The global dietary supplement industry generates more than $400 billion a year. Supplements are alleged to treat many health concerns, from immune conditions and cognition to sexual dysfunction and premature wrinkles. Although some supplements have been proven to be helpful, others have no scientific basis.

I can preach all day that a healthy diet rarely needs supplementation. But even as a dietitian, I find it difficult to consistently eat a diet that is both sufficiently varied and adequate to provide for all my nutrition needs. Our patients with kidney disease, surely, are not immune to this plight. They may even be more inclined to nutrient deficiencies, as poor diet is linked to increased incidence and progression of chronic kidney disease (CKD).

I find that patients with kidney disease often have an interest in dietary supplementation, even those with a well-rounded diet. Though we can discourage the use of supplements, or at the very least encourage patient transparency regarding supplement use, many will continue dietary supplementation at the suggestion of their friends, family, or even their preferred daytime talk show host. 

What these patients truly require is education on using supplements that are most beneficial to them. By recommending supplements that address patients’ pain points like inflammation, dyslipidemia, cardiovascular health, and reduced progression to end-stage renal disease (ESRD), we can improve patient health and, hopefully, decrease use of questionable supplements.
 

Probiotics

Although probiotics have been used in the treatment of digestive issues for many years, the gut-kidney axis is only recently being explored. Studies show that the microbiota of patients with CKD is altered, even in the early stages of disease, producing additional inflammation and metabolic dysfunction. This can be remedied, or at least alleviated, by introducing a probiotic supplement.

Some probiotics have been shown to decrease inflammation, decrease fasting blood glucose, decrease low-density lipoprotein cholesterol, triglycerides, and total cholesterol, increase estimated glomerular filtration rate (eGFR), decrease blood urea nitrogen and urea, and decrease uric acid

Probiotic-rich foods like kimchi or fermented pickles may not be appropriate because of excessive sodium content or simply because of patient preference — kombucha isn’t for everyone. However, adding a probiotic supplement can improve gut microbiota without undermining dietary concerns. 

When recommending probiotics, patients should be educated to ensure that their probiotic has strains that have been proven to be beneficial for kidney health. Lactobacillus acidophilus, Lactobacillus casei, ^{Bifidobacterium} species, and Streptococcus thermophilus have been shown to have a positive effect on kidney health and decreasing progression of CKD at a dosage of 109 colony-forming units per day.
 

Fish Oil

Though nephrology and cardiology are separate fields, it cannot be overstated that kidney patients are also heart patients. 

Patients with CKD and an eGFR < 60 mL/min per 1.73 m²are most likely to die from cardiovascular causes, and this likelihood increases as eGFR decreases. CKD-associated dyslipidemia results in elevated triglycerides and reduced high-density lipoprotein cholesterol often accompanied by proteinuria, and has been linked to an increase in atherosclerosis.

A simple fish oil supplement can work to decrease oxidative stress, relieve inflammation, and improve serum lipids, leading to improved kidney and cardiovascular health. One meta-analysis found that high-dose fish oil supplementation, though it had no effect on serum creatinine or eGFR, was associated with a lower risk for proteinuria and progression to ESRD. 

Fish oil’s popularity in recent years bodes well for the kidney patient. It is now easily obtained over the counter in high doses to meet the recommended adequate intake of omega-3s, which is 1100 mg/d for women and 1600 mg/d for men. There are also more burpless varieties of these supplements to increase compliance. 
 

Vitamin D

Patients with renal disease are prone to vitamin D deficiency through inadequate intake and limited sunlight, which is exacerbated by the diseased kidney’s inability to effectively convert calcidiol to calcitriol. Vitamin D deficiency is linked to poor bone health, fatigue, muscle pain, impaired wound healing, and depression. Low vitamin D status has also been linked to poor outcomes in cancer, multiple sclerosis, cardiovascular disease, type 2 diabetes, and weight loss.

A meta-analysis of over 6000 patients with CKD found that high levels of 25-hydroxy vitamin D (25[OH]D) are associated with significantly improved survival rates regardless of CKD or ESRD status. 

Kidney Disease: Improving Global Outcomes guidelines recommend supplementing with ergocalciferol or cholecalciferol to correct (OH)D deficiency. This ensures adequate supply for conversion to calcitriol, but it cannot affect bone and mineral metabolism without further intervention in the form of calcitriol supplementation. By supplementing with ergocalciferol or cholecalciferol to meet the recommended daily allowance of 15 µg (600 IU) for adults under 70 years and 20 µg (800 IU) for adults over 70 years, the primary care team can ensure that the body has all the building blocks required for the nephrology team to then address mineral and bone disorder in CKD without the fear of promoting hypercalcemia. 
 

Safe Purchasing Practices

Patients should be reminded to purchase dietary supplements from reputable dealers, especially when purchasing online. Retailers like Amazon are increasing the barriers required to sell supplements to improve the quality of products sold on the site. But other online retailers may sell products from outside of the United States that fall outside of the Food and Drug Administration’s jurisdiction. 

Patients should also be reminded that “more is not always better” and counseled on appropriate dosages for individual needs. 
 

In Summary

Patients will probably continue to lean on dietary supplements, regardless of our approval. Transparency and education are important when working with patients with CKD, especially in regard to dietary supplements. 

When recommended appropriately, however, the supplements discussed can lead to better outcomes with improvements in kidney health by addressing inflammation, serum lipids, glycemic control, and cardiovascular health.

Ms. Winfree Root is a renal dietitian in private practice in Mary Esther, Florida. She disclosed no relevant conflicts of interest.

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

The global dietary supplement industry generates more than $400 billion a year. Supplements are alleged to treat many health concerns, from immune conditions and cognition to sexual dysfunction and premature wrinkles. Although some supplements have been proven to be helpful, others have no scientific basis.

I can preach all day that a healthy diet rarely needs supplementation. But even as a dietitian, I find it difficult to consistently eat a diet that is both sufficiently varied and adequate to provide for all my nutrition needs. Our patients with kidney disease, surely, are not immune to this plight. They may even be more inclined to nutrient deficiencies, as poor diet is linked to increased incidence and progression of chronic kidney disease (CKD).

I find that patients with kidney disease often have an interest in dietary supplementation, even those with a well-rounded diet. Though we can discourage the use of supplements, or at the very least encourage patient transparency regarding supplement use, many will continue dietary supplementation at the suggestion of their friends, family, or even their preferred daytime talk show host. 

What these patients truly require is education on using supplements that are most beneficial to them. By recommending supplements that address patients’ pain points like inflammation, dyslipidemia, cardiovascular health, and reduced progression to end-stage renal disease (ESRD), we can improve patient health and, hopefully, decrease use of questionable supplements.
 

Probiotics

Although probiotics have been used in the treatment of digestive issues for many years, the gut-kidney axis is only recently being explored. Studies show that the microbiota of patients with CKD is altered, even in the early stages of disease, producing additional inflammation and metabolic dysfunction. This can be remedied, or at least alleviated, by introducing a probiotic supplement.

Some probiotics have been shown to decrease inflammation, decrease fasting blood glucose, decrease low-density lipoprotein cholesterol, triglycerides, and total cholesterol, increase estimated glomerular filtration rate (eGFR), decrease blood urea nitrogen and urea, and decrease uric acid

Probiotic-rich foods like kimchi or fermented pickles may not be appropriate because of excessive sodium content or simply because of patient preference — kombucha isn’t for everyone. However, adding a probiotic supplement can improve gut microbiota without undermining dietary concerns. 

When recommending probiotics, patients should be educated to ensure that their probiotic has strains that have been proven to be beneficial for kidney health. Lactobacillus acidophilus, Lactobacillus casei, ^{Bifidobacterium} species, and Streptococcus thermophilus have been shown to have a positive effect on kidney health and decreasing progression of CKD at a dosage of 109 colony-forming units per day.
 

Fish Oil

Though nephrology and cardiology are separate fields, it cannot be overstated that kidney patients are also heart patients. 

Patients with CKD and an eGFR < 60 mL/min per 1.73 m²are most likely to die from cardiovascular causes, and this likelihood increases as eGFR decreases. CKD-associated dyslipidemia results in elevated triglycerides and reduced high-density lipoprotein cholesterol often accompanied by proteinuria, and has been linked to an increase in atherosclerosis.

A simple fish oil supplement can work to decrease oxidative stress, relieve inflammation, and improve serum lipids, leading to improved kidney and cardiovascular health. One meta-analysis found that high-dose fish oil supplementation, though it had no effect on serum creatinine or eGFR, was associated with a lower risk for proteinuria and progression to ESRD. 

Fish oil’s popularity in recent years bodes well for the kidney patient. It is now easily obtained over the counter in high doses to meet the recommended adequate intake of omega-3s, which is 1100 mg/d for women and 1600 mg/d for men. There are also more burpless varieties of these supplements to increase compliance. 
 

Vitamin D

Patients with renal disease are prone to vitamin D deficiency through inadequate intake and limited sunlight, which is exacerbated by the diseased kidney’s inability to effectively convert calcidiol to calcitriol. Vitamin D deficiency is linked to poor bone health, fatigue, muscle pain, impaired wound healing, and depression. Low vitamin D status has also been linked to poor outcomes in cancer, multiple sclerosis, cardiovascular disease, type 2 diabetes, and weight loss.

A meta-analysis of over 6000 patients with CKD found that high levels of 25-hydroxy vitamin D (25[OH]D) are associated with significantly improved survival rates regardless of CKD or ESRD status. 

Kidney Disease: Improving Global Outcomes guidelines recommend supplementing with ergocalciferol or cholecalciferol to correct (OH)D deficiency. This ensures adequate supply for conversion to calcitriol, but it cannot affect bone and mineral metabolism without further intervention in the form of calcitriol supplementation. By supplementing with ergocalciferol or cholecalciferol to meet the recommended daily allowance of 15 µg (600 IU) for adults under 70 years and 20 µg (800 IU) for adults over 70 years, the primary care team can ensure that the body has all the building blocks required for the nephrology team to then address mineral and bone disorder in CKD without the fear of promoting hypercalcemia. 
 

