Dermatology News

Six medical societies from across the globe are emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time.

The statement, “Joint Guidance on Vitamin D in the Era of COVID-19,” is supported by the American Society for Bone and Mineral Research, the Endocrine Society, and the American Association of Clinical Endocrinologists, among others.

They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15-30 minutes per day, while taking care to avoid sunburn.

The statement noted that “vitamin D is very safe when taken at reasonable dosages and is important for musculoskeletal health. Levels are likely to decline as individuals reduce outside activity (sun exposure) during the pandemic.”

It added that “most older and younger adults can safely take 400-1000 IU daily to keep vitamin D levels within the optimal range as recommended by [the US] Institute of Medicine guidelines.”

The statement also noted that the scientific evidence clearly supports the benefits that vitamin D (in combination with calcium intake) plays in building a strong skeleton and preventing bone loss.

Other societies supporting the statement are the European Calcified Tissue Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation.

What role for vitamin D in COVID-19?

Over recent months, the role of vitamin D in relation to prevention of COVID-19 has been the subject of intense debate. Now, these societies have joined forces and endorsed evidence-based guidance to clarify the issue around obtaining the daily recommended dosage of vitamin D.

During the pandemic, orders to stay at home meant individuals were likely to spend less time outdoors and have less opportunity to draw their vitamin D directly from sunlight, which is its main source, other than a limited number of foods or as a dietary supplement, the societies explained.

However, they acknowledged that the role of vitamin D in COVID-19 remains unclear.

“The current data do not provide any evidence that vitamin D supplementation will help prevent or treat COVID-19 infection; however, our guidance does not preclude further study of the potential effects of vitamin D on COVID-19,” the joint statement said.

Research to date suggests that vitamin D may play a role in enhancing the immune response, and given prior work demonstrating a role for the activated form of vitamin D – 1,25(OH)2D – in immune responses, “further research into vitamin D supplementation in COVID-19 disease is warranted,” it added. “Trials to date have been observational and there have been no randomized, controlled trials from which firm conclusions about causal relationships can be drawn. Observational studies suggest associations between low vitamin D concentrations and higher rates of COVID-19 infection.”

Medscape Medical News previously reported on the existing observational data regarding vitamin D in COVID-19. A recent rapid evidence review by the National Institute for Health and Care Excellence failed to find any evidence that vitamin D supplementation reduces the risk or severity of COVID-19.

A version of this article originally appeared on Medscape.com.

Six medical societies from across the globe are emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time.

The statement, “Joint Guidance on Vitamin D in the Era of COVID-19,” is supported by the American Society for Bone and Mineral Research, the Endocrine Society, and the American Association of Clinical Endocrinologists, among others.

They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15-30 minutes per day, while taking care to avoid sunburn.

The statement noted that “vitamin D is very safe when taken at reasonable dosages and is important for musculoskeletal health. Levels are likely to decline as individuals reduce outside activity (sun exposure) during the pandemic.”

It added that “most older and younger adults can safely take 400-1000 IU daily to keep vitamin D levels within the optimal range as recommended by [the US] Institute of Medicine guidelines.”

The statement also noted that the scientific evidence clearly supports the benefits that vitamin D (in combination with calcium intake) plays in building a strong skeleton and preventing bone loss.

Other societies supporting the statement are the European Calcified Tissue Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation.

What role for vitamin D in COVID-19?

Over recent months, the role of vitamin D in relation to prevention of COVID-19 has been the subject of intense debate. Now, these societies have joined forces and endorsed evidence-based guidance to clarify the issue around obtaining the daily recommended dosage of vitamin D.

During the pandemic, orders to stay at home meant individuals were likely to spend less time outdoors and have less opportunity to draw their vitamin D directly from sunlight, which is its main source, other than a limited number of foods or as a dietary supplement, the societies explained.

However, they acknowledged that the role of vitamin D in COVID-19 remains unclear.

“The current data do not provide any evidence that vitamin D supplementation will help prevent or treat COVID-19 infection; however, our guidance does not preclude further study of the potential effects of vitamin D on COVID-19,” the joint statement said.

Research to date suggests that vitamin D may play a role in enhancing the immune response, and given prior work demonstrating a role for the activated form of vitamin D – 1,25(OH)2D – in immune responses, “further research into vitamin D supplementation in COVID-19 disease is warranted,” it added. “Trials to date have been observational and there have been no randomized, controlled trials from which firm conclusions about causal relationships can be drawn. Observational studies suggest associations between low vitamin D concentrations and higher rates of COVID-19 infection.”

Medscape Medical News previously reported on the existing observational data regarding vitamin D in COVID-19. A recent rapid evidence review by the National Institute for Health and Care Excellence failed to find any evidence that vitamin D supplementation reduces the risk or severity of COVID-19.

A version of this article originally appeared on Medscape.com.

Six medical societies from across the globe are emphasizing the importance of individuals obtaining the daily recommended dose of vitamin D, especially given the impact of the COVID-19 pandemic on outdoor time.

The statement, “Joint Guidance on Vitamin D in the Era of COVID-19,” is supported by the American Society for Bone and Mineral Research, the Endocrine Society, and the American Association of Clinical Endocrinologists, among others.

They felt the need to clarify the recommendations for clinicians. Central to the guidance is the recommendation to directly expose the skin to sunlight for 15-30 minutes per day, while taking care to avoid sunburn.

The statement noted that “vitamin D is very safe when taken at reasonable dosages and is important for musculoskeletal health. Levels are likely to decline as individuals reduce outside activity (sun exposure) during the pandemic.”

It added that “most older and younger adults can safely take 400-1000 IU daily to keep vitamin D levels within the optimal range as recommended by [the US] Institute of Medicine guidelines.”

The statement also noted that the scientific evidence clearly supports the benefits that vitamin D (in combination with calcium intake) plays in building a strong skeleton and preventing bone loss.

Other societies supporting the statement are the European Calcified Tissue Society, the National Osteoporosis Foundation, and the International Osteoporosis Foundation.

What role for vitamin D in COVID-19?

Over recent months, the role of vitamin D in relation to prevention of COVID-19 has been the subject of intense debate. Now, these societies have joined forces and endorsed evidence-based guidance to clarify the issue around obtaining the daily recommended dosage of vitamin D.

During the pandemic, orders to stay at home meant individuals were likely to spend less time outdoors and have less opportunity to draw their vitamin D directly from sunlight, which is its main source, other than a limited number of foods or as a dietary supplement, the societies explained.

However, they acknowledged that the role of vitamin D in COVID-19 remains unclear.

“The current data do not provide any evidence that vitamin D supplementation will help prevent or treat COVID-19 infection; however, our guidance does not preclude further study of the potential effects of vitamin D on COVID-19,” the joint statement said.

Research to date suggests that vitamin D may play a role in enhancing the immune response, and given prior work demonstrating a role for the activated form of vitamin D – 1,25(OH)2D – in immune responses, “further research into vitamin D supplementation in COVID-19 disease is warranted,” it added. “Trials to date have been observational and there have been no randomized, controlled trials from which firm conclusions about causal relationships can be drawn. Observational studies suggest associations between low vitamin D concentrations and higher rates of COVID-19 infection.”

Medscape Medical News previously reported on the existing observational data regarding vitamin D in COVID-19. A recent rapid evidence review by the National Institute for Health and Care Excellence failed to find any evidence that vitamin D supplementation reduces the risk or severity of COVID-19.

A version of this article originally appeared on Medscape.com.

Adding subcutaneous nemolizumab to topical treatments for atopic dermatitis patients significantly improved their itching, compared with a placebo, in a phase 3 study of 215 patients in Japan.

Controlling the pruritus associated with atopic dermatitis (AD) can have a significant impact on patients’ quality of life, wrote Kenji Kabashima, MD, PhD, of the department of dermatology at Kyoto University, and coauthors. Frequent scratching can cause not only mechanical skin damage, but also may enhance inflammatory reactions and contribute to sleep problems.

In earlier phase studies, nemolizumab, a humanized monoclonal antibody against interleukin-31 receptor A, showed efficacy in reducing pruritus in patients with AD, but has not been well studied in patients who are also using topical agents, they wrote.

In the study published in the New England Journal of Medicine, the researchers randomized 143 patients with AD and moderate to severe pruritus to 60 mg of subcutaneous nemolizumab and 72 patients to a placebo every 4 weeks for 16 weeks. All patients were aged 13 years and older with a confirmed AD diagnosis and a history of inadequate response to or inability to use treatments, including topical glucocorticoids and oral antihistamines. Their average age was 40 years, approximately two-thirds were male, and the average disease duration was approximately 30 years. Topical treatments included a medium potency glucocorticoid in 97% of patients in both groups, and a topical calcineurin inhibitor in 41% of those on nemolizumab, and 40% of those on placebo; almost 90% of the patients in both groups were on oral antihistamines.

