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Patient, heal thyself!
Octavio has prostate cancer. His prostate growth is large but localized.
“What do your doctors suggest?” I asked him.
“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”
“How will you decide?”
“I’ll do some reading,” he said.
“What about the doctor who sent you to them?”
“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”
Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:
. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.
This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:
1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”
2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”
Is “trying to influence” the same as making the decision for the patient?
Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.
Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?
You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.
Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?
Octavio chose surgery. I asked him how he decided.
“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”
Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.
You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.
“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”
Did I influence her health care decision? Sure. Guilty as charged, with no apologies. When I am a patient, I want nothing less for myself: sympathetic, experienced guidance, shared by someone who knows me and appears to care one way or the other how I do.
Lord preserve us, doctors and patients both, from dogmatists who would demand otherwise.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].
Octavio has prostate cancer. His prostate growth is large but localized.
“What do your doctors suggest?” I asked him.
“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”
“How will you decide?”
“I’ll do some reading,” he said.
“What about the doctor who sent you to them?”
“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”
Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:
. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.
This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:
1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”
2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”
Is “trying to influence” the same as making the decision for the patient?
Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.
Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?
You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.
Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?
Octavio chose surgery. I asked him how he decided.
“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”
Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.
You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.
“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”
Did I influence her health care decision? Sure. Guilty as charged, with no apologies. When I am a patient, I want nothing less for myself: sympathetic, experienced guidance, shared by someone who knows me and appears to care one way or the other how I do.
Lord preserve us, doctors and patients both, from dogmatists who would demand otherwise.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].
Octavio has prostate cancer. His prostate growth is large but localized.
“What do your doctors suggest?” I asked him.
“They sent me to two specialists at the medical center,” he said. “One does robotic surgery, the other does radiation. Each one told me why they recommend their technique.”
“How will you decide?”
“I’ll do some reading,” he said.
“What about the doctor who sent you to them?”
“He hasn’t discussed the choice with me, just sent me to get opinions. I have to make up own mind.”
Out of training for some time, I gather from students and family medical interactions that patient autonomy is now a reigning principle. Here is one definition:
. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.
This sounds sensible, even admirable: no more paternalistic physicians talking down to patients and ordering them around. Yet a closer look shows a contradiction:
1. The second sentence says that patient autonomy “does not allow the health care provider to make the decision for the patient.”
2. But the first one says that patients should decide, “without their health care provider trying to influence the decision.”
Is “trying to influence” the same as making the decision for the patient?
Some would argue that it is: The power discrepancy between the parties makes a doctor’s attempt to influence amount to coercion.
Do you agree, esteemed colleagues, those of you who, like me, treat patients all day? If the choice is between freezing an actinic keratosis, burning it, or using topical chemotherapy, do you just lay all three options out there and ask the patient to pick one? What if your patient works in public and doesn’t have 2 weeks to wait while the reaction to topical 5-fluorouracil that makes his skin look like raw lobster subsides? Can you point that out? Or would that be “trying to influence” and thus not allowed?
You and I can think of many other examples, about medical choices large and small, where we could pose similar questions. This is not abstract philosophy; it is what we do all day.
Look up robot-assisted surgery and radiation for prostate cancer. You will find proponents of both, each making claims concerning survival, recurrence, discomfort, complications. Which is more important – a 15% greater chance of living 2 years longer or a 22% lower risk of incontinence? Will reading such statistics make your choice easier? What if other studies show different numbers?
Octavio chose surgery. I asked him how he decided.
“I talked with an internist I know socially,” he said. “He shared his experience with patients he’s referred for my problem and advised surgery as the better choice. I also saw a story online about a lawyer who chose one method, then 5 years later had to do the other.”
Octavio is sophisticated and well read. He lives near Boston, the self-described hub of medical expertise and academic excellence. Yet he makes up his mind the way everybody does: by asking a trusted adviser, by hearing an arresting anecdote. It’s not science. It’s how people think.
You don’t have to be a behavioral psychologist to know how hard it is for patients, especially frightened ones, to interpret statistical variances or compare disparate categories. Which is better – shorter life with less pain or longer life with more? How much less? How much more? There are ways to address such questions, but having an expert, trusted, and sympathetic adviser is a pretty good way to start. Only an abstract ethicist with no practical exposure to (or sympathy with) actual existing patients and their actual existing providers could possibly think otherwise.
“Let’s freeze those actinics off,” I suggest to a patient. “That won’t scar, you won’t need a dozen shots of lidocaine, and you won’t have to hide for 3 weeks.”
Did I influence her health care decision? Sure. Guilty as charged, with no apologies. When I am a patient, I want nothing less for myself: sympathetic, experienced guidance, shared by someone who knows me and appears to care one way or the other how I do.
Lord preserve us, doctors and patients both, from dogmatists who would demand otherwise.
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].
Pediatric pruritus requires distinct approach to assessment and management
WASHINGTON – Suephy C. Chen, MD, said at the annual meeting of the American Academy of Dermatology.
Using special scales to measure itch in children and understanding that quality of life concerns may be different for children should also be kept in mind, said Dr. Chen, professor of dermatology at Emory University, Atlanta. Furthermore, several psychiatric comorbidities that have been associated with pediatric pruritus, such as ADHD and suicidal thoughts. Another consideration is that a child’s pruritus can have significant effects on his or her parents.
Measuring itch is challenging in children, who may have difficulty responding to visual analogue scales, verbal rating scales, and numerical rating scales. Dr. Chen and her colleagues developed the ItchyQuant scale as a self-report measure of itch severity (J Invest Dermatol. 2017 Jan;137[1]:57-61). It is a scale from 0 to 10 with cartoon illustrations depicting increasing itch severity, from no itch to the “worst itch imaginable.” Currently it is validated only in adults, but they are working towards getting it validated in children.
Another itch assessment scale for children, Itch Man, is available, but has only been studied in children who have survived burns.
The ItchyQOL scale measures the extent to which itch affects quality of life in adults. It examines the symptoms associated with itch, as well as its functional and emotional effects. But children’s concerns about quality of life are not the same as those of adults, so Dr. Chen and her colleagues used ItchyQOL as a basis for the “Tween ItchyQOL,” which is intended for children aged 8-17 years, and the “Kids ItchyQOL,” which is intended for children aged 6-7 years. The Tween ItchyQOL includes items (such as being made fun of) that are not in the ItchyQOL and eliminates items (such as working and spending money) that do not apply to children. The Kids ItchyQOL includes cartoons to help children understand the questions.
Dermatologists often use parents as proxies to measure their children’s itch, assuming that the latter’s responses might be unreliable. But when Dr. Chen and her colleagues administered the ItchyQuant to children with pruritus, parents, and their medical providers to evaluate the extent of agreement among assessors, they found that parents’ scores were higher than their children’s scores, although the difference was not significant.
Providers’ scores, however, were significantly lower than those of children and parents. All scores were in the moderate range. Dr. Chen and colleagues also found that, for each 1-point increase in the difference between children’s and parents’ responses, parents were 1.25 times less likely to have experience with chronic pruritus, outside of their children. This finding provides a gauge of how well a parent can serve as a proxy to characterize his or her child’s itch.
Adolescents are in general a troubled group, and caregivers have concerns about suicide in the adolescent population, Dr. Chen said. She referred to a large study of adolescents published in 2012, which indicated that the prevalence of suicidal ideation was 8.4% among adolescents with no itch, compared with 21.1% among adolescents with severe itch (Acta Derm Venereol. 2012 Sep;92[5]:543-6).
In the study, those with severe itch were three times more likely to have suicidal ideation than the general population, which Dr. Chen noted was comparable with that of suicidal ideation in patients with chronic pain in the study (odds ratio, 3.8).
Cross-sectional data suggest a link between itching and ADHD, but “it’s a chicken-and-egg phenomenon,” she said. “If you’re so itchy and squirmy, you’re not going to pay attention. Then again, if you’re not paying attention, maybe you’re that much more prone to scratch.” Longitudinal data indicate that improving itch correlates with improvement in ADHD symptoms.
In addition, pruritus affects the genders disproportionately. Girls report a significantly greater impact on quality of life than boys when itching is severe, with much of the difference in emotional impact, said Dr. Chen. Boys may report more functional impact than girls.
Chronic pruritus also affects parents, who may have disturbed sleep, feel stress about their own parenting, and have difficulty enforcing discipline. “They feel an incredible amount of guilt and blame for giving this to their child,” she commented. “As more and more places develop itch centers, it would be good to have a multidisciplinary approach bringing in mental health providers and social workers, because the impact of itch on parents can be quite profound.”
Dr. Chen reported disclosures with several companies, including BioPharmX, Dermecular Therapeutics, Leo Pharma, and Unilever.
WASHINGTON – Suephy C. Chen, MD, said at the annual meeting of the American Academy of Dermatology.
Using special scales to measure itch in children and understanding that quality of life concerns may be different for children should also be kept in mind, said Dr. Chen, professor of dermatology at Emory University, Atlanta. Furthermore, several psychiatric comorbidities that have been associated with pediatric pruritus, such as ADHD and suicidal thoughts. Another consideration is that a child’s pruritus can have significant effects on his or her parents.
Measuring itch is challenging in children, who may have difficulty responding to visual analogue scales, verbal rating scales, and numerical rating scales. Dr. Chen and her colleagues developed the ItchyQuant scale as a self-report measure of itch severity (J Invest Dermatol. 2017 Jan;137[1]:57-61). It is a scale from 0 to 10 with cartoon illustrations depicting increasing itch severity, from no itch to the “worst itch imaginable.” Currently it is validated only in adults, but they are working towards getting it validated in children.
Another itch assessment scale for children, Itch Man, is available, but has only been studied in children who have survived burns.
The ItchyQOL scale measures the extent to which itch affects quality of life in adults. It examines the symptoms associated with itch, as well as its functional and emotional effects. But children’s concerns about quality of life are not the same as those of adults, so Dr. Chen and her colleagues used ItchyQOL as a basis for the “Tween ItchyQOL,” which is intended for children aged 8-17 years, and the “Kids ItchyQOL,” which is intended for children aged 6-7 years. The Tween ItchyQOL includes items (such as being made fun of) that are not in the ItchyQOL and eliminates items (such as working and spending money) that do not apply to children. The Kids ItchyQOL includes cartoons to help children understand the questions.
Dermatologists often use parents as proxies to measure their children’s itch, assuming that the latter’s responses might be unreliable. But when Dr. Chen and her colleagues administered the ItchyQuant to children with pruritus, parents, and their medical providers to evaluate the extent of agreement among assessors, they found that parents’ scores were higher than their children’s scores, although the difference was not significant.
Providers’ scores, however, were significantly lower than those of children and parents. All scores were in the moderate range. Dr. Chen and colleagues also found that, for each 1-point increase in the difference between children’s and parents’ responses, parents were 1.25 times less likely to have experience with chronic pruritus, outside of their children. This finding provides a gauge of how well a parent can serve as a proxy to characterize his or her child’s itch.
Adolescents are in general a troubled group, and caregivers have concerns about suicide in the adolescent population, Dr. Chen said. She referred to a large study of adolescents published in 2012, which indicated that the prevalence of suicidal ideation was 8.4% among adolescents with no itch, compared with 21.1% among adolescents with severe itch (Acta Derm Venereol. 2012 Sep;92[5]:543-6).
In the study, those with severe itch were three times more likely to have suicidal ideation than the general population, which Dr. Chen noted was comparable with that of suicidal ideation in patients with chronic pain in the study (odds ratio, 3.8).
Cross-sectional data suggest a link between itching and ADHD, but “it’s a chicken-and-egg phenomenon,” she said. “If you’re so itchy and squirmy, you’re not going to pay attention. Then again, if you’re not paying attention, maybe you’re that much more prone to scratch.” Longitudinal data indicate that improving itch correlates with improvement in ADHD symptoms.
In addition, pruritus affects the genders disproportionately. Girls report a significantly greater impact on quality of life than boys when itching is severe, with much of the difference in emotional impact, said Dr. Chen. Boys may report more functional impact than girls.
Chronic pruritus also affects parents, who may have disturbed sleep, feel stress about their own parenting, and have difficulty enforcing discipline. “They feel an incredible amount of guilt and blame for giving this to their child,” she commented. “As more and more places develop itch centers, it would be good to have a multidisciplinary approach bringing in mental health providers and social workers, because the impact of itch on parents can be quite profound.”
Dr. Chen reported disclosures with several companies, including BioPharmX, Dermecular Therapeutics, Leo Pharma, and Unilever.
WASHINGTON – Suephy C. Chen, MD, said at the annual meeting of the American Academy of Dermatology.
Using special scales to measure itch in children and understanding that quality of life concerns may be different for children should also be kept in mind, said Dr. Chen, professor of dermatology at Emory University, Atlanta. Furthermore, several psychiatric comorbidities that have been associated with pediatric pruritus, such as ADHD and suicidal thoughts. Another consideration is that a child’s pruritus can have significant effects on his or her parents.
