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‘Astonishing’ 4-year survival in NSCLC with pembro plus chemo
The results are from a 4-year follow-up of 160 patients with previously untreated stage IV non–small cell lung cancer (NSCLC) taking part in the KEYNOTE-189 trial of immunotherapy with pembrolizumab plus pemetrexed–platinum chemotherapy versus chemotherapy plus placebo.
After a median follow-up of 46.3 months, the median overall survival (OS) in the intention-to-treat population was 22.0 months with the combination versus 10.6 months with chemotherapy alone (hazard ratio, 0.60).
A similar pattern was seen for progression-free survival (PFS), with patients receiving the combination having a longer median PFS, at 9.0 months versus 4.9 months with chemotherapy alone (HR, 0.50).
“Stellar data,” Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, Royal Tunbridge Wells, England, exclaimed on Twitter.
He described the results for the programmed death-ligand 1 (PD-L1) expression subgroups as “astonishing” and singled out the performance of the combination therapy in patients with very low (<1%) tumor PD-L1 expression, showing more than 23% of patients were alive at 3 years versus just over 5% in the group given chemotherapy alone.
Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Penn Medicine, Philadelphia, said the outcomes with the combination of chemotherapy and immunotherapy were “terrific.”
Sandip P. Patel, MD, medical oncologist, associate professor of medicine, University of California, San Diego, agreed that these long-term results were “very impressive.” However, he noted the “full effect” of chemotherapy plus immunotherapy has not “fully been captured in our overall cancer mortality statistics in the U.S. yet.”
The new results were presented at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.
Previous results from KEYNOTE-189 had already demonstrated that, after a median follow-up of 10.5 months, adding pembrolizumab to chemotherapy significantly improves both OS and PFS, compared with chemotherapy alone.
The latest results show that the combination “continued to provide overall survival and progression-free survival benefit” in extended follow-up, said study presenter Jhanelle Elaine Gray, MD, chair, department of thoracic oncology, Moffitt Cancer Center, Tampa.
The 3-year OS rate with pembrolizumab plus chemotherapy, compared with chemotherapy alone was 31.3% versus 17.4%, and the estimated 3-year PFS was 11.8% versus 1.3%.
Substantial improvements were even seen in patients with tumors that had a low level of PD-L1 expression (measured as the PD-L1 tumor proportion score [TPS]).
Dr. Gray highlighted the finding that the survival benefit with pembrolizumab plus chemotherapy was seen regardless of PD-L1 expression in the tumor, with a hazard ratio versus chemotherapy alone of 0.71 in patients with a TPS ≥ 50%, 0.66 in those with a TPS of 1%-49%, and 0.52 in patients with a TPS less than 1%. A similar pattern was seen with PFS, with a hazard ratio of 0.36 in patients with a TPS of at least 50%, 0.54 in those with a TPS of 1%-49%, and 0.68 in patients with a TPS less than 1%.
In addition, overall response rate and duration of response were also improved with combination therapy, regardless of tumor PD-L1 expression.
Among 56 patients who completed 35 cycles of pembrolizumab, the objective response rate was 87.5% (with 10.7% having a complete response and 76.8% a partial response).
At the data cutoff, 45 patients were alive, 28 did not have progressive disease, and seven had started a second course of pembrolizumab.
The side effect profile of the combination was “manageable,” Dr. Gray reported.
The combination arm was associated with more grade 3-5 treatment-related adverse events than the chemotherapy alone arm, at 52.1% versus 42.1%, and more grade 3-5 immune-related adverse events and infusion reactions, at 27.7% versus 13.4%.
Events leading to treatment discontinuation were also more common with pembrolizumab plus chemotherapy than chemotherapy, at 27.4% versus 9.9%.
The combination of pembrolizumab plus pemetrexed-platinum has already become “a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC,” Dr. Gray commented.
The study was funded by Merck. Dr. Gray disclosed relationships with Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, and Merck.
A version of this article first appeared on Medscape.com.
The results are from a 4-year follow-up of 160 patients with previously untreated stage IV non–small cell lung cancer (NSCLC) taking part in the KEYNOTE-189 trial of immunotherapy with pembrolizumab plus pemetrexed–platinum chemotherapy versus chemotherapy plus placebo.
After a median follow-up of 46.3 months, the median overall survival (OS) in the intention-to-treat population was 22.0 months with the combination versus 10.6 months with chemotherapy alone (hazard ratio, 0.60).
A similar pattern was seen for progression-free survival (PFS), with patients receiving the combination having a longer median PFS, at 9.0 months versus 4.9 months with chemotherapy alone (HR, 0.50).
“Stellar data,” Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, Royal Tunbridge Wells, England, exclaimed on Twitter.
He described the results for the programmed death-ligand 1 (PD-L1) expression subgroups as “astonishing” and singled out the performance of the combination therapy in patients with very low (<1%) tumor PD-L1 expression, showing more than 23% of patients were alive at 3 years versus just over 5% in the group given chemotherapy alone.
Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Penn Medicine, Philadelphia, said the outcomes with the combination of chemotherapy and immunotherapy were “terrific.”
Sandip P. Patel, MD, medical oncologist, associate professor of medicine, University of California, San Diego, agreed that these long-term results were “very impressive.” However, he noted the “full effect” of chemotherapy plus immunotherapy has not “fully been captured in our overall cancer mortality statistics in the U.S. yet.”
The new results were presented at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.
Previous results from KEYNOTE-189 had already demonstrated that, after a median follow-up of 10.5 months, adding pembrolizumab to chemotherapy significantly improves both OS and PFS, compared with chemotherapy alone.
The latest results show that the combination “continued to provide overall survival and progression-free survival benefit” in extended follow-up, said study presenter Jhanelle Elaine Gray, MD, chair, department of thoracic oncology, Moffitt Cancer Center, Tampa.
The 3-year OS rate with pembrolizumab plus chemotherapy, compared with chemotherapy alone was 31.3% versus 17.4%, and the estimated 3-year PFS was 11.8% versus 1.3%.
Substantial improvements were even seen in patients with tumors that had a low level of PD-L1 expression (measured as the PD-L1 tumor proportion score [TPS]).
Dr. Gray highlighted the finding that the survival benefit with pembrolizumab plus chemotherapy was seen regardless of PD-L1 expression in the tumor, with a hazard ratio versus chemotherapy alone of 0.71 in patients with a TPS ≥ 50%, 0.66 in those with a TPS of 1%-49%, and 0.52 in patients with a TPS less than 1%. A similar pattern was seen with PFS, with a hazard ratio of 0.36 in patients with a TPS of at least 50%, 0.54 in those with a TPS of 1%-49%, and 0.68 in patients with a TPS less than 1%.
In addition, overall response rate and duration of response were also improved with combination therapy, regardless of tumor PD-L1 expression.
Among 56 patients who completed 35 cycles of pembrolizumab, the objective response rate was 87.5% (with 10.7% having a complete response and 76.8% a partial response).
At the data cutoff, 45 patients were alive, 28 did not have progressive disease, and seven had started a second course of pembrolizumab.
The side effect profile of the combination was “manageable,” Dr. Gray reported.
The combination arm was associated with more grade 3-5 treatment-related adverse events than the chemotherapy alone arm, at 52.1% versus 42.1%, and more grade 3-5 immune-related adverse events and infusion reactions, at 27.7% versus 13.4%.
Events leading to treatment discontinuation were also more common with pembrolizumab plus chemotherapy than chemotherapy, at 27.4% versus 9.9%.
The combination of pembrolizumab plus pemetrexed-platinum has already become “a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC,” Dr. Gray commented.
The study was funded by Merck. Dr. Gray disclosed relationships with Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, and Merck.
A version of this article first appeared on Medscape.com.
The results are from a 4-year follow-up of 160 patients with previously untreated stage IV non–small cell lung cancer (NSCLC) taking part in the KEYNOTE-189 trial of immunotherapy with pembrolizumab plus pemetrexed–platinum chemotherapy versus chemotherapy plus placebo.
After a median follow-up of 46.3 months, the median overall survival (OS) in the intention-to-treat population was 22.0 months with the combination versus 10.6 months with chemotherapy alone (hazard ratio, 0.60).
A similar pattern was seen for progression-free survival (PFS), with patients receiving the combination having a longer median PFS, at 9.0 months versus 4.9 months with chemotherapy alone (HR, 0.50).
“Stellar data,” Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, Royal Tunbridge Wells, England, exclaimed on Twitter.
He described the results for the programmed death-ligand 1 (PD-L1) expression subgroups as “astonishing” and singled out the performance of the combination therapy in patients with very low (<1%) tumor PD-L1 expression, showing more than 23% of patients were alive at 3 years versus just over 5% in the group given chemotherapy alone.
Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Penn Medicine, Philadelphia, said the outcomes with the combination of chemotherapy and immunotherapy were “terrific.”
Sandip P. Patel, MD, medical oncologist, associate professor of medicine, University of California, San Diego, agreed that these long-term results were “very impressive.” However, he noted the “full effect” of chemotherapy plus immunotherapy has not “fully been captured in our overall cancer mortality statistics in the U.S. yet.”
The new results were presented at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.
Previous results from KEYNOTE-189 had already demonstrated that, after a median follow-up of 10.5 months, adding pembrolizumab to chemotherapy significantly improves both OS and PFS, compared with chemotherapy alone.
The latest results show that the combination “continued to provide overall survival and progression-free survival benefit” in extended follow-up, said study presenter Jhanelle Elaine Gray, MD, chair, department of thoracic oncology, Moffitt Cancer Center, Tampa.
The 3-year OS rate with pembrolizumab plus chemotherapy, compared with chemotherapy alone was 31.3% versus 17.4%, and the estimated 3-year PFS was 11.8% versus 1.3%.
Substantial improvements were even seen in patients with tumors that had a low level of PD-L1 expression (measured as the PD-L1 tumor proportion score [TPS]).
Dr. Gray highlighted the finding that the survival benefit with pembrolizumab plus chemotherapy was seen regardless of PD-L1 expression in the tumor, with a hazard ratio versus chemotherapy alone of 0.71 in patients with a TPS ≥ 50%, 0.66 in those with a TPS of 1%-49%, and 0.52 in patients with a TPS less than 1%. A similar pattern was seen with PFS, with a hazard ratio of 0.36 in patients with a TPS of at least 50%, 0.54 in those with a TPS of 1%-49%, and 0.68 in patients with a TPS less than 1%.
In addition, overall response rate and duration of response were also improved with combination therapy, regardless of tumor PD-L1 expression.
