” to psychotic medication “because trying to get people better and functioning as well as they can is our primary aim,” Francey said.
The STAGES study was supported by the Australian National Health and Medical Research Council. The British study was funded by the UK Department of Health, the National Institute of Health Research, and the Medical Research Council. Francey and Krishnadas have reported no relevant financial relationships. Palaniyappan has received grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and the Canadian Psychiatric Association.
This article first appeared on Medscape.com.
Two new studies highlight the importance of early intervention in first-episode psychosis (FEP).
In the first study, Australian investigators conclude that, for some FEP patients, early psychosocial interventions may fend off the need for immediate treatment with antipsychotic medications.
In the second study, UK researchers show that long duration of untreated psychosis (DUP) is linked to a significantly reduced treatment response.
For both studies, the findings highlight the importance of rapid access to a comprehensive range of treatments in the first weeks after FEP onset.
“In a select group of people with first-episode psychosis, we found there was no difference in symptoms and functioning between those who had antipsychotic medication and those who didn’t,” lead author Shona M. Francey, PhD, clinical psychologist at Orygen, the National Center of Excellence in Youth Mental Health, Parkville, Australia, told Medscape Medical News.
“These findings supported our idea that, in the early phases of psychosis, with close monitoring and good psychosocial intervention, antipsychotic medication can be delayed,” Francey said.
The Australian study was published in Schizophrenia Bulletin Open. The British study was published in Lancet Psychiatry.
Adverse effects
Francey and colleagues note that, in comparison with standard treatment, early interventions produce superior outcomes for patients with psychosis. Although there are a variety of treatment options, low-dose second-generation antipsychotics typically play a central role.
However, atypical antipsychotics have rapid metabolic side effects, including weight gain and altered glucose metabolism, that increase the risk for cardiovascular disease and premature mortality. Importantly, such adverse effects are amplified among patients with FEP, who tend to be younger and treatment naive.
On the other hand, a growing body of evidence shows the benefit of nonpharmacologic interventions for patients with FEP, the investigators note. In addition, clinical staging models appear to support the use of less aggressive treatment early in the disease course.
“We have been working in early intervention for psychosis for a number of years and have found it’s possible to intervene early with young people and either prevent the onset of psychosis or ameliorate its impact,” said Francey.
“Since we can see some improvement in people in the prepsychotic phase, we wanted to know if we can also see some benefit without medication after the onset of what we would call full-threshold psychosis,” she added.
Staged Treatment and Acceptability Guidelines in Early Psychosis (STAGES) was a 6-month, triple-blind, randomized controlled noninferiority study that included 90 participants between the ages of 15 and 25 years who had FEP.
To maximize safety, patients were required to have low levels of suicidality and aggression, a DUP of less than 6 months, and to be living in stable accommodation with social support.
Participants were randomly assigned to two groups – one in which patients underwent intensive psychosocial therapy and received low-dose antipsychotic medication (n = 44), and one in which patients underwent intensive psychosocial therapy and were given placebo (n = 46).
Depending on the timing of study enrollment, those in the medication group received risperidone 1 mg or paliperidone 3 mg.
that is strongly focused on therapeutic engagement.
CBCM delivers formulation-driven cognitive-behavioral therapy and psychoeducation within a therapeutic case management framework, Francey said.
The primary outcome was level of functioning at 6, 12, and 24 months, as measured by the Social and Occupational Functioning Scale (SOFAS). The primary prespecified endpoint was outcome at 6 months. A noninferiority margin of 10.5 on the SOFAS was used as the smallest value representing a clinically important effect.
Other assessment tools included the BPRS-4 to test for positive psychotic symptoms, the Scale for the Assessment of Negative Symptoms (SANS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety.
At baseline, the two treatment groups were comparable with respect to all measures of functioning and psychopathology.
The study’s discontinuation rate was high. At 6 months, only 16 patients in the psychosocial group had completed therapy, compared with 11 in the antipsychotic group.
At this point, the two groups were comparable in terms of psychopathology and functioning ratings. Both groups had lower symptoms, higher functioning scores, and higher Quality of Life Scale (QLS) scores than at baseline.
SOFAS scores were not significantly different between the groups at this time point. The mean score was 61.7 ± 16.8 in the psychosocial group and 61.5 ± 13.4 in the medication group.
The researchers note that, because the upper limit of the confidence interval (CI) was less than the study’s a priori inferiority margin of 10.5, psychosocial therapy was not inferior to medication at the 6-month assessment point.
Antipsychotics: Use with caution
Although between-group differences in SOFAS scores were not significant at 12 and 24 months, noninferiority of psychosocial therapy alone could not be confirmed because the CIs included the inferiority margin at each time point.
The two groups were statistically comparable at 6 months with respect to all other measures of psychopathology and the QLS. Similar results were found at 12 and 24 months.
The lone exception was with SANS at 12 months, on which patients in the placebo group had significantly higher negative symptom scores than the patients in the medication group.
There were no significant differences between study groups with respect to the number of adverse events.
Francey noted that the findings are important because they suggest that some young people with early-stage FEP and short DUP may be able to achieve symptom remission and function better without antipsychotic medication, provided they receive psychological interventions and comprehensive case management.
This challenges conventional wisdom that antipsychotic medications should be used for all patients who experience psychosis, she added.
However, managing FEP with psychosocial interventions should only be considered when it is safe to do so, Francey noted. In addition, the benefits of psychosocial interventions in these patients are less clear at 12 and 24 months.
Given these caveats, she noted that antipsychotics still play an important role in the treatment of these patients.
“I think there is definitely a place for medications. But I think they should be used cautiously, and you need a good, strong relationship between your treating team and your [patient] to work out what is needed and when it’s needed,” said Francey.
In addition, “when we do use medications, we should use the smallest possible dose that we can and also incorporate psychological support. I think that’s a really important part of it as well,” she said.
Timing matters
In the Lancet Psychiatry study, the researchers note that prolonged DUP is associated with worse outcomes, including increased symptoms, diminished social functioning, and poorer quality of life. The mechanism by which delayed treatment causes more harm remains unclear.
It is possible that symptoms simply accumulate over time, thereby worsening presentation. Another possibility is that continued psychosis after an initial critical period may cause long-term harm, they write.
They hypothesize that untreated psychosis can cause general treatment resistance by exacerbating underlying disease processes and that such damage progresses faster in the early stages of illness and then slows over time.