Measuring itch is challenging in children, who may have difficulty responding to visual analogue scales, verbal rating scales, and numerical rating scales. Dr. Chen and her colleagues developed the ItchyQuant scale as a self-report measure of itch severity (J Invest Dermatol. 2017 Jan;137[1]:57-61). It is a scale from 0 to 10 with cartoon illustrations depicting increasing itch severity, from no itch to the “worst itch imaginable.” Currently it is validated only in adults, but they are working towards getting it validated in children.
Another itch assessment scale for children, Itch Man, is available, but has only been studied in children who have survived burns.
The ItchyQOL scale measures the extent to which itch affects quality of life in adults. It examines the symptoms associated with itch, as well as its functional and emotional effects. But children’s concerns about quality of life are not the same as those of adults, so Dr. Chen and her colleagues used ItchyQOL as a basis for the “Tween ItchyQOL,” which is intended for children aged 8-17 years, and the “Kids ItchyQOL,” which is intended for children aged 6-7 years. The Tween ItchyQOL includes items (such as being made fun of) that are not in the ItchyQOL and eliminates items (such as working and spending money) that do not apply to children. The Kids ItchyQOL includes cartoons to help children understand the questions.
Dermatologists often use parents as proxies to measure their children’s itch, assuming that the latter’s responses might be unreliable. But when Dr. Chen and her colleagues administered the ItchyQuant to children with pruritus, parents, and their medical providers to evaluate the extent of agreement among assessors, they found that parents’ scores were higher than their children’s scores, although the difference was not significant.
Providers’ scores, however, were significantly lower than those of children and parents. All scores were in the moderate range. Dr. Chen and colleagues also found that, for each 1-point increase in the difference between children’s and parents’ responses, parents were 1.25 times less likely to have experience with chronic pruritus, outside of their children. This finding provides a gauge of how well a parent can serve as a proxy to characterize his or her child’s itch.
Adolescents are in general a troubled group, and caregivers have concerns about suicide in the adolescent population, Dr. Chen said. She referred to a large study of adolescents published in 2012, which indicated that the prevalence of suicidal ideation was 8.4% among adolescents with no itch, compared with 21.1% among adolescents with severe itch (Acta Derm Venereol. 2012 Sep;92[5]:543-6).
In the study, those with severe itch were three times more likely to have suicidal ideation than the general population, which Dr. Chen noted was comparable with that of suicidal ideation in patients with chronic pain in the study (odds ratio, 3.8).
Cross-sectional data suggest a link between itching and ADHD, but “it’s a chicken-and-egg phenomenon,” she said. “If you’re so itchy and squirmy, you’re not going to pay attention. Then again, if you’re not paying attention, maybe you’re that much more prone to scratch.” Longitudinal data indicate that improving itch correlates with improvement in ADHD symptoms.
In addition, pruritus affects the genders disproportionately. Girls report a significantly greater impact on quality of life than boys when itching is severe, with much of the difference in emotional impact, said Dr. Chen. Boys may report more functional impact than girls.
Chronic pruritus also affects parents, who may have disturbed sleep, feel stress about their own parenting, and have difficulty enforcing discipline. “They feel an incredible amount of guilt and blame for giving this to their child,” she commented. “As more and more places develop itch centers, it would be good to have a multidisciplinary approach bringing in mental health providers and social workers, because the impact of itch on parents can be quite profound.”
Dr. Chen reported disclosures with several companies, including BioPharmX, Dermecular Therapeutics, Leo Pharma, and Unilever.
REPORTING FROM AAD 2019
Bermekimab reduces lesions, cuts pain in patients with hidradenitis suppurativa
WASHINGTON – It was nearly as effective in patients refractory to anti–tumor necrosis factor (TNF) therapy as it was to those naive to the treatment.
The antibody, which is derived directly from healthy human volunteers and then lab expanded, also improved patients’ quality of life in a “clinically meaningful way,” Alice Gottlieb, MD, PhD said at the annual meeting of the American Academy of Dermatology.
“These are sick people, and improvement of this kind is really something very important,” said Dr. Gottlieb of Mount Sinai Medical Center in New York. “I think what we see here supports the movement of bermekimab into phase 3 studies for HS [hidradenitis suppurativa].”
Bermekimab is the first inhibitor of IL-1 alpha to be investigated in HS. An overabundance of the cytokine produces several potentially problematic effects. IL-1 alpha induces inflammatory cells to migrate into the skin, drives neoangiogenesis, potentiates pain, and induces matrix metalloproteinase. The last two are particularly an issue in patients with HS. The abscesses and fistulas cause severe pain, which Dr. Gottlieb said is an undertreated and an underappreciated driver of disease disability. The tissue breakdown characteristic of the disease can also be highly disfiguring. “Many patients, especially my female patients, look as if they are basically autodigesting.”
IL-1 alpha also induces procollagen type I and III and fibroblast proliferation, contributing to the scarring many patients experience.
“Ten years ago, I thought it would be a potential target for HS,” Dr, Gottlieb said, and the idea has finally come to fruition through studies by biopharmaceutical company XBiotech in Austin, Tex. Dr. Gottlieb designed the treatment protocol and was a principal investigator on the study.
A similarly positive 2018 study employed twice-weekly intravenous infusions; this study utilized a more-concentrated form of the antibody delivered subcutaneously from prefilled syringes.
The study comprised 42 patients, 24 of whom had failed a course of anti-TNF therapy and 18 of whom were anti-TNF naive. Each group received bermekimab 400 mg subcutaneous once a week for 12 weeks. The primary endpoint was change on the Hidradenitis Suppurativa Clinical Response Score; good response was deemed at least a 50% reduction in abscesses and inflammatory nodules, with no new abscesses or draining fistulas. Secondary endpoints included pain scores, patient quality of life, and the physicians global clinical assessment.
At baseline, subjects in the anti-TNF–refractory group had a worse clinical profile than the naive patients, with more abscesses and inflammatory nodules (mean, 14 vs. 6) and worse scores on the Physicians Global Assessment. But they reported similar pain on a 10-point scale (around 8) and negative quality of life (17/30). Both groups experienced anxiety and depression.
Eight patients dropped out before finishing the trial for a variety of reasons, including family and transportation issues and comorbid illness. Only one discontinued for a reaction to the study drug (injection site redness). These patients were included in the final analysis in a last observation carried forward.
About 10% of patients began to experience improvement as soon as 2 weeks after the first injection. By week 6, 40% of the refractory patients and 10% of the naive patents had experienced a lesion reduction of at least 50%. By the end of the study, however, about 62% of patients in each group achieved that goal.
By week 12, the mean improvement in the Physicians Global Assessment was about 23% in the refractory group and 53% in the naive group. Both results were significant improvements over baseline.
The mean improvement in the pain score was about 54% in the refractory group and 65% in the naive group. In a scale that measured patients’ view of their disease severity, refractory patients reported a mean 40% improvement, and naive patients, a mean 67% improvement.
There were 57 adverse events recorded; 94% were grade 1 or 2. There were two serious adverse events requiring hospitalization – a fall and an admission for HS pain. Neither were judged related to the study drug. Two patients experienced injection site reactions and one patient experienced six bouts of nausea. There were no serious infections, no major cardiovascular events, and no neoplasms.
Dr. Gottlieb designed the study protocol and was a principal investigator. She did not receive financial compensation from the company.
WASHINGTON – It was nearly as effective in patients refractory to anti–tumor necrosis factor (TNF) therapy as it was to those naive to the treatment.
The antibody, which is derived directly from healthy human volunteers and then lab expanded, also improved patients’ quality of life in a “clinically meaningful way,” Alice Gottlieb, MD, PhD said at the annual meeting of the American Academy of Dermatology.
“These are sick people, and improvement of this kind is really something very important,” said Dr. Gottlieb of Mount Sinai Medical Center in New York. “I think what we see here supports the movement of bermekimab into phase 3 studies for HS [hidradenitis suppurativa].”
Bermekimab is the first inhibitor of IL-1 alpha to be investigated in HS. An overabundance of the cytokine produces several potentially problematic effects. IL-1 alpha induces inflammatory cells to migrate into the skin, drives neoangiogenesis, potentiates pain, and induces matrix metalloproteinase. The last two are particularly an issue in patients with HS. The abscesses and fistulas cause severe pain, which Dr. Gottlieb said is an undertreated and an underappreciated driver of disease disability. The tissue breakdown characteristic of the disease can also be highly disfiguring. “Many patients, especially my female patients, look as if they are basically autodigesting.”
IL-1 alpha also induces procollagen type I and III and fibroblast proliferation, contributing to the scarring many patients experience.
“Ten years ago, I thought it would be a potential target for HS,” Dr, Gottlieb said, and the idea has finally come to fruition through studies by biopharmaceutical company XBiotech in Austin, Tex. Dr. Gottlieb designed the treatment protocol and was a principal investigator on the study.
A similarly positive 2018 study employed twice-weekly intravenous infusions; this study utilized a more-concentrated form of the antibody delivered subcutaneously from prefilled syringes.
The study comprised 42 patients, 24 of whom had failed a course of anti-TNF therapy and 18 of whom were anti-TNF naive. Each group received bermekimab 400 mg subcutaneous once a week for 12 weeks. The primary endpoint was change on the Hidradenitis Suppurativa Clinical Response Score; good response was deemed at least a 50% reduction in abscesses and inflammatory nodules, with no new abscesses or draining fistulas. Secondary endpoints included pain scores, patient quality of life, and the physicians global clinical assessment.
At baseline, subjects in the anti-TNF–refractory group had a worse clinical profile than the naive patients, with more abscesses and inflammatory nodules (mean, 14 vs. 6) and worse scores on the Physicians Global Assessment. But they reported similar pain on a 10-point scale (around 8) and negative quality of life (17/30). Both groups experienced anxiety and depression.
Eight patients dropped out before finishing the trial for a variety of reasons, including family and transportation issues and comorbid illness. Only one discontinued for a reaction to the study drug (injection site redness). These patients were included in the final analysis in a last observation carried forward.
About 10% of patients began to experience improvement as soon as 2 weeks after the first injection. By week 6, 40% of the refractory patients and 10% of the naive patents had experienced a lesion reduction of at least 50%. By the end of the study, however, about 62% of patients in each group achieved that goal.
By week 12, the mean improvement in the Physicians Global Assessment was about 23% in the refractory group and 53% in the naive group. Both results were significant improvements over baseline.
The mean improvement in the pain score was about 54% in the refractory group and 65% in the naive group. In a scale that measured patients’ view of their disease severity, refractory patients reported a mean 40% improvement, and naive patients, a mean 67% improvement.
There were 57 adverse events recorded; 94% were grade 1 or 2. There were two serious adverse events requiring hospitalization – a fall and an admission for HS pain. Neither were judged related to the study drug. Two patients experienced injection site reactions and one patient experienced six bouts of nausea. There were no serious infections, no major cardiovascular events, and no neoplasms.
Dr. Gottlieb designed the study protocol and was a principal investigator. She did not receive financial compensation from the company.
WASHINGTON – It was nearly as effective in patients refractory to anti–tumor necrosis factor (TNF) therapy as it was to those naive to the treatment.
The antibody, which is derived directly from healthy human volunteers and then lab expanded, also improved patients’ quality of life in a “clinically meaningful way,” Alice Gottlieb, MD, PhD said at the annual meeting of the American Academy of Dermatology.
“These are sick people, and improvement of this kind is really something very important,” said Dr. Gottlieb of Mount Sinai Medical Center in New York. “I think what we see here supports the movement of bermekimab into phase 3 studies for HS [hidradenitis suppurativa].”
Bermekimab is the first inhibitor of IL-1 alpha to be investigated in HS. An overabundance of the cytokine produces several potentially problematic effects. IL-1 alpha induces inflammatory cells to migrate into the skin, drives neoangiogenesis, potentiates pain, and induces matrix metalloproteinase. The last two are particularly an issue in patients with HS. The abscesses and fistulas cause severe pain, which Dr. Gottlieb said is an undertreated and an underappreciated driver of disease disability. The tissue breakdown characteristic of the disease can also be highly disfiguring. “Many patients, especially my female patients, look as if they are basically autodigesting.”
IL-1 alpha also induces procollagen type I and III and fibroblast proliferation, contributing to the scarring many patients experience.
“Ten years ago, I thought it would be a potential target for HS,” Dr, Gottlieb said, and the idea has finally come to fruition through studies by biopharmaceutical company XBiotech in Austin, Tex. Dr. Gottlieb designed the treatment protocol and was a principal investigator on the study.
A similarly positive 2018 study employed twice-weekly intravenous infusions; this study utilized a more-concentrated form of the antibody delivered subcutaneously from prefilled syringes.
The study comprised 42 patients, 24 of whom had failed a course of anti-TNF therapy and 18 of whom were anti-TNF naive. Each group received bermekimab 400 mg subcutaneous once a week for 12 weeks. The primary endpoint was change on the Hidradenitis Suppurativa Clinical Response Score; good response was deemed at least a 50% reduction in abscesses and inflammatory nodules, with no new abscesses or draining fistulas. Secondary endpoints included pain scores, patient quality of life, and the physicians global clinical assessment.
At baseline, subjects in the anti-TNF–refractory group had a worse clinical profile than the naive patients, with more abscesses and inflammatory nodules (mean, 14 vs. 6) and worse scores on the Physicians Global Assessment. But they reported similar pain on a 10-point scale (around 8) and negative quality of life (17/30). Both groups experienced anxiety and depression.