Among 56 patients who completed 35 cycles of pembrolizumab, the objective response rate was 87.5% (with 10.7% having a complete response and 76.8% a partial response).
At the data cutoff, 45 patients were alive, 28 did not have progressive disease, and seven had started a second course of pembrolizumab.
The side effect profile of the combination was “manageable,” Dr. Gray reported.
The combination arm was associated with more grade 3-5 treatment-related adverse events than the chemotherapy alone arm, at 52.1% versus 42.1%, and more grade 3-5 immune-related adverse events and infusion reactions, at 27.7% versus 13.4%.
Events leading to treatment discontinuation were also more common with pembrolizumab plus chemotherapy than chemotherapy, at 27.4% versus 9.9%.
The combination of pembrolizumab plus pemetrexed-platinum has already become “a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC,” Dr. Gray commented.
The study was funded by Merck. Dr. Gray disclosed relationships with Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, and Merck.
A version of this article first appeared on Medscape.com.
Scaly lesion on forearm
The suspicion raised by the dermoscopy results led to a shave biopsy, which confirmed the diagnosis of squamous cell carcinoma (SCC) in situ, also known as Bowen disease.
Bowen disease typically manifests as a scaly erythematous patch, often on sun-exposed skin. If untreated, these lesions have the potential to develop into invasive SCCs. Generally, the lesions are preceded by the formation of actinic keratosis (AK). In a 2009 trial performed by the Department of Veterans Affairs, up to 65% of SCCs were found to have previously been diagnosed as AK lesions.1
The selection of treatments includes excision, electrodessication and curettage, cryotherapy, and topical options such as fluorouracil bid for 4 weeks or imiquimod qd for 9 weeks.
After the physician outlined the treatment options, this patient opted for an elliptical excision. At the patient’s next follow-up appointment, she was found to have multiple AKs on her face; they were treated with cryotherapy. Patients with a diagnosis of precancerous or cancerous skin lesions are at high risk for additional AKs and skin cancer, so they should be counseled regarding the use of sun protective measures and the importance of annual screening for new lesions.
Image courtesy of Carlos Cano, MD, and text courtesy of Carlos Cano, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
1. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the veterans affairs topical tretinoin chemoprevention trial. Cancer. 2009;115:2523-2530. doi: 10.1002/cncr.24284.
The suspicion raised by the dermoscopy results led to a shave biopsy, which confirmed the diagnosis of squamous cell carcinoma (SCC) in situ, also known as Bowen disease.
Bowen disease typically manifests as a scaly erythematous patch, often on sun-exposed skin. If untreated, these lesions have the potential to develop into invasive SCCs. Generally, the lesions are preceded by the formation of actinic keratosis (AK). In a 2009 trial performed by the Department of Veterans Affairs, up to 65% of SCCs were found to have previously been diagnosed as AK lesions.1
The selection of treatments includes excision, electrodessication and curettage, cryotherapy, and topical options such as fluorouracil bid for 4 weeks or imiquimod qd for 9 weeks.
After the physician outlined the treatment options, this patient opted for an elliptical excision. At the patient’s next follow-up appointment, she was found to have multiple AKs on her face; they were treated with cryotherapy. Patients with a diagnosis of precancerous or cancerous skin lesions are at high risk for additional AKs and skin cancer, so they should be counseled regarding the use of sun protective measures and the importance of annual screening for new lesions.
Image courtesy of Carlos Cano, MD, and text courtesy of Carlos Cano, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
The suspicion raised by the dermoscopy results led to a shave biopsy, which confirmed the diagnosis of squamous cell carcinoma (SCC) in situ, also known as Bowen disease.
Bowen disease typically manifests as a scaly erythematous patch, often on sun-exposed skin. If untreated, these lesions have the potential to develop into invasive SCCs. Generally, the lesions are preceded by the formation of actinic keratosis (AK). In a 2009 trial performed by the Department of Veterans Affairs, up to 65% of SCCs were found to have previously been diagnosed as AK lesions.1
The selection of treatments includes excision, electrodessication and curettage, cryotherapy, and topical options such as fluorouracil bid for 4 weeks or imiquimod qd for 9 weeks.
After the physician outlined the treatment options, this patient opted for an elliptical excision. At the patient’s next follow-up appointment, she was found to have multiple AKs on her face; they were treated with cryotherapy. Patients with a diagnosis of precancerous or cancerous skin lesions are at high risk for additional AKs and skin cancer, so they should be counseled regarding the use of sun protective measures and the importance of annual screening for new lesions.
Image courtesy of Carlos Cano, MD, and text courtesy of Carlos Cano, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.
1. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the veterans affairs topical tretinoin chemoprevention trial. Cancer. 2009;115:2523-2530. doi: 10.1002/cncr.24284.
1. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the veterans affairs topical tretinoin chemoprevention trial. Cancer. 2009;115:2523-2530. doi: 10.1002/cncr.24284.
PURE: High refined-grain intake boosts death, CVD events
That’s one finding from an assessment of a more than 137,000 people in 21 countries that documented a clear link between a high level of consumption of refined grains and a significantly increased risk for death from any cause or major cardiovascular disease (CVD) event during a median follow-up of 9.5 years.
The results showed that people who reported eating at least 350 g (seven servings) of refined grain daily had a significant 29% increased risk of either death or a major CVD event (MI, stroke, or heart failure), compared with those who consumed less than one serving per day (fewer than 50 g) of refined grain after adjustment for multiple potential confounders, according to a report from the Prospective Urban Rural Epidemiology (PURE) study published in the BMJ on Feb. 3, 2021.
The analysis also showed no significant association between levels of whole grains or white rice in the diet and CVD events. Rice was considered a separate grain in the analysis because nearly two-thirds of the PURE study population reside in Asia, where rice is a staple food.
The findings show that “reduction in the quantity of refined grains and sugar, and improvement in the quality of carbohydrates is essential for better health outcomes, although we do not suggest complete elimination of refined grains,” said Mahshid Dehghan, PhD, lead investigator for this report and a researcher in nutrition epidemiology at the Population Health Research Institute of McMaster University, Hamilton, Ont.
‘Widely applicable’ results from large, diverse study
Although prior evidence had already shown the CVD risk from eating larger amounts of refined grains, “our findings are robust and more widely applicable because our large study recorded over 9,000 deaths and 3,500 major CVD events across a broad range of refined grain intake, and in a variety of different settings and cultures with varying dietary patterns,” Dr. Dehghan said in an interview.
“This is an important paper, with the strength of data from diverse countries. The associations are robust,” commented Dariush Mozaffarian, MD, DrPH, professor and dean of the Friedman School of Nutrition Science and Policy at Tufts University, Boston, who was not involved in the new report.
“The public and the public health community think about added sugar in food as harmful, but starch has gotten a free pass,” he said in an interview. Recently revised U.S. dietary guidelines recommend that refined grains constitute less than half of a person’s carbohydrate consumption, but that limitation remains set too high, Dr. Mozaffarian cautioned. A much safer daily consumption limit would cap refined grains to no more than one serving a day.
The data for the current PURE analysis came from more than 148,000 people aged 35-70 years at entry in 21 geographically and economically diverse countries. Excluding patients with known CVD at baseline left a cohort of 137,130 people.
The results showed no significant association between the quantity of whole grains consumed and the main outcome, nor a link between higher amounts of white rice consumption and the main outcome.
“Our findings suggest that intake of up to 350 g of cooked rice daily may not pose a significant health risk,” said Dr. Dehghan.
Refined grains produce a glucose surge
Dr. Dehghan and associates speculated that possible explanations for their findings are that “varieties of rice such as long-grain rice and especially parboiled white rice may have both a definite glycemic advantage and an overall nutritional advantage over refined wheat products. Also, depending on the culture and the nature of the rice eaten, rice may be displacing less desirable foods.”
In contrast, refined grains undergo “rapid action by digestive enzymes and quick absorption from the small intestines [that] could lead to an increase in postprandial blood glucose concentrations. The rise in glucose concentrations increases the insulin concentrations, which leads to hypoglycemia, lipolysis, and the stimulation of hunger and food intake,” the authors wrote.
“It’s similar to eating sugar, or candy,” noted Dr. Mozaffarian, as refined grain “is 100% glucose.” Whole grains differ by entering the gut packaged in cell structures that slow digestion and avoid delivering sugar in an unnaturally rapid way.
“We are providing new evidence, and we hope that dietary guidelines in North America encourage individuals to lower their refined grain and sugar intake,” Dr. Dehghan said.
PURE has received partial funding with unrestricted grants from several drug companies. Dr. Dehghan had no disclosures. Dr. Mozaffarian has been an adviser to or has received personal fees from several food companies, but had no relevant disclosures.
That’s one finding from an assessment of a more than 137,000 people in 21 countries that documented a clear link between a high level of consumption of refined grains and a significantly increased risk for death from any cause or major cardiovascular disease (CVD) event during a median follow-up of 9.5 years.
The results showed that people who reported eating at least 350 g (seven servings) of refined grain daily had a significant 29% increased risk of either death or a major CVD event (MI, stroke, or heart failure), compared with those who consumed less than one serving per day (fewer than 50 g) of refined grain after adjustment for multiple potential confounders, according to a report from the Prospective Urban Rural Epidemiology (PURE) study published in the BMJ on Feb. 3, 2021.
The analysis also showed no significant association between levels of whole grains or white rice in the diet and CVD events. Rice was considered a separate grain in the analysis because nearly two-thirds of the PURE study population reside in Asia, where rice is a staple food.
The findings show that “reduction in the quantity of refined grains and sugar, and improvement in the quality of carbohydrates is essential for better health outcomes, although we do not suggest complete elimination of refined grains,” said Mahshid Dehghan, PhD, lead investigator for this report and a researcher in nutrition epidemiology at the Population Health Research Institute of McMaster University, Hamilton, Ont.
‘Widely applicable’ results from large, diverse study
Although prior evidence had already shown the CVD risk from eating larger amounts of refined grains, “our findings are robust and more widely applicable because our large study recorded over 9,000 deaths and 3,500 major CVD events across a broad range of refined grain intake, and in a variety of different settings and cultures with varying dietary patterns,” Dr. Dehghan said in an interview.
“This is an important paper, with the strength of data from diverse countries. The associations are robust,” commented Dariush Mozaffarian, MD, DrPH, professor and dean of the Friedman School of Nutrition Science and Policy at Tufts University, Boston, who was not involved in the new report.
“The public and the public health community think about added sugar in food as harmful, but starch has gotten a free pass,” he said in an interview. Recently revised U.S. dietary guidelines recommend that refined grains constitute less than half of a person’s carbohydrate consumption, but that limitation remains set too high, Dr. Mozaffarian cautioned. A much safer daily consumption limit would cap refined grains to no more than one serving a day.