In addition, socially disruptive symptoms that are evident prior to FEP presentation may have a confounding effect, thereby leading to earlier presentation.
The investigators used data from two longitudinal cohort studies – the National Evaluation of Development of Early Intervention Network (NEDEN) study and the Outlook study.
In the NEDEN trial, 290 of 901 FEP patients (32%) were assessed within 3 weeks of presentation. In Outlook, 69 of 332 patients (21%) were assessed within 3 weeks of presentation.
In both studies, patients were examined at baseline, 6 months, and 12 months using the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia, the Mania Rating Scale, the Insight Scale, and SOFAS. The latter two measures were used only at baseline and 12-month follow-up. Logistic regression analyses were used to determine the association between DUP and outcomes.
In the NEDEN study, 751 patients were assessed at 6 months, and 719 were assessed at 12 months. In the Outlook study, 238 and 220 were assessed at the same two time points, respectively.
Results showed a curvilinear relationship between DUP and symptom severity. Longer DUP was predictive of reduced treatment response. However, patient response worsened more slowly as DUP lengthened.
For example, increasing DUP by ten times was predictive of less improvement in PANSS total score by 7.34 (95% CI, 5.76 – 8.92; P < .0001) in NEDEN and by 3.85 (95% CI, 1.69 – 600; P =. 0005) in Outlook. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN.
The findings seem to support that the potential harm incurred by delaying treatment among patients with FEP is greatest in the early weeks of psychosis and then levels off, the investigators note.
Given these insights, mental health professionals might consider focusing their efforts on the early detection and treatment of patients for whom DUP is short.
Similarly, because DUP was directly associated with all symptoms, early access to comprehensive treatment “might be preferable to early delivery of particular treatments with particular effects (eg, dopamine antagonists),” they write.
“A pragmatic call”
Commenting on the British study in an accompanying editorial, Lena K. Palaniyappan, MD, University of Western Ontario, London, Canada, and Rajeev Krishnadas, MD, University of Glasgow, Scotland, write that any illness left untreated can become more challenging to treat, including psychosis.
“This should make early intervention in psychosis a pragmatic call with no prima facie argument against it,” they write. A reduction in DUP “underpins the rationale behind early detection and intervention in psychosis.”
The editorialists note that the relationship between DUP and successful treatment in early psychosis “strengthens the argument for more proactive early assessment and intervention to shorten treatment delay.
“As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis,” they write.
Francey also recognizes the value of early intervention in FEP. However, she noted that comprehensive psychosocial therapy might well prove effective enough to stave off antipsychotic therapy in a certain subset of patients.
“For some people, antipsychotics may never need to be introduced,” she said. “Some people recover from their first episode of psychosis and don’t go on to have any more, while others have an episodic illness,” she said.
If another episode develops and the symptoms come back, further psychosocial interventions could then be tried “or you might want to move on” to psychotic medication “because trying to get people better and functioning as well as they can is our primary aim,” Francey said.
The STAGES study was supported by the Australian National Health and Medical Research Council. The British study was funded by the UK Department of Health, the National Institute of Health Research, and the Medical Research Council. Francey and Krishnadas have reported no relevant financial relationships. Palaniyappan has received grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and the Canadian Psychiatric Association.
This article first appeared on Medscape.com.
Why are many of my patients doing better during the pandemic?
The COVID-19 pandemic has, like it or not, made experimental labs rats out of us all.
Since the U.S. “shutdown” began in March, we have all had to adjust to a situation in which we are home more, stuck seeing less of our friends, exercising less, often eating and drinking more, or using recreational substances more – in part because of the severe stress. We have been ripped away from many of the social “anchors” of our weeks; that is, the spiritual, social and physical, and tactile supports that sustain and motivate us in our lives.
And yet, many of us, of all ages, stripes, and colors are thriving. Why is that so? Without necessarily being fully fledged, card carrying misanthropes, many of us are actually not bereft when forced to spend some alone time.
We may be self-starters and have hobbies and interests that we may have neglected but can fall back on with alacrity. Activities such as gardening, cooking, reading, working at our day jobs, listening to music, streaming TV, and so on are now more available to us.
The pandemic has produced unforeseen side effects, such as decreased pollution, less seismic “noise” on our planet, increasingly bold activity by wild life, and we can actually hear bird songs in our yards. Likewise, the social isolation has enabled us to focus more on “back burner” projects and to motivate us toward accessing and achieving other internally driven goals.
Also, to many, it has provided a surprising and unexpected privilege to meaningfully connect while in close quarters with spouses, children, and other loved ones, which has improved and cemented relationships under some level of duress, perhaps.
Similarly, and perhaps surprisingly, in addition to the above reasons, many of our patients with chronic mental illness may be functioning reasonably well, too, even better than their “walking wounded” loved ones and peers. They may be reaping the rewards of many years of consistent biopsychosocial support in strong mental health programs.
But another reason might be the lowered expectations. I’m just so much more relaxed; I’ve got this.” And certainly the Freudian “schadenfreude” defense has something to do with this as well. Seeing family members lose their jobs, become financially vulnerable, being unable to or stymied from demonstrating mastery in many different situations and skill sets elicit the empathy and galvanizes the support of well-managed patients with mental illness – already used to existential threats – for their generally higher functioning loved ones.
As one of my struggling patients said, “Welcome to my world!” Years of hardship, lack of intimate relationships because of social anxiety, and psychotic level obsessive-compulsive disorder have trained, indeed, inured her to the daily pain, constriction, and misery of social isolation. Her life, despite working full time, has remained static, while younger siblings have married, started a family, moved away. She is still living at home with her elderly parents. They now worry about catching COVID-19, while she is now their protector with roles reversed, doing their shopping, and providing moral support and encouragement for the whole family.
Many of us have lost jobs, been furloughed, seen our dreams disappear, and are unable to pay rent or mortgages. Those with chronic mental illness, especially those living in states with a strong social safety net, are continuing to receive their Social Security disability checks, and maintain their in-home health and family supports. They also have continued their adherence with the mental health system structure by continuing with telemedicine therapy and regular medications or monthly intramuscular shots. Their families are especially cognizant of the need for ongoing structure and stability, which is now easier to provide. And what of those patients who endured severe anxiety and panic disorders in their prepandemic states? It is true that many do require higher doses of their anxiolytics, especially benzodiazepines. They do know how to “roll with the punches” with their lifetime experience, as opposed to the “newbies” whose incipient anxiety is brought to the forefront and who might not even recognize these debilitating symptoms and are not keen, for reasons of stigma, to be seen by a mental health expert unless compelled to.