Eight patients dropped out before finishing the trial for a variety of reasons, including family and transportation issues and comorbid illness. Only one discontinued for a reaction to the study drug (injection site redness). These patients were included in the final analysis in a last observation carried forward.
About 10% of patients began to experience improvement as soon as 2 weeks after the first injection. By week 6, 40% of the refractory patients and 10% of the naive patents had experienced a lesion reduction of at least 50%. By the end of the study, however, about 62% of patients in each group achieved that goal.
By week 12, the mean improvement in the Physicians Global Assessment was about 23% in the refractory group and 53% in the naive group. Both results were significant improvements over baseline.
The mean improvement in the pain score was about 54% in the refractory group and 65% in the naive group. In a scale that measured patients’ view of their disease severity, refractory patients reported a mean 40% improvement, and naive patients, a mean 67% improvement.
There were 57 adverse events recorded; 94% were grade 1 or 2. There were two serious adverse events requiring hospitalization – a fall and an admission for HS pain. Neither were judged related to the study drug. Two patients experienced injection site reactions and one patient experienced six bouts of nausea. There were no serious infections, no major cardiovascular events, and no neoplasms.
Dr. Gottlieb designed the study protocol and was a principal investigator. She did not receive financial compensation from the company.
REPORTING FROM AAD 2019
Many common dermatologic drugs can be safely used during pregnancy
WASHINGTON – With proper counseling and oversight, many drugs used for psoriasis, pemphigus, and atopic dermatitis are safe to use during pregnancy, Jenny Murase, MD, said at the annual meeting of the American Academy of Dermatology.
But it’s important to have an early talk about potential pregnancies, because most dermatologists don’t think about it unless a patient is taking a known teratogen, like isotretinoin, said Dr. Murase of the University of California, San Francisco. “It’s only about 10% of the time that the dermatologist brings it up. In patients with these chronic skin diseases, we need to address family planning proactively. Most women don’t discover they’re pregnant until they’re 2-5 weeks along, and by that time the development of major organs has already started.”
As part of her expertise in this topic, Dr. Murase published two comprehensive reports on the safety of dermatologic drugs in pregnancy and lactation. They were grouped according to the newest federal guidance, the Food and Drug Administration Pregnancy and Lactation Label Ruling. Issued in 2014, it requires the inclusion of any contact information for drug registries and covers reproductive risks or both males and females. Slowly being phased in as new drugs are approved, the ruling is replacing the old category A, B, and C.
The articles were published in the Journal of the American Academy of Dermatology and in the international Journal of Women’s Dermatology, an open-access journal Dr. Murase founded.
Corticosteroids
These dermatology workhorses are largely safe in pregnancy, Dr. Murase said. Some very early reports suggested that systemic cortisone might be associated with oral clefts, but that has never been borne out in prospective data. Prednisone may be the safest as it has the most limited placental transport; betamethasone and dexamethasone cross the placenta easily.
In a Cochrane review, only one study showed an increased risk of orofacial clefts. A 2013 study of about 10,000 women suggested an increased risk of low birth weight associated with a total dose of more than 300 grams during the pregnancy.
Antihistamines
First-generation antihistamines, including hydroxyzine, have been used as antiemetics in pregnant women. Hydroxyzine is generally considered safe, but should be discussed carefully, as it carries a slightly increased risk of congenital malformations (5.8% vs. 2.3% background risk).
Newborns exposed to large doses of hydroxyzine (150 mg or more daily) have also exhibited withdrawal symptoms at birth, including irritability, poor feeding, and tonic-clinic seizures.
“Antihistamines can exert oxytocin-like effects, especially in overdose or when given intravenously, so please avoid using them in the last month of pregnancy. There have also been a few reports of retrolental fibroplasia in preterm infants who were exposed to antihistamines within 2 weeks of delivery,” Dr. Murase said.
Immunosuppressants
Mycophenolate is not compatible with pregnancy. In 2007, the FDA changed the labeling of mycophenolate from category C to D, because of reports of congenital malformations arising from the U.S. National Transplantation Pregnancy Registry and other sources.
“You need to treat these patients like you do someone who is going on isotretinoin,” Dr. Murase said. “Any woman prescribed it should be on mandatory contraception at least 4 weeks before beginning the medication and for 6 weeks after completing treatment.”
Thus far there are no reported pregnancy-related safety issues with dupilumab, although data are scarce.
Pregnancy itself exerts a positive effect on psoriasis in many women, but not all. “About half the time a women will improve,” Dr. Murase said. “A quarter of the time, there’s no change and a quarter of the time, she’ll get worse. But the ones who do improve, often improve dramatically with about 80% body surface area clearance.”
She considers light therapy to be the safest treatment during pregnancy, with one caveat: Ultraviolet light can degrade some vitamins, including folic acid. “Every one of my patients of childbearing age I have on folic acid or a prenatal vitamin just in case. You have to be proactive here.”
Cyclosporine appears to be “quite safe,” she said. The possibility of intrauterine growth restriction seen in some studies is tough to tease out, because it was reported mainly in transplant populations among women with other medical comorbidities. Children from these pregnancies have been followed through toddlerhood and showed no neurodevelopmental or kidney issues.
Apremilast is a category C drug. Some animal data suggested increased spontaneous abortions and fetal demise with doses given at two to four times the human dose.
Biologics
Antibodies are an interesting lot, Dr. Murase noted. Maternal antibodies are transported to the fetus across the villi by Fc receptor; most of this transfer happens during the third trimester. The large, hydrophilic monoclonal antibodies infliximab, adalimumab, and ustekinumab travel this way as well. Cord blood can contain 50% higher serum levels than in maternal blood. Etanercept, however, is a fusion protein that diffuses across the placenta. Cord blood levels generally exceed maternal levels by less than 7%.
There is one published report of a fetal death associated with maternal infliximab for Crohn’s disease. The infant was healthy until it received a Bacillus Calmette–Guerin vaccine. It then developed widespread eczematous dermatitis, head lag, and poor weight gain and died at 4.5 months.
“This is another important counseling point,” Dr. Murase said. “Babies who have been exposed to infliximab in utero can’t have that vaccination in the first 9 months of life.”
Perhaps the safest bet for a pregnant women who needs a biologic is PEGylated certolizumab. “Certolizumab is the only PEGylated anti-TNF [tumor necrosis factor] without an Fc region; study of patients greater than 30 weeks pregnant certolizumab levels were below 0.032 mcg/mL in 13 of 14 infant samples at birth.”
Pemphigus
Pemphigus (impetigo herpetiformous) is a serious dermatologic disorder that can manifest in the third trimester, and affect the fetus as well as the mother. “You have to take even mild cases very seriously, because there’s no distinct correlation between the extent of neonatal involvement and the extent of maternal disease,” Dr. Murase said
Oral pemphigus in the mother is especially worrisome, she added. “Fetal skin shares the same desmoglein-3 profile as adult oral mucosa, and neonatal pemphigus is more likely if mother has oral disease. There’s an increased risk of fetal demise as well.”
Treatment would generally start with topical steroids, progressing to systemic low-dose corticosteroids. If more than 20 mg of prednisone a day is required, consider intravenous immunoglobulin (IVIG), azathioprine, dapsone, or rituximab.
“IVIG is very safe for pregnant women, and in fact reproductive endocrinologists use this to increase the chance of pregnancy for infertility cases,” Dr. Murase said.
She reported relationships with Regeneron, UCB, Dermira, and Genzyme/Sanofi.
WASHINGTON – With proper counseling and oversight, many drugs used for psoriasis, pemphigus, and atopic dermatitis are safe to use during pregnancy, Jenny Murase, MD, said at the annual meeting of the American Academy of Dermatology.
But it’s important to have an early talk about potential pregnancies, because most dermatologists don’t think about it unless a patient is taking a known teratogen, like isotretinoin, said Dr. Murase of the University of California, San Francisco. “It’s only about 10% of the time that the dermatologist brings it up. In patients with these chronic skin diseases, we need to address family planning proactively. Most women don’t discover they’re pregnant until they’re 2-5 weeks along, and by that time the development of major organs has already started.”
As part of her expertise in this topic, Dr. Murase published two comprehensive reports on the safety of dermatologic drugs in pregnancy and lactation. They were grouped according to the newest federal guidance, the Food and Drug Administration Pregnancy and Lactation Label Ruling. Issued in 2014, it requires the inclusion of any contact information for drug registries and covers reproductive risks or both males and females. Slowly being phased in as new drugs are approved, the ruling is replacing the old category A, B, and C.
The articles were published in the Journal of the American Academy of Dermatology and in the international Journal of Women’s Dermatology, an open-access journal Dr. Murase founded.
Corticosteroids
These dermatology workhorses are largely safe in pregnancy, Dr. Murase said. Some very early reports suggested that systemic cortisone might be associated with oral clefts, but that has never been borne out in prospective data. Prednisone may be the safest as it has the most limited placental transport; betamethasone and dexamethasone cross the placenta easily.
In a Cochrane review, only one study showed an increased risk of orofacial clefts. A 2013 study of about 10,000 women suggested an increased risk of low birth weight associated with a total dose of more than 300 grams during the pregnancy.
Antihistamines
First-generation antihistamines, including hydroxyzine, have been used as antiemetics in pregnant women. Hydroxyzine is generally considered safe, but should be discussed carefully, as it carries a slightly increased risk of congenital malformations (5.8% vs. 2.3% background risk).
Newborns exposed to large doses of hydroxyzine (150 mg or more daily) have also exhibited withdrawal symptoms at birth, including irritability, poor feeding, and tonic-clinic seizures.
“Antihistamines can exert oxytocin-like effects, especially in overdose or when given intravenously, so please avoid using them in the last month of pregnancy. There have also been a few reports of retrolental fibroplasia in preterm infants who were exposed to antihistamines within 2 weeks of delivery,” Dr. Murase said.
Immunosuppressants
Mycophenolate is not compatible with pregnancy. In 2007, the FDA changed the labeling of mycophenolate from category C to D, because of reports of congenital malformations arising from the U.S. National Transplantation Pregnancy Registry and other sources.
“You need to treat these patients like you do someone who is going on isotretinoin,” Dr. Murase said. “Any woman prescribed it should be on mandatory contraception at least 4 weeks before beginning the medication and for 6 weeks after completing treatment.”
Thus far there are no reported pregnancy-related safety issues with dupilumab, although data are scarce.
Pregnancy itself exerts a positive effect on psoriasis in many women, but not all. “About half the time a women will improve,” Dr. Murase said. “A quarter of the time, there’s no change and a quarter of the time, she’ll get worse. But the ones who do improve, often improve dramatically with about 80% body surface area clearance.”
She considers light therapy to be the safest treatment during pregnancy, with one caveat: Ultraviolet light can degrade some vitamins, including folic acid. “Every one of my patients of childbearing age I have on folic acid or a prenatal vitamin just in case. You have to be proactive here.”
Cyclosporine appears to be “quite safe,” she said. The possibility of intrauterine growth restriction seen in some studies is tough to tease out, because it was reported mainly in transplant populations among women with other medical comorbidities. Children from these pregnancies have been followed through toddlerhood and showed no neurodevelopmental or kidney issues.
Apremilast is a category C drug. Some animal data suggested increased spontaneous abortions and fetal demise with doses given at two to four times the human dose.
Biologics
Antibodies are an interesting lot, Dr. Murase noted. Maternal antibodies are transported to the fetus across the villi by Fc receptor; most of this transfer happens during the third trimester. The large, hydrophilic monoclonal antibodies infliximab, adalimumab, and ustekinumab travel this way as well. Cord blood can contain 50% higher serum levels than in maternal blood. Etanercept, however, is a fusion protein that diffuses across the placenta. Cord blood levels generally exceed maternal levels by less than 7%.
There is one published report of a fetal death associated with maternal infliximab for Crohn’s disease. The infant was healthy until it received a Bacillus Calmette–Guerin vaccine. It then developed widespread eczematous dermatitis, head lag, and poor weight gain and died at 4.5 months.
“This is another important counseling point,” Dr. Murase said. “Babies who have been exposed to infliximab in utero can’t have that vaccination in the first 9 months of life.”
Perhaps the safest bet for a pregnant women who needs a biologic is PEGylated certolizumab. “Certolizumab is the only PEGylated anti-TNF [tumor necrosis factor] without an Fc region; study of patients greater than 30 weeks pregnant certolizumab levels were below 0.032 mcg/mL in 13 of 14 infant samples at birth.”
Pemphigus
Pemphigus (impetigo herpetiformous) is a serious dermatologic disorder that can manifest in the third trimester, and affect the fetus as well as the mother. “You have to take even mild cases very seriously, because there’s no distinct correlation between the extent of neonatal involvement and the extent of maternal disease,” Dr. Murase said
Oral pemphigus in the mother is especially worrisome, she added. “Fetal skin shares the same desmoglein-3 profile as adult oral mucosa, and neonatal pemphigus is more likely if mother has oral disease. There’s an increased risk of fetal demise as well.”