At 16 weeks, scores on the visual analog scale for pruritus (the primary outcome) significantly improved from baseline in the nemolizumab group, compared with the placebo group (a mean change of –42.8% and –21.4%, respectively, P < .001).

In addition, more patients in the nemolizumab group, compared with the placebo group (40% vs. 22%) achieved a score of 4 or less on the Dermatology Life Quality Index, with lower scores reflecting less impact of disease on daily life. In addition, more patients in the nemolizumab group, compared with the placebo group (55% vs. 21%) achieved a score of 7 or less on the Insomnia Severity Index.

During the study, 71% of the patients in each group reported adverse events, most were mild or moderate. The most common adverse event was worsening AD, reported by 24% of the nemolizumab patients and 21% of the placebo patients. Reactions related to the injection occurred in 8% of nemolizumab patients and 3% of placebo patients. Cytokine abnormalities, which included an increased level of thymus and activation regulated chemokine, were reported in 10 (7%) of the patients on nemolizumab, none of which occurred in those on placebo. “Most were not accompanied by a worsening of signs of or the extent of atopic dermatitis,” the authors wrote.

Severe adverse events were reported in three patients (2%) in the nemolizumab group, which were Meniere’s disease, acute pancreatitis, and AD in one patient each. No severe adverse events were reported in the placebo group. In addition, three patients in the nemolizumab group experienced four treatment-related adverse events that led them to discontinue treatment: AD, Meniere’s disease, alopecia, and peripheral edema.

The study findings were limited by several factors including the relatively short treatment period, inclusion only of Japanese patients, inclusion of patients aged as young as 13 years, and the inability to draw conclusions from the secondary endpoints such as quality of life and sleep issues, the researchers noted.

However, the results suggest that “nemolizumab plus topical agents may ameliorate both pruritus and signs of eczema and may lessen the severity of atopic dermatitis by disrupting the itch-scratch cycle,” they added.

“Novel therapies [for AD] are needed, as there are still patients who need better disease control despite current therapies, and AD is a heterogeneous disease that may need different treatment approaches,” Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland, said in an interview.

Dr. Simpson, who was not an investigator in this study, said that he was somewhat surprised that the itch reduction was lower in the current study, compared with previous studies by the same group. Also surprising was the increase in cytokine abnormalities in the nemolizumab group, which “needs further study.”

Overall, the data “provide support that blockade of the IL-31 receptor improves itch in AD and appears to have some effect on inflammation,” Dr. Simpson said.

One challenge to the clinical use of nemolizumab will be identifying “where this type of drug fits into the treatment paradigm,” and determining whether specific patients whose disease is driven more by this neuroimmune pathway could benefit more than with the traditional IL-4 or IL-13 blockade, he said.

The study was supported by Maruho. Dr. Kabashima disclosed consulting fees from Maruho and two coauthors were Maruho employees. Dr. Simpson had no financial conflicts relevant to this study, but he reported receiving research grants and other financial relationships with manufacturers of AD therapies.

SOURCE: Kabashima K et al. N Engl J Med. 2020 Jul 9. doi: 10.1056/NEJMoa1917006.

Adding subcutaneous nemolizumab to topical treatments for atopic dermatitis patients significantly improved their itching, compared with a placebo, in a phase 3 study of 215 patients in Japan.

Controlling the pruritus associated with atopic dermatitis (AD) can have a significant impact on patients’ quality of life, wrote Kenji Kabashima, MD, PhD, of the department of dermatology at Kyoto University, and coauthors. Frequent scratching can cause not only mechanical skin damage, but also may enhance inflammatory reactions and contribute to sleep problems.

In earlier phase studies, nemolizumab, a humanized monoclonal antibody against interleukin-31 receptor A, showed efficacy in reducing pruritus in patients with AD, but has not been well studied in patients who are also using topical agents, they wrote.

In the study published in the New England Journal of Medicine, the researchers randomized 143 patients with AD and moderate to severe pruritus to 60 mg of subcutaneous nemolizumab and 72 patients to a placebo every 4 weeks for 16 weeks. All patients were aged 13 years and older with a confirmed AD diagnosis and a history of inadequate response to or inability to use treatments, including topical glucocorticoids and oral antihistamines. Their average age was 40 years, approximately two-thirds were male, and the average disease duration was approximately 30 years. Topical treatments included a medium potency glucocorticoid in 97% of patients in both groups, and a topical calcineurin inhibitor in 41% of those on nemolizumab, and 40% of those on placebo; almost 90% of the patients in both groups were on oral antihistamines.

At 16 weeks, scores on the visual analog scale for pruritus (the primary outcome) significantly improved from baseline in the nemolizumab group, compared with the placebo group (a mean change of –42.8% and –21.4%, respectively, P < .001).

In addition, more patients in the nemolizumab group, compared with the placebo group (40% vs. 22%) achieved a score of 4 or less on the Dermatology Life Quality Index, with lower scores reflecting less impact of disease on daily life. In addition, more patients in the nemolizumab group, compared with the placebo group (55% vs. 21%) achieved a score of 7 or less on the Insomnia Severity Index.

During the study, 71% of the patients in each group reported adverse events, most were mild or moderate. The most common adverse event was worsening AD, reported by 24% of the nemolizumab patients and 21% of the placebo patients. Reactions related to the injection occurred in 8% of nemolizumab patients and 3% of placebo patients. Cytokine abnormalities, which included an increased level of thymus and activation regulated chemokine, were reported in 10 (7%) of the patients on nemolizumab, none of which occurred in those on placebo. “Most were not accompanied by a worsening of signs of or the extent of atopic dermatitis,” the authors wrote.

Severe adverse events were reported in three patients (2%) in the nemolizumab group, which were Meniere’s disease, acute pancreatitis, and AD in one patient each. No severe adverse events were reported in the placebo group. In addition, three patients in the nemolizumab group experienced four treatment-related adverse events that led them to discontinue treatment: AD, Meniere’s disease, alopecia, and peripheral edema.

The study findings were limited by several factors including the relatively short treatment period, inclusion only of Japanese patients, inclusion of patients aged as young as 13 years, and the inability to draw conclusions from the secondary endpoints such as quality of life and sleep issues, the researchers noted.

However, the results suggest that “nemolizumab plus topical agents may ameliorate both pruritus and signs of eczema and may lessen the severity of atopic dermatitis by disrupting the itch-scratch cycle,” they added.

“Novel therapies [for AD] are needed, as there are still patients who need better disease control despite current therapies, and AD is a heterogeneous disease that may need different treatment approaches,” Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland, said in an interview.

Dr. Simpson, who was not an investigator in this study, said that he was somewhat surprised that the itch reduction was lower in the current study, compared with previous studies by the same group. Also surprising was the increase in cytokine abnormalities in the nemolizumab group, which “needs further study.”

Overall, the data “provide support that blockade of the IL-31 receptor improves itch in AD and appears to have some effect on inflammation,” Dr. Simpson said.

One challenge to the clinical use of nemolizumab will be identifying “where this type of drug fits into the treatment paradigm,” and determining whether specific patients whose disease is driven more by this neuroimmune pathway could benefit more than with the traditional IL-4 or IL-13 blockade, he said.

The study was supported by Maruho. Dr. Kabashima disclosed consulting fees from Maruho and two coauthors were Maruho employees. Dr. Simpson had no financial conflicts relevant to this study, but he reported receiving research grants and other financial relationships with manufacturers of AD therapies.

SOURCE: Kabashima K et al. N Engl J Med. 2020 Jul 9. doi: 10.1056/NEJMoa1917006.

Adding subcutaneous nemolizumab to topical treatments for atopic dermatitis patients significantly improved their itching, compared with a placebo, in a phase 3 study of 215 patients in Japan.

Controlling the pruritus associated with atopic dermatitis (AD) can have a significant impact on patients’ quality of life, wrote Kenji Kabashima, MD, PhD, of the department of dermatology at Kyoto University, and coauthors. Frequent scratching can cause not only mechanical skin damage, but also may enhance inflammatory reactions and contribute to sleep problems.

In earlier phase studies, nemolizumab, a humanized monoclonal antibody against interleukin-31 receptor A, showed efficacy in reducing pruritus in patients with AD, but has not been well studied in patients who are also using topical agents, they wrote.