Safe Purchasing Practices

Patients should be reminded to purchase dietary supplements from reputable dealers, especially when purchasing online. Retailers like Amazon are increasing the barriers required to sell supplements to improve the quality of products sold on the site. But other online retailers may sell products from outside of the United States that fall outside of the Food and Drug Administration’s jurisdiction. 

Patients should also be reminded that “more is not always better” and counseled on appropriate dosages for individual needs. 
 

In Summary

Patients will probably continue to lean on dietary supplements, regardless of our approval. Transparency and education are important when working with patients with CKD, especially in regard to dietary supplements. 

When recommended appropriately, however, the supplements discussed can lead to better outcomes with improvements in kidney health by addressing inflammation, serum lipids, glycemic control, and cardiovascular health.

Ms. Winfree Root is a renal dietitian in private practice in Mary Esther, Florida. She disclosed no relevant conflicts of interest.

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

The global dietary supplement industry generates more than $400 billion a year. Supplements are alleged to treat many health concerns, from immune conditions and cognition to sexual dysfunction and premature wrinkles. Although some supplements have been proven to be helpful, others have no scientific basis.

I can preach all day that a healthy diet rarely needs supplementation. But even as a dietitian, I find it difficult to consistently eat a diet that is both sufficiently varied and adequate to provide for all my nutrition needs. Our patients with kidney disease, surely, are not immune to this plight. They may even be more inclined to nutrient deficiencies, as poor diet is linked to increased incidence and progression of chronic kidney disease (CKD).

I find that patients with kidney disease often have an interest in dietary supplementation, even those with a well-rounded diet. Though we can discourage the use of supplements, or at the very least encourage patient transparency regarding supplement use, many will continue dietary supplementation at the suggestion of their friends, family, or even their preferred daytime talk show host. 

What these patients truly require is education on using supplements that are most beneficial to them. By recommending supplements that address patients’ pain points like inflammation, dyslipidemia, cardiovascular health, and reduced progression to end-stage renal disease (ESRD), we can improve patient health and, hopefully, decrease use of questionable supplements.
 

Probiotics

Although probiotics have been used in the treatment of digestive issues for many years, the gut-kidney axis is only recently being explored. Studies show that the microbiota of patients with CKD is altered, even in the early stages of disease, producing additional inflammation and metabolic dysfunction. This can be remedied, or at least alleviated, by introducing a probiotic supplement.

Some probiotics have been shown to decrease inflammation, decrease fasting blood glucose, decrease low-density lipoprotein cholesterol, triglycerides, and total cholesterol, increase estimated glomerular filtration rate (eGFR), decrease blood urea nitrogen and urea, and decrease uric acid

Probiotic-rich foods like kimchi or fermented pickles may not be appropriate because of excessive sodium content or simply because of patient preference — kombucha isn’t for everyone. However, adding a probiotic supplement can improve gut microbiota without undermining dietary concerns. 

When recommending probiotics, patients should be educated to ensure that their probiotic has strains that have been proven to be beneficial for kidney health. Lactobacillus acidophilus, Lactobacillus casei, ^{Bifidobacterium} species, and Streptococcus thermophilus have been shown to have a positive effect on kidney health and decreasing progression of CKD at a dosage of 109 colony-forming units per day.
 

Fish Oil

Though nephrology and cardiology are separate fields, it cannot be overstated that kidney patients are also heart patients. 

Patients with CKD and an eGFR < 60 mL/min per 1.73 m²are most likely to die from cardiovascular causes, and this likelihood increases as eGFR decreases. CKD-associated dyslipidemia results in elevated triglycerides and reduced high-density lipoprotein cholesterol often accompanied by proteinuria, and has been linked to an increase in atherosclerosis.

A simple fish oil supplement can work to decrease oxidative stress, relieve inflammation, and improve serum lipids, leading to improved kidney and cardiovascular health. One meta-analysis found that high-dose fish oil supplementation, though it had no effect on serum creatinine or eGFR, was associated with a lower risk for proteinuria and progression to ESRD. 

Fish oil’s popularity in recent years bodes well for the kidney patient. It is now easily obtained over the counter in high doses to meet the recommended adequate intake of omega-3s, which is 1100 mg/d for women and 1600 mg/d for men. There are also more burpless varieties of these supplements to increase compliance. 
 

Vitamin D

Patients with renal disease are prone to vitamin D deficiency through inadequate intake and limited sunlight, which is exacerbated by the diseased kidney’s inability to effectively convert calcidiol to calcitriol. Vitamin D deficiency is linked to poor bone health, fatigue, muscle pain, impaired wound healing, and depression. Low vitamin D status has also been linked to poor outcomes in cancer, multiple sclerosis, cardiovascular disease, type 2 diabetes, and weight loss.

A meta-analysis of over 6000 patients with CKD found that high levels of 25-hydroxy vitamin D (25[OH]D) are associated with significantly improved survival rates regardless of CKD or ESRD status. 

Kidney Disease: Improving Global Outcomes guidelines recommend supplementing with ergocalciferol or cholecalciferol to correct (OH)D deficiency. This ensures adequate supply for conversion to calcitriol, but it cannot affect bone and mineral metabolism without further intervention in the form of calcitriol supplementation. By supplementing with ergocalciferol or cholecalciferol to meet the recommended daily allowance of 15 µg (600 IU) for adults under 70 years and 20 µg (800 IU) for adults over 70 years, the primary care team can ensure that the body has all the building blocks required for the nephrology team to then address mineral and bone disorder in CKD without the fear of promoting hypercalcemia. 
 

Safe Purchasing Practices

Patients should be reminded to purchase dietary supplements from reputable dealers, especially when purchasing online. Retailers like Amazon are increasing the barriers required to sell supplements to improve the quality of products sold on the site. But other online retailers may sell products from outside of the United States that fall outside of the Food and Drug Administration’s jurisdiction. 

Patients should also be reminded that “more is not always better” and counseled on appropriate dosages for individual needs. 
 

In Summary

Patients will probably continue to lean on dietary supplements, regardless of our approval. Transparency and education are important when working with patients with CKD, especially in regard to dietary supplements. 

When recommended appropriately, however, the supplements discussed can lead to better outcomes with improvements in kidney health by addressing inflammation, serum lipids, glycemic control, and cardiovascular health.

Ms. Winfree Root is a renal dietitian in private practice in Mary Esther, Florida. She disclosed no relevant conflicts of interest.

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

This transcript has been edited for clarity.

In my job, I spend 99% of my time thinking about ethical issues that arise in the care of human beings. That is the focus of our medical school, and that’s what we do. 

However, there are behaviors that are emerging with respect to pets that bear on human health and require the attention of doctors and nurses who deal with people who are pet owners.

Recently, there has been a great increase in the number of pet owners who are saying, “I’m not going to vaccinate my pets.” As horrible as this sounds, what’s happening is vaccine hesitancy about vaccines used in humans is extending through some people to their pets. 

The number of people who say they don’t trust things like rabies vaccine to be effective or safe for their pet animals is 40%, at least in surveys, and the American Veterinary Medical Association reports that 15%-18% of pet owners are not, in fact, vaccinating their pets against rabies.

Rabies, as I hope everybody knows, is one horrible disease. Even the treatment of it, should you get bitten by a rabid animal, is no fun, expensive, and hopefully something that can be administered quickly. It’s not always the case. Worldwide, at least 70,000 people die from rabies every year.

Obviously, there are many countries that are so terrified of rabies, they won’t let you bring pets in without quarantining them, say, England, for at least 6 months to a year, I believe, because they don’t want rabies getting into their country. They’re very strict about the movement of pets.

It is inexcusable for people, first, not to give their pets vaccines that prevent them getting distemper, parvovirus, or many other diseases that harm the pet. It’s also inexcusable to shorten your pet’s life or ask your patients to care for pets who get sick from many of these diseases that are vaccine preventable.

Worst of all, it’s inexcusable for any pet owner not to give a rabies vaccine to their pets. Were it up to me, I’d say you have to license your pet, and as part of that, you must mandate rabies vaccines for your dogs, cats, and other pets. 

We know what happens when people encounter wild animals like raccoons and rabbits. It is not a good situation. Your pets can easily encounter a rabid animal and then put themselves in a position where they can harm their human owners. 

We have an efficacious, safe treatment. If you’re dealing with someone, it might make sense to ask them, “Do you own a pet? Are you vaccinating?” It may not be something you’d ever thought about, but what we don’t need is rabies back in a bigger way in the United States than it’s been in the past.

I think, as a matter of prudence and public health, maybe firing up that question, “Got a pet in the house and are you vaccinating,” could be part of taking a good history.

 

Dr. Caplan is director of the division of medical ethics at New York University Langone Medical Center, New York City. He disclosed conflicts of interest with Johnson & Johnson and Medscape.

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

This transcript has been edited for clarity.

In my job, I spend 99% of my time thinking about ethical issues that arise in the care of human beings. That is the focus of our medical school, and that’s what we do. 

However, there are behaviors that are emerging with respect to pets that bear on human health and require the attention of doctors and nurses who deal with people who are pet owners.

Recently, there has been a great increase in the number of pet owners who are saying, “I’m not going to vaccinate my pets.” As horrible as this sounds, what’s happening is vaccine hesitancy about vaccines used in humans is extending through some people to their pets. 

The number of people who say they don’t trust things like rabies vaccine to be effective or safe for their pet animals is 40%, at least in surveys, and the American Veterinary Medical Association reports that 15%-18% of pet owners are not, in fact, vaccinating their pets against rabies.

Rabies, as I hope everybody knows, is one horrible disease. Even the treatment of it, should you get bitten by a rabid animal, is no fun, expensive, and hopefully something that can be administered quickly. It’s not always the case. Worldwide, at least 70,000 people die from rabies every year.