Treatment would generally start with topical steroids, progressing to systemic low-dose corticosteroids. If more than 20 mg of prednisone a day is required, consider intravenous immunoglobulin (IVIG), azathioprine, dapsone, or rituximab.
“IVIG is very safe for pregnant women, and in fact reproductive endocrinologists use this to increase the chance of pregnancy for infertility cases,” Dr. Murase said.
She reported relationships with Regeneron, UCB, Dermira, and Genzyme/Sanofi.
WASHINGTON – With proper counseling and oversight, many drugs used for psoriasis, pemphigus, and atopic dermatitis are safe to use during pregnancy, Jenny Murase, MD, said at the annual meeting of the American Academy of Dermatology.
But it’s important to have an early talk about potential pregnancies, because most dermatologists don’t think about it unless a patient is taking a known teratogen, like isotretinoin, said Dr. Murase of the University of California, San Francisco. “It’s only about 10% of the time that the dermatologist brings it up. In patients with these chronic skin diseases, we need to address family planning proactively. Most women don’t discover they’re pregnant until they’re 2-5 weeks along, and by that time the development of major organs has already started.”
As part of her expertise in this topic, Dr. Murase published two comprehensive reports on the safety of dermatologic drugs in pregnancy and lactation. They were grouped according to the newest federal guidance, the Food and Drug Administration Pregnancy and Lactation Label Ruling. Issued in 2014, it requires the inclusion of any contact information for drug registries and covers reproductive risks or both males and females. Slowly being phased in as new drugs are approved, the ruling is replacing the old category A, B, and C.
The articles were published in the Journal of the American Academy of Dermatology and in the international Journal of Women’s Dermatology, an open-access journal Dr. Murase founded.
Corticosteroids
These dermatology workhorses are largely safe in pregnancy, Dr. Murase said. Some very early reports suggested that systemic cortisone might be associated with oral clefts, but that has never been borne out in prospective data. Prednisone may be the safest as it has the most limited placental transport; betamethasone and dexamethasone cross the placenta easily.
In a Cochrane review, only one study showed an increased risk of orofacial clefts. A 2013 study of about 10,000 women suggested an increased risk of low birth weight associated with a total dose of more than 300 grams during the pregnancy.
Antihistamines
First-generation antihistamines, including hydroxyzine, have been used as antiemetics in pregnant women. Hydroxyzine is generally considered safe, but should be discussed carefully, as it carries a slightly increased risk of congenital malformations (5.8% vs. 2.3% background risk).
Newborns exposed to large doses of hydroxyzine (150 mg or more daily) have also exhibited withdrawal symptoms at birth, including irritability, poor feeding, and tonic-clinic seizures.
“Antihistamines can exert oxytocin-like effects, especially in overdose or when given intravenously, so please avoid using them in the last month of pregnancy. There have also been a few reports of retrolental fibroplasia in preterm infants who were exposed to antihistamines within 2 weeks of delivery,” Dr. Murase said.
Immunosuppressants
Mycophenolate is not compatible with pregnancy. In 2007, the FDA changed the labeling of mycophenolate from category C to D, because of reports of congenital malformations arising from the U.S. National Transplantation Pregnancy Registry and other sources.
“You need to treat these patients like you do someone who is going on isotretinoin,” Dr. Murase said. “Any woman prescribed it should be on mandatory contraception at least 4 weeks before beginning the medication and for 6 weeks after completing treatment.”
Thus far there are no reported pregnancy-related safety issues with dupilumab, although data are scarce.
Pregnancy itself exerts a positive effect on psoriasis in many women, but not all. “About half the time a women will improve,” Dr. Murase said. “A quarter of the time, there’s no change and a quarter of the time, she’ll get worse. But the ones who do improve, often improve dramatically with about 80% body surface area clearance.”
She considers light therapy to be the safest treatment during pregnancy, with one caveat: Ultraviolet light can degrade some vitamins, including folic acid. “Every one of my patients of childbearing age I have on folic acid or a prenatal vitamin just in case. You have to be proactive here.”
Cyclosporine appears to be “quite safe,” she said. The possibility of intrauterine growth restriction seen in some studies is tough to tease out, because it was reported mainly in transplant populations among women with other medical comorbidities. Children from these pregnancies have been followed through toddlerhood and showed no neurodevelopmental or kidney issues.
Apremilast is a category C drug. Some animal data suggested increased spontaneous abortions and fetal demise with doses given at two to four times the human dose.
Biologics
Antibodies are an interesting lot, Dr. Murase noted. Maternal antibodies are transported to the fetus across the villi by Fc receptor; most of this transfer happens during the third trimester. The large, hydrophilic monoclonal antibodies infliximab, adalimumab, and ustekinumab travel this way as well. Cord blood can contain 50% higher serum levels than in maternal blood. Etanercept, however, is a fusion protein that diffuses across the placenta. Cord blood levels generally exceed maternal levels by less than 7%.
There is one published report of a fetal death associated with maternal infliximab for Crohn’s disease. The infant was healthy until it received a Bacillus Calmette–Guerin vaccine. It then developed widespread eczematous dermatitis, head lag, and poor weight gain and died at 4.5 months.
“This is another important counseling point,” Dr. Murase said. “Babies who have been exposed to infliximab in utero can’t have that vaccination in the first 9 months of life.”
Perhaps the safest bet for a pregnant women who needs a biologic is PEGylated certolizumab. “Certolizumab is the only PEGylated anti-TNF [tumor necrosis factor] without an Fc region; study of patients greater than 30 weeks pregnant certolizumab levels were below 0.032 mcg/mL in 13 of 14 infant samples at birth.”
Pemphigus
Pemphigus (impetigo herpetiformous) is a serious dermatologic disorder that can manifest in the third trimester, and affect the fetus as well as the mother. “You have to take even mild cases very seriously, because there’s no distinct correlation between the extent of neonatal involvement and the extent of maternal disease,” Dr. Murase said
Oral pemphigus in the mother is especially worrisome, she added. “Fetal skin shares the same desmoglein-3 profile as adult oral mucosa, and neonatal pemphigus is more likely if mother has oral disease. There’s an increased risk of fetal demise as well.”
Treatment would generally start with topical steroids, progressing to systemic low-dose corticosteroids. If more than 20 mg of prednisone a day is required, consider intravenous immunoglobulin (IVIG), azathioprine, dapsone, or rituximab.
“IVIG is very safe for pregnant women, and in fact reproductive endocrinologists use this to increase the chance of pregnancy for infertility cases,” Dr. Murase said.
She reported relationships with Regeneron, UCB, Dermira, and Genzyme/Sanofi.
EXPERT ANALYSIS FROM AAD 2019
FDA: More safety data needed for 12 sunscreen active ingredients
including some of those frequently used in over-the-counter products.
The ingredients requiring additional investigation are cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. The FDA actions were announced during a press briefing Feb. 21 held to discuss the proposed rule to update regulatory requirements for most sunscreen products marketed in the United States.
There are no urgent safety matters associated with these ingredients. The rule is part of FDA’s charge to construct an over-the-counter (OTC) monograph detailing all available data on sunscreen ingredients, as required by the Sunscreen Innovation Act.
OTC monographs establish conditions under which ingredients may be marketed without approved new drug applications because they are generally recognized as safe and effective (GRASE) “and not misbranded,” according to the FDA. The proposed rule classifies active ingredients and other conditions as Category I (proposed to be GRASE and not misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III (additional data needed).
“We are proposing that these ingredients require additional data before a positive GRASE determination can be made,” FDA press officer Sandy Walsh said in an interview, referring to the 12 ingredients. “This proposed rule does not represent a conclusion by the FDA that the sunscreen active ingredients proposed as having insufficient data are unsafe for use in sunscreens. Rather, we are requesting additional information on these ingredients so that we can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and evolving information about the potential risks associated with these products since they were originally evaluated.”
Among its provisions, the proposal addresses sunscreen active-ingredient safety, dosage forms, and sun protection factor (SPF) and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information
Thus far, the agency says that only two active ingredients – titanium dioxide and zinc oxide – can be marketed without approved new drug applications because they are GRASE.
However, two other ingredients – PABA and trolamine salicylate – are not GRASE for use in sunscreens because of safety issues, Theresa Michele, MD, director of the Division of Nonprescription Drug Products Division of Nonprescription Drug Products in the FDA’s Center for Drug Evaluation and Research. Products that combine sunscreen and insect repellent also not fit the criteria, she said
“There are 12 ingredients for which there are insufficient safety data to make a positive GRASE determination at this time. To address these 12 ingredients, the FDA is asking industry and other interested parties for additional data. The FDA is working closely with industry and has published several guidances to make sure companies understand what data the agency believes is necessary for the FDA to evaluate safety and effectiveness for sunscreen active ingredients, including the 12 ingredients for which the FDA is seeking more data,” she said.
In addition to seeking these additional data, the rule also proposes the following:
- Dosage forms that are GRASE for use as sunscreens should include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. While powders are proposed to be eligible for inclusion in the monograph, more data are being requested before powders are included. “Wipes, towelettes, body washes, shampoos, and other dosage forms are proposed to be categorized as new drugs because the FDA has not received data showing they are eligible for inclusion in the monograph,” according to the FDA statement outlining the proposed regulation.
- The maximum proposed SPF value on sunscreen labels should be raised from SPF 50 or higher to SPF 60 or higher. “There are not enough data to suggest that consumers get any extra benefit from products with an SPF of more than 60,” Dr. Michele said.
- Sunscreens with an SPF value of 15 or higher should be required to also provide broad-spectrum protection, and for broad-spectrum products, as SPF increases, the magnitude of protection against UVA radiation should also increase. “These proposals are designed to ensure that these products provide consumers with the protections that they expect,” the statement said.
- New sunscreen product labels should be required to make it easier for consumers to identify important information, “including the addition of the active ingredients on the front of the package to bring sunscreen in line with other OTC drugs; a notification on the front label for consumers to read the skin cancer/skin aging alert for sunscreens that have not been shown to help prevent skin cancer; and revised formats for SPF, broad spectrum, and water resistance statements,” the statement said.
- Products that combine sunscreens with insect repellents are not GRASE.
In the meantime, though, consumers should continue to use sunscreens regularly as part of a comprehensive sun protection program, FDA Commissioner Scott Gottlieb, MD, said during the briefing. “Broad spectrum sunscreens with SPF values of at least 15 are critical to the arsenal of tools for preventing skin cancer and protecting the skin from damage caused by the sun’s rays,” he continued. “Given the recognized public health benefits of sunscreen use, Americans should continue to use sunscreens in conjunction with other sun protective measures (such as protective clothing) as this important rule-making effort moves forward.”
To submit comments on this proposed rule, go to https://www.regulations.gov and follow instructions for submitting comments.
including some of those frequently used in over-the-counter products.
The ingredients requiring additional investigation are cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. The FDA actions were announced during a press briefing Feb. 21 held to discuss the proposed rule to update regulatory requirements for most sunscreen products marketed in the United States.
There are no urgent safety matters associated with these ingredients. The rule is part of FDA’s charge to construct an over-the-counter (OTC) monograph detailing all available data on sunscreen ingredients, as required by the Sunscreen Innovation Act.
OTC monographs establish conditions under which ingredients may be marketed without approved new drug applications because they are generally recognized as safe and effective (GRASE) “and not misbranded,” according to the FDA. The proposed rule classifies active ingredients and other conditions as Category I (proposed to be GRASE and not misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III (additional data needed).
“We are proposing that these ingredients require additional data before a positive GRASE determination can be made,” FDA press officer Sandy Walsh said in an interview, referring to the 12 ingredients. “This proposed rule does not represent a conclusion by the FDA that the sunscreen active ingredients proposed as having insufficient data are unsafe for use in sunscreens. Rather, we are requesting additional information on these ingredients so that we can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and evolving information about the potential risks associated with these products since they were originally evaluated.”
Among its provisions, the proposal addresses sunscreen active-ingredient safety, dosage forms, and sun protection factor (SPF) and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information
Thus far, the agency says that only two active ingredients – titanium dioxide and zinc oxide – can be marketed without approved new drug applications because they are GRASE.
However, two other ingredients – PABA and trolamine salicylate – are not GRASE for use in sunscreens because of safety issues, Theresa Michele, MD, director of the Division of Nonprescription Drug Products Division of Nonprescription Drug Products in the FDA’s Center for Drug Evaluation and Research. Products that combine sunscreen and insect repellent also not fit the criteria, she said
“There are 12 ingredients for which there are insufficient safety data to make a positive GRASE determination at this time. To address these 12 ingredients, the FDA is asking industry and other interested parties for additional data. The FDA is working closely with industry and has published several guidances to make sure companies understand what data the agency believes is necessary for the FDA to evaluate safety and effectiveness for sunscreen active ingredients, including the 12 ingredients for which the FDA is seeking more data,” she said.
In addition to seeking these additional data, the rule also proposes the following:
- Dosage forms that are GRASE for use as sunscreens should include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. While powders are proposed to be eligible for inclusion in the monograph, more data are being requested before powders are included. “Wipes, towelettes, body washes, shampoos, and other dosage forms are proposed to be categorized as new drugs because the FDA has not received data showing they are eligible for inclusion in the monograph,” according to the FDA statement outlining the proposed regulation.