It is up to us as psychiatrists and other mental health clinicians to minimize dependence on those medications by using alternative non–dependence-forming anxiolytics and encouraging our patients to hone and develop the skills from cognitive-behavioral therapy. COVID-19 is just one more stressor, superimposed on many others, and unlikely to precipitate any “tipping point” in functioning, even if there are significant losses among loved ones to the virus.
How about our child and adolescent patients? As a rule of thumb, those with anxiety disorders, social anxiety, selective mutism – and those experiencing challenges and bullying in the rough and tumble world of schools – are doing significantly better. Those with ADHD and impulse control disorders, however, might be struggling with school, especially with Zoom calls and very high distractibility, boredom, and motivational challenges. They may need their doses of medications adjusted up, and their parents are struggling. The risk for unwitnessed and unmonitored abuse in home situations is higher.
Those with chronic mental illness often do have increased risk factors for COVID-19 that might be compounded by their psychopharmacologic treatment for conditions/behaviors such as diabetes, obesity, cardiovascular disease, and substance use. By proactively monitoring those comorbid disorders in a multimodal treatment program, we can help mitigate those baseline challenges.
This aspect of the COVID-19 pandemic is, alas, likely to prove to be an illusory positive “blip” on the radar screen for many with chronic mental illness. Nevertheless, the self-knowledge and awareness of hidden strengths rather than weakness, resilience rather than shrinking from challenges, is not insignificant. This “flight into normality” may be a change that can be internalized and nurtured once vaccines are available and life on planet Earth returns to a new normal.
Dr. Tofler is affiliated with Kaiser Permanente Psychiatry in Los Angeles. He also is a visiting faculty member in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Dr. Tofler has no conflicts of interest.
The COVID-19 pandemic has, like it or not, made experimental labs rats out of us all.
Since the U.S. “shutdown” began in March, we have all had to adjust to a situation in which we are home more, stuck seeing less of our friends, exercising less, often eating and drinking more, or using recreational substances more – in part because of the severe stress. We have been ripped away from many of the social “anchors” of our weeks; that is, the spiritual, social and physical, and tactile supports that sustain and motivate us in our lives.
And yet, many of us, of all ages, stripes, and colors are thriving. Why is that so? Without necessarily being fully fledged, card carrying misanthropes, many of us are actually not bereft when forced to spend some alone time.
We may be self-starters and have hobbies and interests that we may have neglected but can fall back on with alacrity. Activities such as gardening, cooking, reading, working at our day jobs, listening to music, streaming TV, and so on are now more available to us.
The pandemic has produced unforeseen side effects, such as decreased pollution, less seismic “noise” on our planet, increasingly bold activity by wild life, and we can actually hear bird songs in our yards. Likewise, the social isolation has enabled us to focus more on “back burner” projects and to motivate us toward accessing and achieving other internally driven goals.
Also, to many, it has provided a surprising and unexpected privilege to meaningfully connect while in close quarters with spouses, children, and other loved ones, which has improved and cemented relationships under some level of duress, perhaps.
Similarly, and perhaps surprisingly, in addition to the above reasons, many of our patients with chronic mental illness may be functioning reasonably well, too, even better than their “walking wounded” loved ones and peers. They may be reaping the rewards of many years of consistent biopsychosocial support in strong mental health programs.
But another reason might be the lowered expectations. I’m just so much more relaxed; I’ve got this.” And certainly the Freudian “schadenfreude” defense has something to do with this as well. Seeing family members lose their jobs, become financially vulnerable, being unable to or stymied from demonstrating mastery in many different situations and skill sets elicit the empathy and galvanizes the support of well-managed patients with mental illness – already used to existential threats – for their generally higher functioning loved ones.
As one of my struggling patients said, “Welcome to my world!” Years of hardship, lack of intimate relationships because of social anxiety, and psychotic level obsessive-compulsive disorder have trained, indeed, inured her to the daily pain, constriction, and misery of social isolation. Her life, despite working full time, has remained static, while younger siblings have married, started a family, moved away. She is still living at home with her elderly parents. They now worry about catching COVID-19, while she is now their protector with roles reversed, doing their shopping, and providing moral support and encouragement for the whole family.
Many of us have lost jobs, been furloughed, seen our dreams disappear, and are unable to pay rent or mortgages. Those with chronic mental illness, especially those living in states with a strong social safety net, are continuing to receive their Social Security disability checks, and maintain their in-home health and family supports. They also have continued their adherence with the mental health system structure by continuing with telemedicine therapy and regular medications or monthly intramuscular shots. Their families are especially cognizant of the need for ongoing structure and stability, which is now easier to provide. And what of those patients who endured severe anxiety and panic disorders in their prepandemic states? It is true that many do require higher doses of their anxiolytics, especially benzodiazepines. They do know how to “roll with the punches” with their lifetime experience, as opposed to the “newbies” whose incipient anxiety is brought to the forefront and who might not even recognize these debilitating symptoms and are not keen, for reasons of stigma, to be seen by a mental health expert unless compelled to.
It is up to us as psychiatrists and other mental health clinicians to minimize dependence on those medications by using alternative non–dependence-forming anxiolytics and encouraging our patients to hone and develop the skills from cognitive-behavioral therapy. COVID-19 is just one more stressor, superimposed on many others, and unlikely to precipitate any “tipping point” in functioning, even if there are significant losses among loved ones to the virus.
How about our child and adolescent patients? As a rule of thumb, those with anxiety disorders, social anxiety, selective mutism – and those experiencing challenges and bullying in the rough and tumble world of schools – are doing significantly better. Those with ADHD and impulse control disorders, however, might be struggling with school, especially with Zoom calls and very high distractibility, boredom, and motivational challenges. They may need their doses of medications adjusted up, and their parents are struggling. The risk for unwitnessed and unmonitored abuse in home situations is higher.
Those with chronic mental illness often do have increased risk factors for COVID-19 that might be compounded by their psychopharmacologic treatment for conditions/behaviors such as diabetes, obesity, cardiovascular disease, and substance use. By proactively monitoring those comorbid disorders in a multimodal treatment program, we can help mitigate those baseline challenges.