In the study published in the New England Journal of Medicine, the researchers randomized 143 patients with AD and moderate to severe pruritus to 60 mg of subcutaneous nemolizumab and 72 patients to a placebo every 4 weeks for 16 weeks. All patients were aged 13 years and older with a confirmed AD diagnosis and a history of inadequate response to or inability to use treatments, including topical glucocorticoids and oral antihistamines. Their average age was 40 years, approximately two-thirds were male, and the average disease duration was approximately 30 years. Topical treatments included a medium potency glucocorticoid in 97% of patients in both groups, and a topical calcineurin inhibitor in 41% of those on nemolizumab, and 40% of those on placebo; almost 90% of the patients in both groups were on oral antihistamines.

At 16 weeks, scores on the visual analog scale for pruritus (the primary outcome) significantly improved from baseline in the nemolizumab group, compared with the placebo group (a mean change of –42.8% and –21.4%, respectively, P < .001).

In addition, more patients in the nemolizumab group, compared with the placebo group (40% vs. 22%) achieved a score of 4 or less on the Dermatology Life Quality Index, with lower scores reflecting less impact of disease on daily life. In addition, more patients in the nemolizumab group, compared with the placebo group (55% vs. 21%) achieved a score of 7 or less on the Insomnia Severity Index.

During the study, 71% of the patients in each group reported adverse events, most were mild or moderate. The most common adverse event was worsening AD, reported by 24% of the nemolizumab patients and 21% of the placebo patients. Reactions related to the injection occurred in 8% of nemolizumab patients and 3% of placebo patients. Cytokine abnormalities, which included an increased level of thymus and activation regulated chemokine, were reported in 10 (7%) of the patients on nemolizumab, none of which occurred in those on placebo. “Most were not accompanied by a worsening of signs of or the extent of atopic dermatitis,” the authors wrote.

Severe adverse events were reported in three patients (2%) in the nemolizumab group, which were Meniere’s disease, acute pancreatitis, and AD in one patient each. No severe adverse events were reported in the placebo group. In addition, three patients in the nemolizumab group experienced four treatment-related adverse events that led them to discontinue treatment: AD, Meniere’s disease, alopecia, and peripheral edema.

The study findings were limited by several factors including the relatively short treatment period, inclusion only of Japanese patients, inclusion of patients aged as young as 13 years, and the inability to draw conclusions from the secondary endpoints such as quality of life and sleep issues, the researchers noted.

However, the results suggest that “nemolizumab plus topical agents may ameliorate both pruritus and signs of eczema and may lessen the severity of atopic dermatitis by disrupting the itch-scratch cycle,” they added.

“Novel therapies [for AD] are needed, as there are still patients who need better disease control despite current therapies, and AD is a heterogeneous disease that may need different treatment approaches,” Eric Simpson, MD, professor of dermatology at Oregon Health & Science University, Portland, said in an interview.

Dr. Simpson, who was not an investigator in this study, said that he was somewhat surprised that the itch reduction was lower in the current study, compared with previous studies by the same group. Also surprising was the increase in cytokine abnormalities in the nemolizumab group, which “needs further study.”

Overall, the data “provide support that blockade of the IL-31 receptor improves itch in AD and appears to have some effect on inflammation,” Dr. Simpson said.

One challenge to the clinical use of nemolizumab will be identifying “where this type of drug fits into the treatment paradigm,” and determining whether specific patients whose disease is driven more by this neuroimmune pathway could benefit more than with the traditional IL-4 or IL-13 blockade, he said.

The study was supported by Maruho. Dr. Kabashima disclosed consulting fees from Maruho and two coauthors were Maruho employees. Dr. Simpson had no financial conflicts relevant to this study, but he reported receiving research grants and other financial relationships with manufacturers of AD therapies.

SOURCE: Kabashima K et al. N Engl J Med. 2020 Jul 9. doi: 10.1056/NEJMoa1917006.

The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.

“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”

A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, molluscum contagiosum (MC) lesions often appear on the face, neck, armpits, arms, and tops of the hands in children. The abdomen and inner thighs can also be affected. “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.

An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”

The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”

The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”

MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”

MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”

He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.

He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.

He reported having no financial disclosures.

[email protected]

The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.

“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”

A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, molluscum contagiosum (MC) lesions often appear on the face, neck, armpits, arms, and tops of the hands in children. The abdomen and inner thighs can also be affected. “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.

An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”

The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”

The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”

MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”

MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”

He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.

He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.

He reported having no financial disclosures.

[email protected]

The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.

“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”

A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, molluscum contagiosum (MC) lesions often appear on the face, neck, armpits, arms, and tops of the hands in children. The abdomen and inner thighs can also be affected. “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.

An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”

The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”

The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”

MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”

MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”

He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.

He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.

He reported having no financial disclosures.

[email protected]

This Acne and Rosacea supplement to Dermatology News includes commentary from Dr Hilary E. Baldwin

Topics Included:

Pathogenic Pathway As Target In Rosacea Treatment / 5
Acne In Skin Of Color / 6
Under FDA Review Of Novel Acne Treatment / 7
Chemical Peels For Acne / 8
Isotretinoin And Psychiatric Conditions / 10
Pregnancy Reports For Isotretinoin / 11
Rosacea Triggers / 12
Topical Treatment Of Demodex / 13
Social Media And Acne / 14

Read Here

This Acne and Rosacea supplement to Dermatology News includes commentary from Dr Hilary E. Baldwin

Topics Included:

Pathogenic Pathway As Target In Rosacea Treatment / 5
Acne In Skin Of Color / 6
Under FDA Review Of Novel Acne Treatment / 7
Chemical Peels For Acne / 8
Isotretinoin And Psychiatric Conditions / 10
Pregnancy Reports For Isotretinoin / 11
Rosacea Triggers / 12
Topical Treatment Of Demodex / 13
Social Media And Acne / 14

Read Here

This Acne and Rosacea supplement to Dermatology News includes commentary from Dr Hilary E. Baldwin

Topics Included:

Pathogenic Pathway As Target In Rosacea Treatment / 5
Acne In Skin Of Color / 6
Under FDA Review Of Novel Acne Treatment / 7
Chemical Peels For Acne / 8
Isotretinoin And Psychiatric Conditions / 10
Pregnancy Reports For Isotretinoin / 11
Rosacea Triggers / 12
Topical Treatment Of Demodex / 13
Social Media And Acne / 14

Read Here

There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.

Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.

Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).

Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.

Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.

In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
 

Angiogenesis, SFRP2, and VEGF

Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.

The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.

Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).

Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.

Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.

The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.

Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.

Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.

Lipid metabolism and treatment resistance

A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).

The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.

Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.

When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.

When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.

These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.

Striving to understand a complex system

For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.

To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.

Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.

She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.

As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.

Dr. Weeraratna reported having no disclosures.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
 

SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.

There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.

Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.

Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).

Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.

Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.

In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
 

Angiogenesis, SFRP2, and VEGF

Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.

The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.

Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).

Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.

Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.

The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.

Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.

Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.

Lipid metabolism and treatment resistance

A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).

The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.

Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.

When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.

When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.

These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.

Striving to understand a complex system

For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.

To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.

Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.

She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.

As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.

Dr. Weeraratna reported having no disclosures.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
 

SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.

There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.

Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.

Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).

Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.

Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.

In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
 

Angiogenesis, SFRP2, and VEGF

Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.

The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.

Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).

Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.

Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.

The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.

Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.

Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.

Lipid metabolism and treatment resistance

A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).

The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.

Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.

When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.

When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.

These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.

Striving to understand a complex system

For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.

To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.

Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.

She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.

As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.

Dr. Weeraratna reported having no disclosures.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
 

SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.

What do you do now?

Your waiting room is filled with mask-wearing individuals, except for one person. Your staff offers a mask to this person, citing your office policy of requiring masks for all persons in order to prevent asymptomatic COVID-19 spread, and the patient refuses to put it on.

What can you/should you/must you do? Are you required to see a patient who refuses to wear a mask? If you ask the patient to leave without being seen, can you be accused of patient abandonment? If you allow the patient to stay, could you be liable for negligence for exposing others to a deadly illness?

The rules on mask-wearing, while initially downright confusing, have inexorably come to a rough consensus. By governors’ orders, masks are now mandatory in most states, though when and where they are required varies. For example, effective July 7, the governor of Washington has ordered that a business not allow a customer to enter without a face covering.

So far, there are no cases or court decisions to guide us about whether it is negligence to allow an unmasked patient to commingle in a medical practice. Nor do we have case law to help us determine whether patient abandonment would apply if a patient is sent home without being seen.

We can apply the legal principles and cases from other situations to this one, however, to tell us what constitutes negligence or patient abandonment. The practical questions, legally, are who might sue and on what basis?

Who might sue?

Someone who is injured in a public place may sue the owner for negligence if the owner knew or should have known of a danger and didn’t do anything about it. For example, individuals have sued grocery stores successfully after they slipped on a banana peel and fell. If, say, the banana peel was black, that indicates that it had been there for a while, and judges have found that the store management should have known about it and removed it.