- The maximum proposed SPF value on sunscreen labels should be raised from SPF 50 or higher to SPF 60 or higher. “There are not enough data to suggest that consumers get any extra benefit from products with an SPF of more than 60,” Dr. Michele said.
- Sunscreens with an SPF value of 15 or higher should be required to also provide broad-spectrum protection, and for broad-spectrum products, as SPF increases, the magnitude of protection against UVA radiation should also increase. “These proposals are designed to ensure that these products provide consumers with the protections that they expect,” the statement said.
- New sunscreen product labels should be required to make it easier for consumers to identify important information, “including the addition of the active ingredients on the front of the package to bring sunscreen in line with other OTC drugs; a notification on the front label for consumers to read the skin cancer/skin aging alert for sunscreens that have not been shown to help prevent skin cancer; and revised formats for SPF, broad spectrum, and water resistance statements,” the statement said.
- Products that combine sunscreens with insect repellents are not GRASE.
In the meantime, though, consumers should continue to use sunscreens regularly as part of a comprehensive sun protection program, FDA Commissioner Scott Gottlieb, MD, said during the briefing. “Broad spectrum sunscreens with SPF values of at least 15 are critical to the arsenal of tools for preventing skin cancer and protecting the skin from damage caused by the sun’s rays,” he continued. “Given the recognized public health benefits of sunscreen use, Americans should continue to use sunscreens in conjunction with other sun protective measures (such as protective clothing) as this important rule-making effort moves forward.”
To submit comments on this proposed rule, go to https://www.regulations.gov and follow instructions for submitting comments.
including some of those frequently used in over-the-counter products.
The ingredients requiring additional investigation are cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, padimate O, sulisobenzone, oxybenzone, and avobenzone. The FDA actions were announced during a press briefing Feb. 21 held to discuss the proposed rule to update regulatory requirements for most sunscreen products marketed in the United States.
There are no urgent safety matters associated with these ingredients. The rule is part of FDA’s charge to construct an over-the-counter (OTC) monograph detailing all available data on sunscreen ingredients, as required by the Sunscreen Innovation Act.
OTC monographs establish conditions under which ingredients may be marketed without approved new drug applications because they are generally recognized as safe and effective (GRASE) “and not misbranded,” according to the FDA. The proposed rule classifies active ingredients and other conditions as Category I (proposed to be GRASE and not misbranded), Category II (proposed to be not GRASE or to be misbranded), or Category III (additional data needed).
“We are proposing that these ingredients require additional data before a positive GRASE determination can be made,” FDA press officer Sandy Walsh said in an interview, referring to the 12 ingredients. “This proposed rule does not represent a conclusion by the FDA that the sunscreen active ingredients proposed as having insufficient data are unsafe for use in sunscreens. Rather, we are requesting additional information on these ingredients so that we can evaluate their GRASE status in light of changed conditions, including substantially increased sunscreen usage and evolving information about the potential risks associated with these products since they were originally evaluated.”
Among its provisions, the proposal addresses sunscreen active-ingredient safety, dosage forms, and sun protection factor (SPF) and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information
Thus far, the agency says that only two active ingredients – titanium dioxide and zinc oxide – can be marketed without approved new drug applications because they are GRASE.
However, two other ingredients – PABA and trolamine salicylate – are not GRASE for use in sunscreens because of safety issues, Theresa Michele, MD, director of the Division of Nonprescription Drug Products Division of Nonprescription Drug Products in the FDA’s Center for Drug Evaluation and Research. Products that combine sunscreen and insect repellent also not fit the criteria, she said
“There are 12 ingredients for which there are insufficient safety data to make a positive GRASE determination at this time. To address these 12 ingredients, the FDA is asking industry and other interested parties for additional data. The FDA is working closely with industry and has published several guidances to make sure companies understand what data the agency believes is necessary for the FDA to evaluate safety and effectiveness for sunscreen active ingredients, including the 12 ingredients for which the FDA is seeking more data,” she said.
In addition to seeking these additional data, the rule also proposes the following:
- Dosage forms that are GRASE for use as sunscreens should include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. While powders are proposed to be eligible for inclusion in the monograph, more data are being requested before powders are included. “Wipes, towelettes, body washes, shampoos, and other dosage forms are proposed to be categorized as new drugs because the FDA has not received data showing they are eligible for inclusion in the monograph,” according to the FDA statement outlining the proposed regulation.
- The maximum proposed SPF value on sunscreen labels should be raised from SPF 50 or higher to SPF 60 or higher. “There are not enough data to suggest that consumers get any extra benefit from products with an SPF of more than 60,” Dr. Michele said.
- Sunscreens with an SPF value of 15 or higher should be required to also provide broad-spectrum protection, and for broad-spectrum products, as SPF increases, the magnitude of protection against UVA radiation should also increase. “These proposals are designed to ensure that these products provide consumers with the protections that they expect,” the statement said.
- New sunscreen product labels should be required to make it easier for consumers to identify important information, “including the addition of the active ingredients on the front of the package to bring sunscreen in line with other OTC drugs; a notification on the front label for consumers to read the skin cancer/skin aging alert for sunscreens that have not been shown to help prevent skin cancer; and revised formats for SPF, broad spectrum, and water resistance statements,” the statement said.
- Products that combine sunscreens with insect repellents are not GRASE.
In the meantime, though, consumers should continue to use sunscreens regularly as part of a comprehensive sun protection program, FDA Commissioner Scott Gottlieb, MD, said during the briefing. “Broad spectrum sunscreens with SPF values of at least 15 are critical to the arsenal of tools for preventing skin cancer and protecting the skin from damage caused by the sun’s rays,” he continued. “Given the recognized public health benefits of sunscreen use, Americans should continue to use sunscreens in conjunction with other sun protective measures (such as protective clothing) as this important rule-making effort moves forward.”
To submit comments on this proposed rule, go to https://www.regulations.gov and follow instructions for submitting comments.
List of medications linked to drug-induced lupus expands
leaving the overall number now standing at 118.
Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.
Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).
In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.
“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.
Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.
The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.
They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.
Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.
“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.
The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.
“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.
“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.
The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.
The authors had no outside funding for the study and reported having no conflicts of interest.
SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.
This new and updated list of possible lupus-inducing drugs includes a growing range of treatment categories, chemical structures, and pharmacologic actions. Yet it is still unclear what the common denominator is that links them.
Drug-induced lupus (DIL) is a peculiar adverse drug reaction that appears to be unrelated to any known property of the inducing agent, although cytokine modulating biologics are a possible exception. Nevertheless, the in vivo metabolism of dissimilar drugs to products with a common, reactive property may go some way to explaining how compounds with different pharmacologic and chemical structures could induce similar adverse reactions.
The findings by Arnaud et al. need better documentation than just positive pharmacovigilance signals. For example, a drug with a relatively high signal does not necessarily translate to a high propensity for causing lupus-like symptoms. It may be a reflection of high drug usage or an awareness of the report contributors for detecting new-onset systemic lupus erythematosus.
Regardless, this research serves to help and inform the medical community to increase the vigilance of previously unreported DIL and perhaps motivate the publication of novel, convincing case reports.
Robert L. Rubin, PhD, is with the University of New Mexico, Albuquerque. His comments are adapted from an editorial accompanying the report by Arnaud et al. (Ann Rheum Dis. 2019 Feb 13. doi: annrheumdis-2018-214785). He reported having no relevant disclosures.
This new and updated list of possible lupus-inducing drugs includes a growing range of treatment categories, chemical structures, and pharmacologic actions. Yet it is still unclear what the common denominator is that links them.
Drug-induced lupus (DIL) is a peculiar adverse drug reaction that appears to be unrelated to any known property of the inducing agent, although cytokine modulating biologics are a possible exception. Nevertheless, the in vivo metabolism of dissimilar drugs to products with a common, reactive property may go some way to explaining how compounds with different pharmacologic and chemical structures could induce similar adverse reactions.
The findings by Arnaud et al. need better documentation than just positive pharmacovigilance signals. For example, a drug with a relatively high signal does not necessarily translate to a high propensity for causing lupus-like symptoms. It may be a reflection of high drug usage or an awareness of the report contributors for detecting new-onset systemic lupus erythematosus.
Regardless, this research serves to help and inform the medical community to increase the vigilance of previously unreported DIL and perhaps motivate the publication of novel, convincing case reports.
Robert L. Rubin, PhD, is with the University of New Mexico, Albuquerque. His comments are adapted from an editorial accompanying the report by Arnaud et al. (Ann Rheum Dis. 2019 Feb 13. doi: annrheumdis-2018-214785). He reported having no relevant disclosures.
This new and updated list of possible lupus-inducing drugs includes a growing range of treatment categories, chemical structures, and pharmacologic actions. Yet it is still unclear what the common denominator is that links them.
Drug-induced lupus (DIL) is a peculiar adverse drug reaction that appears to be unrelated to any known property of the inducing agent, although cytokine modulating biologics are a possible exception. Nevertheless, the in vivo metabolism of dissimilar drugs to products with a common, reactive property may go some way to explaining how compounds with different pharmacologic and chemical structures could induce similar adverse reactions.
The findings by Arnaud et al. need better documentation than just positive pharmacovigilance signals. For example, a drug with a relatively high signal does not necessarily translate to a high propensity for causing lupus-like symptoms. It may be a reflection of high drug usage or an awareness of the report contributors for detecting new-onset systemic lupus erythematosus.
Regardless, this research serves to help and inform the medical community to increase the vigilance of previously unreported DIL and perhaps motivate the publication of novel, convincing case reports.
Robert L. Rubin, PhD, is with the University of New Mexico, Albuquerque. His comments are adapted from an editorial accompanying the report by Arnaud et al. (Ann Rheum Dis. 2019 Feb 13. doi: annrheumdis-2018-214785). He reported having no relevant disclosures.
leaving the overall number now standing at 118.
Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.
Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).
In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.
“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.
Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.
The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.
They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.
Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.
“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.
The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.
“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.
“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.
The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.
The authors had no outside funding for the study and reported having no conflicts of interest.
SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.
leaving the overall number now standing at 118.
Among the 118 suspected drugs found in VigiBase, the WHO’s global deduplicated individual case safety reports (ICSR) database, 42 had not been previously reported in association with drug-induced lupus (DIL) and 76 had been previously reported in association with DIL in Medline. DIL was reported as a serious adverse event in 55.4% of cases, according to French researchers led by Laurent Arnaud, MD, PhD, of the department of rheumatology at Hôpitaux Universitaires de Strasbourg and Centre National de Références des Maladies Systémiques Rares, Strasbourg, France.
Dr. Arnaud and his colleagues conducted a case-noncase analysis for each drug associated with DIL in order to compare the proportion of specific adverse drug reactions (ADRs) reported for a single drug with the proportion of the same ADR for all other treatments in VigiBase, which receives reports from more than 130 country members of the WHO Programme for International Drug Monitoring and contains over 16 million deduplicated ICSRs recorded by pharmacovigilance centers since 1967. They searched for cases classified as systemic lupus erythematosus (SLE) and identified 12,166 ICSRs of DIL; from these they found 118 suspected drugs with significant pharmacovigilance signal from 8,163 ICSRs that mostly originated from the Americas (65%) and Europe (23%).
In line with what the study authors expected, the drugs associated with the highest number of DIL cases were the antitumor necrosis factor agents infliximab, adalimumab, and etanercept, and the drugs associated with the highest disproportional reporting of DIL were procainamide and hydralazine.
“This is an important finding because these are the two drugs associated with the highest risk of DIL in the literature, therefore confirming the reliability of our approach using a large pharmacovigilance database,” the researchers wrote in Annals of the Rheumatic Diseases.
Overall, DIL was considered definite for 9 drugs (procainamide, hydralazine, minocycline, quinidine, isoniazid, terbinafine, methyldopa, dihydralazine, and chlorpromazine), probable for 19 drugs, and possible for 45 drugs.
The median age of DIL onset was 49 years, which the authors noted was about 2 decades older than that of spontaneous SLE.
They also observed a marked predominance in females (female to male sex ratio, 4.3), a finding that contrasted with previous studies reporting a female to male sex ratio closer to 1:1.
Dr. Arnaud and his colleagues stated that their finding of a median delay between the reported start of suspected treatment and DIL occurrence of 172 days (interquartile range, 35-610 days) suggested that DIL mostly appears after a few months and usually within the first 2 years of treatment with the suspected drug.
“The analysis of the median reporting years for each suspected drug shows a clear evolution of suspected drugs during the past decades. This further underlines that the constantly changing spectrum of DIL should be monitored continuously, and further validates the interest of our approach using the WHO international pharmacovigilance database, the biggest database of this kind with over 16 million deduplicated ICSRs,” they wrote.
The researchers added that distinguishing DIL from SLE is important because its prognosis is usually good when the drug is withdrawn, but the spectrum of DIL is constantly evolving, with drugs once described as strongly linked to DIL now prescribed less frequently.
“The first case of DIL was reported in 1945 with sulfadiazine, while hydralazine DIL was first reported in 1953. Since then, pharmacopoeia has strongly evolved, and one could hypothesize that so has the spectrum of drugs that can induce DIL,” they wrote.