This aspect of the COVID-19 pandemic is, alas, likely to prove to be an illusory positive “blip” on the radar screen for many with chronic mental illness. Nevertheless, the self-knowledge and awareness of hidden strengths rather than weakness, resilience rather than shrinking from challenges, is not insignificant. This “flight into normality” may be a change that can be internalized and nurtured once vaccines are available and life on planet Earth returns to a new normal.
Dr. Tofler is affiliated with Kaiser Permanente Psychiatry in Los Angeles. He also is a visiting faculty member in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Dr. Tofler has no conflicts of interest.
The COVID-19 pandemic has, like it or not, made experimental labs rats out of us all.
Since the U.S. “shutdown” began in March, we have all had to adjust to a situation in which we are home more, stuck seeing less of our friends, exercising less, often eating and drinking more, or using recreational substances more – in part because of the severe stress. We have been ripped away from many of the social “anchors” of our weeks; that is, the spiritual, social and physical, and tactile supports that sustain and motivate us in our lives.
And yet, many of us, of all ages, stripes, and colors are thriving. Why is that so? Without necessarily being fully fledged, card carrying misanthropes, many of us are actually not bereft when forced to spend some alone time.
We may be self-starters and have hobbies and interests that we may have neglected but can fall back on with alacrity. Activities such as gardening, cooking, reading, working at our day jobs, listening to music, streaming TV, and so on are now more available to us.
The pandemic has produced unforeseen side effects, such as decreased pollution, less seismic “noise” on our planet, increasingly bold activity by wild life, and we can actually hear bird songs in our yards. Likewise, the social isolation has enabled us to focus more on “back burner” projects and to motivate us toward accessing and achieving other internally driven goals.
Also, to many, it has provided a surprising and unexpected privilege to meaningfully connect while in close quarters with spouses, children, and other loved ones, which has improved and cemented relationships under some level of duress, perhaps.
Similarly, and perhaps surprisingly, in addition to the above reasons, many of our patients with chronic mental illness may be functioning reasonably well, too, even better than their “walking wounded” loved ones and peers. They may be reaping the rewards of many years of consistent biopsychosocial support in strong mental health programs.
But another reason might be the lowered expectations. I’m just so much more relaxed; I’ve got this.” And certainly the Freudian “schadenfreude” defense has something to do with this as well. Seeing family members lose their jobs, become financially vulnerable, being unable to or stymied from demonstrating mastery in many different situations and skill sets elicit the empathy and galvanizes the support of well-managed patients with mental illness – already used to existential threats – for their generally higher functioning loved ones.
As one of my struggling patients said, “Welcome to my world!” Years of hardship, lack of intimate relationships because of social anxiety, and psychotic level obsessive-compulsive disorder have trained, indeed, inured her to the daily pain, constriction, and misery of social isolation. Her life, despite working full time, has remained static, while younger siblings have married, started a family, moved away. She is still living at home with her elderly parents. They now worry about catching COVID-19, while she is now their protector with roles reversed, doing their shopping, and providing moral support and encouragement for the whole family.
Many of us have lost jobs, been furloughed, seen our dreams disappear, and are unable to pay rent or mortgages. Those with chronic mental illness, especially those living in states with a strong social safety net, are continuing to receive their Social Security disability checks, and maintain their in-home health and family supports. They also have continued their adherence with the mental health system structure by continuing with telemedicine therapy and regular medications or monthly intramuscular shots. Their families are especially cognizant of the need for ongoing structure and stability, which is now easier to provide. And what of those patients who endured severe anxiety and panic disorders in their prepandemic states? It is true that many do require higher doses of their anxiolytics, especially benzodiazepines. They do know how to “roll with the punches” with their lifetime experience, as opposed to the “newbies” whose incipient anxiety is brought to the forefront and who might not even recognize these debilitating symptoms and are not keen, for reasons of stigma, to be seen by a mental health expert unless compelled to.
It is up to us as psychiatrists and other mental health clinicians to minimize dependence on those medications by using alternative non–dependence-forming anxiolytics and encouraging our patients to hone and develop the skills from cognitive-behavioral therapy. COVID-19 is just one more stressor, superimposed on many others, and unlikely to precipitate any “tipping point” in functioning, even if there are significant losses among loved ones to the virus.
How about our child and adolescent patients? As a rule of thumb, those with anxiety disorders, social anxiety, selective mutism – and those experiencing challenges and bullying in the rough and tumble world of schools – are doing significantly better. Those with ADHD and impulse control disorders, however, might be struggling with school, especially with Zoom calls and very high distractibility, boredom, and motivational challenges. They may need their doses of medications adjusted up, and their parents are struggling. The risk for unwitnessed and unmonitored abuse in home situations is higher.
Those with chronic mental illness often do have increased risk factors for COVID-19 that might be compounded by their psychopharmacologic treatment for conditions/behaviors such as diabetes, obesity, cardiovascular disease, and substance use. By proactively monitoring those comorbid disorders in a multimodal treatment program, we can help mitigate those baseline challenges.
This aspect of the COVID-19 pandemic is, alas, likely to prove to be an illusory positive “blip” on the radar screen for many with chronic mental illness. Nevertheless, the self-knowledge and awareness of hidden strengths rather than weakness, resilience rather than shrinking from challenges, is not insignificant. This “flight into normality” may be a change that can be internalized and nurtured once vaccines are available and life on planet Earth returns to a new normal.
Dr. Tofler is affiliated with Kaiser Permanente Psychiatry in Los Angeles. He also is a visiting faculty member in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Dr. Tofler has no conflicts of interest.
Antihistamines synergistically induce CLL cell death with TK inhibitors
Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.
In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.
Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.
Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.
Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
Effective synergy
The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.
Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.
“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.
The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.
SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.
Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.
In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.
Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.
Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.
Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
Effective synergy
The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.
Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.
“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.
The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.
SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.
Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.
In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.
Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.
Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.
Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
Effective synergy
The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.
Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.
“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.
The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.
SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.
FROM LEUKEMIA RESEARCH
Being a pediatric hospitalist during the COVID-19 pandemic
“Times of great calamity and confusion have been productive for the greatest minds. The purest ore is produced from the hottest furnace. The brightest thunderbolt is elicited from the darkest storm.” – Charles Caleb Colton
I walk inside the pediatric unit of our hospital, only to be welcomed by an eerie silence. There are a handful of nurses at the nursing station, faces covered with masks sitting 6 feet apart and quietly working on their computers. The resident work lounge also depicts a similar picture of emptiness. Just over a month ago, these halls were bustling with children, parents, consultants, and a host of ancillary staff. I recall times in which I was running around from one patient room to another talking to families and attending to patient needs. For the past 2 months I have often spent hours alone in my office waiting to see a patient. This is the new norm for many of us.