Compare the banana peel scenario with the scenario where most news outlets and health departments are telling people, every day, to wear masks while in indoor public spaces, yet owners of a medical practice or facility allow individuals who are not wearing masks to sit in their waiting room. If an individual who was also in the waiting room with the unmasked individual develops COVID-19 2 days later, the ill individual may sue the medical practice for negligence for not removing the unmasked individual.

What about the individual’s responsibility to move away from the person not wearing a mask? That is the aspect of this scenario that attorneys and experts could argue about, for days, in a court case. But to go back to the banana peel case, one could argue that a customer in a grocery store should be looking out for banana peels on the floor and avoid them, yet courts have assigned liability to grocery stores when customers slip and fall.

Let’s review the four elements of negligence which a plaintiff would need to prove:

• Duty: Obligation of one person to another
• Breach: Improper act or omission, in the context of proper behavior to avoid imposing undue risks of harm to other persons and their property
• Damage
• Causation: That the act or omission caused the harm

Those who run medical offices and facilities have a duty to provide reasonably safe public spaces. Unmasked individuals are a risk to others nearby, so the “breach” element is satisfied if a practice fails to impose safety measures. Causation could be proven, or at least inferred, if contact tracing of an individual with COVID-19 showed that the only contact likely to have exposed the ill individual to the virus was an unmasked individual in a medical practice’s waiting room, especially if the unmasked individual was COVID-19 positive before, during, or shortly after the visit to the practice.

What about patient abandonment?

“Patient abandonment” is the legal term for terminating the physician-patient relationship in such a manner that the patient is denied necessary medical care. It is a form of negligence.

Refusing to see a patient unless the patient wears a mask is not denying care, in this attorney’s view, but rather establishing reasonable conditions for getting care. The patient simply needs to put on a mask.

What about the patient who refuses to wear a mask for medical reasons? There are exceptions in most of the governors’ orders for individuals with medical conditions that preclude covering nose and mouth with a mask. A medical office is the perfect place to test an individual’s ability or inability to breathe well while wearing a mask. “Put the mask on and we’ll see how you do” is a reasonable response. Monitor the patient visually and apply a pulse oximeter with mask off and mask on.

One physician recently wrote about measuring her own oxygen levels while wearing four different masks for 5 minutes each, with no change in breathing.

Editor’s note: Read more about mask exemptions in a Medscape interview with pulmonologist Albert Rizzo, MD, chief medical officer of the American Lung Association.

What are some practical tips?

Assuming that a patient is not in acute distress, options in this scenario include:

• Send the patient home and offer a return visit if masked or when the pandemic is over.
• Offer a telehealth visit, with the patient at home.

What if the unmasked person is not a patient but the companion of a patient? What if the individual refusing to wear a mask is an employee? In neither of these two hypotheticals is there a basis for legal action against a practice whose policy requires that everyone wear masks on the premises.

A companion who arrives without a mask should leave the office. An employee who refuses to mask up could be sent home. If the employee has a disability covered by the Americans with Disabilities Act, then the practice may need to make reasonable accommodations so that the employee works in a room alone if unable to work from home.

Those who manage medical practices should check the websites of the state health department and medical societies at least weekly, to see whether the agencies have issued guidance. For example, the Texas Medical Association has issued limited guidance.

A version of this article originally appeared on Medscape.com.

What do you do now?

Your waiting room is filled with mask-wearing individuals, except for one person. Your staff offers a mask to this person, citing your office policy of requiring masks for all persons in order to prevent asymptomatic COVID-19 spread, and the patient refuses to put it on.

What can you/should you/must you do? Are you required to see a patient who refuses to wear a mask? If you ask the patient to leave without being seen, can you be accused of patient abandonment? If you allow the patient to stay, could you be liable for negligence for exposing others to a deadly illness?

The rules on mask-wearing, while initially downright confusing, have inexorably come to a rough consensus. By governors’ orders, masks are now mandatory in most states, though when and where they are required varies. For example, effective July 7, the governor of Washington has ordered that a business not allow a customer to enter without a face covering.

So far, there are no cases or court decisions to guide us about whether it is negligence to allow an unmasked patient to commingle in a medical practice. Nor do we have case law to help us determine whether patient abandonment would apply if a patient is sent home without being seen.

We can apply the legal principles and cases from other situations to this one, however, to tell us what constitutes negligence or patient abandonment. The practical questions, legally, are who might sue and on what basis?

Who might sue?

Someone who is injured in a public place may sue the owner for negligence if the owner knew or should have known of a danger and didn’t do anything about it. For example, individuals have sued grocery stores successfully after they slipped on a banana peel and fell. If, say, the banana peel was black, that indicates that it had been there for a while, and judges have found that the store management should have known about it and removed it.

Compare the banana peel scenario with the scenario where most news outlets and health departments are telling people, every day, to wear masks while in indoor public spaces, yet owners of a medical practice or facility allow individuals who are not wearing masks to sit in their waiting room. If an individual who was also in the waiting room with the unmasked individual develops COVID-19 2 days later, the ill individual may sue the medical practice for negligence for not removing the unmasked individual.

What about the individual’s responsibility to move away from the person not wearing a mask? That is the aspect of this scenario that attorneys and experts could argue about, for days, in a court case. But to go back to the banana peel case, one could argue that a customer in a grocery store should be looking out for banana peels on the floor and avoid them, yet courts have assigned liability to grocery stores when customers slip and fall.

Let’s review the four elements of negligence which a plaintiff would need to prove:

• Duty: Obligation of one person to another
• Breach: Improper act or omission, in the context of proper behavior to avoid imposing undue risks of harm to other persons and their property
• Damage
• Causation: That the act or omission caused the harm

Those who run medical offices and facilities have a duty to provide reasonably safe public spaces. Unmasked individuals are a risk to others nearby, so the “breach” element is satisfied if a practice fails to impose safety measures. Causation could be proven, or at least inferred, if contact tracing of an individual with COVID-19 showed that the only contact likely to have exposed the ill individual to the virus was an unmasked individual in a medical practice’s waiting room, especially if the unmasked individual was COVID-19 positive before, during, or shortly after the visit to the practice.

What about patient abandonment?

“Patient abandonment” is the legal term for terminating the physician-patient relationship in such a manner that the patient is denied necessary medical care. It is a form of negligence.

Refusing to see a patient unless the patient wears a mask is not denying care, in this attorney’s view, but rather establishing reasonable conditions for getting care. The patient simply needs to put on a mask.

What about the patient who refuses to wear a mask for medical reasons? There are exceptions in most of the governors’ orders for individuals with medical conditions that preclude covering nose and mouth with a mask. A medical office is the perfect place to test an individual’s ability or inability to breathe well while wearing a mask. “Put the mask on and we’ll see how you do” is a reasonable response. Monitor the patient visually and apply a pulse oximeter with mask off and mask on.

One physician recently wrote about measuring her own oxygen levels while wearing four different masks for 5 minutes each, with no change in breathing.

Editor’s note: Read more about mask exemptions in a Medscape interview with pulmonologist Albert Rizzo, MD, chief medical officer of the American Lung Association.

What are some practical tips?

Assuming that a patient is not in acute distress, options in this scenario include:

• Send the patient home and offer a return visit if masked or when the pandemic is over.
• Offer a telehealth visit, with the patient at home.

What if the unmasked person is not a patient but the companion of a patient? What if the individual refusing to wear a mask is an employee? In neither of these two hypotheticals is there a basis for legal action against a practice whose policy requires that everyone wear masks on the premises.

A companion who arrives without a mask should leave the office. An employee who refuses to mask up could be sent home. If the employee has a disability covered by the Americans with Disabilities Act, then the practice may need to make reasonable accommodations so that the employee works in a room alone if unable to work from home.

Those who manage medical practices should check the websites of the state health department and medical societies at least weekly, to see whether the agencies have issued guidance. For example, the Texas Medical Association has issued limited guidance.

A version of this article originally appeared on Medscape.com.

What do you do now?

Your waiting room is filled with mask-wearing individuals, except for one person. Your staff offers a mask to this person, citing your office policy of requiring masks for all persons in order to prevent asymptomatic COVID-19 spread, and the patient refuses to put it on.

What can you/should you/must you do? Are you required to see a patient who refuses to wear a mask? If you ask the patient to leave without being seen, can you be accused of patient abandonment? If you allow the patient to stay, could you be liable for negligence for exposing others to a deadly illness?

The rules on mask-wearing, while initially downright confusing, have inexorably come to a rough consensus. By governors’ orders, masks are now mandatory in most states, though when and where they are required varies. For example, effective July 7, the governor of Washington has ordered that a business not allow a customer to enter without a face covering.