The data for the current PURE analysis came from more than 148,000 people aged 35-70 years at entry in 21 geographically and economically diverse countries. Excluding patients with known CVD at baseline left a cohort of 137,130 people.
The results showed no significant association between the quantity of whole grains consumed and the main outcome, nor a link between higher amounts of white rice consumption and the main outcome.
“Our findings suggest that intake of up to 350 g of cooked rice daily may not pose a significant health risk,” said Dr. Dehghan.
Refined grains produce a glucose surge
Dr. Dehghan and associates speculated that possible explanations for their findings are that “varieties of rice such as long-grain rice and especially parboiled white rice may have both a definite glycemic advantage and an overall nutritional advantage over refined wheat products. Also, depending on the culture and the nature of the rice eaten, rice may be displacing less desirable foods.”
In contrast, refined grains undergo “rapid action by digestive enzymes and quick absorption from the small intestines [that] could lead to an increase in postprandial blood glucose concentrations. The rise in glucose concentrations increases the insulin concentrations, which leads to hypoglycemia, lipolysis, and the stimulation of hunger and food intake,” the authors wrote.
“It’s similar to eating sugar, or candy,” noted Dr. Mozaffarian, as refined grain “is 100% glucose.” Whole grains differ by entering the gut packaged in cell structures that slow digestion and avoid delivering sugar in an unnaturally rapid way.
“We are providing new evidence, and we hope that dietary guidelines in North America encourage individuals to lower their refined grain and sugar intake,” Dr. Dehghan said.
PURE has received partial funding with unrestricted grants from several drug companies. Dr. Dehghan had no disclosures. Dr. Mozaffarian has been an adviser to or has received personal fees from several food companies, but had no relevant disclosures.
That’s one finding from an assessment of a more than 137,000 people in 21 countries that documented a clear link between a high level of consumption of refined grains and a significantly increased risk for death from any cause or major cardiovascular disease (CVD) event during a median follow-up of 9.5 years.
The results showed that people who reported eating at least 350 g (seven servings) of refined grain daily had a significant 29% increased risk of either death or a major CVD event (MI, stroke, or heart failure), compared with those who consumed less than one serving per day (fewer than 50 g) of refined grain after adjustment for multiple potential confounders, according to a report from the Prospective Urban Rural Epidemiology (PURE) study published in the BMJ on Feb. 3, 2021.
The analysis also showed no significant association between levels of whole grains or white rice in the diet and CVD events. Rice was considered a separate grain in the analysis because nearly two-thirds of the PURE study population reside in Asia, where rice is a staple food.
The findings show that “reduction in the quantity of refined grains and sugar, and improvement in the quality of carbohydrates is essential for better health outcomes, although we do not suggest complete elimination of refined grains,” said Mahshid Dehghan, PhD, lead investigator for this report and a researcher in nutrition epidemiology at the Population Health Research Institute of McMaster University, Hamilton, Ont.
‘Widely applicable’ results from large, diverse study
Although prior evidence had already shown the CVD risk from eating larger amounts of refined grains, “our findings are robust and more widely applicable because our large study recorded over 9,000 deaths and 3,500 major CVD events across a broad range of refined grain intake, and in a variety of different settings and cultures with varying dietary patterns,” Dr. Dehghan said in an interview.
“This is an important paper, with the strength of data from diverse countries. The associations are robust,” commented Dariush Mozaffarian, MD, DrPH, professor and dean of the Friedman School of Nutrition Science and Policy at Tufts University, Boston, who was not involved in the new report.
“The public and the public health community think about added sugar in food as harmful, but starch has gotten a free pass,” he said in an interview. Recently revised U.S. dietary guidelines recommend that refined grains constitute less than half of a person’s carbohydrate consumption, but that limitation remains set too high, Dr. Mozaffarian cautioned. A much safer daily consumption limit would cap refined grains to no more than one serving a day.
The data for the current PURE analysis came from more than 148,000 people aged 35-70 years at entry in 21 geographically and economically diverse countries. Excluding patients with known CVD at baseline left a cohort of 137,130 people.
The results showed no significant association between the quantity of whole grains consumed and the main outcome, nor a link between higher amounts of white rice consumption and the main outcome.
“Our findings suggest that intake of up to 350 g of cooked rice daily may not pose a significant health risk,” said Dr. Dehghan.
Refined grains produce a glucose surge
Dr. Dehghan and associates speculated that possible explanations for their findings are that “varieties of rice such as long-grain rice and especially parboiled white rice may have both a definite glycemic advantage and an overall nutritional advantage over refined wheat products. Also, depending on the culture and the nature of the rice eaten, rice may be displacing less desirable foods.”
In contrast, refined grains undergo “rapid action by digestive enzymes and quick absorption from the small intestines [that] could lead to an increase in postprandial blood glucose concentrations. The rise in glucose concentrations increases the insulin concentrations, which leads to hypoglycemia, lipolysis, and the stimulation of hunger and food intake,” the authors wrote.
“It’s similar to eating sugar, or candy,” noted Dr. Mozaffarian, as refined grain “is 100% glucose.” Whole grains differ by entering the gut packaged in cell structures that slow digestion and avoid delivering sugar in an unnaturally rapid way.
“We are providing new evidence, and we hope that dietary guidelines in North America encourage individuals to lower their refined grain and sugar intake,” Dr. Dehghan said.
PURE has received partial funding with unrestricted grants from several drug companies. Dr. Dehghan had no disclosures. Dr. Mozaffarian has been an adviser to or has received personal fees from several food companies, but had no relevant disclosures.
A minimally invasive modification for fascia lata mid-urethral sling
mid-urethral sling
mid-urethral sling
mid-urethral sling
Weekly COVID-19 cases in children continue to drop
Despite a drop in the number of weekly COVID-19 cases, children made up a larger share of cases for the fourth consecutive week, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.
Just over 140,000 new cases of COVID-19 in children were reported for the week of Jan. 22-28, down from 165,000 the week before and down from the record high of 211,000 2 weeks earlier, the AAP and the CHA said in their weekly COVID-19 report.
Since the beginning of January, however, the proportion of weekly cases occurring in children has risen from 12.9% to 15.1%, based on data collected by the AAP/CHA from the health department websites of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.
Since the beginning of the pandemic, 2.81 million children have been infected by the coronavirus, representing 12.8% of the total for all ages, which is almost 22 million. The cumulative rate since the start of the pandemic passed 3,700 cases per 100,000 children after increasing by 5.2% over the previous week, the AAP and CHA said in their report.
Cumulative hospitalizations in children just passed 11,000 in the 24 states (and New York City) that are reporting data for children, which represents 1.8% of COVID-19–related admissions for all ages, a proportion that has not changed since mid-November. Ten more deaths in children were reported during Jan. 22-28, bringing the total to 215 in the 43 states, along with New York City and Guam, that are tracking mortality.
In the 10 states that are reporting data on testing, rates of positive results in children range from 7.1% in Indiana, in which children make up the largest proportion of total tests performed (18.1%) to 28.4% in Iowa, where children make up the smallest proportion of tests (6.0%), the AAP and CHA said.
Despite a drop in the number of weekly COVID-19 cases, children made up a larger share of cases for the fourth consecutive week, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.
Just over 140,000 new cases of COVID-19 in children were reported for the week of Jan. 22-28, down from 165,000 the week before and down from the record high of 211,000 2 weeks earlier, the AAP and the CHA said in their weekly COVID-19 report.
Since the beginning of January, however, the proportion of weekly cases occurring in children has risen from 12.9% to 15.1%, based on data collected by the AAP/CHA from the health department websites of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.
Since the beginning of the pandemic, 2.81 million children have been infected by the coronavirus, representing 12.8% of the total for all ages, which is almost 22 million. The cumulative rate since the start of the pandemic passed 3,700 cases per 100,000 children after increasing by 5.2% over the previous week, the AAP and CHA said in their report.
Cumulative hospitalizations in children just passed 11,000 in the 24 states (and New York City) that are reporting data for children, which represents 1.8% of COVID-19–related admissions for all ages, a proportion that has not changed since mid-November. Ten more deaths in children were reported during Jan. 22-28, bringing the total to 215 in the 43 states, along with New York City and Guam, that are tracking mortality.
In the 10 states that are reporting data on testing, rates of positive results in children range from 7.1% in Indiana, in which children make up the largest proportion of total tests performed (18.1%) to 28.4% in Iowa, where children make up the smallest proportion of tests (6.0%), the AAP and CHA said.
Despite a drop in the number of weekly COVID-19 cases, children made up a larger share of cases for the fourth consecutive week, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.
Just over 140,000 new cases of COVID-19 in children were reported for the week of Jan. 22-28, down from 165,000 the week before and down from the record high of 211,000 2 weeks earlier, the AAP and the CHA said in their weekly COVID-19 report.
Since the beginning of January, however, the proportion of weekly cases occurring in children has risen from 12.9% to 15.1%, based on data collected by the AAP/CHA from the health department websites of 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.
Since the beginning of the pandemic, 2.81 million children have been infected by the coronavirus, representing 12.8% of the total for all ages, which is almost 22 million. The cumulative rate since the start of the pandemic passed 3,700 cases per 100,000 children after increasing by 5.2% over the previous week, the AAP and CHA said in their report.
Cumulative hospitalizations in children just passed 11,000 in the 24 states (and New York City) that are reporting data for children, which represents 1.8% of COVID-19–related admissions for all ages, a proportion that has not changed since mid-November. Ten more deaths in children were reported during Jan. 22-28, bringing the total to 215 in the 43 states, along with New York City and Guam, that are tracking mortality.
In the 10 states that are reporting data on testing, rates of positive results in children range from 7.1% in Indiana, in which children make up the largest proportion of total tests performed (18.1%) to 28.4% in Iowa, where children make up the smallest proportion of tests (6.0%), the AAP and CHA said.
COVID-19 in pregnancy tied to hypertension, preeclampsia
Having COVID-19 during pregnancy is linked to a significantly increased risk for gestational hypertension and preeclampsia compared with not having COVID-19 while pregnant, according to findings from a retrospective study presented Jan. 28 at the Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.
“This was not entirely surprising given that inflammation has been implicated in the pathogenesis of both hypertensive disorders of pregnancy and COVID-19 infection and thus may serve to exacerbate each other,” Nigel Madden, MD, a resident physician in the ob.gyn. department at Columbia University, New York. , told this news organization after she presented the results.