Across the board in hospitals, pediatric census has dropped since the start of the COVID-19 pandemic. Reasons for these are nonspecific but may include fear among parents of “exposure” to the virus by bringing their sick children to the hospital to get evaluated for other concerns. A few patients that we have seen in our hospital are sicker when they have arrived because their parents avoided seeking medical care earlier, plagued by the same fear. Social distancing and school closure have also limited the amount of infectious diseases going around, which are responsible for a bulk of pediatric admissions.
While many of us are still coming in to see the limited number of patients we have, we are not in the true sense frontline providers during this pandemic. There have been limited cases of COVID-19 in children, most of which – fortunately – present with mild symptoms. Although multisystem inflammatory syndrome in children (MIS-C) is a new disease that COVID-19 has brought us closer to, many of us have yet to see our first case because of its rarity.
I have read through the news daily in the past few months to find many adult provider physicians succumbing to COVID-19 and felt a pang of guilt. My social media is full of heartbreaking stories as adult hospitalists are having difficult conversations with families and supporting them through this unknown territory, often sacrificing their own safety. I feel so proud of them and my profession. My heart tells me, though, I personally may not be living up to the true calling I was expected to have as a physician.
As pediatric hospitalists, while we sit and wait for this pandemic to pass, we have been ruminating on and anxious about our future. As census drops, there is a financial strain that many of us are feeling. Job cuts and furloughing of health care workers in our surroundings leave us with a sense of insecurity and low morale. Many small inpatient pediatric units have had to be shut down temporarily either so they could be used for adult patients or because of lack of pediatric patients. Limiting staffing to avoid exposure and cohorting providers has also been a challenge.
A big question that has risen in these times is how to ensure productivity and stay useful while at the same time being prepared for the unknown that lies ahead. The economics of medicine is staring hard at our years of hard work, questioning the need for our specialty in the first place.
In smaller community settings, the closure of pediatric units has put an additional strain on the overall framework of the community, parents, and referring primary care providers. With the absence of local resources, children who have needed care have had to be transferred to bigger referral centers that are still taking care of pediatric patients. On one end of the spectrum there is concern for pediatric inpatient units not being productive enough for the hospital, but that coexists with a worry that, as we pass through this pandemic, we could see more hospitalizations for vaccine-preventable illnesses, child abuse/medical neglect, and respiratory syncytial virus plus COVID.
The question remains about how best to cope and use this time of uncertainty to be productive and prepare for the worst. A few solutions and suggestions are highlighted below.
- Helping adult providers: Many pediatric hospitalist colleagues in highly affected states have filled the increasing need for clinicians and taken care of adult patients. As pediatric units have closed, providers have continued to offer care where it is needed. Pediatric hospitalists have used this time to take urgent refresher courses in advanced cardiac life support and adult critical care. In states that are not as severely hit, many pediatric hospitalists have utilized this time to plan and prepare protocols for the future as information continues coming in regarding MIS-C and COVID-19 in pediatric patients.
- Use of telemedicine: With the ease in restrictions for use of telemedicine in many states, pediatric hospitalists can consider using it to restructure their staffing model whenever feasible. This can help in cohorting and allowing high risk and quarantined providers to work from home. This model simultaneously provides opportunities for pediatric hospitalists to continue providing their services, while at the same time decreasing financial burden on their institution.
- Reaching out to the community: Engaging with the community during these times can help ensure services and options remain available to our referral providers and patients for pediatric services. Information about COVID-19 can be widely disseminated. We can also play our part by continuing to encourage parents in our maximum capacity to obtain care for their children when needed and to not avoid the hospital because of fears of exposure.
- Supporting each other: There is no doubt that these times are unsettling for the pediatric hospitalist community, and the uncertainty that surrounds us can feel crippling. Strong team building is imperative in these times. While we may not be frequently meeting in work lounges and sharing meals, a good sense of support and camaraderie will go a long way in building morale for the future. Seeking mental health resources if needed is essential for us and should not be looked at with shame or guilt. This is something that many of us have never seen before, and it is okay to ask for help. Seeking help is and always will be a sign of strength.
Today, as I envision myself walking in the hospital on the other side of this pandemic I see a cheerful pediatric unit, smiling faces without masks, my 3-year-old patient cruising around the hallways in a toy car, our therapy dog walking around bringing joy to many, and many healthy patients feeling better and ready to go home. A time when we are not scared to hug each other, shake hands, or share emotion. When our teams are stronger and more well bonded. A time when parents are not scared to bring their sick children to the hospital. Will it be many months before this happens? I don’t know. But I do know that the children I take care of are known for their resilience. I will live up to them today by practicing the same.
Dr. Fatima is a pediatric hospitalist at Wesley Children’s Hospital and assistant professor of pediatrics at Kansas University School of Medicine, both in Wichita. Her research interests include medical errors, medical education, and high-value care.
“Times of great calamity and confusion have been productive for the greatest minds. The purest ore is produced from the hottest furnace. The brightest thunderbolt is elicited from the darkest storm.” – Charles Caleb Colton
I walk inside the pediatric unit of our hospital, only to be welcomed by an eerie silence. There are a handful of nurses at the nursing station, faces covered with masks sitting 6 feet apart and quietly working on their computers. The resident work lounge also depicts a similar picture of emptiness. Just over a month ago, these halls were bustling with children, parents, consultants, and a host of ancillary staff. I recall times in which I was running around from one patient room to another talking to families and attending to patient needs. For the past 2 months I have often spent hours alone in my office waiting to see a patient. This is the new norm for many of us.
Across the board in hospitals, pediatric census has dropped since the start of the COVID-19 pandemic. Reasons for these are nonspecific but may include fear among parents of “exposure” to the virus by bringing their sick children to the hospital to get evaluated for other concerns. A few patients that we have seen in our hospital are sicker when they have arrived because their parents avoided seeking medical care earlier, plagued by the same fear. Social distancing and school closure have also limited the amount of infectious diseases going around, which are responsible for a bulk of pediatric admissions.