So far, there are no cases or court decisions to guide us about whether it is negligence to allow an unmasked patient to commingle in a medical practice. Nor do we have case law to help us determine whether patient abandonment would apply if a patient is sent home without being seen.

We can apply the legal principles and cases from other situations to this one, however, to tell us what constitutes negligence or patient abandonment. The practical questions, legally, are who might sue and on what basis?

Who might sue?

Someone who is injured in a public place may sue the owner for negligence if the owner knew or should have known of a danger and didn’t do anything about it. For example, individuals have sued grocery stores successfully after they slipped on a banana peel and fell. If, say, the banana peel was black, that indicates that it had been there for a while, and judges have found that the store management should have known about it and removed it.

Compare the banana peel scenario with the scenario where most news outlets and health departments are telling people, every day, to wear masks while in indoor public spaces, yet owners of a medical practice or facility allow individuals who are not wearing masks to sit in their waiting room. If an individual who was also in the waiting room with the unmasked individual develops COVID-19 2 days later, the ill individual may sue the medical practice for negligence for not removing the unmasked individual.

What about the individual’s responsibility to move away from the person not wearing a mask? That is the aspect of this scenario that attorneys and experts could argue about, for days, in a court case. But to go back to the banana peel case, one could argue that a customer in a grocery store should be looking out for banana peels on the floor and avoid them, yet courts have assigned liability to grocery stores when customers slip and fall.

Let’s review the four elements of negligence which a plaintiff would need to prove:

• Duty: Obligation of one person to another
• Breach: Improper act or omission, in the context of proper behavior to avoid imposing undue risks of harm to other persons and their property
• Damage
• Causation: That the act or omission caused the harm

Those who run medical offices and facilities have a duty to provide reasonably safe public spaces. Unmasked individuals are a risk to others nearby, so the “breach” element is satisfied if a practice fails to impose safety measures. Causation could be proven, or at least inferred, if contact tracing of an individual with COVID-19 showed that the only contact likely to have exposed the ill individual to the virus was an unmasked individual in a medical practice’s waiting room, especially if the unmasked individual was COVID-19 positive before, during, or shortly after the visit to the practice.

What about patient abandonment?

“Patient abandonment” is the legal term for terminating the physician-patient relationship in such a manner that the patient is denied necessary medical care. It is a form of negligence.

Refusing to see a patient unless the patient wears a mask is not denying care, in this attorney’s view, but rather establishing reasonable conditions for getting care. The patient simply needs to put on a mask.

What about the patient who refuses to wear a mask for medical reasons? There are exceptions in most of the governors’ orders for individuals with medical conditions that preclude covering nose and mouth with a mask. A medical office is the perfect place to test an individual’s ability or inability to breathe well while wearing a mask. “Put the mask on and we’ll see how you do” is a reasonable response. Monitor the patient visually and apply a pulse oximeter with mask off and mask on.

One physician recently wrote about measuring her own oxygen levels while wearing four different masks for 5 minutes each, with no change in breathing.

Editor’s note: Read more about mask exemptions in a Medscape interview with pulmonologist Albert Rizzo, MD, chief medical officer of the American Lung Association.

What are some practical tips?

Assuming that a patient is not in acute distress, options in this scenario include:

• Send the patient home and offer a return visit if masked or when the pandemic is over.
• Offer a telehealth visit, with the patient at home.

What if the unmasked person is not a patient but the companion of a patient? What if the individual refusing to wear a mask is an employee? In neither of these two hypotheticals is there a basis for legal action against a practice whose policy requires that everyone wear masks on the premises.

A companion who arrives without a mask should leave the office. An employee who refuses to mask up could be sent home. If the employee has a disability covered by the Americans with Disabilities Act, then the practice may need to make reasonable accommodations so that the employee works in a room alone if unable to work from home.

Those who manage medical practices should check the websites of the state health department and medical societies at least weekly, to see whether the agencies have issued guidance. For example, the Texas Medical Association has issued limited guidance.

A version of this article originally appeared on Medscape.com.

Oral difelikefalin significantly reduced the intense itching associated with stage 3-5 chronic kidney disease, with or without hemodialysis, in a first-of-its-kind randomized clinical trial, Gil Yosipovitch, MD, said at the virtual annual meeting of the American Academy of Dermatology.

“Difelikefalin at 1.0 mg was associated with clinically meaningful improvements in pruritus. The improvement in itch was significant by week 2. And nearly 40% of patients achieved a complete response, which was more than two-and-one-half times more than with placebo,” noted Dr. Yosipovitch, professor of dermatology and director of the Miami Itch Center at the University of Miami.

Pruritus associated with chronic kidney disease (CKD) is a common, underrecognized, and distressing condition that causes markedly impaired quality of life. It occurs in patients across all stages of CKD, not just in those on hemodialysis, as is widely but mistakenly believed. And at present there is no approved drug in any country for treatment of CKD-associated itch.

Difelikefalin, a novel selective agonist of peripheral kappa opioid receptors, is designed to have very limited CNS penetration. The drug, which is renally excreted, doesn’t bind to mu or delta opioid receptors. Its antipruritic effect arises from activation of kappa opioid receptors on peripheral sensory neurons and immune cells, the dermatologist explained.

Dr. Yosipovitch presented the results of a phase 2, randomized, double-blind, placebo-controlled, 12-week trial in which 240 patients with severe chronic pruritus and stage 3-5 CKD were assigned to once-daily oral difelikefalin at 0.25 mg, 0.5 mg, or 1.0 mg, or placebo. More than 80% of participants were not on dialysis. Indeed, this was the first-ever clinical trial targeting itch in patients across such a broad spectrum of CKD stages.

The primary study endpoint was change from baseline to week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale. The average baseline score was 7, considered severe pruritus on the 0-10 scale. Patients randomized to difelikefalin at 1.0 mg/day had a mean 4.4-point decrease, a significantly greater improvement than the 3.3-point reduction in placebo-treated controls.

“More than a 4-point decrease is considered a very meaningful itch reduction,” Dr. Yosipovitch noted.

The mean reductions in itch score in patients on 0.25 mg and 0.5 mg/day of difelikefalin were 4.0 and 3.8 points, respectively, which fell short of statistical significance versus placebo.

A key prespecified secondary endpoint was the proportion of subjects with at least a 3-point improvement in itch score over 12 weeks. This was achieved in 72% of patients on the top dose of difelikefalin, compared with 58% of controls, a significant difference. A 4-point or larger decrease in itch score occurred in 65% of patients on 1.0 mg/day of the kappa opioid recent agonist, versus 50% of controls, also a significant difference.

A complete response, defined as an itch score of 0 or 1 at least 80% of the time, was significantly more common in all three active treatment groups than in controls, with rates of 33%, 31.6%, and 38.6% at difelikefalin 0.25, 0.5, and 1.0 mg, compared with 4.4% among those on placebo.

Falls occurred in 1.5% of patients on difelikefalin. “The therapy does seem to increase the risk of dizziness, falls, fatigue, and GI complaints,” according to the investigator.

Still, most of these adverse events were mild or moderate in severity. Only about 1% of participants discontinued treatment for such reasons.

Earlier this year, a positive phase 3 trial of an intravenous formulation of difelikefalin for pruritus was reported in CKD patients on hemodialysis (N Engl J Med. 2020 Jan 16;382[3]:222-32).

In an interview, Dr. Yosipovitch said that this new phase 2 oral dose-finding study wasn’t powered to detect differences in treatment efficacy between the dialysis and nondialysis groups. However, the proportion of patients with at least a 3-point improvement in itch at week 12 was similar in the two groups.

“The oral formulation would of course be more convenient and would be preferred for patients not undergoing hemodialysis,” he said. “I would expect that the IV formulation would be the preferred route of administration for a patient undergoing hemodialysis. An IV formulation would be very convenient for such patients because it’s administered at the dialysis clinic at the end of the hemodialysis session.”

The oral difelikefalin phase 3 program is scheduled to start later in 2020.

CKD-associated itch poses a therapeutic challenge because it has so many contributory factors. These include CKD-induced peripheral neuropathy, functional and structural neuropathic changes in the brain, cutaneous mast cell activation, an imbalance between mu opioid receptor overexpression and kappa opioid receptor downregulation, secondary parathyroidism, and systemic accumulation of aluminum, beta 2 microglobulin, and other dialysis-related substances, the dermatologist observed.

Dr. Yosipovitch reported receiving research grants from a half-dozen pharmaceutical companies. He also serves as a consultant to numerous companies, including Cara Therapeutics, which sponsored the phase 2 trial.

[email protected]

Oral difelikefalin significantly reduced the intense itching associated with stage 3-5 chronic kidney disease, with or without hemodialysis, in a first-of-its-kind randomized clinical trial, Gil Yosipovitch, MD, said at the virtual annual meeting of the American Academy of Dermatology.