Obviously, there are many countries that are so terrified of rabies, they won’t let you bring pets in without quarantining them, say, England, for at least 6 months to a year, I believe, because they don’t want rabies getting into their country. They’re very strict about the movement of pets.

It is inexcusable for people, first, not to give their pets vaccines that prevent them getting distemper, parvovirus, or many other diseases that harm the pet. It’s also inexcusable to shorten your pet’s life or ask your patients to care for pets who get sick from many of these diseases that are vaccine preventable.

Worst of all, it’s inexcusable for any pet owner not to give a rabies vaccine to their pets. Were it up to me, I’d say you have to license your pet, and as part of that, you must mandate rabies vaccines for your dogs, cats, and other pets. 

We know what happens when people encounter wild animals like raccoons and rabbits. It is not a good situation. Your pets can easily encounter a rabid animal and then put themselves in a position where they can harm their human owners. 

We have an efficacious, safe treatment. If you’re dealing with someone, it might make sense to ask them, “Do you own a pet? Are you vaccinating?” It may not be something you’d ever thought about, but what we don’t need is rabies back in a bigger way in the United States than it’s been in the past.

I think, as a matter of prudence and public health, maybe firing up that question, “Got a pet in the house and are you vaccinating,” could be part of taking a good history.

 

Dr. Caplan is director of the division of medical ethics at New York University Langone Medical Center, New York City. He disclosed conflicts of interest with Johnson & Johnson and Medscape.

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

This transcript has been edited for clarity.

In my job, I spend 99% of my time thinking about ethical issues that arise in the care of human beings. That is the focus of our medical school, and that’s what we do. 

However, there are behaviors that are emerging with respect to pets that bear on human health and require the attention of doctors and nurses who deal with people who are pet owners.

Recently, there has been a great increase in the number of pet owners who are saying, “I’m not going to vaccinate my pets.” As horrible as this sounds, what’s happening is vaccine hesitancy about vaccines used in humans is extending through some people to their pets. 

The number of people who say they don’t trust things like rabies vaccine to be effective or safe for their pet animals is 40%, at least in surveys, and the American Veterinary Medical Association reports that 15%-18% of pet owners are not, in fact, vaccinating their pets against rabies.

Rabies, as I hope everybody knows, is one horrible disease. Even the treatment of it, should you get bitten by a rabid animal, is no fun, expensive, and hopefully something that can be administered quickly. It’s not always the case. Worldwide, at least 70,000 people die from rabies every year.

Obviously, there are many countries that are so terrified of rabies, they won’t let you bring pets in without quarantining them, say, England, for at least 6 months to a year, I believe, because they don’t want rabies getting into their country. They’re very strict about the movement of pets.

It is inexcusable for people, first, not to give their pets vaccines that prevent them getting distemper, parvovirus, or many other diseases that harm the pet. It’s also inexcusable to shorten your pet’s life or ask your patients to care for pets who get sick from many of these diseases that are vaccine preventable.

Worst of all, it’s inexcusable for any pet owner not to give a rabies vaccine to their pets. Were it up to me, I’d say you have to license your pet, and as part of that, you must mandate rabies vaccines for your dogs, cats, and other pets. 

We know what happens when people encounter wild animals like raccoons and rabbits. It is not a good situation. Your pets can easily encounter a rabid animal and then put themselves in a position where they can harm their human owners. 

We have an efficacious, safe treatment. If you’re dealing with someone, it might make sense to ask them, “Do you own a pet? Are you vaccinating?” It may not be something you’d ever thought about, but what we don’t need is rabies back in a bigger way in the United States than it’s been in the past.

I think, as a matter of prudence and public health, maybe firing up that question, “Got a pet in the house and are you vaccinating,” could be part of taking a good history.

 

Dr. Caplan is director of the division of medical ethics at New York University Langone Medical Center, New York City. He disclosed conflicts of interest with Johnson & Johnson and Medscape.

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

TOPLINE:

When starting a regular exercise program, the skeletal muscle of sedentary men and women with overweight and obesity differs in burning sugar and fatty acids, but regular training can lessen these differences and promote similar positive metabolic changes in both biological sexes.

METHODOLOGY:

• By stimulating skeletal muscle, exercise can help prevent muscle loss associated with weight loss and improve insulin sensitivity and glucose control in type 2 diabetes, but biological sex-based differences have been reported for many measures.
• This study of sedentary men and women evaluated the molecular differences in skeletal muscle in response to a training program.
• Researchers collected muscle biopsies from 16 women and nine men with overweight or obesity (average age, 30 years) at three time points — baseline, after the first exercise session, and after the last session at the end of training.
• Training involved 1 hour of moderate to intense endurance exercise under supervision (30 minutes cycling on an ergometer and 30 minutes walking on a treadmill) thrice a week for 8 weeks.
• The biopsies were profiled for patterns of three sets of omics data — DNA methylation for insight into genes switched on and off (epigenomics), RNA molecules transcribed from genes (transcriptomics), and proteins (proteomics).

TAKEAWAY:

• At baseline, sex-specific differences were observed most tellingly in 120 proteins and also in DNA methylation sites of 16,012 genes and in 1366 RNA transcripts.
• Men displayed a higher abundance of glycolysis-related proteins and other fast-twitch fiber–type proteins, which are involved in the processing of glucose, while women showed more proteins responsible for regulating fatty acid metabolism.
• The response to the first exercise session differed between men and women, with the cellular stress response upregulated predominantly in men.
• The 8-week exercise training mitigated these sex-specific differences in the skeletal muscle, leading to an upregulation of mitochondrial proteins responsible for substrate oxidation and ATP generation in both men and women.

IN PRACTICE:

“This is important because the increased capacity after exercise to use glucose and lipids for energy production is generally regarded as key to prevent type 2 diabetes,” study leader Professor Cora Weigert from the University of Tübingen, Germany, said in a news release from the meeting organizers. “While initial response of skeletal muscles to exercise differs between females and males, repeated exercise appears to cancel out these differences and trigger beneficial metabolic changes in both sexes,” she added.

SOURCE:

The study was led by Simon I. Dreher, PhD, Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Tübingen, Germany. It was published on August 15, 2024, as an early release from the annual meeting of the European Association for the Study of Diabetes 2024, Madrid, September 9-13.

LIMITATIONS:

This abstract did not discuss any limitations.

DISCLOSURES:

The authors did not disclose any funding information. The authors declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

When starting a regular exercise program, the skeletal muscle of sedentary men and women with overweight and obesity differs in burning sugar and fatty acids, but regular training can lessen these differences and promote similar positive metabolic changes in both biological sexes.

METHODOLOGY:

• By stimulating skeletal muscle, exercise can help prevent muscle loss associated with weight loss and improve insulin sensitivity and glucose control in type 2 diabetes, but biological sex-based differences have been reported for many measures.
• This study of sedentary men and women evaluated the molecular differences in skeletal muscle in response to a training program.
• Researchers collected muscle biopsies from 16 women and nine men with overweight or obesity (average age, 30 years) at three time points — baseline, after the first exercise session, and after the last session at the end of training.
• Training involved 1 hour of moderate to intense endurance exercise under supervision (30 minutes cycling on an ergometer and 30 minutes walking on a treadmill) thrice a week for 8 weeks.
• The biopsies were profiled for patterns of three sets of omics data — DNA methylation for insight into genes switched on and off (epigenomics), RNA molecules transcribed from genes (transcriptomics), and proteins (proteomics).

TAKEAWAY:

• At baseline, sex-specific differences were observed most tellingly in 120 proteins and also in DNA methylation sites of 16,012 genes and in 1366 RNA transcripts.
• Men displayed a higher abundance of glycolysis-related proteins and other fast-twitch fiber–type proteins, which are involved in the processing of glucose, while women showed more proteins responsible for regulating fatty acid metabolism.
• The response to the first exercise session differed between men and women, with the cellular stress response upregulated predominantly in men.
• The 8-week exercise training mitigated these sex-specific differences in the skeletal muscle, leading to an upregulation of mitochondrial proteins responsible for substrate oxidation and ATP generation in both men and women.

IN PRACTICE:

“This is important because the increased capacity after exercise to use glucose and lipids for energy production is generally regarded as key to prevent type 2 diabetes,” study leader Professor Cora Weigert from the University of Tübingen, Germany, said in a news release from the meeting organizers. “While initial response of skeletal muscles to exercise differs between females and males, repeated exercise appears to cancel out these differences and trigger beneficial metabolic changes in both sexes,” she added.

SOURCE:

The study was led by Simon I. Dreher, PhD, Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Tübingen, Germany. It was published on August 15, 2024, as an early release from the annual meeting of the European Association for the Study of Diabetes 2024, Madrid, September 9-13.

LIMITATIONS:

This abstract did not discuss any limitations.

DISCLOSURES:

The authors did not disclose any funding information. The authors declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

When starting a regular exercise program, the skeletal muscle of sedentary men and women with overweight and obesity differs in burning sugar and fatty acids, but regular training can lessen these differences and promote similar positive metabolic changes in both biological sexes.

METHODOLOGY:

• By stimulating skeletal muscle, exercise can help prevent muscle loss associated with weight loss and improve insulin sensitivity and glucose control in type 2 diabetes, but biological sex-based differences have been reported for many measures.
• This study of sedentary men and women evaluated the molecular differences in skeletal muscle in response to a training program.
• Researchers collected muscle biopsies from 16 women and nine men with overweight or obesity (average age, 30 years) at three time points — baseline, after the first exercise session, and after the last session at the end of training.
• Training involved 1 hour of moderate to intense endurance exercise under supervision (30 minutes cycling on an ergometer and 30 minutes walking on a treadmill) thrice a week for 8 weeks.
• The biopsies were profiled for patterns of three sets of omics data — DNA methylation for insight into genes switched on and off (epigenomics), RNA molecules transcribed from genes (transcriptomics), and proteins (proteomics).