While many of us are still coming in to see the limited number of patients we have, we are not in the true sense frontline providers during this pandemic. There have been limited cases of COVID-19 in children, most of which – fortunately – present with mild symptoms. Although multisystem inflammatory syndrome in children (MIS-C) is a new disease that COVID-19 has brought us closer to, many of us have yet to see our first case because of its rarity.
I have read through the news daily in the past few months to find many adult provider physicians succumbing to COVID-19 and felt a pang of guilt. My social media is full of heartbreaking stories as adult hospitalists are having difficult conversations with families and supporting them through this unknown territory, often sacrificing their own safety. I feel so proud of them and my profession. My heart tells me, though, I personally may not be living up to the true calling I was expected to have as a physician.
As pediatric hospitalists, while we sit and wait for this pandemic to pass, we have been ruminating on and anxious about our future. As census drops, there is a financial strain that many of us are feeling. Job cuts and furloughing of health care workers in our surroundings leave us with a sense of insecurity and low morale. Many small inpatient pediatric units have had to be shut down temporarily either so they could be used for adult patients or because of lack of pediatric patients. Limiting staffing to avoid exposure and cohorting providers has also been a challenge.
A big question that has risen in these times is how to ensure productivity and stay useful while at the same time being prepared for the unknown that lies ahead. The economics of medicine is staring hard at our years of hard work, questioning the need for our specialty in the first place.
In smaller community settings, the closure of pediatric units has put an additional strain on the overall framework of the community, parents, and referring primary care providers. With the absence of local resources, children who have needed care have had to be transferred to bigger referral centers that are still taking care of pediatric patients. On one end of the spectrum there is concern for pediatric inpatient units not being productive enough for the hospital, but that coexists with a worry that, as we pass through this pandemic, we could see more hospitalizations for vaccine-preventable illnesses, child abuse/medical neglect, and respiratory syncytial virus plus COVID.
The question remains about how best to cope and use this time of uncertainty to be productive and prepare for the worst. A few solutions and suggestions are highlighted below.
- Helping adult providers: Many pediatric hospitalist colleagues in highly affected states have filled the increasing need for clinicians and taken care of adult patients. As pediatric units have closed, providers have continued to offer care where it is needed. Pediatric hospitalists have used this time to take urgent refresher courses in advanced cardiac life support and adult critical care. In states that are not as severely hit, many pediatric hospitalists have utilized this time to plan and prepare protocols for the future as information continues coming in regarding MIS-C and COVID-19 in pediatric patients.
- Use of telemedicine: With the ease in restrictions for use of telemedicine in many states, pediatric hospitalists can consider using it to restructure their staffing model whenever feasible. This can help in cohorting and allowing high risk and quarantined providers to work from home. This model simultaneously provides opportunities for pediatric hospitalists to continue providing their services, while at the same time decreasing financial burden on their institution.
- Reaching out to the community: Engaging with the community during these times can help ensure services and options remain available to our referral providers and patients for pediatric services. Information about COVID-19 can be widely disseminated. We can also play our part by continuing to encourage parents in our maximum capacity to obtain care for their children when needed and to not avoid the hospital because of fears of exposure.
- Supporting each other: There is no doubt that these times are unsettling for the pediatric hospitalist community, and the uncertainty that surrounds us can feel crippling. Strong team building is imperative in these times. While we may not be frequently meeting in work lounges and sharing meals, a good sense of support and camaraderie will go a long way in building morale for the future. Seeking mental health resources if needed is essential for us and should not be looked at with shame or guilt. This is something that many of us have never seen before, and it is okay to ask for help. Seeking help is and always will be a sign of strength.
Today, as I envision myself walking in the hospital on the other side of this pandemic I see a cheerful pediatric unit, smiling faces without masks, my 3-year-old patient cruising around the hallways in a toy car, our therapy dog walking around bringing joy to many, and many healthy patients feeling better and ready to go home. A time when we are not scared to hug each other, shake hands, or share emotion. When our teams are stronger and more well bonded. A time when parents are not scared to bring their sick children to the hospital. Will it be many months before this happens? I don’t know. But I do know that the children I take care of are known for their resilience. I will live up to them today by practicing the same.
Dr. Fatima is a pediatric hospitalist at Wesley Children’s Hospital and assistant professor of pediatrics at Kansas University School of Medicine, both in Wichita. Her research interests include medical errors, medical education, and high-value care.
“Times of great calamity and confusion have been productive for the greatest minds. The purest ore is produced from the hottest furnace. The brightest thunderbolt is elicited from the darkest storm.” – Charles Caleb Colton
I walk inside the pediatric unit of our hospital, only to be welcomed by an eerie silence. There are a handful of nurses at the nursing station, faces covered with masks sitting 6 feet apart and quietly working on their computers. The resident work lounge also depicts a similar picture of emptiness. Just over a month ago, these halls were bustling with children, parents, consultants, and a host of ancillary staff. I recall times in which I was running around from one patient room to another talking to families and attending to patient needs. For the past 2 months I have often spent hours alone in my office waiting to see a patient. This is the new norm for many of us.
Across the board in hospitals, pediatric census has dropped since the start of the COVID-19 pandemic. Reasons for these are nonspecific but may include fear among parents of “exposure” to the virus by bringing their sick children to the hospital to get evaluated for other concerns. A few patients that we have seen in our hospital are sicker when they have arrived because their parents avoided seeking medical care earlier, plagued by the same fear. Social distancing and school closure have also limited the amount of infectious diseases going around, which are responsible for a bulk of pediatric admissions.
While many of us are still coming in to see the limited number of patients we have, we are not in the true sense frontline providers during this pandemic. There have been limited cases of COVID-19 in children, most of which – fortunately – present with mild symptoms. Although multisystem inflammatory syndrome in children (MIS-C) is a new disease that COVID-19 has brought us closer to, many of us have yet to see our first case because of its rarity.
I have read through the news daily in the past few months to find many adult provider physicians succumbing to COVID-19 and felt a pang of guilt. My social media is full of heartbreaking stories as adult hospitalists are having difficult conversations with families and supporting them through this unknown territory, often sacrificing their own safety. I feel so proud of them and my profession. My heart tells me, though, I personally may not be living up to the true calling I was expected to have as a physician.