Hypertensive disorders of pregnancy occur in 10%-15% of all pregnancies and are the leading cause of maternal and perinatal morbidity and mortality worldwide, Dr. Madden told attendees of the meeting. Although it’s not clear what causes hypertensive diseases in pregnancy generally, “it is possible that the acute inflammatory state of the COVID infection may incite or exacerbate hypertensive disease of pregnancy,” Dr. Madden said.
The researchers conducted a retrospective chart review of 1,715 patients who had a singleton pregnancy and who underwent routine nasal polymerase chain reaction testing at admission to one institution’s labor and delivery department between March and June 2020. The researchers excluded patients who had a history of chronic hypertension.
Overall, 10% of the patients tested positive for COVID-19 (n = 167), and 90% tested negative (n = 1,548). There were several differences at baseline between the groups. Those who tested positive tended to be younger, with an average age of 28, compared with an average age of 31 years for the group that tested negative. The group that tested negative also had a higher proportion of mothers aged 35 and older (P < .01). There were also significant differences in the racial makeup of the groups. Half of those in the COVID-positive group reported “other” for their race. The biggest baseline disparity between the groups was with regard to insurance type: 73% of those who tested positive for COVID-19 used Medicaid; only 36% of patients in the COVID-negative group used Medicaid. Those with private insurance were more likely to test negative (43%) than positive (25%) (P < .01).
The researchers defined gestational hypertension as having a systolic blood pressure greater than or equal to 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg on two occasions at least 4 hours apart. A preeclampsia diagnosis required elevated blood pressure (using the same definition as for hypertension) as well as proteinuria, characterized by a protein/creatine ratio greater than or equal to 0.3 mg/dL or greater than or equal to 300 mg of protein on a 24-hour urine collection. Preeclampsia with severe features required prespecified laboratory abnormalities, pulmonary edema, or symptoms of headache, vision changes, chest pain, shortness of breath, or right upper quadrant pain.
More than twice as many patients with COVID had a hypertensive disorder of pregnancy (18%) as those who tested negative (8%). The patients who were COVID positive were significantly more likely than those who tested negative to have gestational hypertension and preeclampsia without severe features. Rates of preeclampsia with severe features were not significantly different between the groups.
The severity of hypertensive disease did not differ between the groups. Limitations of the study included its retrospective design, the small number of COVID-positive patients, and the fact that it was conducted at a single institution in New York. However, the study population was diverse, and it was conducted during the height of infections at the epicenter of the COVID-19 pandemic.
“This was a study of great clinical significance,” said Kim Boggess, MD, of the University of North Carolina at Chapel Hill, while moderating the session. “I would argue that you guys in New York are the best poised to answer some of the questions that need to be answered as it relates to the effect of coronavirus infection in pregnancy.”
Dr. Boggess asked whether the study examined associations related to the severity of COVID-19. Only 10 of the patients were symptomatic, Dr. Madden said, and only one of those patients developed preeclampsia with severe features.
Michelle Y. Owens, MD, professor and chief of maternal fetal medicine at the University of Mississippi Medical Center, Jackson, who also moderated the session, said in an interview that the findings call for physicians to remain vigilant about evaluating patients who test positive for COVID-19 for hypertensive disease and disorders.
“Additionally, these women should be educated about hypertensive disorders and the common symptoms to facilitate early diagnosis and treatment when indicated,” Dr. Owens said. “I believe this is of particular interest in those women who are not severely affected by COVID, as these changes may occur while they are undergoing quarantine or being monitored remotely. This amplifies the need for remote assessment or home monitoring of maternal blood pressures.”
Dr. Madden, Dr. Boggess, and Dr. Owens have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Having COVID-19 during pregnancy is linked to a significantly increased risk for gestational hypertension and preeclampsia compared with not having COVID-19 while pregnant, according to findings from a retrospective study presented Jan. 28 at the Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.
“This was not entirely surprising given that inflammation has been implicated in the pathogenesis of both hypertensive disorders of pregnancy and COVID-19 infection and thus may serve to exacerbate each other,” Nigel Madden, MD, a resident physician in the ob.gyn. department at Columbia University, New York. , told this news organization after she presented the results.
Hypertensive disorders of pregnancy occur in 10%-15% of all pregnancies and are the leading cause of maternal and perinatal morbidity and mortality worldwide, Dr. Madden told attendees of the meeting. Although it’s not clear what causes hypertensive diseases in pregnancy generally, “it is possible that the acute inflammatory state of the COVID infection may incite or exacerbate hypertensive disease of pregnancy,” Dr. Madden said.
The researchers conducted a retrospective chart review of 1,715 patients who had a singleton pregnancy and who underwent routine nasal polymerase chain reaction testing at admission to one institution’s labor and delivery department between March and June 2020. The researchers excluded patients who had a history of chronic hypertension.
Overall, 10% of the patients tested positive for COVID-19 (n = 167), and 90% tested negative (n = 1,548). There were several differences at baseline between the groups. Those who tested positive tended to be younger, with an average age of 28, compared with an average age of 31 years for the group that tested negative. The group that tested negative also had a higher proportion of mothers aged 35 and older (P < .01). There were also significant differences in the racial makeup of the groups. Half of those in the COVID-positive group reported “other” for their race. The biggest baseline disparity between the groups was with regard to insurance type: 73% of those who tested positive for COVID-19 used Medicaid; only 36% of patients in the COVID-negative group used Medicaid. Those with private insurance were more likely to test negative (43%) than positive (25%) (P < .01).
The researchers defined gestational hypertension as having a systolic blood pressure greater than or equal to 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg on two occasions at least 4 hours apart. A preeclampsia diagnosis required elevated blood pressure (using the same definition as for hypertension) as well as proteinuria, characterized by a protein/creatine ratio greater than or equal to 0.3 mg/dL or greater than or equal to 300 mg of protein on a 24-hour urine collection. Preeclampsia with severe features required prespecified laboratory abnormalities, pulmonary edema, or symptoms of headache, vision changes, chest pain, shortness of breath, or right upper quadrant pain.
More than twice as many patients with COVID had a hypertensive disorder of pregnancy (18%) as those who tested negative (8%). The patients who were COVID positive were significantly more likely than those who tested negative to have gestational hypertension and preeclampsia without severe features. Rates of preeclampsia with severe features were not significantly different between the groups.
The severity of hypertensive disease did not differ between the groups. Limitations of the study included its retrospective design, the small number of COVID-positive patients, and the fact that it was conducted at a single institution in New York. However, the study population was diverse, and it was conducted during the height of infections at the epicenter of the COVID-19 pandemic.
“This was a study of great clinical significance,” said Kim Boggess, MD, of the University of North Carolina at Chapel Hill, while moderating the session. “I would argue that you guys in New York are the best poised to answer some of the questions that need to be answered as it relates to the effect of coronavirus infection in pregnancy.”
Dr. Boggess asked whether the study examined associations related to the severity of COVID-19. Only 10 of the patients were symptomatic, Dr. Madden said, and only one of those patients developed preeclampsia with severe features.
Michelle Y. Owens, MD, professor and chief of maternal fetal medicine at the University of Mississippi Medical Center, Jackson, who also moderated the session, said in an interview that the findings call for physicians to remain vigilant about evaluating patients who test positive for COVID-19 for hypertensive disease and disorders.
“Additionally, these women should be educated about hypertensive disorders and the common symptoms to facilitate early diagnosis and treatment when indicated,” Dr. Owens said. “I believe this is of particular interest in those women who are not severely affected by COVID, as these changes may occur while they are undergoing quarantine or being monitored remotely. This amplifies the need for remote assessment or home monitoring of maternal blood pressures.”
Dr. Madden, Dr. Boggess, and Dr. Owens have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Having COVID-19 during pregnancy is linked to a significantly increased risk for gestational hypertension and preeclampsia compared with not having COVID-19 while pregnant, according to findings from a retrospective study presented Jan. 28 at the Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.
“This was not entirely surprising given that inflammation has been implicated in the pathogenesis of both hypertensive disorders of pregnancy and COVID-19 infection and thus may serve to exacerbate each other,” Nigel Madden, MD, a resident physician in the ob.gyn. department at Columbia University, New York. , told this news organization after she presented the results.
Hypertensive disorders of pregnancy occur in 10%-15% of all pregnancies and are the leading cause of maternal and perinatal morbidity and mortality worldwide, Dr. Madden told attendees of the meeting. Although it’s not clear what causes hypertensive diseases in pregnancy generally, “it is possible that the acute inflammatory state of the COVID infection may incite or exacerbate hypertensive disease of pregnancy,” Dr. Madden said.
The researchers conducted a retrospective chart review of 1,715 patients who had a singleton pregnancy and who underwent routine nasal polymerase chain reaction testing at admission to one institution’s labor and delivery department between March and June 2020. The researchers excluded patients who had a history of chronic hypertension.
Overall, 10% of the patients tested positive for COVID-19 (n = 167), and 90% tested negative (n = 1,548). There were several differences at baseline between the groups. Those who tested positive tended to be younger, with an average age of 28, compared with an average age of 31 years for the group that tested negative. The group that tested negative also had a higher proportion of mothers aged 35 and older (P < .01). There were also significant differences in the racial makeup of the groups. Half of those in the COVID-positive group reported “other” for their race. The biggest baseline disparity between the groups was with regard to insurance type: 73% of those who tested positive for COVID-19 used Medicaid; only 36% of patients in the COVID-negative group used Medicaid. Those with private insurance were more likely to test negative (43%) than positive (25%) (P < .01).
The researchers defined gestational hypertension as having a systolic blood pressure greater than or equal to 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg on two occasions at least 4 hours apart. A preeclampsia diagnosis required elevated blood pressure (using the same definition as for hypertension) as well as proteinuria, characterized by a protein/creatine ratio greater than or equal to 0.3 mg/dL or greater than or equal to 300 mg of protein on a 24-hour urine collection. Preeclampsia with severe features required prespecified laboratory abnormalities, pulmonary edema, or symptoms of headache, vision changes, chest pain, shortness of breath, or right upper quadrant pain.
More than twice as many patients with COVID had a hypertensive disorder of pregnancy (18%) as those who tested negative (8%). The patients who were COVID positive were significantly more likely than those who tested negative to have gestational hypertension and preeclampsia without severe features. Rates of preeclampsia with severe features were not significantly different between the groups.
The severity of hypertensive disease did not differ between the groups. Limitations of the study included its retrospective design, the small number of COVID-positive patients, and the fact that it was conducted at a single institution in New York. However, the study population was diverse, and it was conducted during the height of infections at the epicenter of the COVID-19 pandemic.