TAKEAWAY:

• At baseline, sex-specific differences were observed most tellingly in 120 proteins and also in DNA methylation sites of 16,012 genes and in 1366 RNA transcripts.
• Men displayed a higher abundance of glycolysis-related proteins and other fast-twitch fiber–type proteins, which are involved in the processing of glucose, while women showed more proteins responsible for regulating fatty acid metabolism.
• The response to the first exercise session differed between men and women, with the cellular stress response upregulated predominantly in men.
• The 8-week exercise training mitigated these sex-specific differences in the skeletal muscle, leading to an upregulation of mitochondrial proteins responsible for substrate oxidation and ATP generation in both men and women.

IN PRACTICE:

“This is important because the increased capacity after exercise to use glucose and lipids for energy production is generally regarded as key to prevent type 2 diabetes,” study leader Professor Cora Weigert from the University of Tübingen, Germany, said in a news release from the meeting organizers. “While initial response of skeletal muscles to exercise differs between females and males, repeated exercise appears to cancel out these differences and trigger beneficial metabolic changes in both sexes,” she added.

SOURCE:

The study was led by Simon I. Dreher, PhD, Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Tübingen, Germany. It was published on August 15, 2024, as an early release from the annual meeting of the European Association for the Study of Diabetes 2024, Madrid, September 9-13.

LIMITATIONS:

This abstract did not discuss any limitations.

DISCLOSURES:

The authors did not disclose any funding information. The authors declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

High-dose psilocybin is associated with greater relief from depressive symptoms than placebo or escitalopram, with no increased risk for severe adverse events, a new meta-analysis suggests.
 

METHODOLOGY:

• Researchers conducted a network meta-analysis to evaluate the comparative effectiveness of oral monotherapy with psychedelics versus escitalopram in patients with clinically diagnosed depression.
• The meta-analysis included 811 participants (mean age, 42.49 years; 54.2% women) with clinically diagnosed depression across 15 psychedelic trials and 1968 participants (mean age, 39.35 years; 62.5% women) across five escitalopram trials.
• Trials evaluated oral monotherapy with psychedelics (psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine [MDMA], and ayahuasca), fixed-dose escitalopram (up to 20 mg/d) versus placebo, and psychedelic versus escitalopram monotherapy.
• The primary outcome was a change in depressive symptoms from baseline.

TAKEAWAY:

• Placebo responses in antidepressant trials (mean difference, 3.79; 95% CI, 0.77-6.80) and extremely low-dose psilocybin (mean difference, 3.96; 95% CI, 0.61-7.17) were better than those in psychedelic trials.
• High-dose psilocybin (20 mg or more) performed better than placebo in the antidepressant trials (mean difference, > 3). However, when comparing high-dose psilocybin with the placebo used in antidepressant trials, the effect size was smaller. The standardized mean difference dropped from 0.88 to 0.31, indicating that the effect of high-dose psilocybin was similar to that of current antidepressants.
• High-dose psilocybin was associated with a greater response than escitalopram at 10 mg (4.66; 95% CI, 1.36-7.74) and 20 mg (4.69; 95% CI, 1.64-7.54).
• No interventions were associated with an increased risk for all-cause discontinuation or severe adverse events.

IN PRACTICE:

“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs, showing a mean standardized mean difference of 0.3,” the authors wrote.

SOURCE:

The study was led by Tien-Wei Hsu, MD, I-Shou University and Kaohsiung Medical University, Kaohsiung City, Taiwan. It was published online in The BMJ. 

LIMITATIONS:

The study did not assess long-term effects of the interventions. Participants in the MDMA trials were primarily diagnosed with posttraumatic stress disorder, which may not be representative of the general population with depressive symptoms. Moreover, the sample size of the psychedelic trials was small. Using extremely low-dose psychedelics as a reference group may have eliminated some pharmacologic effects as these doses cannot be considered a placebo.

DISCLOSURES:

The study was supported by grants from the National Science and Technology Council. The authors declared no financial relationships with any organizations outside the submitted work in the past 3 years. Full disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

High-dose psilocybin is associated with greater relief from depressive symptoms than placebo or escitalopram, with no increased risk for severe adverse events, a new meta-analysis suggests.
 

METHODOLOGY:

• Researchers conducted a network meta-analysis to evaluate the comparative effectiveness of oral monotherapy with psychedelics versus escitalopram in patients with clinically diagnosed depression.
• The meta-analysis included 811 participants (mean age, 42.49 years; 54.2% women) with clinically diagnosed depression across 15 psychedelic trials and 1968 participants (mean age, 39.35 years; 62.5% women) across five escitalopram trials.
• Trials evaluated oral monotherapy with psychedelics (psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine [MDMA], and ayahuasca), fixed-dose escitalopram (up to 20 mg/d) versus placebo, and psychedelic versus escitalopram monotherapy.
• The primary outcome was a change in depressive symptoms from baseline.

TAKEAWAY:

• Placebo responses in antidepressant trials (mean difference, 3.79; 95% CI, 0.77-6.80) and extremely low-dose psilocybin (mean difference, 3.96; 95% CI, 0.61-7.17) were better than those in psychedelic trials.
• High-dose psilocybin (20 mg or more) performed better than placebo in the antidepressant trials (mean difference, > 3). However, when comparing high-dose psilocybin with the placebo used in antidepressant trials, the effect size was smaller. The standardized mean difference dropped from 0.88 to 0.31, indicating that the effect of high-dose psilocybin was similar to that of current antidepressants.
• High-dose psilocybin was associated with a greater response than escitalopram at 10 mg (4.66; 95% CI, 1.36-7.74) and 20 mg (4.69; 95% CI, 1.64-7.54).
• No interventions were associated with an increased risk for all-cause discontinuation or severe adverse events.

IN PRACTICE:

“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs, showing a mean standardized mean difference of 0.3,” the authors wrote.

SOURCE:

The study was led by Tien-Wei Hsu, MD, I-Shou University and Kaohsiung Medical University, Kaohsiung City, Taiwan. It was published online in The BMJ. 

LIMITATIONS:

The study did not assess long-term effects of the interventions. Participants in the MDMA trials were primarily diagnosed with posttraumatic stress disorder, which may not be representative of the general population with depressive symptoms. Moreover, the sample size of the psychedelic trials was small. Using extremely low-dose psychedelics as a reference group may have eliminated some pharmacologic effects as these doses cannot be considered a placebo.

DISCLOSURES:

The study was supported by grants from the National Science and Technology Council. The authors declared no financial relationships with any organizations outside the submitted work in the past 3 years. Full disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

High-dose psilocybin is associated with greater relief from depressive symptoms than placebo or escitalopram, with no increased risk for severe adverse events, a new meta-analysis suggests.
 

METHODOLOGY:

• Researchers conducted a network meta-analysis to evaluate the comparative effectiveness of oral monotherapy with psychedelics versus escitalopram in patients with clinically diagnosed depression.
• The meta-analysis included 811 participants (mean age, 42.49 years; 54.2% women) with clinically diagnosed depression across 15 psychedelic trials and 1968 participants (mean age, 39.35 years; 62.5% women) across five escitalopram trials.
• Trials evaluated oral monotherapy with psychedelics (psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine [MDMA], and ayahuasca), fixed-dose escitalopram (up to 20 mg/d) versus placebo, and psychedelic versus escitalopram monotherapy.
• The primary outcome was a change in depressive symptoms from baseline.

TAKEAWAY:

• Placebo responses in antidepressant trials (mean difference, 3.79; 95% CI, 0.77-6.80) and extremely low-dose psilocybin (mean difference, 3.96; 95% CI, 0.61-7.17) were better than those in psychedelic trials.
• High-dose psilocybin (20 mg or more) performed better than placebo in the antidepressant trials (mean difference, > 3). However, when comparing high-dose psilocybin with the placebo used in antidepressant trials, the effect size was smaller. The standardized mean difference dropped from 0.88 to 0.31, indicating that the effect of high-dose psilocybin was similar to that of current antidepressants.
• High-dose psilocybin was associated with a greater response than escitalopram at 10 mg (4.66; 95% CI, 1.36-7.74) and 20 mg (4.69; 95% CI, 1.64-7.54).
• No interventions were associated with an increased risk for all-cause discontinuation or severe adverse events.

IN PRACTICE:

“Taken together, our study findings suggest that among psychedelic treatments, high-dose psilocybin is more likely to reach the minimal important difference for depressive symptoms in studies with adequate blinding design, while the effect size of psilocybin was similar to that of current antidepressant drugs, showing a mean standardized mean difference of 0.3,” the authors wrote.

SOURCE:

The study was led by Tien-Wei Hsu, MD, I-Shou University and Kaohsiung Medical University, Kaohsiung City, Taiwan. It was published online in The BMJ. 

LIMITATIONS:

The study did not assess long-term effects of the interventions. Participants in the MDMA trials were primarily diagnosed with posttraumatic stress disorder, which may not be representative of the general population with depressive symptoms. Moreover, the sample size of the psychedelic trials was small. Using extremely low-dose psychedelics as a reference group may have eliminated some pharmacologic effects as these doses cannot be considered a placebo.

DISCLOSURES:

The study was supported by grants from the National Science and Technology Council. The authors declared no financial relationships with any organizations outside the submitted work in the past 3 years. Full disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Certain extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD) have distinct clinical, serologic, and genetic associations that reveal underlying mechanisms and indicate targets for new or existing drugs, according to a recent study.

For instance, antinuclear cytoplastic antibody is associated with primary sclerosing cholangitis (PSC) in Crohn’s disease, and CPEB4 genetic variation is associated with skin manifestations.

“Up to 40% of people with IBD suffer with symptoms from inflammation that occurs outside the gut, particularly affecting the liver, skin, and joints. These symptoms can often have a bigger impact on quality of life than the gut inflammation itself and can actually be life-threatening,” said senior author Dermot McGovern, MD, PhD, AGAF, director of translational medicine at the F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles.