“Difelikefalin at 1.0 mg was associated with clinically meaningful improvements in pruritus. The improvement in itch was significant by week 2. And nearly 40% of patients achieved a complete response, which was more than two-and-one-half times more than with placebo,” noted Dr. Yosipovitch, professor of dermatology and director of the Miami Itch Center at the University of Miami.

Pruritus associated with chronic kidney disease (CKD) is a common, underrecognized, and distressing condition that causes markedly impaired quality of life. It occurs in patients across all stages of CKD, not just in those on hemodialysis, as is widely but mistakenly believed. And at present there is no approved drug in any country for treatment of CKD-associated itch.

Difelikefalin, a novel selective agonist of peripheral kappa opioid receptors, is designed to have very limited CNS penetration. The drug, which is renally excreted, doesn’t bind to mu or delta opioid receptors. Its antipruritic effect arises from activation of kappa opioid receptors on peripheral sensory neurons and immune cells, the dermatologist explained.

Dr. Yosipovitch presented the results of a phase 2, randomized, double-blind, placebo-controlled, 12-week trial in which 240 patients with severe chronic pruritus and stage 3-5 CKD were assigned to once-daily oral difelikefalin at 0.25 mg, 0.5 mg, or 1.0 mg, or placebo. More than 80% of participants were not on dialysis. Indeed, this was the first-ever clinical trial targeting itch in patients across such a broad spectrum of CKD stages.

The primary study endpoint was change from baseline to week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale. The average baseline score was 7, considered severe pruritus on the 0-10 scale. Patients randomized to difelikefalin at 1.0 mg/day had a mean 4.4-point decrease, a significantly greater improvement than the 3.3-point reduction in placebo-treated controls.

“More than a 4-point decrease is considered a very meaningful itch reduction,” Dr. Yosipovitch noted.

The mean reductions in itch score in patients on 0.25 mg and 0.5 mg/day of difelikefalin were 4.0 and 3.8 points, respectively, which fell short of statistical significance versus placebo.

A key prespecified secondary endpoint was the proportion of subjects with at least a 3-point improvement in itch score over 12 weeks. This was achieved in 72% of patients on the top dose of difelikefalin, compared with 58% of controls, a significant difference. A 4-point or larger decrease in itch score occurred in 65% of patients on 1.0 mg/day of the kappa opioid recent agonist, versus 50% of controls, also a significant difference.

A complete response, defined as an itch score of 0 or 1 at least 80% of the time, was significantly more common in all three active treatment groups than in controls, with rates of 33%, 31.6%, and 38.6% at difelikefalin 0.25, 0.5, and 1.0 mg, compared with 4.4% among those on placebo.

Falls occurred in 1.5% of patients on difelikefalin. “The therapy does seem to increase the risk of dizziness, falls, fatigue, and GI complaints,” according to the investigator.

Still, most of these adverse events were mild or moderate in severity. Only about 1% of participants discontinued treatment for such reasons.

Earlier this year, a positive phase 3 trial of an intravenous formulation of difelikefalin for pruritus was reported in CKD patients on hemodialysis (N Engl J Med. 2020 Jan 16;382[3]:222-32).

In an interview, Dr. Yosipovitch said that this new phase 2 oral dose-finding study wasn’t powered to detect differences in treatment efficacy between the dialysis and nondialysis groups. However, the proportion of patients with at least a 3-point improvement in itch at week 12 was similar in the two groups.

“The oral formulation would of course be more convenient and would be preferred for patients not undergoing hemodialysis,” he said. “I would expect that the IV formulation would be the preferred route of administration for a patient undergoing hemodialysis. An IV formulation would be very convenient for such patients because it’s administered at the dialysis clinic at the end of the hemodialysis session.”

The oral difelikefalin phase 3 program is scheduled to start later in 2020.

CKD-associated itch poses a therapeutic challenge because it has so many contributory factors. These include CKD-induced peripheral neuropathy, functional and structural neuropathic changes in the brain, cutaneous mast cell activation, an imbalance between mu opioid receptor overexpression and kappa opioid receptor downregulation, secondary parathyroidism, and systemic accumulation of aluminum, beta 2 microglobulin, and other dialysis-related substances, the dermatologist observed.

Dr. Yosipovitch reported receiving research grants from a half-dozen pharmaceutical companies. He also serves as a consultant to numerous companies, including Cara Therapeutics, which sponsored the phase 2 trial.

[email protected]

Oral difelikefalin significantly reduced the intense itching associated with stage 3-5 chronic kidney disease, with or without hemodialysis, in a first-of-its-kind randomized clinical trial, Gil Yosipovitch, MD, said at the virtual annual meeting of the American Academy of Dermatology.

“Difelikefalin at 1.0 mg was associated with clinically meaningful improvements in pruritus. The improvement in itch was significant by week 2. And nearly 40% of patients achieved a complete response, which was more than two-and-one-half times more than with placebo,” noted Dr. Yosipovitch, professor of dermatology and director of the Miami Itch Center at the University of Miami.

Pruritus associated with chronic kidney disease (CKD) is a common, underrecognized, and distressing condition that causes markedly impaired quality of life. It occurs in patients across all stages of CKD, not just in those on hemodialysis, as is widely but mistakenly believed. And at present there is no approved drug in any country for treatment of CKD-associated itch.

Difelikefalin, a novel selective agonist of peripheral kappa opioid receptors, is designed to have very limited CNS penetration. The drug, which is renally excreted, doesn’t bind to mu or delta opioid receptors. Its antipruritic effect arises from activation of kappa opioid receptors on peripheral sensory neurons and immune cells, the dermatologist explained.

Dr. Yosipovitch presented the results of a phase 2, randomized, double-blind, placebo-controlled, 12-week trial in which 240 patients with severe chronic pruritus and stage 3-5 CKD were assigned to once-daily oral difelikefalin at 0.25 mg, 0.5 mg, or 1.0 mg, or placebo. More than 80% of participants were not on dialysis. Indeed, this was the first-ever clinical trial targeting itch in patients across such a broad spectrum of CKD stages.

The primary study endpoint was change from baseline to week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale. The average baseline score was 7, considered severe pruritus on the 0-10 scale. Patients randomized to difelikefalin at 1.0 mg/day had a mean 4.4-point decrease, a significantly greater improvement than the 3.3-point reduction in placebo-treated controls.

“More than a 4-point decrease is considered a very meaningful itch reduction,” Dr. Yosipovitch noted.

The mean reductions in itch score in patients on 0.25 mg and 0.5 mg/day of difelikefalin were 4.0 and 3.8 points, respectively, which fell short of statistical significance versus placebo.

A key prespecified secondary endpoint was the proportion of subjects with at least a 3-point improvement in itch score over 12 weeks. This was achieved in 72% of patients on the top dose of difelikefalin, compared with 58% of controls, a significant difference. A 4-point or larger decrease in itch score occurred in 65% of patients on 1.0 mg/day of the kappa opioid recent agonist, versus 50% of controls, also a significant difference.

A complete response, defined as an itch score of 0 or 1 at least 80% of the time, was significantly more common in all three active treatment groups than in controls, with rates of 33%, 31.6%, and 38.6% at difelikefalin 0.25, 0.5, and 1.0 mg, compared with 4.4% among those on placebo.

Falls occurred in 1.5% of patients on difelikefalin. “The therapy does seem to increase the risk of dizziness, falls, fatigue, and GI complaints,” according to the investigator.

Still, most of these adverse events were mild or moderate in severity. Only about 1% of participants discontinued treatment for such reasons.

Earlier this year, a positive phase 3 trial of an intravenous formulation of difelikefalin for pruritus was reported in CKD patients on hemodialysis (N Engl J Med. 2020 Jan 16;382[3]:222-32).

In an interview, Dr. Yosipovitch said that this new phase 2 oral dose-finding study wasn’t powered to detect differences in treatment efficacy between the dialysis and nondialysis groups. However, the proportion of patients with at least a 3-point improvement in itch at week 12 was similar in the two groups.

“The oral formulation would of course be more convenient and would be preferred for patients not undergoing hemodialysis,” he said. “I would expect that the IV formulation would be the preferred route of administration for a patient undergoing hemodialysis. An IV formulation would be very convenient for such patients because it’s administered at the dialysis clinic at the end of the hemodialysis session.”

The oral difelikefalin phase 3 program is scheduled to start later in 2020.

CKD-associated itch poses a therapeutic challenge because it has so many contributory factors. These include CKD-induced peripheral neuropathy, functional and structural neuropathic changes in the brain, cutaneous mast cell activation, an imbalance between mu opioid receptor overexpression and kappa opioid receptor downregulation, secondary parathyroidism, and systemic accumulation of aluminum, beta 2 microglobulin, and other dialysis-related substances, the dermatologist observed.