“This was a study of great clinical significance,” said Kim Boggess, MD, of the University of North Carolina at Chapel Hill, while moderating the session. “I would argue that you guys in New York are the best poised to answer some of the questions that need to be answered as it relates to the effect of coronavirus infection in pregnancy.”
Dr. Boggess asked whether the study examined associations related to the severity of COVID-19. Only 10 of the patients were symptomatic, Dr. Madden said, and only one of those patients developed preeclampsia with severe features.
Michelle Y. Owens, MD, professor and chief of maternal fetal medicine at the University of Mississippi Medical Center, Jackson, who also moderated the session, said in an interview that the findings call for physicians to remain vigilant about evaluating patients who test positive for COVID-19 for hypertensive disease and disorders.
“Additionally, these women should be educated about hypertensive disorders and the common symptoms to facilitate early diagnosis and treatment when indicated,” Dr. Owens said. “I believe this is of particular interest in those women who are not severely affected by COVID, as these changes may occur while they are undergoing quarantine or being monitored remotely. This amplifies the need for remote assessment or home monitoring of maternal blood pressures.”
Dr. Madden, Dr. Boggess, and Dr. Owens have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FDA approves intramuscular administration for peginterferon beta-1a in MS
“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.
Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.
Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.
The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.
Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.
The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.
The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.
A version of this article first appeared on Medscape.com.
“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.
Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.
Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.
The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.
Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.
The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.
The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.
A version of this article first appeared on Medscape.com.
“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.
Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.
Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.
The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.
Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.
The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.
The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.
A version of this article first appeared on Medscape.com.
Severe Refractory Hailey-Hailey Disease Treated With Electron Beam Radiotherapy and Low-Level Laser Therapy
To the Editor:
Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.3 Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.4 Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.5 Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.4 Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.6 Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.
A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.
At the time of presentation to the radiation oncology clinic, she continued to have extensive involvement of the intertriginous areas as well as involvement of the right neck at sites of skin chafing from clothing. Consistent with the limited available evidence, a dose of 20 Gy in 10 fractions was first prescribed to the axillae to assess response in the event of radiosensitivity, resulting in brisk desquamation. The conventional fractionation of 2 Gy per fraction allowed for assessment of response/tolerance and the opportunity to stop the treatment in the unlikely event of a severe skin reaction. Her skin tolerated treatment well with slight dryness and mild irritation that was less severe than the typical HHD flares. Concurrently with the axillary radiotherapy, we delivered a trial of low-level laser therapy to areas of severe disease in both inguinal regions in the hope that it could be used instead of radiotherapy to avoid any associated risks of radiation. Low-level laser therapy was administered with a light-emitting diode cluster probe at 2.5 Hz for 1 minute to 2 sites in each inguinal area daily for a total of 10 treatments. Unfortunately, this therapy temporarily exacerbated exudation present in the skin before it resolved to its pretreatment state with no improvement.
One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.
Our experience with low-level laser therapy indicated that it should be completely avoided in HHD. Our patient’s treatment with radiotherapy demonstrated excellent short-term responses in areas of pemphigus but later proved to be a mixed response with further follow-up including a mild posttreatment flare of the inframammary region that responded to steroids and new popliteal region involvement. As summarized in the Table, earlier reports of radiotherapy for the treatment of HHD have yielded varied results.6-8 The mixed response seen in our patient suggests that response to radiotherapy may be site specific, related to underlying inflammation from microbial overgrowth, or a function of the disease severity.
Although the number of reports on radiotherapy in HHD is small, there have been several reports of Darier disease, another acantholytic autosomal-dominant genodermatosis affecting the ATP2A2 gene, successfully treated incidentally with radiation.9,10 Total skin electron beam therapy also has been employed in the treatment of Darier disease; this patient experienced a severe flare after a relatively low treatment dose that required intensive care monitoring, possibly highlighting the potential radiosensitivity of patients with underlying genodermatoses and cautioning against radiotherapy dose escalation.11 In light of the mixed responses seen, radiation therapy should be used sparingly for severe relapsing cases that have failed a plethora of prior treatments. The risk of second cancer induction is especially of concern when using radiotherapy in a benign disease.12 We observed excellent initial responses in our patient, both with conventionally fractionated radiotherapy and hypofractionation. The risk of second malignancy induction is a linear function of radiotherapy dose.12 Thus, utilization of hypofractionated regimens such as 4 Gy times 2 fractions seems most prudent. It remains unclear if further dose de-escalation may yield a similar response, as seen in studies utilizing radiotherapy for other benign disease.13,14 Overall, given our mixed results with short follow-up, we conclude that the consideration of radiotherapy should be limited to patients with severe recalcitrant HHD.
- Dhitavat J, Fairclough RJ, Hovnanian A, et al. Calcium pumps and keratinocytes: lessons from Darier’s disease and Hailey-Hailey disease. Br J Dermatol. 2004;150:821-828.
- Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65.
- Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126:275-282.
- Chiaravalloti A, Payette M. Hailey-Hailey disease and review of management. J Drugs Dermatol. 2014;13:1254-1257.
- Zhang F, Yan X, Jiang D, et al. Eight novel mutations of ATP2C1 identified in 17 Chinese families with Hailey-Hailey disease. Dermatology. 2007;215:277-283.
- Narbutt J, Chrusciel A, Rychter A, et al. Persistent improvement of previously recalcitrant Hailey-Hailey disease with electron beam radiotherapy. Acta Derm Venereol. 2010;90:179-182.
- Sarkany I. Grenz-ray treatment of familial benign chronic pemphigus. Br J Dermatol. 1959;71:247-252.
- Roos DE, Reid CM. Benign familial pemphigus: little benefit from superficial radiotherapy. Australas J Dermatol. 2002;43:305-308.
- Podgornii A, Ciammella P, Ramundo D, et al. Efficacy of the radiotherapy on Darier’s disease: an indirect evidence. Case Rep Dermatol Med. 2013;2013:907802.
- Mac Manus MP, Cavalleri G, Ball DL, et al. Exacerbation, then clearance, of mutation-proven Darier’s disease of the skin after radiotherapy for bronchial carcinoma: a case of radiation-induced epidermal differentiation? Radiat Res. 2001;156:724-730.
- Kittridge A, Wahlgren C, Fuhrer R, et al. Treatment of recalcitrant Darier’s disease with electron beam therapy. Dermatol Ther. 2010;23:302-304.
- Preston DL, Shimizu Y, Pierce DA, et al. Studies of mortality of atomic bomb survivors. report 13: solid cancer and noncancer disease mortality: 1950-1997. Radiat Res. 2003;160:381-407.
- Fröhlich D, Baaske D, Glatzel M. Radiotherapy of hidradenitis suppurativa—still valid today? [in German]. Strahlenther Onkol. 2000;176:286-289.
- Heyd R, Tselis N, Ackermann H, et al. Radiation therapy for painful heel spurs: results of a prospective randomized study. Strahlenther Onkol. 2007;183:3-9.
To the Editor:
Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.3 Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.4 Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.5 Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.4 Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.6 Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.
A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.
At the time of presentation to the radiation oncology clinic, she continued to have extensive involvement of the intertriginous areas as well as involvement of the right neck at sites of skin chafing from clothing. Consistent with the limited available evidence, a dose of 20 Gy in 10 fractions was first prescribed to the axillae to assess response in the event of radiosensitivity, resulting in brisk desquamation. The conventional fractionation of 2 Gy per fraction allowed for assessment of response/tolerance and the opportunity to stop the treatment in the unlikely event of a severe skin reaction. Her skin tolerated treatment well with slight dryness and mild irritation that was less severe than the typical HHD flares. Concurrently with the axillary radiotherapy, we delivered a trial of low-level laser therapy to areas of severe disease in both inguinal regions in the hope that it could be used instead of radiotherapy to avoid any associated risks of radiation. Low-level laser therapy was administered with a light-emitting diode cluster probe at 2.5 Hz for 1 minute to 2 sites in each inguinal area daily for a total of 10 treatments. Unfortunately, this therapy temporarily exacerbated exudation present in the skin before it resolved to its pretreatment state with no improvement.
One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.
Our experience with low-level laser therapy indicated that it should be completely avoided in HHD. Our patient’s treatment with radiotherapy demonstrated excellent short-term responses in areas of pemphigus but later proved to be a mixed response with further follow-up including a mild posttreatment flare of the inframammary region that responded to steroids and new popliteal region involvement. As summarized in the Table, earlier reports of radiotherapy for the treatment of HHD have yielded varied results.6-8 The mixed response seen in our patient suggests that response to radiotherapy may be site specific, related to underlying inflammation from microbial overgrowth, or a function of the disease severity.
Although the number of reports on radiotherapy in HHD is small, there have been several reports of Darier disease, another acantholytic autosomal-dominant genodermatosis affecting the ATP2A2 gene, successfully treated incidentally with radiation.9,10 Total skin electron beam therapy also has been employed in the treatment of Darier disease; this patient experienced a severe flare after a relatively low treatment dose that required intensive care monitoring, possibly highlighting the potential radiosensitivity of patients with underlying genodermatoses and cautioning against radiotherapy dose escalation.11 In light of the mixed responses seen, radiation therapy should be used sparingly for severe relapsing cases that have failed a plethora of prior treatments. The risk of second cancer induction is especially of concern when using radiotherapy in a benign disease.12 We observed excellent initial responses in our patient, both with conventionally fractionated radiotherapy and hypofractionation. The risk of second malignancy induction is a linear function of radiotherapy dose.12 Thus, utilization of hypofractionated regimens such as 4 Gy times 2 fractions seems most prudent. It remains unclear if further dose de-escalation may yield a similar response, as seen in studies utilizing radiotherapy for other benign disease.13,14 Overall, given our mixed results with short follow-up, we conclude that the consideration of radiotherapy should be limited to patients with severe recalcitrant HHD.
To the Editor:
Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.3 Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.4 Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.5 Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.4 Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.6 Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.
A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.
At the time of presentation to the radiation oncology clinic, she continued to have extensive involvement of the intertriginous areas as well as involvement of the right neck at sites of skin chafing from clothing. Consistent with the limited available evidence, a dose of 20 Gy in 10 fractions was first prescribed to the axillae to assess response in the event of radiosensitivity, resulting in brisk desquamation. The conventional fractionation of 2 Gy per fraction allowed for assessment of response/tolerance and the opportunity to stop the treatment in the unlikely event of a severe skin reaction. Her skin tolerated treatment well with slight dryness and mild irritation that was less severe than the typical HHD flares. Concurrently with the axillary radiotherapy, we delivered a trial of low-level laser therapy to areas of severe disease in both inguinal regions in the hope that it could be used instead of radiotherapy to avoid any associated risks of radiation. Low-level laser therapy was administered with a light-emitting diode cluster probe at 2.5 Hz for 1 minute to 2 sites in each inguinal area daily for a total of 10 treatments. Unfortunately, this therapy temporarily exacerbated exudation present in the skin before it resolved to its pretreatment state with no improvement.