Cedars-Sinai Medical Center

“With the advances in therapies for IBD, including availability of gut-selective agents, treatment choices often incorporate whether a patient has one of these manifestations or not,” he said. “We need to understand who is at increased risk of these and why.”

The study was published in Gastroenterology .
 

Analyzing Associations

Dr. McGovern and colleagues analyzed data for 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs across four cohorts in the Cedars-Sinai Medical Center IBD Research Repository, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease.

In particular, the researchers looked at EIM phenotypes such as ankylosing spondylitis and sacroiliitis, PSC, peripheral arthritis, and skin and ocular manifestations. They analyzed clinical and serologic parameters through regression analyses using a mixed-effects model, as well as within-case logistic regression for genetic associations.

Overall, 14% of patients had at least one EIM. Contrary to previous reports, only 2% had multiple EIMs, and most co-occurrences were negatively correlated. Nearly all EIMs were more common in Crohn’s disease, except for PSC, which was more common in ulcerative colitis.

In general, EIMs occurred more often in women, particularly with Crohn’s disease and colonic disease location, and in patients who required surgery. Jewish ancestry was associated with psoriasis and overall skin manifestations.

Smoking increased the risk for multiple EIMs, except for PSC, where there appeared to be a “protective” effect. Older age at diagnosis and a family history of IBD were associated with increased risk for certain EIMs as well.

In addition, the research team noted multiple serologic associations, such as immunoglobulin (Ig) G and IgA, perinuclear antinuclear cytoplastic antibodies, and anti–Pseudomonas fluorescens–associated sequences with any EIM, as well as particular associations with PSC, such as anti-Saccharomyces cerevisiae antibodies and anti-flagellin.

There were also genome-wide significant associations within the major histocompatibility complex and CPEB4. Genetic associations implicated tumor necrosis factor, Janus kinase-signal transducer and activator of transcription, and interleukin 6 as potential targets for EIMs.

“We are working with colleagues across the world to increase the sample size, as we believe there is more to find,” Dr. McGovern said. “Importantly, this includes non-European ancestry subjects, as there is an urgent need to increase the diversity of populations we study so advances in clinical care are available to all communities.”
 

Considering Target Therapies

As medicine becomes more specialized, physicians should remember to consider the whole patient while choosing treatment strategies.

“Sometimes doctors wear blinders to the whole person, and it’s important to be aware of a holistic approach, where a gastroenterologist also asks about potential joint inflammation or a rheumatologist asks about bowel inflammation,” said David Rubin, MD, AGAF, chief of the Section of Gastroenterology, Hepatology and Nutrition at the University of Chicago Medicine, Chicago.

Dr. Rubin, who wasn’t involved with this study, has researched and published on EIMs in IBD. He and colleagues analyzed the prevalence, pathophysiology, and clinical presentation of EIMs to better understand possibilities for disease management.

A version of this article appeared on Medscape.com.

Certain extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD) have distinct clinical, serologic, and genetic associations that reveal underlying mechanisms and indicate targets for new or existing drugs, according to a recent study.

For instance, antinuclear cytoplastic antibody is associated with primary sclerosing cholangitis (PSC) in Crohn’s disease, and CPEB4 genetic variation is associated with skin manifestations.

“Up to 40% of people with IBD suffer with symptoms from inflammation that occurs outside the gut, particularly affecting the liver, skin, and joints. These symptoms can often have a bigger impact on quality of life than the gut inflammation itself and can actually be life-threatening,” said senior author Dermot McGovern, MD, PhD, AGAF, director of translational medicine at the F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles.

Cedars-Sinai Medical Center

“With the advances in therapies for IBD, including availability of gut-selective agents, treatment choices often incorporate whether a patient has one of these manifestations or not,” he said. “We need to understand who is at increased risk of these and why.”

The study was published in Gastroenterology .
 

Analyzing Associations

Dr. McGovern and colleagues analyzed data for 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs across four cohorts in the Cedars-Sinai Medical Center IBD Research Repository, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease.

In particular, the researchers looked at EIM phenotypes such as ankylosing spondylitis and sacroiliitis, PSC, peripheral arthritis, and skin and ocular manifestations. They analyzed clinical and serologic parameters through regression analyses using a mixed-effects model, as well as within-case logistic regression for genetic associations.

Overall, 14% of patients had at least one EIM. Contrary to previous reports, only 2% had multiple EIMs, and most co-occurrences were negatively correlated. Nearly all EIMs were more common in Crohn’s disease, except for PSC, which was more common in ulcerative colitis.

In general, EIMs occurred more often in women, particularly with Crohn’s disease and colonic disease location, and in patients who required surgery. Jewish ancestry was associated with psoriasis and overall skin manifestations.

Smoking increased the risk for multiple EIMs, except for PSC, where there appeared to be a “protective” effect. Older age at diagnosis and a family history of IBD were associated with increased risk for certain EIMs as well.

In addition, the research team noted multiple serologic associations, such as immunoglobulin (Ig) G and IgA, perinuclear antinuclear cytoplastic antibodies, and anti–Pseudomonas fluorescens–associated sequences with any EIM, as well as particular associations with PSC, such as anti-Saccharomyces cerevisiae antibodies and anti-flagellin.

There were also genome-wide significant associations within the major histocompatibility complex and CPEB4. Genetic associations implicated tumor necrosis factor, Janus kinase-signal transducer and activator of transcription, and interleukin 6 as potential targets for EIMs.

“We are working with colleagues across the world to increase the sample size, as we believe there is more to find,” Dr. McGovern said. “Importantly, this includes non-European ancestry subjects, as there is an urgent need to increase the diversity of populations we study so advances in clinical care are available to all communities.”
 

Considering Target Therapies

As medicine becomes more specialized, physicians should remember to consider the whole patient while choosing treatment strategies.

“Sometimes doctors wear blinders to the whole person, and it’s important to be aware of a holistic approach, where a gastroenterologist also asks about potential joint inflammation or a rheumatologist asks about bowel inflammation,” said David Rubin, MD, AGAF, chief of the Section of Gastroenterology, Hepatology and Nutrition at the University of Chicago Medicine, Chicago.

Dr. Rubin, who wasn’t involved with this study, has researched and published on EIMs in IBD. He and colleagues analyzed the prevalence, pathophysiology, and clinical presentation of EIMs to better understand possibilities for disease management.

A version of this article appeared on Medscape.com.

Certain extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD) have distinct clinical, serologic, and genetic associations that reveal underlying mechanisms and indicate targets for new or existing drugs, according to a recent study.

For instance, antinuclear cytoplastic antibody is associated with primary sclerosing cholangitis (PSC) in Crohn’s disease, and CPEB4 genetic variation is associated with skin manifestations.

“Up to 40% of people with IBD suffer with symptoms from inflammation that occurs outside the gut, particularly affecting the liver, skin, and joints. These symptoms can often have a bigger impact on quality of life than the gut inflammation itself and can actually be life-threatening,” said senior author Dermot McGovern, MD, PhD, AGAF, director of translational medicine at the F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles.

Cedars-Sinai Medical Center

“With the advances in therapies for IBD, including availability of gut-selective agents, treatment choices often incorporate whether a patient has one of these manifestations or not,” he said. “We need to understand who is at increased risk of these and why.”

The study was published in Gastroenterology .
 

Analyzing Associations

Dr. McGovern and colleagues analyzed data for 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs across four cohorts in the Cedars-Sinai Medical Center IBD Research Repository, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease.

In particular, the researchers looked at EIM phenotypes such as ankylosing spondylitis and sacroiliitis, PSC, peripheral arthritis, and skin and ocular manifestations. They analyzed clinical and serologic parameters through regression analyses using a mixed-effects model, as well as within-case logistic regression for genetic associations.

Overall, 14% of patients had at least one EIM. Contrary to previous reports, only 2% had multiple EIMs, and most co-occurrences were negatively correlated. Nearly all EIMs were more common in Crohn’s disease, except for PSC, which was more common in ulcerative colitis.

In general, EIMs occurred more often in women, particularly with Crohn’s disease and colonic disease location, and in patients who required surgery. Jewish ancestry was associated with psoriasis and overall skin manifestations.

Smoking increased the risk for multiple EIMs, except for PSC, where there appeared to be a “protective” effect. Older age at diagnosis and a family history of IBD were associated with increased risk for certain EIMs as well.

In addition, the research team noted multiple serologic associations, such as immunoglobulin (Ig) G and IgA, perinuclear antinuclear cytoplastic antibodies, and anti–Pseudomonas fluorescens–associated sequences with any EIM, as well as particular associations with PSC, such as anti-Saccharomyces cerevisiae antibodies and anti-flagellin.

There were also genome-wide significant associations within the major histocompatibility complex and CPEB4. Genetic associations implicated tumor necrosis factor, Janus kinase-signal transducer and activator of transcription, and interleukin 6 as potential targets for EIMs.

“We are working with colleagues across the world to increase the sample size, as we believe there is more to find,” Dr. McGovern said. “Importantly, this includes non-European ancestry subjects, as there is an urgent need to increase the diversity of populations we study so advances in clinical care are available to all communities.”
 

Considering Target Therapies

As medicine becomes more specialized, physicians should remember to consider the whole patient while choosing treatment strategies.

“Sometimes doctors wear blinders to the whole person, and it’s important to be aware of a holistic approach, where a gastroenterologist also asks about potential joint inflammation or a rheumatologist asks about bowel inflammation,” said David Rubin, MD, AGAF, chief of the Section of Gastroenterology, Hepatology and Nutrition at the University of Chicago Medicine, Chicago.

Dr. Rubin, who wasn’t involved with this study, has researched and published on EIMs in IBD. He and colleagues analyzed the prevalence, pathophysiology, and clinical presentation of EIMs to better understand possibilities for disease management.