“The detailed list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. Altogether, these findings may help in improving the identification of this constantly evolving disease,” they concluded.
The current study was limited by the lack of a uniform set of criteria for the diagnosis of DIL and by the level of reported details available in VigiBase.
The authors had no outside funding for the study and reported having no conflicts of interest.
SOURCE: Arnaud L et al. Ann Rheum Dis. 2019 Feb 4. doi: 10.1136/annrheumdis-2018-214598.
FROM ANNALS OF THE RHEUMATIC DISEASES
When to suspect a severe skin reaction to an AED
NEW ORLEANS – Most skin eruptions in patients taking antiepileptic drugs (AEDs) are relatively benign. With close supervision, some patients with epilepsy may continue treatment despite having a benign drug rash, according to a lecture at the annual meeting of the American Epilepsy Society.
“When do you know that you’re not dealing with that kind of eruption?” said Jeanne M. Young, MD, assistant professor of dermatology at the University of Virginia in Charlottesville.
Signs and symptoms that raise concerns about severe cutaneous reactions include swelling of the face; lesions that are fluid-filled, dusky, or painful; mucus membrane involvement; and signs of systemic involvement.
Associations with anticonvulsants
Diffuse swelling of the face is a hallmark symptom of DRESS. Fluid-filled lesions such as pustules, vesicles, and bullae indicate a condition other than a benign drug eruption. Signs of systemic involvement may include fever, marked eosinophilia, transaminitis, and evidence of lymphocyte activation. “In general, I want to see systemic involvement that can’t be explained by the patient’s other systemic diseases,” Dr. Young said.
A 2018 study found that AEDs are associated with SJS and TEN, and the labels for lamotrigine and carbamazepine include black box warnings about the risk of severe cutaneous adverse events. Carbamazepine’s warning, which was added in 2007, notes that SJS and TEN are significantly more common in patients of Asian ancestry with the human leukocyte antigen allele HLA-B*1502 and that physicians should screen at-risk patients before starting treatment.
Benign drug rashes
Morbilliform drug eruptions, sometimes called benign exanthems, are “by far the most common drug rash that we see” and typically are “the rashes that people refer to as drug rashes,” Dr. Young said. The mechanisms appear to be primarily immune complex mediated and cell mediated. “When the drug is stopped, these rashes tend to go away quite predictably in 2-3 weeks.”
For any class of drug, about 1% of people taking that medication may have this type of reaction, Dr. Young said. “We expect to see erythematous papules and plaques that oftentimes become confluent on the skin.” These reactions generally occur 7-10 days after the first exposure to the medication, and most patients do not have other symptoms, although the rash may itch. In addition, patients may have erythroderma with desquamation. “I think it’s important to point out the difference between desquamation, which is loss of the stratum corneum, and epidermal sloughing, which is what you see in something like [SJS] or TEN, where you’re actually losing the entire epidermis,” Dr. Young said. Recovering from desquamation is “sort of like recovering from a sun burn, and it’s not particularly dangerous.” Management of morbilliform drug eruptions is largely symptomatic.
Treat through, taper, or rechallenge
In the case a benign drug rash, “if you feel like you … need to keep a patient on a drug, you do have that option with close supervision,” Dr. Young said. “Communicate that with the dermatologist. Say, ‘I have really struggled getting this patient stabilized. Can we keep them on this drug?’ ”
The dermatologist may not fully realize the implications of stopping an effective AED in a patient with seizures that have been difficult to control. If the drug rash is benign, treating through may be an option. Patients often resolve the rash while continuing the medication, which may be because of desensitization, Dr. Young said. If a patient’s symptoms are too great to continue the drug, neurologists have the option of slowly tapering the drug and reinitiating with a new drug, Dr. Young said. Neurologists also may choose to rechallenge.
If a patient is on several medications, making it difficult to elucidate a causative agent, after stopping those drugs and allowing the rash to resolve, “there is little danger in restarting a medication,” she said.
Benign rash or DRESS?
“When I see a morbilliform eruption, usually what’s on my mind is, ‘Is this just a drug rash or is this DRESS?’ ” Dr. Young said. DRESS often starts with a morbilliform eruption that is indistinguishable from a benign drug eruption.
“Timing is a major difference,” she said. “If a patient develops a morbilliform drug eruption much later than I would expect, then my suspicion [for DRESS] goes up.” Patients with DRESS often have fever and systemic symptoms. Proposed DRESS diagnostic criteria can be useful, but clinical judgment still plays a key role. If a patient does not satisfy diagnostic criteria but has some signs and is taking a drug that is associated with DRESS, “it is going to make me more suspicious and maybe make me recommend stopping that drug sooner,” she said. Anticonvulsants such as carbamazepine, lamotrigine, and phenobarbital are among the drugs most commonly associated with DRESS.
Toxic erythemas
Patients may present with toxic erythemas, such as fixed drug reactions, erythema multiforme, SJS, and TEN. These drug reactions appear similar on biopsy but have different courses.
A patient with a fixed drug reaction often has a single lesion, and the lesion will occur in the same location every time the patient is exposed to the drug. Patients may develop additional lesions with subsequent exposures. These lesions typically are large, erythematous, well-demarcated plaques with central duskiness. “They can be bullous in the center, and they typically will heal with pigmentation, which is unique to this particular drug reaction,” said Dr. Young. “When it gets more concerning and most important to differentiate is when you get generalized bullous fixed drug eruption.” Generalized bullous fixed drug eruptions mimic and are difficult to clinically distinguish from TEN, which has a much has a much poorer prognosis.
Patients with a fixed drug eruption are not as ill as patients with TEN and tend not to slough their skin to the extent seen with TEN. Interferon gamma, perforin, and Fas ligand have been implicated as mechanisms involved in fixed drug reactions. Unlike in TEN, regulatory T cells are abundant, which may explain why TEN and fixed drug reactions progress differently even though they appear to share pathologic mechanisms, Dr. Young said.
Erythema multiforme generally presents with classic target lesions and little mucosal involvement. Infections, most commonly herpes simplex virus (HSV) 1 and 2, may trigger erythema multiforme. Dr. Young recommends evaluating patients for HSV and checking serologies, even if patients have never had a herpes outbreak. “If you have no evidence for infection, you do have to consider discontinuing a medication,” she said.
Stevens–Johnson syndrome and TEN
SJS and TEN are “the rarest of the severe cutaneous adverse drug reactions” and have “the highest morbidity and mortality,” Dr. Young said. They appear to exist on a continuum where SJS may represent early TEN.
“This is a situation where you expect to see blistering of the skin [and] always mucosal involvement. You need to stop the drug immediately when you suspect this drug reaction,” Dr. Young said.
One reason to distinguish SJS or early TEN from later TEN is that high-dose steroids may play a role in the treatment of SJS or early TEN. “Once you get past about 10% total body surface area, there is good evidence that steroids actually increase morbidity and mortality,” she said.
If the eruption has occurred before, that factor suggests that a diagnosis of erythema multiforme or fixed drug reaction may be more likely than TEN.
An apparent lack of regulatory T cells in TEN could explain why patients with HIV infection are at much higher risk of developing SJS and TEN. Understanding the role that regulatory T cells play in severe drug eruptions may lead to new therapeutic options in the future, Dr. Young said.
Dr. Young had no disclosures.
NEW ORLEANS – Most skin eruptions in patients taking antiepileptic drugs (AEDs) are relatively benign. With close supervision, some patients with epilepsy may continue treatment despite having a benign drug rash, according to a lecture at the annual meeting of the American Epilepsy Society.
“When do you know that you’re not dealing with that kind of eruption?” said Jeanne M. Young, MD, assistant professor of dermatology at the University of Virginia in Charlottesville.
Signs and symptoms that raise concerns about severe cutaneous reactions include swelling of the face; lesions that are fluid-filled, dusky, or painful; mucus membrane involvement; and signs of systemic involvement.
Associations with anticonvulsants
Diffuse swelling of the face is a hallmark symptom of DRESS. Fluid-filled lesions such as pustules, vesicles, and bullae indicate a condition other than a benign drug eruption. Signs of systemic involvement may include fever, marked eosinophilia, transaminitis, and evidence of lymphocyte activation. “In general, I want to see systemic involvement that can’t be explained by the patient’s other systemic diseases,” Dr. Young said.
A 2018 study found that AEDs are associated with SJS and TEN, and the labels for lamotrigine and carbamazepine include black box warnings about the risk of severe cutaneous adverse events. Carbamazepine’s warning, which was added in 2007, notes that SJS and TEN are significantly more common in patients of Asian ancestry with the human leukocyte antigen allele HLA-B*1502 and that physicians should screen at-risk patients before starting treatment.
Benign drug rashes
Morbilliform drug eruptions, sometimes called benign exanthems, are “by far the most common drug rash that we see” and typically are “the rashes that people refer to as drug rashes,” Dr. Young said. The mechanisms appear to be primarily immune complex mediated and cell mediated. “When the drug is stopped, these rashes tend to go away quite predictably in 2-3 weeks.”
For any class of drug, about 1% of people taking that medication may have this type of reaction, Dr. Young said. “We expect to see erythematous papules and plaques that oftentimes become confluent on the skin.” These reactions generally occur 7-10 days after the first exposure to the medication, and most patients do not have other symptoms, although the rash may itch. In addition, patients may have erythroderma with desquamation. “I think it’s important to point out the difference between desquamation, which is loss of the stratum corneum, and epidermal sloughing, which is what you see in something like [SJS] or TEN, where you’re actually losing the entire epidermis,” Dr. Young said. Recovering from desquamation is “sort of like recovering from a sun burn, and it’s not particularly dangerous.” Management of morbilliform drug eruptions is largely symptomatic.
Treat through, taper, or rechallenge
In the case a benign drug rash, “if you feel like you … need to keep a patient on a drug, you do have that option with close supervision,” Dr. Young said. “Communicate that with the dermatologist. Say, ‘I have really struggled getting this patient stabilized. Can we keep them on this drug?’ ”
The dermatologist may not fully realize the implications of stopping an effective AED in a patient with seizures that have been difficult to control. If the drug rash is benign, treating through may be an option. Patients often resolve the rash while continuing the medication, which may be because of desensitization, Dr. Young said. If a patient’s symptoms are too great to continue the drug, neurologists have the option of slowly tapering the drug and reinitiating with a new drug, Dr. Young said. Neurologists also may choose to rechallenge.
If a patient is on several medications, making it difficult to elucidate a causative agent, after stopping those drugs and allowing the rash to resolve, “there is little danger in restarting a medication,” she said.
Benign rash or DRESS?
“When I see a morbilliform eruption, usually what’s on my mind is, ‘Is this just a drug rash or is this DRESS?’ ” Dr. Young said. DRESS often starts with a morbilliform eruption that is indistinguishable from a benign drug eruption.
“Timing is a major difference,” she said. “If a patient develops a morbilliform drug eruption much later than I would expect, then my suspicion [for DRESS] goes up.” Patients with DRESS often have fever and systemic symptoms. Proposed DRESS diagnostic criteria can be useful, but clinical judgment still plays a key role. If a patient does not satisfy diagnostic criteria but has some signs and is taking a drug that is associated with DRESS, “it is going to make me more suspicious and maybe make me recommend stopping that drug sooner,” she said. Anticonvulsants such as carbamazepine, lamotrigine, and phenobarbital are among the drugs most commonly associated with DRESS.
Toxic erythemas
Patients may present with toxic erythemas, such as fixed drug reactions, erythema multiforme, SJS, and TEN. These drug reactions appear similar on biopsy but have different courses.
A patient with a fixed drug reaction often has a single lesion, and the lesion will occur in the same location every time the patient is exposed to the drug. Patients may develop additional lesions with subsequent exposures. These lesions typically are large, erythematous, well-demarcated plaques with central duskiness. “They can be bullous in the center, and they typically will heal with pigmentation, which is unique to this particular drug reaction,” said Dr. Young. “When it gets more concerning and most important to differentiate is when you get generalized bullous fixed drug eruption.” Generalized bullous fixed drug eruptions mimic and are difficult to clinically distinguish from TEN, which has a much has a much poorer prognosis.
Patients with a fixed drug eruption are not as ill as patients with TEN and tend not to slough their skin to the extent seen with TEN. Interferon gamma, perforin, and Fas ligand have been implicated as mechanisms involved in fixed drug reactions. Unlike in TEN, regulatory T cells are abundant, which may explain why TEN and fixed drug reactions progress differently even though they appear to share pathologic mechanisms, Dr. Young said.
Erythema multiforme generally presents with classic target lesions and little mucosal involvement. Infections, most commonly herpes simplex virus (HSV) 1 and 2, may trigger erythema multiforme. Dr. Young recommends evaluating patients for HSV and checking serologies, even if patients have never had a herpes outbreak. “If you have no evidence for infection, you do have to consider discontinuing a medication,” she said.
Stevens–Johnson syndrome and TEN
SJS and TEN are “the rarest of the severe cutaneous adverse drug reactions” and have “the highest morbidity and mortality,” Dr. Young said. They appear to exist on a continuum where SJS may represent early TEN.
“This is a situation where you expect to see blistering of the skin [and] always mucosal involvement. You need to stop the drug immediately when you suspect this drug reaction,” Dr. Young said.