One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.
Our experience with low-level laser therapy indicated that it should be completely avoided in HHD. Our patient’s treatment with radiotherapy demonstrated excellent short-term responses in areas of pemphigus but later proved to be a mixed response with further follow-up including a mild posttreatment flare of the inframammary region that responded to steroids and new popliteal region involvement. As summarized in the Table, earlier reports of radiotherapy for the treatment of HHD have yielded varied results.6-8 The mixed response seen in our patient suggests that response to radiotherapy may be site specific, related to underlying inflammation from microbial overgrowth, or a function of the disease severity.
Although the number of reports on radiotherapy in HHD is small, there have been several reports of Darier disease, another acantholytic autosomal-dominant genodermatosis affecting the ATP2A2 gene, successfully treated incidentally with radiation.9,10 Total skin electron beam therapy also has been employed in the treatment of Darier disease; this patient experienced a severe flare after a relatively low treatment dose that required intensive care monitoring, possibly highlighting the potential radiosensitivity of patients with underlying genodermatoses and cautioning against radiotherapy dose escalation.11 In light of the mixed responses seen, radiation therapy should be used sparingly for severe relapsing cases that have failed a plethora of prior treatments. The risk of second cancer induction is especially of concern when using radiotherapy in a benign disease.12 We observed excellent initial responses in our patient, both with conventionally fractionated radiotherapy and hypofractionation. The risk of second malignancy induction is a linear function of radiotherapy dose.12 Thus, utilization of hypofractionated regimens such as 4 Gy times 2 fractions seems most prudent. It remains unclear if further dose de-escalation may yield a similar response, as seen in studies utilizing radiotherapy for other benign disease.13,14 Overall, given our mixed results with short follow-up, we conclude that the consideration of radiotherapy should be limited to patients with severe recalcitrant HHD.
- Dhitavat J, Fairclough RJ, Hovnanian A, et al. Calcium pumps and keratinocytes: lessons from Darier’s disease and Hailey-Hailey disease. Br J Dermatol. 2004;150:821-828.
- Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65.
- Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126:275-282.
- Chiaravalloti A, Payette M. Hailey-Hailey disease and review of management. J Drugs Dermatol. 2014;13:1254-1257.
- Zhang F, Yan X, Jiang D, et al. Eight novel mutations of ATP2C1 identified in 17 Chinese families with Hailey-Hailey disease. Dermatology. 2007;215:277-283.
- Narbutt J, Chrusciel A, Rychter A, et al. Persistent improvement of previously recalcitrant Hailey-Hailey disease with electron beam radiotherapy. Acta Derm Venereol. 2010;90:179-182.
- Sarkany I. Grenz-ray treatment of familial benign chronic pemphigus. Br J Dermatol. 1959;71:247-252.
- Roos DE, Reid CM. Benign familial pemphigus: little benefit from superficial radiotherapy. Australas J Dermatol. 2002;43:305-308.
- Podgornii A, Ciammella P, Ramundo D, et al. Efficacy of the radiotherapy on Darier’s disease: an indirect evidence. Case Rep Dermatol Med. 2013;2013:907802.
- Mac Manus MP, Cavalleri G, Ball DL, et al. Exacerbation, then clearance, of mutation-proven Darier’s disease of the skin after radiotherapy for bronchial carcinoma: a case of radiation-induced epidermal differentiation? Radiat Res. 2001;156:724-730.
- Kittridge A, Wahlgren C, Fuhrer R, et al. Treatment of recalcitrant Darier’s disease with electron beam therapy. Dermatol Ther. 2010;23:302-304.
- Preston DL, Shimizu Y, Pierce DA, et al. Studies of mortality of atomic bomb survivors. report 13: solid cancer and noncancer disease mortality: 1950-1997. Radiat Res. 2003;160:381-407.
- Fröhlich D, Baaske D, Glatzel M. Radiotherapy of hidradenitis suppurativa—still valid today? [in German]. Strahlenther Onkol. 2000;176:286-289.
- Heyd R, Tselis N, Ackermann H, et al. Radiation therapy for painful heel spurs: results of a prospective randomized study. Strahlenther Onkol. 2007;183:3-9.
- Dhitavat J, Fairclough RJ, Hovnanian A, et al. Calcium pumps and keratinocytes: lessons from Darier’s disease and Hailey-Hailey disease. Br J Dermatol. 2004;150:821-828.
- Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65.
- Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126:275-282.
- Chiaravalloti A, Payette M. Hailey-Hailey disease and review of management. J Drugs Dermatol. 2014;13:1254-1257.
- Zhang F, Yan X, Jiang D, et al. Eight novel mutations of ATP2C1 identified in 17 Chinese families with Hailey-Hailey disease. Dermatology. 2007;215:277-283.
- Narbutt J, Chrusciel A, Rychter A, et al. Persistent improvement of previously recalcitrant Hailey-Hailey disease with electron beam radiotherapy. Acta Derm Venereol. 2010;90:179-182.
- Sarkany I. Grenz-ray treatment of familial benign chronic pemphigus. Br J Dermatol. 1959;71:247-252.
- Roos DE, Reid CM. Benign familial pemphigus: little benefit from superficial radiotherapy. Australas J Dermatol. 2002;43:305-308.
- Podgornii A, Ciammella P, Ramundo D, et al. Efficacy of the radiotherapy on Darier’s disease: an indirect evidence. Case Rep Dermatol Med. 2013;2013:907802.
- Mac Manus MP, Cavalleri G, Ball DL, et al. Exacerbation, then clearance, of mutation-proven Darier’s disease of the skin after radiotherapy for bronchial carcinoma: a case of radiation-induced epidermal differentiation? Radiat Res. 2001;156:724-730.
- Kittridge A, Wahlgren C, Fuhrer R, et al. Treatment of recalcitrant Darier’s disease with electron beam therapy. Dermatol Ther. 2010;23:302-304.
- Preston DL, Shimizu Y, Pierce DA, et al. Studies of mortality of atomic bomb survivors. report 13: solid cancer and noncancer disease mortality: 1950-1997. Radiat Res. 2003;160:381-407.
- Fröhlich D, Baaske D, Glatzel M. Radiotherapy of hidradenitis suppurativa—still valid today? [in German]. Strahlenther Onkol. 2000;176:286-289.
- Heyd R, Tselis N, Ackermann H, et al. Radiation therapy for painful heel spurs: results of a prospective randomized study. Strahlenther Onkol. 2007;183:3-9.
Practice Points
- Hailey-Hailey disease (HHD) is a rare blistering dermatosis characterized by recurrent erythematous plaques with a predilection for the intertriginous areas.
- Electron beam radiotherapy is a potential treatment option for local control in patients with recalcitrant HHD.
Complete PCI beats culprit-lesion-only PCI in STEMI patients with multivessel CAD
Background: Previous trials have shown a reduction in composite outcomes if STEMI patients undergo staged PCI of nonculprit lesions discovered incidentally at the time of primary PCI for STEMI. However, no randomized trial has had the power to assess if staged PCI of nonculprit lesions reduces cardiovascular death or MI.
Study design: Prospective randomized clinical trial.
Setting: PCI-capable centers in 31 countries.
Synopsis: In this study, if multivessel disease was identified during primary PCI for STEMI, patients were randomized to either culprit-lesion-only PCI or complete revascularization with staged PCI of all suitable nonculprit lesions (either during the index hospitalization or up to 45 days after randomization).
Overall, 4,041 patients from 140 centers were randomized with median 3-year follow-up. The complete revascularization group had lower rates of the primary composite outcome of death from cardiovascular disease or new MI (absolute reduction, 2.7%; 7.8% vs. 10.5%; number needed to treat, 37; hazard ratio, 0.74; 95% confidence interval, 0.60-0.91; P = .004). This finding was driven by lower incidence of new MI in the complete revascularization group – the incidence of death was similar between the groups. A coprimary composite outcome of death from cardiovascular causes, new MI, or ischemia-driven revascularization also favored complete revascularization, with an absolute risk reduction of 7.8% (8.9% vs. 16.7%; NNT, 13; HR, 0.51; 95% CI, 0.43-0.61; P less than .001). No statistically significant differences between groups were noted for the safety outcomes of major bleeding, stroke, stent thrombosis, or contrast-induced kidney injury.
Bottom line: Patients with STEMI who have multivessel disease incidentally discovered during primary PCI have a lower incidence of new MI and ischemia-driven revascularization when they undergo complete revascularization of all suitable lesions, as opposed to PCI of only their culprit lesion.
Citation: Mehta SR et al. Complete revascularization with multivessel PCI for myocardial infarction. N Engl J Med. 2019 Oct 10;381:1411-21.
Dr. Porter is chief quality and safety resident at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.
Background: Previous trials have shown a reduction in composite outcomes if STEMI patients undergo staged PCI of nonculprit lesions discovered incidentally at the time of primary PCI for STEMI. However, no randomized trial has had the power to assess if staged PCI of nonculprit lesions reduces cardiovascular death or MI.
Study design: Prospective randomized clinical trial.
Setting: PCI-capable centers in 31 countries.
Synopsis: In this study, if multivessel disease was identified during primary PCI for STEMI, patients were randomized to either culprit-lesion-only PCI or complete revascularization with staged PCI of all suitable nonculprit lesions (either during the index hospitalization or up to 45 days after randomization).
Overall, 4,041 patients from 140 centers were randomized with median 3-year follow-up. The complete revascularization group had lower rates of the primary composite outcome of death from cardiovascular disease or new MI (absolute reduction, 2.7%; 7.8% vs. 10.5%; number needed to treat, 37; hazard ratio, 0.74; 95% confidence interval, 0.60-0.91; P = .004). This finding was driven by lower incidence of new MI in the complete revascularization group – the incidence of death was similar between the groups. A coprimary composite outcome of death from cardiovascular causes, new MI, or ischemia-driven revascularization also favored complete revascularization, with an absolute risk reduction of 7.8% (8.9% vs. 16.7%; NNT, 13; HR, 0.51; 95% CI, 0.43-0.61; P less than .001). No statistically significant differences between groups were noted for the safety outcomes of major bleeding, stroke, stent thrombosis, or contrast-induced kidney injury.