A version of this article appeared on Medscape.com.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

TOPLINE:

Intermittent energy restriction (IER) and continuous energy restriction (CER) reduced body mass index (BMI) in adolescents with obesity after 52 weeks, with no major differences found in body composition or cardiometabolic outcomes.

METHODOLOGY:

• Researchers conducted a 52-week randomized clinical trial at two pediatric centers in Australia that involved 141 adolescents aged 13-17 years with obesity and at least one associated complication.
• Participants were divided into two groups: IER and CER, with three phases: Very low-energy diet (weeks 0-4), intensive intervention (weeks 5-16), and continued intervention/maintenance (weeks 17-52).
• Interventions included a very low-energy diet of 3350 kJ/d (800 kcal/d) for the first 4 weeks, followed by either IER intervention (2500-2950 kJ [600-700 kcal 3 days/wk]) or a daily CER intervention (6000-8000 kJ/d based on age; 1430-1670 kcal/d for teens aged 13-14 years and 1670-1900 kcal/d for teens aged 15-17 years).
• Participants were provided with multivitamins and met with dietitians regularly, with additional support via telephone, text message, or email.

TAKEAWAY:

• Teens in both the IER and CER groups showed a 0.28 reduction in BMI z-scores at 52 weeks with no significant differences between the two.
• The researchers observed no differences in body composition or cardiometabolic outcomes between the IER and CER groups.
• The occurrence of insulin resistance was reduced in both groups at week 16, but this effect was maintained only in the CER group at week 52.
• The study found no significant differences in the occurrence of dyslipidemia or impaired hepatic function between the IER and CER groups.

IN PRACTICE:

“These findings suggest that for adolescents with obesity-associated complications, IER can be incorporated into a behavioral weight management program, providing an option in addition to CER and offering participants more choice,” the authors of the study wrote.

SOURCE:

The study was led by Natalie B. Lister, PhD, of the University of Sydney in Australia and was published online in JAMA Pediatrics.

LIMITATIONS:

The COVID-19 pandemic and subsequent lockdowns limited the sample size. Some dietitian visits were conducted via telehealth.

DISCLOSURES:

Dr. Lister received grants from the National Health and Medical Research Council of Australia. A coauthor, Louise A. Baur, MBBS, PhD, received speakers’ fees from Novo Nordisk and served as a member of the Eli Lilly Advisory Committee.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Intermittent energy restriction (IER) and continuous energy restriction (CER) reduced body mass index (BMI) in adolescents with obesity after 52 weeks, with no major differences found in body composition or cardiometabolic outcomes.

METHODOLOGY:

• Researchers conducted a 52-week randomized clinical trial at two pediatric centers in Australia that involved 141 adolescents aged 13-17 years with obesity and at least one associated complication.
• Participants were divided into two groups: IER and CER, with three phases: Very low-energy diet (weeks 0-4), intensive intervention (weeks 5-16), and continued intervention/maintenance (weeks 17-52).
• Interventions included a very low-energy diet of 3350 kJ/d (800 kcal/d) for the first 4 weeks, followed by either IER intervention (2500-2950 kJ [600-700 kcal 3 days/wk]) or a daily CER intervention (6000-8000 kJ/d based on age; 1430-1670 kcal/d for teens aged 13-14 years and 1670-1900 kcal/d for teens aged 15-17 years).
• Participants were provided with multivitamins and met with dietitians regularly, with additional support via telephone, text message, or email.

TAKEAWAY:

• Teens in both the IER and CER groups showed a 0.28 reduction in BMI z-scores at 52 weeks with no significant differences between the two.
• The researchers observed no differences in body composition or cardiometabolic outcomes between the IER and CER groups.
• The occurrence of insulin resistance was reduced in both groups at week 16, but this effect was maintained only in the CER group at week 52.
• The study found no significant differences in the occurrence of dyslipidemia or impaired hepatic function between the IER and CER groups.

IN PRACTICE:

“These findings suggest that for adolescents with obesity-associated complications, IER can be incorporated into a behavioral weight management program, providing an option in addition to CER and offering participants more choice,” the authors of the study wrote.

SOURCE:

The study was led by Natalie B. Lister, PhD, of the University of Sydney in Australia and was published online in JAMA Pediatrics.

LIMITATIONS:

The COVID-19 pandemic and subsequent lockdowns limited the sample size. Some dietitian visits were conducted via telehealth.

DISCLOSURES:

Dr. Lister received grants from the National Health and Medical Research Council of Australia. A coauthor, Louise A. Baur, MBBS, PhD, received speakers’ fees from Novo Nordisk and served as a member of the Eli Lilly Advisory Committee.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Intermittent energy restriction (IER) and continuous energy restriction (CER) reduced body mass index (BMI) in adolescents with obesity after 52 weeks, with no major differences found in body composition or cardiometabolic outcomes.

METHODOLOGY:

• Researchers conducted a 52-week randomized clinical trial at two pediatric centers in Australia that involved 141 adolescents aged 13-17 years with obesity and at least one associated complication.
• Participants were divided into two groups: IER and CER, with three phases: Very low-energy diet (weeks 0-4), intensive intervention (weeks 5-16), and continued intervention/maintenance (weeks 17-52).
• Interventions included a very low-energy diet of 3350 kJ/d (800 kcal/d) for the first 4 weeks, followed by either IER intervention (2500-2950 kJ [600-700 kcal 3 days/wk]) or a daily CER intervention (6000-8000 kJ/d based on age; 1430-1670 kcal/d for teens aged 13-14 years and 1670-1900 kcal/d for teens aged 15-17 years).
• Participants were provided with multivitamins and met with dietitians regularly, with additional support via telephone, text message, or email.

TAKEAWAY:

• Teens in both the IER and CER groups showed a 0.28 reduction in BMI z-scores at 52 weeks with no significant differences between the two.
• The researchers observed no differences in body composition or cardiometabolic outcomes between the IER and CER groups.
• The occurrence of insulin resistance was reduced in both groups at week 16, but this effect was maintained only in the CER group at week 52.
• The study found no significant differences in the occurrence of dyslipidemia or impaired hepatic function between the IER and CER groups.

IN PRACTICE:

“These findings suggest that for adolescents with obesity-associated complications, IER can be incorporated into a behavioral weight management program, providing an option in addition to CER and offering participants more choice,” the authors of the study wrote.

SOURCE:

The study was led by Natalie B. Lister, PhD, of the University of Sydney in Australia and was published online in JAMA Pediatrics.

LIMITATIONS:

The COVID-19 pandemic and subsequent lockdowns limited the sample size. Some dietitian visits were conducted via telehealth.

DISCLOSURES:

Dr. Lister received grants from the National Health and Medical Research Council of Australia. A coauthor, Louise A. Baur, MBBS, PhD, received speakers’ fees from Novo Nordisk and served as a member of the Eli Lilly Advisory Committee.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Financial relationships between physicians and industry are prevalent and complex and may have implications for patient care. A 2007 study reported that 94% of 3167 physicians surveyed had established some form of paid relationship with companies in the pharmaceutical industry.¹ To facilitate increased transparency around these relationships, lawmakers passed the Physician Payments Sunshine Act in 2010, which requires pharmaceutical companies and device manufacturers to report all payments made to physicians.² Mandatory disclosures include meals, honoraria, travel expenses, grants, and ownership or investment interests greater than $10. The information is displayed publicly in the Open Payments database (OPD)(https://openpayments-data.cms.gov/), a platform run by the Centers for Medicare and Medicaid Services.

The OPD allows for in-depth analyses of industry payments made to physicians. Many medical specialties—including orthopedics,^3-5 plastic surgery,^6,7 ophthalmology,⁸ and gastroenterology⁹—have published extensive literature characterizing the nature of these payments and disparities in the distribution of payments based on sex, geographic distribution, and other factors. After the first full year of OPD data collection for dermatology in 2014, Feng et al¹⁰ examined the number, amount, and nature of industry payments to dermatologists, as well as their geographic distribution for that year. As a follow-up to this initial research, Schlager et al¹¹ characterized payments made to dermatologists for the year 2016 and found an increase in the total payments, mean payments, and number of dermatologists receiving payments compared with the 2014 data.

Our study aimed to characterize the last 5 years of available OPD data—from January 1, 2017, to December 31, 2021—to further explore trends in industry payments made to dermatologists. In particular, we examined the effects of the COVID-19 pandemic on payments as well as sex disparities and the distribution of industry payments.

Methods

We performed a retrospective analysis of the OPD for the general payment datasets from January 1, 2017, to December 31, 2021. The results were filtered to include only payments made to dermatologists, excluding physicians from other specialties, physician assistants, and other types of practitioners. Data for each physician were grouped by National Provider Identifier (NPI) for providers included in the set, allowing for analysis at the individual level. Data on sex were extracted from the National Plan & Provider Enumeration System’s monthly data dissemination for NPIs for July 2023 (when the study was conducted) and were joined to the OPD data using the NPI number reported for each physician. All data were extracted, transformed, and analyzed using R software (version 4.2.1). Figures and visualizations were produced using Microsoft Excel 2016.

Results

In 2017, a total of 358,884 payments were made by industry to dermatologists, accounting for nearly $58.0 million. The mean total value of payments received per dermatologist was $5231.74, and the mean payment amount was $161.49. In 2018, the total number of payments increased year-over-year by 5.5% (378,509 payments), the total value of payments received increased by 7.5% (approximately $62.3 million), and the mean total value of payments received per dermatologist increased by 5.3% ($5508.98). In 2019, the total number of payments increased by 3.0% (389,670 total payments), the total value of payments recieved increased by 13.2% (approximately $70.5 million), and the mean total value of payments received per dermatologist increased by 11.3% ($6133.45). All of these values decreased in 2020, likely due to COVID-19–related restrictions on travel and meetings (total number of payments, 208,470 [−46.5%]; total value of payments received, approximately $37.5 million [−46.9%], mean total value of payments received per dermatologist, $3757.27 [−38.7%]), but the mean payment amount remained stable at $179.47. In 2021, the total number of payments (295,808 [+41.9%]), total value of payments received (approximately $50.3 million [+34.4%]), and mean total value of payments received per dermatologist ($4707.88 [+25.3%]) all rebounded, but not to pre-2020 levels (Table 1). When looking at the geographic distribution of payments, the top 5 states receiving the highest total value of payments during the study period included California ($41.51 million), New York ($32.26 million), Florida ($21.38 million), Texas ($19.93 million), and Pennsylvania ($11.69 million).