Dr. Yosipovitch reported receiving research grants from a half-dozen pharmaceutical companies. He also serves as a consultant to numerous companies, including Cara Therapeutics, which sponsored the phase 2 trial.

[email protected]

Children appear less likely than adults to be the first cases of COVID-19 within a household, based on data from families of 39 children younger than 16 years.

Courtesy NIAID

“Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission,” said Klara M. Posfay-Barbe, MD, of the University of Geneva, Switzerland, and colleagues.

In a study published in Pediatrics, the researchers analyzed data from all COVID-19 patients younger than 16 years who were identified between March 10, 2020, and April 10, 2020, through a hospital surveillance network. Parents and household contacts were called for contact tracing.

In 31 of 39 (79%) households, at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before onset of symptoms in the child. These findings support data from previous studies suggesting that children mainly become infected from adult family members rather than transmitting the virus to them, the researchers said

In only 3 of 39 (8%) households was the study child the first to develop symptoms. “Surprisingly, in 33% of households, symptomatic HHCs [household contacts] tested negative despite belonging to a familial cluster with confirmed SARS-CoV-2 cases, suggesting an underreporting of cases,” Dr. Posfay-Barbe and associates noted.

The findings were limited by several factors including potential underreporting of cases because those with mild or atypical presentations may not have sought medical care, and the inability to confirm child-to-adult transmission. The results were strengthened by the extensive contact tracing and very few individuals lost to follow-up, they said; however, more diagnostic screening and contact tracing are needed to improve understanding of household transmission of SARS-CoV-2, they concluded.

Resolving the issue of how much children contribute to transmission of SARS-CoV-2 is essential to making informed decisions about public health, including how to structure schools and child-care facility reopening, Benjamin Lee, MD, and William V. Raszka Jr., MD, both of the University of Vermont, Burlington, said in an accompanying editorial (Pediatrics. 2020 Jul 10. doi: 10.1542/peds/2020-004879).

The data in the current study support other studies of transmission among household contacts in China suggesting that, in most cases of childhood infections, “the child was not the source of infection and that children most frequently acquire COVID-19 from adults, rather than transmitting it to them,” they wrote.

In addition, the limited data on transmission of SARS-CoV-2 by children outside of the household show few cases of secondary infection from children identified with SARS-CoV-2 in school settings in studies from France and Australia, Dr. Lee and Dr. Raszka noted.

“On the basis of these data, SARS-CoV2 transmission in schools may be less important in community transmission than initially feared,” the editorialists wrote. “This would be another manner by which SARS-CoV2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy.”

“Therefore, serious consideration should be paid toward strategies that allow schools to remain open, even during periods of COVID-19 spread,” the editorialists concluded. “In doing so, we could minimize the potentially profound adverse social, developmental, and health costs that our children will continue to suffer until an effective treatment or vaccine can be developed and distributed or, failing that, until we reach herd immunity,” Dr. Lee and Dr. Raszka emphasized.

The study received no outside funding. The researchers and editorialists had no financial conflicts to disclose.

SOURCE: Posfay-Barbe KM et al. Pediatrics. 2020 Jul 10. doi: 10.1542/peds.2020-1576.

Children appear less likely than adults to be the first cases of COVID-19 within a household, based on data from families of 39 children younger than 16 years.

Courtesy NIAID

“Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission,” said Klara M. Posfay-Barbe, MD, of the University of Geneva, Switzerland, and colleagues.

In a study published in Pediatrics, the researchers analyzed data from all COVID-19 patients younger than 16 years who were identified between March 10, 2020, and April 10, 2020, through a hospital surveillance network. Parents and household contacts were called for contact tracing.

In 31 of 39 (79%) households, at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before onset of symptoms in the child. These findings support data from previous studies suggesting that children mainly become infected from adult family members rather than transmitting the virus to them, the researchers said

In only 3 of 39 (8%) households was the study child the first to develop symptoms. “Surprisingly, in 33% of households, symptomatic HHCs [household contacts] tested negative despite belonging to a familial cluster with confirmed SARS-CoV-2 cases, suggesting an underreporting of cases,” Dr. Posfay-Barbe and associates noted.

The findings were limited by several factors including potential underreporting of cases because those with mild or atypical presentations may not have sought medical care, and the inability to confirm child-to-adult transmission. The results were strengthened by the extensive contact tracing and very few individuals lost to follow-up, they said; however, more diagnostic screening and contact tracing are needed to improve understanding of household transmission of SARS-CoV-2, they concluded.

Resolving the issue of how much children contribute to transmission of SARS-CoV-2 is essential to making informed decisions about public health, including how to structure schools and child-care facility reopening, Benjamin Lee, MD, and William V. Raszka Jr., MD, both of the University of Vermont, Burlington, said in an accompanying editorial (Pediatrics. 2020 Jul 10. doi: 10.1542/peds/2020-004879).

The data in the current study support other studies of transmission among household contacts in China suggesting that, in most cases of childhood infections, “the child was not the source of infection and that children most frequently acquire COVID-19 from adults, rather than transmitting it to them,” they wrote.

In addition, the limited data on transmission of SARS-CoV-2 by children outside of the household show few cases of secondary infection from children identified with SARS-CoV-2 in school settings in studies from France and Australia, Dr. Lee and Dr. Raszka noted.

“On the basis of these data, SARS-CoV2 transmission in schools may be less important in community transmission than initially feared,” the editorialists wrote. “This would be another manner by which SARS-CoV2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy.”

“Therefore, serious consideration should be paid toward strategies that allow schools to remain open, even during periods of COVID-19 spread,” the editorialists concluded. “In doing so, we could minimize the potentially profound adverse social, developmental, and health costs that our children will continue to suffer until an effective treatment or vaccine can be developed and distributed or, failing that, until we reach herd immunity,” Dr. Lee and Dr. Raszka emphasized.

The study received no outside funding. The researchers and editorialists had no financial conflicts to disclose.

SOURCE: Posfay-Barbe KM et al. Pediatrics. 2020 Jul 10. doi: 10.1542/peds.2020-1576.

Children appear less likely than adults to be the first cases of COVID-19 within a household, based on data from families of 39 children younger than 16 years.

Courtesy NIAID

“Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission,” said Klara M. Posfay-Barbe, MD, of the University of Geneva, Switzerland, and colleagues.

In a study published in Pediatrics, the researchers analyzed data from all COVID-19 patients younger than 16 years who were identified between March 10, 2020, and April 10, 2020, through a hospital surveillance network. Parents and household contacts were called for contact tracing.

In 31 of 39 (79%) households, at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before onset of symptoms in the child. These findings support data from previous studies suggesting that children mainly become infected from adult family members rather than transmitting the virus to them, the researchers said

In only 3 of 39 (8%) households was the study child the first to develop symptoms. “Surprisingly, in 33% of households, symptomatic HHCs [household contacts] tested negative despite belonging to a familial cluster with confirmed SARS-CoV-2 cases, suggesting an underreporting of cases,” Dr. Posfay-Barbe and associates noted.

The findings were limited by several factors including potential underreporting of cases because those with mild or atypical presentations may not have sought medical care, and the inability to confirm child-to-adult transmission. The results were strengthened by the extensive contact tracing and very few individuals lost to follow-up, they said; however, more diagnostic screening and contact tracing are needed to improve understanding of household transmission of SARS-CoV-2, they concluded.

Resolving the issue of how much children contribute to transmission of SARS-CoV-2 is essential to making informed decisions about public health, including how to structure schools and child-care facility reopening, Benjamin Lee, MD, and William V. Raszka Jr., MD, both of the University of Vermont, Burlington, said in an accompanying editorial (Pediatrics. 2020 Jul 10. doi: 10.1542/peds/2020-004879).

The data in the current study support other studies of transmission among household contacts in China suggesting that, in most cases of childhood infections, “the child was not the source of infection and that children most frequently acquire COVID-19 from adults, rather than transmitting it to them,” they wrote.

In addition, the limited data on transmission of SARS-CoV-2 by children outside of the household show few cases of secondary infection from children identified with SARS-CoV-2 in school settings in studies from France and Australia, Dr. Lee and Dr. Raszka noted.

“On the basis of these data, SARS-CoV2 transmission in schools may be less important in community transmission than initially feared,” the editorialists wrote. “This would be another manner by which SARS-CoV2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy.”

“Therefore, serious consideration should be paid toward strategies that allow schools to remain open, even during periods of COVID-19 spread,” the editorialists concluded. “In doing so, we could minimize the potentially profound adverse social, developmental, and health costs that our children will continue to suffer until an effective treatment or vaccine can be developed and distributed or, failing that, until we reach herd immunity,” Dr. Lee and Dr. Raszka emphasized.