One reason to distinguish SJS or early TEN from later TEN is that high-dose steroids may play a role in the treatment of SJS or early TEN. “Once you get past about 10% total body surface area, there is good evidence that steroids actually increase morbidity and mortality,” she said.
If the eruption has occurred before, that factor suggests that a diagnosis of erythema multiforme or fixed drug reaction may be more likely than TEN.
An apparent lack of regulatory T cells in TEN could explain why patients with HIV infection are at much higher risk of developing SJS and TEN. Understanding the role that regulatory T cells play in severe drug eruptions may lead to new therapeutic options in the future, Dr. Young said.
Dr. Young had no disclosures.
NEW ORLEANS – Most skin eruptions in patients taking antiepileptic drugs (AEDs) are relatively benign. With close supervision, some patients with epilepsy may continue treatment despite having a benign drug rash, according to a lecture at the annual meeting of the American Epilepsy Society.
“When do you know that you’re not dealing with that kind of eruption?” said Jeanne M. Young, MD, assistant professor of dermatology at the University of Virginia in Charlottesville.
Signs and symptoms that raise concerns about severe cutaneous reactions include swelling of the face; lesions that are fluid-filled, dusky, or painful; mucus membrane involvement; and signs of systemic involvement.
Associations with anticonvulsants
Diffuse swelling of the face is a hallmark symptom of DRESS. Fluid-filled lesions such as pustules, vesicles, and bullae indicate a condition other than a benign drug eruption. Signs of systemic involvement may include fever, marked eosinophilia, transaminitis, and evidence of lymphocyte activation. “In general, I want to see systemic involvement that can’t be explained by the patient’s other systemic diseases,” Dr. Young said.
A 2018 study found that AEDs are associated with SJS and TEN, and the labels for lamotrigine and carbamazepine include black box warnings about the risk of severe cutaneous adverse events. Carbamazepine’s warning, which was added in 2007, notes that SJS and TEN are significantly more common in patients of Asian ancestry with the human leukocyte antigen allele HLA-B*1502 and that physicians should screen at-risk patients before starting treatment.
Benign drug rashes
Morbilliform drug eruptions, sometimes called benign exanthems, are “by far the most common drug rash that we see” and typically are “the rashes that people refer to as drug rashes,” Dr. Young said. The mechanisms appear to be primarily immune complex mediated and cell mediated. “When the drug is stopped, these rashes tend to go away quite predictably in 2-3 weeks.”
For any class of drug, about 1% of people taking that medication may have this type of reaction, Dr. Young said. “We expect to see erythematous papules and plaques that oftentimes become confluent on the skin.” These reactions generally occur 7-10 days after the first exposure to the medication, and most patients do not have other symptoms, although the rash may itch. In addition, patients may have erythroderma with desquamation. “I think it’s important to point out the difference between desquamation, which is loss of the stratum corneum, and epidermal sloughing, which is what you see in something like [SJS] or TEN, where you’re actually losing the entire epidermis,” Dr. Young said. Recovering from desquamation is “sort of like recovering from a sun burn, and it’s not particularly dangerous.” Management of morbilliform drug eruptions is largely symptomatic.
Treat through, taper, or rechallenge
In the case a benign drug rash, “if you feel like you … need to keep a patient on a drug, you do have that option with close supervision,” Dr. Young said. “Communicate that with the dermatologist. Say, ‘I have really struggled getting this patient stabilized. Can we keep them on this drug?’ ”
The dermatologist may not fully realize the implications of stopping an effective AED in a patient with seizures that have been difficult to control. If the drug rash is benign, treating through may be an option. Patients often resolve the rash while continuing the medication, which may be because of desensitization, Dr. Young said. If a patient’s symptoms are too great to continue the drug, neurologists have the option of slowly tapering the drug and reinitiating with a new drug, Dr. Young said. Neurologists also may choose to rechallenge.
If a patient is on several medications, making it difficult to elucidate a causative agent, after stopping those drugs and allowing the rash to resolve, “there is little danger in restarting a medication,” she said.
Benign rash or DRESS?
“When I see a morbilliform eruption, usually what’s on my mind is, ‘Is this just a drug rash or is this DRESS?’ ” Dr. Young said. DRESS often starts with a morbilliform eruption that is indistinguishable from a benign drug eruption.
“Timing is a major difference,” she said. “If a patient develops a morbilliform drug eruption much later than I would expect, then my suspicion [for DRESS] goes up.” Patients with DRESS often have fever and systemic symptoms. Proposed DRESS diagnostic criteria can be useful, but clinical judgment still plays a key role. If a patient does not satisfy diagnostic criteria but has some signs and is taking a drug that is associated with DRESS, “it is going to make me more suspicious and maybe make me recommend stopping that drug sooner,” she said. Anticonvulsants such as carbamazepine, lamotrigine, and phenobarbital are among the drugs most commonly associated with DRESS.
Toxic erythemas
Patients may present with toxic erythemas, such as fixed drug reactions, erythema multiforme, SJS, and TEN. These drug reactions appear similar on biopsy but have different courses.
A patient with a fixed drug reaction often has a single lesion, and the lesion will occur in the same location every time the patient is exposed to the drug. Patients may develop additional lesions with subsequent exposures. These lesions typically are large, erythematous, well-demarcated plaques with central duskiness. “They can be bullous in the center, and they typically will heal with pigmentation, which is unique to this particular drug reaction,” said Dr. Young. “When it gets more concerning and most important to differentiate is when you get generalized bullous fixed drug eruption.” Generalized bullous fixed drug eruptions mimic and are difficult to clinically distinguish from TEN, which has a much has a much poorer prognosis.
Patients with a fixed drug eruption are not as ill as patients with TEN and tend not to slough their skin to the extent seen with TEN. Interferon gamma, perforin, and Fas ligand have been implicated as mechanisms involved in fixed drug reactions. Unlike in TEN, regulatory T cells are abundant, which may explain why TEN and fixed drug reactions progress differently even though they appear to share pathologic mechanisms, Dr. Young said.
Erythema multiforme generally presents with classic target lesions and little mucosal involvement. Infections, most commonly herpes simplex virus (HSV) 1 and 2, may trigger erythema multiforme. Dr. Young recommends evaluating patients for HSV and checking serologies, even if patients have never had a herpes outbreak. “If you have no evidence for infection, you do have to consider discontinuing a medication,” she said.
Stevens–Johnson syndrome and TEN
SJS and TEN are “the rarest of the severe cutaneous adverse drug reactions” and have “the highest morbidity and mortality,” Dr. Young said. They appear to exist on a continuum where SJS may represent early TEN.
“This is a situation where you expect to see blistering of the skin [and] always mucosal involvement. You need to stop the drug immediately when you suspect this drug reaction,” Dr. Young said.
One reason to distinguish SJS or early TEN from later TEN is that high-dose steroids may play a role in the treatment of SJS or early TEN. “Once you get past about 10% total body surface area, there is good evidence that steroids actually increase morbidity and mortality,” she said.
If the eruption has occurred before, that factor suggests that a diagnosis of erythema multiforme or fixed drug reaction may be more likely than TEN.
An apparent lack of regulatory T cells in TEN could explain why patients with HIV infection are at much higher risk of developing SJS and TEN. Understanding the role that regulatory T cells play in severe drug eruptions may lead to new therapeutic options in the future, Dr. Young said.
Dr. Young had no disclosures.
EXPERT ANALYSIS FROM AES 2018
Small study identifies skin microbiome changes after UV exposure
, in a small pilot study published in Experimental Dermatology.
“Human skin and its microbial inhabitants are also subject to the effects of external and environmental stressors, such as ultraviolet radiation,” wrote Erin M. Burns, MS, PhD, of the department of dermatology at the University of Alabama at Birmingham, and her coauthors. “Environmental factors specific to the individual may modulate colonization of skin microbiota, and knowledge of how they do so can advance our understanding of the delicate balance between host and microorganisms,” they added.
In the study, the researchers conducted a prospective analysis of six males with Fitzpatrick types I or II skin exposed to various sources of UVR, including UVA1 and narrowband UVB. Participants received differing doses of irradiation, which was applied to the left upper or mid-back.
Both pre- and postexposure skin samples were obtained directly and 24 hours following UVR exposure. DNA from the cutaneous swabs was isolated and replicated via sequencing technology, which was used to analyze the microbial makeup of each sample.
After genomic analysis, Dr. Burns and her colleagues found extensive microbial differences among participants at each data collection point. Bacterial composition of the skin biome was altered 24 hours post UVR exposure both within and between study subjects, which included species- and phylum-level changes. While changes varied widely, trends that they identified included a “general increase” in the phylum Cyanobacteria and decreases in the family Lactobacillaceae and Pseudomonadaceae, they wrote.
Two key limitations of the study were the small sample size and inclusion of male participants only, which limits the generalizability of the results, the authors noted.
“These findings could add new insight into the treatment of UV-induced cutaneous inflammation and other skin diseases linked to microbiome shifts or UVR exposure,” they concluded. Future studies, they added, could address “the question of a protective nature of microbial inhabitants of the healthy skin microbiome,” which “may pave the way for the use of prophylactic probiotics for dermatologic health management.”
This study was supported by grant funding from the National Institutes of Health and University of Alabama at Birmingham. The authors – from the University of Alabama as well as Henry Ford Hospital, Detroit, and Florida State University, Tallahassee – reported no conflicts of interest.
SOURCE: Burns EM et al. Exp Dermatol. 2018 Dec 02. doi: 10.1111/exd.13854.
, in a small pilot study published in Experimental Dermatology.
“Human skin and its microbial inhabitants are also subject to the effects of external and environmental stressors, such as ultraviolet radiation,” wrote Erin M. Burns, MS, PhD, of the department of dermatology at the University of Alabama at Birmingham, and her coauthors. “Environmental factors specific to the individual may modulate colonization of skin microbiota, and knowledge of how they do so can advance our understanding of the delicate balance between host and microorganisms,” they added.
In the study, the researchers conducted a prospective analysis of six males with Fitzpatrick types I or II skin exposed to various sources of UVR, including UVA1 and narrowband UVB. Participants received differing doses of irradiation, which was applied to the left upper or mid-back.
Both pre- and postexposure skin samples were obtained directly and 24 hours following UVR exposure. DNA from the cutaneous swabs was isolated and replicated via sequencing technology, which was used to analyze the microbial makeup of each sample.
After genomic analysis, Dr. Burns and her colleagues found extensive microbial differences among participants at each data collection point. Bacterial composition of the skin biome was altered 24 hours post UVR exposure both within and between study subjects, which included species- and phylum-level changes. While changes varied widely, trends that they identified included a “general increase” in the phylum Cyanobacteria and decreases in the family Lactobacillaceae and Pseudomonadaceae, they wrote.
Two key limitations of the study were the small sample size and inclusion of male participants only, which limits the generalizability of the results, the authors noted.
“These findings could add new insight into the treatment of UV-induced cutaneous inflammation and other skin diseases linked to microbiome shifts or UVR exposure,” they concluded. Future studies, they added, could address “the question of a protective nature of microbial inhabitants of the healthy skin microbiome,” which “may pave the way for the use of prophylactic probiotics for dermatologic health management.”
This study was supported by grant funding from the National Institutes of Health and University of Alabama at Birmingham. The authors – from the University of Alabama as well as Henry Ford Hospital, Detroit, and Florida State University, Tallahassee – reported no conflicts of interest.
SOURCE: Burns EM et al. Exp Dermatol. 2018 Dec 02. doi: 10.1111/exd.13854.
, in a small pilot study published in Experimental Dermatology.
“Human skin and its microbial inhabitants are also subject to the effects of external and environmental stressors, such as ultraviolet radiation,” wrote Erin M. Burns, MS, PhD, of the department of dermatology at the University of Alabama at Birmingham, and her coauthors. “Environmental factors specific to the individual may modulate colonization of skin microbiota, and knowledge of how they do so can advance our understanding of the delicate balance between host and microorganisms,” they added.
In the study, the researchers conducted a prospective analysis of six males with Fitzpatrick types I or II skin exposed to various sources of UVR, including UVA1 and narrowband UVB. Participants received differing doses of irradiation, which was applied to the left upper or mid-back.
Both pre- and postexposure skin samples were obtained directly and 24 hours following UVR exposure. DNA from the cutaneous swabs was isolated and replicated via sequencing technology, which was used to analyze the microbial makeup of each sample.
After genomic analysis, Dr. Burns and her colleagues found extensive microbial differences among participants at each data collection point. Bacterial composition of the skin biome was altered 24 hours post UVR exposure both within and between study subjects, which included species- and phylum-level changes. While changes varied widely, trends that they identified included a “general increase” in the phylum Cyanobacteria and decreases in the family Lactobacillaceae and Pseudomonadaceae, they wrote.
Two key limitations of the study were the small sample size and inclusion of male participants only, which limits the generalizability of the results, the authors noted.
“These findings could add new insight into the treatment of UV-induced cutaneous inflammation and other skin diseases linked to microbiome shifts or UVR exposure,” they concluded. Future studies, they added, could address “the question of a protective nature of microbial inhabitants of the healthy skin microbiome,” which “may pave the way for the use of prophylactic probiotics for dermatologic health management.”