For each year from 2017 to 2021, more than 80% of payments made to dermatologists were less than $50. The majority (60.7%–75.8%) were in the $10 to $50 range. Between 4% and 5% of payments were more than $1000 for each year. Fewer than 10% of dermatologists received more than $5000 in total payments per year. Most dermatologists (33.3%–36.9%) received $100 to $500 per year. The distribution of payments stratified by number of payments made by amount and payment amount per dermatologist is further delineated in Table 2.

Comment

Benefits of Physician Relationships With Industry—The Physician Payments Sunshine Act increased transparency of industry payments to physicians by creating the OPD through which these relationships can be reported.¹² The effects of these relationships on treatment practices have been the subject of many studies in recent years. Some have suggested that industry ties may impact prescription patterns of endorsed medications.¹³ It also has been reported that the chance of a research study identifying a positive outcome for a particular treatment is higher when the study is funded by a pharmaceutical company compared to other sponsors.¹⁴ On the other hand, some researchers have argued that, when established and maintained in an ethical manner, industry-physician relationships may help practitioners stay updated on the newest treatment paradigms and benefit patient care.¹⁵ Industry relationships may help drive innovation of new products with direct input from frontline physicians who take care of the patients these products aim to help.

Limitations of the OPD—Critics of the OPD have argued that the reported data lack sufficient context and are not easily interpretable by most patients.¹⁶ In addition, many patients might not know about the existence of the database. Indeed, one national survey-based study showed that only 12% of 3542 respondents knew that this information was publicly available, and only 5% knew whether their own physician had received industry payments.¹⁷

Increased Payments From Industry—Our analysis builds on previously reported data in dermatology from 2014 to 2016.^10,11 We found that the trends of increasing numbers and dollar amounts of payments made by industry to dermatologists continued from 2017 to 2019, which may reflect the intended effects of the Physician Payments Sunshine Act, as more payments are being reported in a transparent manner. It also shows that relationships between industry and dermatologists have become more commonplace over time.

It is important to consider these trends in the context of overall Medicare expenditures and prescription volumes. Between 2008 and 2021, prescription volumes have been increasing at a rate of 1% to 4% per year, with 2020 being an exception as the volume decreased slightly from the year prior due to COVID-19 (−3%). Similarly, total Medicare and Medicaid expenditures have been growing at a rate of almost 5% per year.¹⁸ Based on our study results, it appears the total value of payments made between 2017 and 2021 increased at a rate that outpaced prescription volume and expenditures; however, it is difficult to draw conclusions about the relationship between payments made to dermatologists and spending without examining prescriptions specific to dermatologists in the OPD dataset. This relationship could be further explored in future studies.

COVID-19 Restrictions Impacted Payments in 2021—We hypothesize that COVID-19–related restrictions on traveling and in-person meetings led to a decrease in the number of payments, total payment amount, and mean total value of payments received per dermatologist. Notably, compensation for services other than consulting, including speaking fees, had the most precipitous decrease in total payment amount. On the other hand, honoraria and consulting fees were least impacted, as many dermatologists were still able to maintain relationships with industry on an advisory basis without traveling. From 2020 to 2021, the number of total payments and dollar amounts increased with easing of COVID-19 restrictions; however, they had not yet rebounded to 2019 levels during the study period. It will be interesting to continue monitoring these trends once data from future years become available.

Top-Compensated Dermatologists—Our study results also show that for all years from 2017 through 2021, the majority of industry payments were made to a small concentrated percentage of top-compensated dermatologists, which may reflect larger and more frequent payments to those identified by pharmaceutical companies as thought leaders and key opinion leaders in the field or those who are more willing to establish extensive ties with industry. Similarly skewed distributions in payments have been shown in other medical subspecialties including neurosurgery, plastic surgery, otolaryngology, and orthopedics.^4,6,19,20 It also is apparent that the majority of compensated dermatologists in the OPD maintain relatively small ties with industry. For every year from 2017 to 2021, more than half of compensated dermatologists received total payments of less than $500 per year, most of which stemmed from the food and beverage category. Interestingly, a prior study showed that patient perceptions of industry-physician ties may be more strongly impacted by the payment category than the amount.²¹ For example, respondents viewed payments for meals and lodging more negatively, as they were seen more as personal gifts without direct benefit to patients. Conversely, respondents held more positive views of physicians who received free drug samples, which were perceived as benefiting patients, as well as those receiving consulting fees, which were perceived as a signal of physician expertise. Notably, in the same study, physicians who received no payments from industry were seen as honest but also were viewed by some respondents as being inexperienced or uninformed about new treatments.²¹

The contribution and public perception of dermatologists who conduct investigator-initiated research utilizing other types of funding (eg, government grants) also are important to consider but were not directly assessed within the scope of the current study.

Sex Disparities in Compensation—Multiple studies in the literature have demonstrated that sex inequities exist across medical specialties.^22,23 In dermatology, although women make up slightly more than 50% of board-certified dermatologists, they continue to be underrepresented compared with men in leadership positions, academic rank, research funding, and lectureships at national meetings.^24-27 In survey-based studies specifically examining gender-based physician compensation, male dermatologists were found to earn higher salaries than their female counterparts in both private practice and academic settings, even after adjusting for work hours, practice characteristics, and academic rank.^28,29

Our study contributes to the growing body of evidence suggesting that sex inequities also may exist with regard to financial payments from industry. Our results showed that, although the number of male and female dermatologists with industry relationships was similar each year, the number of payments made and total payment amount were both significantly (P<.001) higher for male dermatologists from 2017 through 2021. In 2021, the mean payment amount ($201.57 for male dermatologists; $117.73 for female dermatologists) and mean total amount of payments received ($6172.89 and $2957.79, respectively) also were significantly higher for male compared with female dermatologists (P<.001). The cause of this disparity likely is multifactorial and warrants additional studies in the future. One hypothesis in the existing literature is that male physicians may be more inclined to seek out relationships with industry; it also is possible that disparities in research funding, academic rank, and speaking opportunities at national conferences detailed previously may contribute to inequities in industry payments as companies seek out perceived leaders in the field.³⁰

Limitations and Future Directions—Several important limitations of our study warrant further consideration. As with any database study, the accuracy of the results presented and the conclusions drawn are highly dependent on the precision of the available data, which is reliant on transparent documentation by pharmaceutical companies and physicians. There are no independent methods of verifying the information reported. There have been reports in the literature questioning the utility of the OPD data and risk for misinterpretation.^16,31 Furthermore, the OPD only includes companies whose products are covered by government-sponsored programs, such as Medicare and Medicaid, and therefore does not encompass the totality of industry-dermatologist relationships. We also focused specifically on board-certified dermatologists and did not analyze the extent of industry relationships involving residents, nurses, physician assistants, and other critical members of health care teams that may impact patient care. Differences between academic and private practice payments also could not be examined using the OPD but could present an interesting area for future studies.

Despite these limitations, our study was extensive, using the publicly available OPD to analyze trends and disparities in financial relationships between dermatologists and industry partners from 2017 through 2021. Notably, these findings are not intended to provide judgment or seek to tease out financial relationships that are beneficial for patient care from those that are not; rather, they are intended only to lend additional transparency, provoke thought, and encourage future studies and discussion surrounding this important topic.

Conclusion

Financial relationships between dermatologists and industry are complex and are becoming more prevalent, as shown in our study. These relationships may be critical to facilitate novel patient-centered research and growth in the field of dermatology; however, they also have the potential to be seen as bias in patient care. Transparent reporting of these relationships is an important step in future research regarding the effects of different payment types and serves as the basis for further understanding industry-dermatologist relationships as well as any inequities that exist in the distribution of payments. We encourage all dermatologists to review their public profiles in the OPD. Physicians have the opportunity to review all payment data reported by companies and challenge the accuracy of the data if necessary.

Financial relationships between physicians and industry are prevalent and complex and may have implications for patient care. A 2007 study reported that 94% of 3167 physicians surveyed had established some form of paid relationship with companies in the pharmaceutical industry.¹ To facilitate increased transparency around these relationships, lawmakers passed the Physician Payments Sunshine Act in 2010, which requires pharmaceutical companies and device manufacturers to report all payments made to physicians.² Mandatory disclosures include meals, honoraria, travel expenses, grants, and ownership or investment interests greater than $10. The information is displayed publicly in the Open Payments database (OPD)(https://openpayments-data.cms.gov/), a platform run by the Centers for Medicare and Medicaid Services.

The OPD allows for in-depth analyses of industry payments made to physicians. Many medical specialties—including orthopedics,^3-5 plastic surgery,^6,7 ophthalmology,⁸ and gastroenterology⁹—have published extensive literature characterizing the nature of these payments and disparities in the distribution of payments based on sex, geographic distribution, and other factors. After the first full year of OPD data collection for dermatology in 2014, Feng et al¹⁰ examined the number, amount, and nature of industry payments to dermatologists, as well as their geographic distribution for that year. As a follow-up to this initial research, Schlager et al¹¹ characterized payments made to dermatologists for the year 2016 and found an increase in the total payments, mean payments, and number of dermatologists receiving payments compared with the 2014 data.

Our study aimed to characterize the last 5 years of available OPD data—from January 1, 2017, to December 31, 2021—to further explore trends in industry payments made to dermatologists. In particular, we examined the effects of the COVID-19 pandemic on payments as well as sex disparities and the distribution of industry payments.