The study received no outside funding. The researchers and editorialists had no financial conflicts to disclose.

SOURCE: Posfay-Barbe KM et al. Pediatrics. 2020 Jul 10. doi: 10.1542/peds.2020-1576.

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

A version of this article originally appeared on Medscape.com.

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

A version of this article originally appeared on Medscape.com.

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

A version of this article originally appeared on Medscape.com.

Localized bullous pemphigoid

Bullous pemphigoid is a systemic, autoimmune bullous disease that classically presents as widespread urticarial plaques or tense bullae with a predilection in the elderly population.¹

Localized variants of bullous pemphigoid (BP) are rare and have been reported to arise at sites of mechanical trauma, prior radiation, lymphedema, surgical scars, burns, fistulas, and ostomies.^1-3 Although the mechanism remains unclear, the Koebner phenomenon is thought to induce dysregulation of immunologic and vascular factors in sites of mechanical shear and trauma in susceptible individuals.³

Localized BP is an important entity for the dermatologist to be familiar with, as the diagnosis is often delayed. The localized, well-defined skin lesions frequently mimic contact dermatitis. In fact, previous reports have shown the most likely misdiagnosis of localized BP is acute allergic contact dermatitis, stasis dermatitis, and eczematous dermatitis.^4,5

In this patient, histopathologic examination of a biopsy revealed a subepidermal blister with numerous eosinophils. Direct immunofluorescence study of perilesional skin showed strong linear IgG and C3 deposits at the basal membrane level. Serum level of autoantibody to BP180 antigen was elevated. Bacterial culture was positive for Staphylococcus aureus. These findings were suggestive of unilateral, localized BP with superimposed bacterial infection. Initial treatment with an extended course of doxycycline 200 mg twice daily, topical triamcinolone 0.1% ointment twice daily with compression therapy, and leg elevation led to clinical improvement with healing of previous lesions on the leg. At follow-up 3 weeks later, the patient had continued to develop new bullous lesions on the trunk and upper thighs. He was subsequently started on systemic immunosuppressive therapy for generalized bullous pemphigoid.

Importantly, localized BP generally follows a more benign disease course, although long-term follow-up is recommended for monitoring given the potential risk of developing the generalized form of BP of approximately 15%.3 Topical corticosteroids and oral antibiotics are recommended as the first-line therapy in these patients, with an escalated systemic therapy if needed for disease progression.^3,5

Our case represents an important differential diagnosis to consider when evaluating an acute localized bullous eruption in an elderly patient.

Dr. Cusick and Dr. Dolohanty are with the department of dermatology, University of Rochester (N.Y.), and provided the case and photo. Donna Bilu Martin, MD, edited the column.
 

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/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Kohroh K et al. J Dermatol. 2007 Jul;34(7):482-5.

2. Nguyen T et al. Dermatology 2014;229(2):88-96.

3. Sen BB et al. Indian J Dermatol Venereol Leprol. 2013;79(4):554.

4. Salomon RJ et al. Arch Dermatol. 1987 Mar;123(3):389-92.

5. Tran JT, Mutasim DF. Int J Dermatol. 2005 Nov;44(11):942-5.

Localized bullous pemphigoid

Bullous pemphigoid is a systemic, autoimmune bullous disease that classically presents as widespread urticarial plaques or tense bullae with a predilection in the elderly population.¹

Localized variants of bullous pemphigoid (BP) are rare and have been reported to arise at sites of mechanical trauma, prior radiation, lymphedema, surgical scars, burns, fistulas, and ostomies.^1-3 Although the mechanism remains unclear, the Koebner phenomenon is thought to induce dysregulation of immunologic and vascular factors in sites of mechanical shear and trauma in susceptible individuals.³

Localized BP is an important entity for the dermatologist to be familiar with, as the diagnosis is often delayed. The localized, well-defined skin lesions frequently mimic contact dermatitis. In fact, previous reports have shown the most likely misdiagnosis of localized BP is acute allergic contact dermatitis, stasis dermatitis, and eczematous dermatitis.^4,5

In this patient, histopathologic examination of a biopsy revealed a subepidermal blister with numerous eosinophils. Direct immunofluorescence study of perilesional skin showed strong linear IgG and C3 deposits at the basal membrane level. Serum level of autoantibody to BP180 antigen was elevated. Bacterial culture was positive for Staphylococcus aureus. These findings were suggestive of unilateral, localized BP with superimposed bacterial infection. Initial treatment with an extended course of doxycycline 200 mg twice daily, topical triamcinolone 0.1% ointment twice daily with compression therapy, and leg elevation led to clinical improvement with healing of previous lesions on the leg. At follow-up 3 weeks later, the patient had continued to develop new bullous lesions on the trunk and upper thighs. He was subsequently started on systemic immunosuppressive therapy for generalized bullous pemphigoid.

Importantly, localized BP generally follows a more benign disease course, although long-term follow-up is recommended for monitoring given the potential risk of developing the generalized form of BP of approximately 15%.3 Topical corticosteroids and oral antibiotics are recommended as the first-line therapy in these patients, with an escalated systemic therapy if needed for disease progression.^3,5

Our case represents an important differential diagnosis to consider when evaluating an acute localized bullous eruption in an elderly patient.

Dr. Cusick and Dr. Dolohanty are with the department of dermatology, University of Rochester (N.Y.), and provided the case and photo. Donna Bilu Martin, MD, edited the column.
 

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/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Kohroh K et al. J Dermatol. 2007 Jul;34(7):482-5.

2. Nguyen T et al. Dermatology 2014;229(2):88-96.

3. Sen BB et al. Indian J Dermatol Venereol Leprol. 2013;79(4):554.

4. Salomon RJ et al. Arch Dermatol. 1987 Mar;123(3):389-92.

5. Tran JT, Mutasim DF. Int J Dermatol. 2005 Nov;44(11):942-5.

Localized bullous pemphigoid

Bullous pemphigoid is a systemic, autoimmune bullous disease that classically presents as widespread urticarial plaques or tense bullae with a predilection in the elderly population.¹

Localized variants of bullous pemphigoid (BP) are rare and have been reported to arise at sites of mechanical trauma, prior radiation, lymphedema, surgical scars, burns, fistulas, and ostomies.^1-3 Although the mechanism remains unclear, the Koebner phenomenon is thought to induce dysregulation of immunologic and vascular factors in sites of mechanical shear and trauma in susceptible individuals.³

Localized BP is an important entity for the dermatologist to be familiar with, as the diagnosis is often delayed. The localized, well-defined skin lesions frequently mimic contact dermatitis. In fact, previous reports have shown the most likely misdiagnosis of localized BP is acute allergic contact dermatitis, stasis dermatitis, and eczematous dermatitis.^4,5

In this patient, histopathologic examination of a biopsy revealed a subepidermal blister with numerous eosinophils. Direct immunofluorescence study of perilesional skin showed strong linear IgG and C3 deposits at the basal membrane level. Serum level of autoantibody to BP180 antigen was elevated. Bacterial culture was positive for Staphylococcus aureus. These findings were suggestive of unilateral, localized BP with superimposed bacterial infection. Initial treatment with an extended course of doxycycline 200 mg twice daily, topical triamcinolone 0.1% ointment twice daily with compression therapy, and leg elevation led to clinical improvement with healing of previous lesions on the leg. At follow-up 3 weeks later, the patient had continued to develop new bullous lesions on the trunk and upper thighs. He was subsequently started on systemic immunosuppressive therapy for generalized bullous pemphigoid.

Importantly, localized BP generally follows a more benign disease course, although long-term follow-up is recommended for monitoring given the potential risk of developing the generalized form of BP of approximately 15%.3 Topical corticosteroids and oral antibiotics are recommended as the first-line therapy in these patients, with an escalated systemic therapy if needed for disease progression.^3,5

Our case represents an important differential diagnosis to consider when evaluating an acute localized bullous eruption in an elderly patient.

Dr. Cusick and Dr. Dolohanty are with the department of dermatology, University of Rochester (N.Y.), and provided the case and photo. Donna Bilu Martin, MD, edited the column.
 

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/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Kohroh K et al. J Dermatol. 2007 Jul;34(7):482-5.

2. Nguyen T et al. Dermatology 2014;229(2):88-96.

3. Sen BB et al. Indian J Dermatol Venereol Leprol. 2013;79(4):554.

4. Salomon RJ et al. Arch Dermatol. 1987 Mar;123(3):389-92.

5. Tran JT, Mutasim DF. Int J Dermatol. 2005 Nov;44(11):942-5.