Bottom line: Patients with STEMI who have multivessel disease incidentally discovered during primary PCI have a lower incidence of new MI and ischemia-driven revascularization when they undergo complete revascularization of all suitable lesions, as opposed to PCI of only their culprit lesion.
Citation: Mehta SR et al. Complete revascularization with multivessel PCI for myocardial infarction. N Engl J Med. 2019 Oct 10;381:1411-21.
Dr. Porter is chief quality and safety resident at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.
Background: Previous trials have shown a reduction in composite outcomes if STEMI patients undergo staged PCI of nonculprit lesions discovered incidentally at the time of primary PCI for STEMI. However, no randomized trial has had the power to assess if staged PCI of nonculprit lesions reduces cardiovascular death or MI.
Study design: Prospective randomized clinical trial.
Setting: PCI-capable centers in 31 countries.
Synopsis: In this study, if multivessel disease was identified during primary PCI for STEMI, patients were randomized to either culprit-lesion-only PCI or complete revascularization with staged PCI of all suitable nonculprit lesions (either during the index hospitalization or up to 45 days after randomization).
Overall, 4,041 patients from 140 centers were randomized with median 3-year follow-up. The complete revascularization group had lower rates of the primary composite outcome of death from cardiovascular disease or new MI (absolute reduction, 2.7%; 7.8% vs. 10.5%; number needed to treat, 37; hazard ratio, 0.74; 95% confidence interval, 0.60-0.91; P = .004). This finding was driven by lower incidence of new MI in the complete revascularization group – the incidence of death was similar between the groups. A coprimary composite outcome of death from cardiovascular causes, new MI, or ischemia-driven revascularization also favored complete revascularization, with an absolute risk reduction of 7.8% (8.9% vs. 16.7%; NNT, 13; HR, 0.51; 95% CI, 0.43-0.61; P less than .001). No statistically significant differences between groups were noted for the safety outcomes of major bleeding, stroke, stent thrombosis, or contrast-induced kidney injury.
Bottom line: Patients with STEMI who have multivessel disease incidentally discovered during primary PCI have a lower incidence of new MI and ischemia-driven revascularization when they undergo complete revascularization of all suitable lesions, as opposed to PCI of only their culprit lesion.
Citation: Mehta SR et al. Complete revascularization with multivessel PCI for myocardial infarction. N Engl J Med. 2019 Oct 10;381:1411-21.
Dr. Porter is chief quality and safety resident at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.
Hair Follicle Bulb Region: A Potential Nidus for the Formation of Osteoma Cutis
The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. 1 It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 2,3 ; in 1868, the multiple miliary form on the face was described. 4 Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.
Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.
A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.
This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.
Clinical Observations
During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.
In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).
Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).
Comment
Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.
Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins5 in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman6 also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”
When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).
The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs
As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.10
Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.8 Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.11 Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.12
Myllylä et al13 described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.13
Some disturbance or imbalance in hair bulb homeostasis leads to overactivity of BMP signaling, causing osteoinduction in the hair bulb region and formation of PONs. The cause of the disturbance could be a traumatic or inflammatory injury to the hair follicle, as in the case of the secondary form of MMOC in association with chronic acne. In the primary form of osteoma cutis, the trigger could be more subtle or subclinical.
Trauma and inflammation are the main initiating factors involved in ossification in patients with fibrodysplasia ossificans progressiva due to ectopic activity of BMPs.9 The primary form of ossification appears to be similar to the mechanism by which intramembranous ossification is laid down (ie, by differentiation of mesenchymal cells into osteoblasts). In the proposed scenario, the cells of FDP, under the influence of BMPs, differentiate into osteoblasts and lay down osteoid, forming a limited-capacity “ossification center” or pilar osteocalcific nodule.
It is difficult to know the exact relationship of PONs or OC to the hair bulb due to the 2-dimensional nature of histologic sections. However, considering the finding of a rare case of osteoid forming within the bulb and in another the presence of melanin within the osteocalcific nodule, it is likely that these lesions are formed within the hair bulb or in situations in which the conditions replicate the biochemical characteristics of the hair bulb (eg, pilomatricoma).
The formation of PONs might act as a terminal phase in the hair cycle that is rarely induced to provide an exit for damaged hair follicles from cyclical perpetuity. An unspecified event or injury might render a hair follicle unable to continue its cyclical growth and cause BMPs to induce premature calcification in or around the hair bulb, which would probably be the only known quasiphysiological mechanism for a damaged hair follicle to exit the hair cycle.
Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.14 Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,15 a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.
Conclusion
Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.
- Burgdorf W, Nasemann T. Cutaneous osteomas: a clinical and histopathologic review. Arch Dermatol Res. 1977;260:121-135.
- Essing M. Osteoma cutis of the forehead. HNO. 1985;33:548-550.
- Bouraoui S, Mlika M, Kort R, et al. Miliary osteoma cutis of the face. J Dermatol Case Rep. 2011;5:77-81.
- Virchow R. Die krankhaften Geschwülste. Vol 2. Hirschwald; 1864.
- Hopkins JG. Multiple miliary osteomas of the skin: report of a case. Arch Derm Syphilol. 1928;18:706-715.
- Rossman RE, Freeman RG. Osteoma cutis, a stage of preosseous calcification. Arch Dermatol. 1964;89:68-73.
- Guha U, Mecklenburg L, Cowin P, et al. Bone morphogenetic protein signaling regulates postnatal hair follicle differentiation and cycling. Am J Pathol. 2004;165:729-740.
- Rendl M, Polak L, Fuchs E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 2008;22:543-557.
- Shi S, de Gorter DJJ, Hoogaars WMH, et al. Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70:407-423.
- Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem. 2010;147:35-51.
- Kurokawa I, Kusumoto K, Bessho K. Immunohistochemical expression of bone morphogenetic protein-2 in pilomatricoma. Br J Dermatol. 2000;143:754-758.
- Myllylä RM, Haapasaari K-M, Lehenkari P, et al. Bone morphogenetic proteins 4 and 2/7 induce osteogenic differentiation of mouse skin derived fibroblast and dermal papilla cells. Cell Tissue Res. 2014;355:463-470.
- Myllylä RM, Haapasaari KM, Palatsi R, et al. Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature. Br J Dermatol. 2011;164:544-552.
- Vickaryous MK, Sire J-Y. The integumentary skeleton of tetrapods: origin, evolution, and development. J Anat. 2009;214:441-464.
- Vickaryous MK, Hall BK. Development of the dermal skeleton in Alligator mississippiensis (Archosauria, Crocodylia) with comments on the homology of osteoderms. J Morphol. 2008;269:398-422.
The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. 1 It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 2,3 ; in 1868, the multiple miliary form on the face was described. 4 Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.
Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.
A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.
This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.
Clinical Observations
During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.
In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).
Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).
Comment
Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.
Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins5 in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman6 also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”
When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).
The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs
As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.10
Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.8 Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.11 Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.12
Myllylä et al13 described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.13
Some disturbance or imbalance in hair bulb homeostasis leads to overactivity of BMP signaling, causing osteoinduction in the hair bulb region and formation of PONs. The cause of the disturbance could be a traumatic or inflammatory injury to the hair follicle, as in the case of the secondary form of MMOC in association with chronic acne. In the primary form of osteoma cutis, the trigger could be more subtle or subclinical.
Trauma and inflammation are the main initiating factors involved in ossification in patients with fibrodysplasia ossificans progressiva due to ectopic activity of BMPs.9 The primary form of ossification appears to be similar to the mechanism by which intramembranous ossification is laid down (ie, by differentiation of mesenchymal cells into osteoblasts). In the proposed scenario, the cells of FDP, under the influence of BMPs, differentiate into osteoblasts and lay down osteoid, forming a limited-capacity “ossification center” or pilar osteocalcific nodule.
It is difficult to know the exact relationship of PONs or OC to the hair bulb due to the 2-dimensional nature of histologic sections. However, considering the finding of a rare case of osteoid forming within the bulb and in another the presence of melanin within the osteocalcific nodule, it is likely that these lesions are formed within the hair bulb or in situations in which the conditions replicate the biochemical characteristics of the hair bulb (eg, pilomatricoma).
The formation of PONs might act as a terminal phase in the hair cycle that is rarely induced to provide an exit for damaged hair follicles from cyclical perpetuity. An unspecified event or injury might render a hair follicle unable to continue its cyclical growth and cause BMPs to induce premature calcification in or around the hair bulb, which would probably be the only known quasiphysiological mechanism for a damaged hair follicle to exit the hair cycle.
Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.14 Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,15 a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.
Conclusion
Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.
The term osteoma cutis (OC) is defined as the ossification or bone formation either in the dermis or hypodermis. 1 It is heterotopic in nature, referring to extraneous bone formation in soft tissue. Osteoma cutis was first described in 1858 2,3 ; in 1868, the multiple miliary form on the face was described. 4 Cutaneous ossification can take many forms, ranging from occurrence in a nevus (nevus of Nanta) to its association with rare genetic disorders, such as fibrodysplasia ossificans progressiva and Albright hereditary osteodystrophy.
Some of these ossifications are classified as primary; others are secondary, depending on the presence of a preexisting lesion (eg, pilomatricoma, basal cell carcinoma). However, certain conditions, such as multiple miliary osteoma of the face, can be difficult to classify due to the presence or absence of a history of acne or dermabrasion, or both. The secondary forms more commonly are encountered due to their incidental association with an excised lesion, such as pilomatricoma.
A precursor of OC has been neglected in the literature despite its common occurrence. It may have been peripherally alluded to in the literature in reference to the miliary form of OC.5,6 The cases reported here demonstrate small round nodules of calcification or ossification, or both, in punch biopsies and excision specimens from hair-bearing areas of skin, especially from the head and neck. These lesions are mainly observed in the peripilar location or more specifically in the approximate location of the hair bulb.
This article reviews a possible mechanism of formation of these osteocalcific micronodules. These often-encountered micronodules are small osteocalcific lesions without typical bone or well-formed OC, such as trabeculae formation or fatty marrow, and may represent earliest stages in the formation of OC.
Clinical Observations
During routine dermatopathologic practice, I observed incidental small osteocalcific micronodules in close proximity to the lower part of the hair follicle in multiple cases. These nodules were not related to the main lesion in the specimen and were not the reason for the biopsy or excision. Most of the time, these micronodules were noted in excision or re-excision specimens or in a punch biopsy.
In my review of multiple unrelated cases over time, incidental osteocalcific micronodules were observed occasionally in punch biopsies and excision specimens during routine practice. These micronodules were mainly located in the vicinity of a hair bulb (Figure 1). If the hair bulb was not present in the sections, these micronodules were noted near or within the fibrous tract (Figure 2) or beneath a sebaceous lobule (Figure 3). In an exceptional case, a small round deposit of osteoid was seen forming just above the dermal papilla of the hair bulb (Figure 4).