This study was supported by grant funding from the National Institutes of Health and University of Alabama at Birmingham. The authors – from the University of Alabama as well as Henry Ford Hospital, Detroit, and Florida State University, Tallahassee – reported no conflicts of interest.
SOURCE: Burns EM et al. Exp Dermatol. 2018 Dec 02. doi: 10.1111/exd.13854.
FROM EXPERIMENTAL DERMATOLOGY
Key clinical point: The makeup of the human skin microbiome was altered following ultraviolet radiation (UVR) exposure.
Major finding: Bacterial composition was changed both qualitatively and quantitatively 24 hours post UVR exposure.
Study details: A pilot study of six men with Fitzpatrick types I or II skin exposed to UVA and UVB radiation.
Disclosures: This study was supported by grant funding from the National Institutes of Health and University of Alabama at Birmingham. The authors reported no conflicts of interest.
Source: Burns EM et al. Exp Dermatol. 2018 Dec 2. doi: 10.1111/exd.13854.
A 60-year-old white woman presented with a 3-month history of a painful, nonhealing ulceration on her left lateral lower leg
It is a vasculopathy rather than a vasculitis as the former is caused by occlusion of blood vessels and the latter results from inflammation of the vessels. Middle-aged women tend to be affected more frequently. Although the exact cause is unclear, systemic diseases, such as hypercoagulable states, may predispose vessels to develop occlusion. Associated disorders include antiphospholipid syndrome, protein C deficiency, factor V mutation, arteriosclerosis, hyperhomocysteinemia, and hepatitis C.
Typically, lesions begin as painful purpura or reticulated macules on the lower extremities that ulcerate and heal very slowly. Ankles, particularly malleoli, are more frequently affected. When they heal, they form painless white stellate scars typical of atrophie blanche. Surrounding erythema, telangiectasias, and sclerosis may be present; livedo reticularis may be seen as well.
Histologically, the epidermis may be atrophic or necrotic. Hyaline thickening of the blood vessel walls is seen. Thrombi may be present. Direct immunofluorescence of perilesional skin may be positive for complement C3 and immunoglobulin (IgM) in dermal blood vessels.
Livedoid vasculopathy can be difficult to treat. Treatment is aimed at reducing clotting and improving blood flow and includes antiplatelet drugs (low-dose aspirin, dipyridamole), anticoagulants, and vasodilating agents (nifedipine). Pentoxifylline two or three times daily may help by altering blood viscosity. A recent literature search reports success in topical dapsone applied to lesions twice daily under occlusion. Leg elevation and compression stockings help healing. Livedoid vasculopathy may have periods of activity and remission.
The case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/edermatologynews.com. To submit a case for possible publication, send an email to [email protected]
It is a vasculopathy rather than a vasculitis as the former is caused by occlusion of blood vessels and the latter results from inflammation of the vessels. Middle-aged women tend to be affected more frequently. Although the exact cause is unclear, systemic diseases, such as hypercoagulable states, may predispose vessels to develop occlusion. Associated disorders include antiphospholipid syndrome, protein C deficiency, factor V mutation, arteriosclerosis, hyperhomocysteinemia, and hepatitis C.
Typically, lesions begin as painful purpura or reticulated macules on the lower extremities that ulcerate and heal very slowly. Ankles, particularly malleoli, are more frequently affected. When they heal, they form painless white stellate scars typical of atrophie blanche. Surrounding erythema, telangiectasias, and sclerosis may be present; livedo reticularis may be seen as well.
Histologically, the epidermis may be atrophic or necrotic. Hyaline thickening of the blood vessel walls is seen. Thrombi may be present. Direct immunofluorescence of perilesional skin may be positive for complement C3 and immunoglobulin (IgM) in dermal blood vessels.
Livedoid vasculopathy can be difficult to treat. Treatment is aimed at reducing clotting and improving blood flow and includes antiplatelet drugs (low-dose aspirin, dipyridamole), anticoagulants, and vasodilating agents (nifedipine). Pentoxifylline two or three times daily may help by altering blood viscosity. A recent literature search reports success in topical dapsone applied to lesions twice daily under occlusion. Leg elevation and compression stockings help healing. Livedoid vasculopathy may have periods of activity and remission.
The case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/edermatologynews.com. To submit a case for possible publication, send an email to [email protected]
It is a vasculopathy rather than a vasculitis as the former is caused by occlusion of blood vessels and the latter results from inflammation of the vessels. Middle-aged women tend to be affected more frequently. Although the exact cause is unclear, systemic diseases, such as hypercoagulable states, may predispose vessels to develop occlusion. Associated disorders include antiphospholipid syndrome, protein C deficiency, factor V mutation, arteriosclerosis, hyperhomocysteinemia, and hepatitis C.
Typically, lesions begin as painful purpura or reticulated macules on the lower extremities that ulcerate and heal very slowly. Ankles, particularly malleoli, are more frequently affected. When they heal, they form painless white stellate scars typical of atrophie blanche. Surrounding erythema, telangiectasias, and sclerosis may be present; livedo reticularis may be seen as well.
Histologically, the epidermis may be atrophic or necrotic. Hyaline thickening of the blood vessel walls is seen. Thrombi may be present. Direct immunofluorescence of perilesional skin may be positive for complement C3 and immunoglobulin (IgM) in dermal blood vessels.
Livedoid vasculopathy can be difficult to treat. Treatment is aimed at reducing clotting and improving blood flow and includes antiplatelet drugs (low-dose aspirin, dipyridamole), anticoagulants, and vasodilating agents (nifedipine). Pentoxifylline two or three times daily may help by altering blood viscosity. A recent literature search reports success in topical dapsone applied to lesions twice daily under occlusion. Leg elevation and compression stockings help healing. Livedoid vasculopathy may have periods of activity and remission.
The case and photo were submitted by Dr. Bilu Martin.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/edermatologynews.com. To submit a case for possible publication, send an email to [email protected]
Hidradenitis suppurativa linked to increased lymphoma risk
Lymphomas appear to be up to four times more likely in patients with hidradenitis suppurativa than among the general population, Rachel Tannenbaum and her colleagues reported in a Research Letter in JAMA Dermatology.
The risks of Hodgkin (HL), non-Hodgkin (NHL), and cutaneous T-cell lymphoma (CTCL) all were significantly higher among patients with HS, wrote Ms. Tannenbaum, Andrew Strunk, and Amit Garg, MD. Males and older patients carried higher risks than females and younger patients, they found.
The team members, of Hofstra University, Hempstead, N.Y., conducted a health care database study comprising 55 million patients included in 27 integrated U.S. health care systems. All the subjects were at least 18 years old; records indicated active HS during the study period of 2013-2018. A regression analysis controlled for age and sex.
The database contained 62,690 patients with HS. The majority (74%) were female and were aged 44 years or younger (57%).
All three lymphomas were more common among HS patients than patients without HS, including non-Hodgkin lymphoma (0.40% vs. 0.35%,) Hodgkin lymphoma (0.17% vs. 0.09%), and cutaneous T-cell lymphoma (0.06% vs. 0.02%).
The multivariate analysis determined that HS patients were twice as likely to develop both non-Hodgkin and Hodgkin lymphoma (odds ratio, 2.0 and 2.21, respectively). They were four times more likely to develop cutaneous T-cell lymphoma (OR, 4.31).
All three lymphomas were more common among males than females: NHL, 0.62% vs. 0.32%; HL, 0.28% vs. 0.13%; and CTCL, 0.09% vs. 0.04%. This translated into significantly increased HS-associated risks, Ms. Tannenbaum and her coauthors noted. “For example, the [odds ratios] for the association between HS and HL were higher in males (OR, 2.97; 95% confidence interval, 2.22-3.99) than in females (OR, 1.86; 95% CI, 1.44-2.39) (P = .02),” they wrote.
Lymphomas were more common among HS patients in every age group. Patients with HS aged 45-64 years were 38% more likely to develop NHL, and those older than 65, about twice as likely (OR, 1.99).
“To our knowledge, this is the first investigation to systematically evaluate this association in a U.S. population of patients with HS,” the research team concluded.
The study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
SOURCE: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.
Lymphomas appear to be up to four times more likely in patients with hidradenitis suppurativa than among the general population, Rachel Tannenbaum and her colleagues reported in a Research Letter in JAMA Dermatology.
The risks of Hodgkin (HL), non-Hodgkin (NHL), and cutaneous T-cell lymphoma (CTCL) all were significantly higher among patients with HS, wrote Ms. Tannenbaum, Andrew Strunk, and Amit Garg, MD. Males and older patients carried higher risks than females and younger patients, they found.
The team members, of Hofstra University, Hempstead, N.Y., conducted a health care database study comprising 55 million patients included in 27 integrated U.S. health care systems. All the subjects were at least 18 years old; records indicated active HS during the study period of 2013-2018. A regression analysis controlled for age and sex.
The database contained 62,690 patients with HS. The majority (74%) were female and were aged 44 years or younger (57%).
All three lymphomas were more common among HS patients than patients without HS, including non-Hodgkin lymphoma (0.40% vs. 0.35%,) Hodgkin lymphoma (0.17% vs. 0.09%), and cutaneous T-cell lymphoma (0.06% vs. 0.02%).
The multivariate analysis determined that HS patients were twice as likely to develop both non-Hodgkin and Hodgkin lymphoma (odds ratio, 2.0 and 2.21, respectively). They were four times more likely to develop cutaneous T-cell lymphoma (OR, 4.31).
All three lymphomas were more common among males than females: NHL, 0.62% vs. 0.32%; HL, 0.28% vs. 0.13%; and CTCL, 0.09% vs. 0.04%. This translated into significantly increased HS-associated risks, Ms. Tannenbaum and her coauthors noted. “For example, the [odds ratios] for the association between HS and HL were higher in males (OR, 2.97; 95% confidence interval, 2.22-3.99) than in females (OR, 1.86; 95% CI, 1.44-2.39) (P = .02),” they wrote.
Lymphomas were more common among HS patients in every age group. Patients with HS aged 45-64 years were 38% more likely to develop NHL, and those older than 65, about twice as likely (OR, 1.99).
“To our knowledge, this is the first investigation to systematically evaluate this association in a U.S. population of patients with HS,” the research team concluded.
The study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
SOURCE: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.
Lymphomas appear to be up to four times more likely in patients with hidradenitis suppurativa than among the general population, Rachel Tannenbaum and her colleagues reported in a Research Letter in JAMA Dermatology.
The risks of Hodgkin (HL), non-Hodgkin (NHL), and cutaneous T-cell lymphoma (CTCL) all were significantly higher among patients with HS, wrote Ms. Tannenbaum, Andrew Strunk, and Amit Garg, MD. Males and older patients carried higher risks than females and younger patients, they found.
The team members, of Hofstra University, Hempstead, N.Y., conducted a health care database study comprising 55 million patients included in 27 integrated U.S. health care systems. All the subjects were at least 18 years old; records indicated active HS during the study period of 2013-2018. A regression analysis controlled for age and sex.
The database contained 62,690 patients with HS. The majority (74%) were female and were aged 44 years or younger (57%).
All three lymphomas were more common among HS patients than patients without HS, including non-Hodgkin lymphoma (0.40% vs. 0.35%,) Hodgkin lymphoma (0.17% vs. 0.09%), and cutaneous T-cell lymphoma (0.06% vs. 0.02%).
The multivariate analysis determined that HS patients were twice as likely to develop both non-Hodgkin and Hodgkin lymphoma (odds ratio, 2.0 and 2.21, respectively). They were four times more likely to develop cutaneous T-cell lymphoma (OR, 4.31).
All three lymphomas were more common among males than females: NHL, 0.62% vs. 0.32%; HL, 0.28% vs. 0.13%; and CTCL, 0.09% vs. 0.04%. This translated into significantly increased HS-associated risks, Ms. Tannenbaum and her coauthors noted. “For example, the [odds ratios] for the association between HS and HL were higher in males (OR, 2.97; 95% confidence interval, 2.22-3.99) than in females (OR, 1.86; 95% CI, 1.44-2.39) (P = .02),” they wrote.
Lymphomas were more common among HS patients in every age group. Patients with HS aged 45-64 years were 38% more likely to develop NHL, and those older than 65, about twice as likely (OR, 1.99).
“To our knowledge, this is the first investigation to systematically evaluate this association in a U.S. population of patients with HS,” the research team concluded.
The study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
SOURCE: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.
FROM JAMA DERMATOLOGY
Key clinical point: Hidradenitis suppurativa appears to increase the risk of cutaneous T-cell lymphoma, Hodgkin, and non-Hodgkin lymphomas.
Major finding: Lymphomas are up to four times more common among patients with hidradenitis suppurativa than those without the chronic inflammatory disorder.
Study details: The database review comprised more than 55 million patients in 27 linked health care systems.
Disclosures: This study was supported by a grant from AbbVie. Ms. Tannenbaum and Mr. Strunk reported no disclosures. Dr. Garg reported financial relationships with AbbVie and several other pharmaceutical companies.
Source: Tannenbaum R et al. JAMA Dermatol. 2019 Jan 30. doi: 10.1001/jamadermatol.2018.5230.