As pediatric hospitalists, while we sit and wait for this pandemic to pass, we have been ruminating on and anxious about our future. As census drops, there is a financial strain that many of us are feeling. Job cuts and furloughing of health care workers in our surroundings leave us with a sense of insecurity and low morale. Many small inpatient pediatric units have had to be shut down temporarily either so they could be used for adult patients or because of lack of pediatric patients. Limiting staffing to avoid exposure and cohorting providers has also been a challenge.
A big question that has risen in these times is how to ensure productivity and stay useful while at the same time being prepared for the unknown that lies ahead. The economics of medicine is staring hard at our years of hard work, questioning the need for our specialty in the first place.
In smaller community settings, the closure of pediatric units has put an additional strain on the overall framework of the community, parents, and referring primary care providers. With the absence of local resources, children who have needed care have had to be transferred to bigger referral centers that are still taking care of pediatric patients. On one end of the spectrum there is concern for pediatric inpatient units not being productive enough for the hospital, but that coexists with a worry that, as we pass through this pandemic, we could see more hospitalizations for vaccine-preventable illnesses, child abuse/medical neglect, and respiratory syncytial virus plus COVID.
The question remains about how best to cope and use this time of uncertainty to be productive and prepare for the worst. A few solutions and suggestions are highlighted below.
- Helping adult providers: Many pediatric hospitalist colleagues in highly affected states have filled the increasing need for clinicians and taken care of adult patients. As pediatric units have closed, providers have continued to offer care where it is needed. Pediatric hospitalists have used this time to take urgent refresher courses in advanced cardiac life support and adult critical care. In states that are not as severely hit, many pediatric hospitalists have utilized this time to plan and prepare protocols for the future as information continues coming in regarding MIS-C and COVID-19 in pediatric patients.
- Use of telemedicine: With the ease in restrictions for use of telemedicine in many states, pediatric hospitalists can consider using it to restructure their staffing model whenever feasible. This can help in cohorting and allowing high risk and quarantined providers to work from home. This model simultaneously provides opportunities for pediatric hospitalists to continue providing their services, while at the same time decreasing financial burden on their institution.
- Reaching out to the community: Engaging with the community during these times can help ensure services and options remain available to our referral providers and patients for pediatric services. Information about COVID-19 can be widely disseminated. We can also play our part by continuing to encourage parents in our maximum capacity to obtain care for their children when needed and to not avoid the hospital because of fears of exposure.
- Supporting each other: There is no doubt that these times are unsettling for the pediatric hospitalist community, and the uncertainty that surrounds us can feel crippling. Strong team building is imperative in these times. While we may not be frequently meeting in work lounges and sharing meals, a good sense of support and camaraderie will go a long way in building morale for the future. Seeking mental health resources if needed is essential for us and should not be looked at with shame or guilt. This is something that many of us have never seen before, and it is okay to ask for help. Seeking help is and always will be a sign of strength.
Today, as I envision myself walking in the hospital on the other side of this pandemic I see a cheerful pediatric unit, smiling faces without masks, my 3-year-old patient cruising around the hallways in a toy car, our therapy dog walking around bringing joy to many, and many healthy patients feeling better and ready to go home. A time when we are not scared to hug each other, shake hands, or share emotion. When our teams are stronger and more well bonded. A time when parents are not scared to bring their sick children to the hospital. Will it be many months before this happens? I don’t know. But I do know that the children I take care of are known for their resilience. I will live up to them today by practicing the same.
Dr. Fatima is a pediatric hospitalist at Wesley Children’s Hospital and assistant professor of pediatrics at Kansas University School of Medicine, both in Wichita. Her research interests include medical errors, medical education, and high-value care.
ESC 2020 looks to make its mark in ‘new era’ of virtual meetings
The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”
“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.
Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.
The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.
Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.
To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.
Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.
“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”
Hot Line Sessions 1-3, Saturday (14:00 CEST)
The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.
Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).
Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.
As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”
Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.
Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.
“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.
Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.
Hot Line Sessions 4-6, Sunday (14:00 CEST)
Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.
Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).
“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”
Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.
Hot Line Sessions 7-9, Monday (14:00 CEST)
The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.
Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.
Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.
Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.
Tuesday Hot Line Sessions 10-12 (14:00 CEST)
The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.
Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.
“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.
COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.
Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
This article first appeared on Medscape.com.
The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”
“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.
Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.
The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.
Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.
To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.
Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.
“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”
Hot Line Sessions 1-3, Saturday (14:00 CEST)
The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.
Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).
Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.
As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”
Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.
Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.
“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.
Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.
Hot Line Sessions 4-6, Sunday (14:00 CEST)
Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.
Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).
“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”
Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.
Hot Line Sessions 7-9, Monday (14:00 CEST)
The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.
Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.
Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.
Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.
Tuesday Hot Line Sessions 10-12 (14:00 CEST)
The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.
Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.
“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.
COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.
Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
This article first appeared on Medscape.com.
The coronavirus may have quashed plans to socialize and stroll the canals of Amsterdam while at this year’s European Society of Cardiology (ESC) Congress, but organizers are promising a historic digital experience that will “once again, be a celebration of discovery and ground-breaking science.”
“My message — if I have to choose only one thing why ESC 2020 will be a historic event — is that the physician working at the Cleveland Clinic, who was planning to attend this year in Amsterdam, as well as the colleague in a bush hospital in Uganda, who would have never have dreamed to be part of the ESC Congress, both will have for the first time the same access at the same time to knowledge shared at the worldwide leading cardiovascular meeting,” Marco Roffi, MD, co-chair of the scientific program, told theheart.org | Medscape Cardiology.
Taking a page from the American College of Cardiology, which set the virtual bar early in the pandemic with its highly interactive ACC 2020, ESC is taking some 80 Hot Line, clinical practice guidelines, and special sessions live with question-and-answer interactions and panel discussions.
The latest COVID-19 research and four new guideline documents — including recommendations on atrial fibrillation (AF), non-ST-segment elevation acute coronary syndromes, sports cardiology and exercise in patients with cardiovascular disease, and adult congenital heart disease — will be featured at the ESC Congress 2020, scheduled for August 29 to September 1.
Presentations will be shorter and sessions more focused, but more than 500 scientific and educational sessions will be streamed in addition to more than 4000 abstracts available live or on demand as full presentations or e-posters, said Roffi, University Hospital of Geneva, Switzerland.
To pull off the virtual event, a digital studio in Amsterdam will host hundreds of key opinion leaders, and ESC employed more than 1000 satellite studios around the world to gather contributions from scientists and experts with the help of 70 behind-the-scenes experts.