Multiple osteocalcific micronodules were identified in a case of cicatricial alopecia. These micronodules were observed in sections taken at the levels of hair bulbs, and more or less corresponded to the size of the bulb (Figure 5A). Fortuitously, the patient was dark-skinned; the remnants of melanin within the micronodules provided evidence that the micronodules were formed within hair bulbs. Melanin staining confirmed the presence of melanin within some of the micronodules (Figure 5B).
Comment
Skeletogenesis in humans takes place by 2 methods: endochondral ossification and intramembranous ossification. In contrast to endochondral ossification, intramembranous ossification does not require a preexisting cartilaginous template. Instead, there is condensation of mesenchymal cells, which differentiate into osteoblasts and lay down osteoid, thus forming an ossification center. Little is known about the mechanism of formation of OC or the nidus of formation of the primary form.
Incidental micronodules of calcification and ossification are routinely encountered during histopathologic review of specimens from hair-bearing areas of the skin in dermatopathology practice. A review of the literature, however, does not reveal any specific dermatopathologic term ascribed to this phenomenon. These lesions might be similar to those described by Hopkins5 in 1928 in the setting of miliary OC of the face secondary to acne. Rossman and Freeman6 also described the same lesions when referring to facial OC as a “stage of pre-osseous calcification.”
When these osteocalcific micronodules are encountered, it usually is in close proximity to a hair follicle bulb. When a hair bulb is not seen in the sections, the micronodules are noted near fibrous tracts, arrector pili muscles, or sebaceous lobules, suggesting a close peripilar or peribulbar location. The micronodules are approximately 0.5 mm in diameter—roughly the size of a hair bulb. Due to the close anatomic association of micronodules and the hair bulb, these lesions can be called pilar osteocalcific nodules (PONs).
The role of bone morphogenetic protein (BMP) signaling in the maintenance of the hair cycle is well established. Bone morphogenetic proteins are extracellular cytokines that belong to the transforming growth factor β family. The hair bulb microenvironment is rich in BMPs
As the name implies, BMPs were discovered in relation to their important role in osteogenesis and tissue homeostasis. More than 20 BMPs have been identified, many of which promote bone formation and repair of bone fracture. Osteoinductive BMPs include BMP-2 and BMP-4 through BMP-10; BMP-2 and BMP-4 are expressed in the hair matrix and BMP-4 and BMP-6 are expressed in the FDP.8,9 All bone-inducing BMPs can cause mesenchymal stem cells to differentiate into osteoblasts in vitro.10
Overactive BMP signaling has been shown to cause heterotopic ossification in patients with fibrodysplasia ossificans progressiva.8 Immunohistochemical expression of BMP-2 has been demonstrated in shadow cells of pilomatricoma.11 Calcification and ossification are seen in as many as 20% of pilomatricomas. Both BMP-2 and BMP-4 have been shown to induce osteogenic differentiation of mouse skin−derived fibroblasts and FDP cells.12
Myllylä et al13 described 4 cases of multiple miliary osteoma cutis (MMOC). They also found 47 reported cases of MMOC, in which there was a history of acne in 55% (26/47). Only 15% (7/47) of these cases were extrafacial on the neck, chest, back, and arms. Osteomas in these cases were not associated with folliculosebaceous units or other adnexal structures, which may have been due to replacement by acne scarring, as all 4 patients had a history of acne vulgaris. The authors postulated a role for the GNAS gene mutation in the morphogenesis of MMOC; however, no supporting evidence was found for this claim. They also postulated a role for BMPs in the formation of MMOC.13
Some disturbance or imbalance in hair bulb homeostasis leads to overactivity of BMP signaling, causing osteoinduction in the hair bulb region and formation of PONs. The cause of the disturbance could be a traumatic or inflammatory injury to the hair follicle, as in the case of the secondary form of MMOC in association with chronic acne. In the primary form of osteoma cutis, the trigger could be more subtle or subclinical.
Trauma and inflammation are the main initiating factors involved in ossification in patients with fibrodysplasia ossificans progressiva due to ectopic activity of BMPs.9 The primary form of ossification appears to be similar to the mechanism by which intramembranous ossification is laid down (ie, by differentiation of mesenchymal cells into osteoblasts). In the proposed scenario, the cells of FDP, under the influence of BMPs, differentiate into osteoblasts and lay down osteoid, forming a limited-capacity “ossification center” or pilar osteocalcific nodule.
It is difficult to know the exact relationship of PONs or OC to the hair bulb due to the 2-dimensional nature of histologic sections. However, considering the finding of a rare case of osteoid forming within the bulb and in another the presence of melanin within the osteocalcific nodule, it is likely that these lesions are formed within the hair bulb or in situations in which the conditions replicate the biochemical characteristics of the hair bulb (eg, pilomatricoma).
The formation of PONs might act as a terminal phase in the hair cycle that is rarely induced to provide an exit for damaged hair follicles from cyclical perpetuity. An unspecified event or injury might render a hair follicle unable to continue its cyclical growth and cause BMPs to induce premature calcification in or around the hair bulb, which would probably be the only known quasiphysiological mechanism for a damaged hair follicle to exit the hair cycle.
Another interesting aspect of osteoma formation in human skin is the similarity to osteoderms or the integumentary skeleton of vertebrates.14 Early in evolution, the dermal skeleton was the predominant skeletal system in some lineages. Phylogenetically, osteoderms are not uniformly distributed, and show a latent ability to manifest in some groups or lay dormant or disappear in others. The occurrence of primary osteomas in the human integument might be a vestigial manifestation of deep homology,15 a latent ability to form structures that have been lost. The embryologic formation of osteoderms in the dermis of vertebrates is thought to depend on the interaction or cross-talk between ectomesenchymal cells of neural crest origin and cells of the stratum basalis of epidermis, which is somewhat similar to the formation of the hair follicles.
Conclusion
Under certain conditions, the bulb region of a hair follicle might provide a nidus for the formation of OC. The hair bulb region contains both the precursor cellular element (mesenchymal cells of FDP) and the trigger cytokine (BMP) for the induction of osteogenic metaplasia.
- Burgdorf W, Nasemann T. Cutaneous osteomas: a clinical and histopathologic review. Arch Dermatol Res. 1977;260:121-135.
- Essing M. Osteoma cutis of the forehead. HNO. 1985;33:548-550.
- Bouraoui S, Mlika M, Kort R, et al. Miliary osteoma cutis of the face. J Dermatol Case Rep. 2011;5:77-81.
- Virchow R. Die krankhaften Geschwülste. Vol 2. Hirschwald; 1864.
- Hopkins JG. Multiple miliary osteomas of the skin: report of a case. Arch Derm Syphilol. 1928;18:706-715.
- Rossman RE, Freeman RG. Osteoma cutis, a stage of preosseous calcification. Arch Dermatol. 1964;89:68-73.
- Guha U, Mecklenburg L, Cowin P, et al. Bone morphogenetic protein signaling regulates postnatal hair follicle differentiation and cycling. Am J Pathol. 2004;165:729-740.
- Rendl M, Polak L, Fuchs E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 2008;22:543-557.
- Shi S, de Gorter DJJ, Hoogaars WMH, et al. Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70:407-423.
- Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem. 2010;147:35-51.
- Kurokawa I, Kusumoto K, Bessho K. Immunohistochemical expression of bone morphogenetic protein-2 in pilomatricoma. Br J Dermatol. 2000;143:754-758.
- Myllylä RM, Haapasaari K-M, Lehenkari P, et al. Bone morphogenetic proteins 4 and 2/7 induce osteogenic differentiation of mouse skin derived fibroblast and dermal papilla cells. Cell Tissue Res. 2014;355:463-470.
- Myllylä RM, Haapasaari KM, Palatsi R, et al. Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature. Br J Dermatol. 2011;164:544-552.
- Vickaryous MK, Sire J-Y. The integumentary skeleton of tetrapods: origin, evolution, and development. J Anat. 2009;214:441-464.
- Vickaryous MK, Hall BK. Development of the dermal skeleton in Alligator mississippiensis (Archosauria, Crocodylia) with comments on the homology of osteoderms. J Morphol. 2008;269:398-422.
- Burgdorf W, Nasemann T. Cutaneous osteomas: a clinical and histopathologic review. Arch Dermatol Res. 1977;260:121-135.
- Essing M. Osteoma cutis of the forehead. HNO. 1985;33:548-550.
- Bouraoui S, Mlika M, Kort R, et al. Miliary osteoma cutis of the face. J Dermatol Case Rep. 2011;5:77-81.
- Virchow R. Die krankhaften Geschwülste. Vol 2. Hirschwald; 1864.
- Hopkins JG. Multiple miliary osteomas of the skin: report of a case. Arch Derm Syphilol. 1928;18:706-715.
- Rossman RE, Freeman RG. Osteoma cutis, a stage of preosseous calcification. Arch Dermatol. 1964;89:68-73.
- Guha U, Mecklenburg L, Cowin P, et al. Bone morphogenetic protein signaling regulates postnatal hair follicle differentiation and cycling. Am J Pathol. 2004;165:729-740.
- Rendl M, Polak L, Fuchs E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 2008;22:543-557.
- Shi S, de Gorter DJJ, Hoogaars WMH, et al. Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70:407-423.
- Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem. 2010;147:35-51.
- Kurokawa I, Kusumoto K, Bessho K. Immunohistochemical expression of bone morphogenetic protein-2 in pilomatricoma. Br J Dermatol. 2000;143:754-758.
- Myllylä RM, Haapasaari K-M, Lehenkari P, et al. Bone morphogenetic proteins 4 and 2/7 induce osteogenic differentiation of mouse skin derived fibroblast and dermal papilla cells. Cell Tissue Res. 2014;355:463-470.
- Myllylä RM, Haapasaari KM, Palatsi R, et al. Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature. Br J Dermatol. 2011;164:544-552.
- Vickaryous MK, Sire J-Y. The integumentary skeleton of tetrapods: origin, evolution, and development. J Anat. 2009;214:441-464.
- Vickaryous MK, Hall BK. Development of the dermal skeleton in Alligator mississippiensis (Archosauria, Crocodylia) with comments on the homology of osteoderms. J Morphol. 2008;269:398-422.
Practice Points
- Understanding the pathogenesis of osteoma cutis (OC) can help physicians devise management of these disfiguring lesions.
- Small osteocalcific nodules in close proximity to the lower aspect of the hair bulb may be an important precursor to OC.