Nevertheless, a “strategic decision” was made to provide free access to the event and its content for 30 days — a strategy that has attracted some 58,000 registrants thus far, up from a record 32,000 attendees at last year’s congress in Paris, Roffi said.
“Obviously, the income will not be the same as a physical congress, but we felt there was too much at stake to make a compromise,” he said. “We believe we are the leaders in cardiovascular meetings in the physical ones and we want to keep this position even in the new era. And we believe this is the beginning of a new era in whatever form will be.”
Hot Line Sessions 1-3, Saturday (14:00 CEST)
The Hot Line sessions will feature 13 clinical trials and kick off with EMPEROR-Reduced, which compared the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) added to standard care in patients with heart failure with reduced ejection fraction (HFrEF), with and without diabetes.
Eli Lilly and Boehringer Ingelheim already announced the trial met its composite primary endpoint of reducing cardiovascular (CV) death or HF hospitalization risk but the details will be important given the SGLT2 inhibitors› rapid shift beyond diabetes to HF and chronic kidney disease (CKD).
Results presented at ESC 2019 from the landmark DAPA-HF trial led to the recent new indication for dapagliflozin (Farxiga, AstraZeneca) for HFrEF in the absence of diabetes. New data will be released in a Sunday Hot Line session looking at the SGLT2 inhibitor among diabetic and nondiabetic CKD patients in DAPA-CKD, which was halted early because of overwhelming efficacy.
As the indication evolved, the SGLT2 inhibitors became truly cardiovascular disease drugs, Roffi said, “so all the cardiologists will have to become familiar with these agents.”
Hot Line 2 will look at the oral cardiac myosin inhibitor mavacamten as an alternative to surgery or percutaneous interventions to treat obstructive hypertrophic cardiomyopathy (HCM). The first-in-class investigational agent is thought to reduce the hypercontractility characteristic of HCM by inhibiting excessive actin-myosin cross-bridges, and it showed promise in the recent phase 2 dose-finding MAVERICK HCM trial.
Investigators are expected to flesh out details from the 251-patient phase 3 EXPLORER-HCM trial, which reported functional and symptomatic gains with once-daily dosing in top-line results released by developer MyoKardia.
“This is really a revolutionary way to treat — hopefully successfully — this very complex disease,” Roffi said.
Rounding out the day is the EAST-AFNET 4 trial, which has been almost 10 years in the making and examined whether early rhythm control with antiarrhythmic drugs and catheter ablation can prevent adverse outcomes in patients with AF compared with usual care alone based on the ESC 2010 AF treatment guidelines.
Hot Line Sessions 4-6, Sunday (14:00 CEST)
Hot Line 4 features the ATPCI study examining the addition of the oral antianginal agent trimetazidine to standard of care in 6007 patients with angina after recent successful percutaneous coronary intervention.
Next up is POPULAR-TAVI looking at aspirin with or without clopidogrel in patients undergoing transcatheter aortic valve implantation (TAVI).
“This is a dilemma that we have every day in the cath lab when we perform a TAVI because we have in front of us patients who, by definition, are at high bleeding risk, are old, and have comorbidities such as renal insufficiencies,” Roffi said. “I like this very much because it’s a very practical study. Whatever the response will be of this study, it will impact clinical practice.”
Hot Line 6 is devoted to the PARALLAX trial comparing sacubitril/valsartan (Entresto, Novartis) with individualized medical therapy in 2569 heart failure with preserved ejection fraction (HFpEF) patients. The primary outcomes are 12-week change in N-terminal pro-brain natriuretic peptide and 24-week change in 6-minute walk distance.
Hot Line Sessions 7-9, Monday (14:00 CEST)
The next day starts with the timely topic of inflammation with the LoDoCo2 trial, in which 5522 patients with stable coronary artery disease were randomized to low-dose colchicine 0.5 mg daily or placebo on top of optimal medical therapy. The primary composite endpoint is CV death, myocardial infarction (MI), ischemic stroke, and ischemia-driven revascularization.
Additional colchicine data also will be presented in a late-breaking science session on Saturday that includes the Australian COPS trial in acute coronary syndromes and new analyses from COLCOT, which demonstrated a 23% reduction in the risk of first ischemic CV events following an MI but no mortality benefit. The low-cost anti-inflammatory drug is also being tested in the mammoth 6000-patient phase 3 Colchicine Coronavirus SARS-CoV-2 (COLCORONA) trial, expected to be completed by the end of September.
Hot Line 8 switches gears with the open-label randomized HOME-PE trial comparing outpatient management of pulmonary embolism (PE) in 1975 select patients based on either the simplified Pulmonary Embolism Severity Index (PESI) score, featured in the most recent ESC acute PE guidelines, or the HESTIA criteria, developed in the HESTIA study. The event-driven primary end point is the composite of recurrent venous thromboembolism, major bleeding, and all-cause death at 30 days.
Last up on Monday is a new analysis on the effects of lowering blood pressure for prevention of CV events across various BP levels from the BPLTTC, which is the largest resource of patient-level randomized clinical trial data, at more than 350,000 patients.
Tuesday Hot Line Sessions 10-12 (14:00 CEST)
The final day of the Congress ends with bang, with the randomized BRACE-CORONA trial examining the effect of continuing or suspending angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in 700 patients with SARS-CoV-2 infection.
Although several cardiovascular societies including ESC recommend continuation of renin-angiotensin-aldosterone system (RAAS) antagonists in COVID-19 patients, randomized data are lacking and patients have been rattled by early observations suggesting that ACE2 upregulation from RAAS antagonists could increase the risk of developing severe COVID-19.
“BRACE-CORONA will answer the question that everybody’s been asking, whether or not you should continue ARBs and ACE inhibitors in COVID-19 patients. This is a randomized trial and we are all very excited about it,” Roffi said.
COVID-19 will also be discussed in a late-breaking science session on Sunday and in three industry Q&A sessions scattered over the 4 days.
Rounding out the last Hot Line session is IMPACT-AFib, a claims database analysis of early vs delayed educational interventions to improve oral anticoagulation use in a whopping 80,000 patients with AF, and REALITY, a much-needed cost-effectiveness analysis of liberal vs restrictive transfusion strategies in 630 patients with acute MI and anemia.
This article first appeared on Medscape.com.