Methods

We performed a retrospective analysis of the OPD for the general payment datasets from January 1, 2017, to December 31, 2021. The results were filtered to include only payments made to dermatologists, excluding physicians from other specialties, physician assistants, and other types of practitioners. Data for each physician were grouped by National Provider Identifier (NPI) for providers included in the set, allowing for analysis at the individual level. Data on sex were extracted from the National Plan & Provider Enumeration System’s monthly data dissemination for NPIs for July 2023 (when the study was conducted) and were joined to the OPD data using the NPI number reported for each physician. All data were extracted, transformed, and analyzed using R software (version 4.2.1). Figures and visualizations were produced using Microsoft Excel 2016.

Results

In 2017, a total of 358,884 payments were made by industry to dermatologists, accounting for nearly $58.0 million. The mean total value of payments received per dermatologist was $5231.74, and the mean payment amount was $161.49. In 2018, the total number of payments increased year-over-year by 5.5% (378,509 payments), the total value of payments received increased by 7.5% (approximately $62.3 million), and the mean total value of payments received per dermatologist increased by 5.3% ($5508.98). In 2019, the total number of payments increased by 3.0% (389,670 total payments), the total value of payments recieved increased by 13.2% (approximately $70.5 million), and the mean total value of payments received per dermatologist increased by 11.3% ($6133.45). All of these values decreased in 2020, likely due to COVID-19–related restrictions on travel and meetings (total number of payments, 208,470 [−46.5%]; total value of payments received, approximately $37.5 million [−46.9%], mean total value of payments received per dermatologist, $3757.27 [−38.7%]), but the mean payment amount remained stable at $179.47. In 2021, the total number of payments (295,808 [+41.9%]), total value of payments received (approximately $50.3 million [+34.4%]), and mean total value of payments received per dermatologist ($4707.88 [+25.3%]) all rebounded, but not to pre-2020 levels (Table 1). When looking at the geographic distribution of payments, the top 5 states receiving the highest total value of payments during the study period included California ($41.51 million), New York ($32.26 million), Florida ($21.38 million), Texas ($19.93 million), and Pennsylvania ($11.69 million).

For each year from 2017 to 2021, more than 80% of payments made to dermatologists were less than $50. The majority (60.7%–75.8%) were in the $10 to $50 range. Between 4% and 5% of payments were more than $1000 for each year. Fewer than 10% of dermatologists received more than $5000 in total payments per year. Most dermatologists (33.3%–36.9%) received $100 to $500 per year. The distribution of payments stratified by number of payments made by amount and payment amount per dermatologist is further delineated in Table 2.

Comment

Benefits of Physician Relationships With Industry—The Physician Payments Sunshine Act increased transparency of industry payments to physicians by creating the OPD through which these relationships can be reported.¹² The effects of these relationships on treatment practices have been the subject of many studies in recent years. Some have suggested that industry ties may impact prescription patterns of endorsed medications.¹³ It also has been reported that the chance of a research study identifying a positive outcome for a particular treatment is higher when the study is funded by a pharmaceutical company compared to other sponsors.¹⁴ On the other hand, some researchers have argued that, when established and maintained in an ethical manner, industry-physician relationships may help practitioners stay updated on the newest treatment paradigms and benefit patient care.¹⁵ Industry relationships may help drive innovation of new products with direct input from frontline physicians who take care of the patients these products aim to help.

Limitations of the OPD—Critics of the OPD have argued that the reported data lack sufficient context and are not easily interpretable by most patients.¹⁶ In addition, many patients might not know about the existence of the database. Indeed, one national survey-based study showed that only 12% of 3542 respondents knew that this information was publicly available, and only 5% knew whether their own physician had received industry payments.¹⁷

Increased Payments From Industry—Our analysis builds on previously reported data in dermatology from 2014 to 2016.^10,11 We found that the trends of increasing numbers and dollar amounts of payments made by industry to dermatologists continued from 2017 to 2019, which may reflect the intended effects of the Physician Payments Sunshine Act, as more payments are being reported in a transparent manner. It also shows that relationships between industry and dermatologists have become more commonplace over time.

It is important to consider these trends in the context of overall Medicare expenditures and prescription volumes. Between 2008 and 2021, prescription volumes have been increasing at a rate of 1% to 4% per year, with 2020 being an exception as the volume decreased slightly from the year prior due to COVID-19 (−3%). Similarly, total Medicare and Medicaid expenditures have been growing at a rate of almost 5% per year.¹⁸ Based on our study results, it appears the total value of payments made between 2017 and 2021 increased at a rate that outpaced prescription volume and expenditures; however, it is difficult to draw conclusions about the relationship between payments made to dermatologists and spending without examining prescriptions specific to dermatologists in the OPD dataset. This relationship could be further explored in future studies.

COVID-19 Restrictions Impacted Payments in 2021—We hypothesize that COVID-19–related restrictions on traveling and in-person meetings led to a decrease in the number of payments, total payment amount, and mean total value of payments received per dermatologist. Notably, compensation for services other than consulting, including speaking fees, had the most precipitous decrease in total payment amount. On the other hand, honoraria and consulting fees were least impacted, as many dermatologists were still able to maintain relationships with industry on an advisory basis without traveling. From 2020 to 2021, the number of total payments and dollar amounts increased with easing of COVID-19 restrictions; however, they had not yet rebounded to 2019 levels during the study period. It will be interesting to continue monitoring these trends once data from future years become available.

Top-Compensated Dermatologists—Our study results also show that for all years from 2017 through 2021, the majority of industry payments were made to a small concentrated percentage of top-compensated dermatologists, which may reflect larger and more frequent payments to those identified by pharmaceutical companies as thought leaders and key opinion leaders in the field or those who are more willing to establish extensive ties with industry. Similarly skewed distributions in payments have been shown in other medical subspecialties including neurosurgery, plastic surgery, otolaryngology, and orthopedics.^4,6,19,20 It also is apparent that the majority of compensated dermatologists in the OPD maintain relatively small ties with industry. For every year from 2017 to 2021, more than half of compensated dermatologists received total payments of less than $500 per year, most of which stemmed from the food and beverage category. Interestingly, a prior study showed that patient perceptions of industry-physician ties may be more strongly impacted by the payment category than the amount.²¹ For example, respondents viewed payments for meals and lodging more negatively, as they were seen more as personal gifts without direct benefit to patients. Conversely, respondents held more positive views of physicians who received free drug samples, which were perceived as benefiting patients, as well as those receiving consulting fees, which were perceived as a signal of physician expertise. Notably, in the same study, physicians who received no payments from industry were seen as honest but also were viewed by some respondents as being inexperienced or uninformed about new treatments.²¹

The contribution and public perception of dermatologists who conduct investigator-initiated research utilizing other types of funding (eg, government grants) also are important to consider but were not directly assessed within the scope of the current study.

Sex Disparities in Compensation—Multiple studies in the literature have demonstrated that sex inequities exist across medical specialties.^22,23 In dermatology, although women make up slightly more than 50% of board-certified dermatologists, they continue to be underrepresented compared with men in leadership positions, academic rank, research funding, and lectureships at national meetings.^24-27 In survey-based studies specifically examining gender-based physician compensation, male dermatologists were found to earn higher salaries than their female counterparts in both private practice and academic settings, even after adjusting for work hours, practice characteristics, and academic rank.^28,29

Our study contributes to the growing body of evidence suggesting that sex inequities also may exist with regard to financial payments from industry. Our results showed that, although the number of male and female dermatologists with industry relationships was similar each year, the number of payments made and total payment amount were both significantly (P<.001) higher for male dermatologists from 2017 through 2021. In 2021, the mean payment amount ($201.57 for male dermatologists; $117.73 for female dermatologists) and mean total amount of payments received ($6172.89 and $2957.79, respectively) also were significantly higher for male compared with female dermatologists (P<.001). The cause of this disparity likely is multifactorial and warrants additional studies in the future. One hypothesis in the existing literature is that male physicians may be more inclined to seek out relationships with industry; it also is possible that disparities in research funding, academic rank, and speaking opportunities at national conferences detailed previously may contribute to inequities in industry payments as companies seek out perceived leaders in the field.³⁰

Limitations and Future Directions—Several important limitations of our study warrant further consideration. As with any database study, the accuracy of the results presented and the conclusions drawn are highly dependent on the precision of the available data, which is reliant on transparent documentation by pharmaceutical companies and physicians. There are no independent methods of verifying the information reported. There have been reports in the literature questioning the utility of the OPD data and risk for misinterpretation.^16,31 Furthermore, the OPD only includes companies whose products are covered by government-sponsored programs, such as Medicare and Medicaid, and therefore does not encompass the totality of industry-dermatologist relationships. We also focused specifically on board-certified dermatologists and did not analyze the extent of industry relationships involving residents, nurses, physician assistants, and other critical members of health care teams that may impact patient care. Differences between academic and private practice payments also could not be examined using the OPD but could present an interesting area for future studies.

Despite these limitations, our study was extensive, using the publicly available OPD to analyze trends and disparities in financial relationships between dermatologists and industry partners from 2017 through 2021. Notably, these findings are not intended to provide judgment or seek to tease out financial relationships that are beneficial for patient care from those that are not; rather, they are intended only to lend additional transparency, provoke thought, and encourage future studies and discussion surrounding this important topic.

Conclusion

Financial relationships between dermatologists and industry are complex and are becoming more prevalent, as shown in our study. These relationships may be critical to facilitate novel patient-centered research and growth in the field of dermatology; however, they also have the potential to be seen as bias in patient care. Transparent reporting of these relationships is an important step in future research regarding the effects of different payment types and serves as the basis for further understanding industry-dermatologist relationships as well as any inequities that exist in the distribution of payments. We encourage all dermatologists to review their public profiles in the OPD. Physicians have the opportunity to review all payment data reported by companies and challenge the accuracy of the data if necessary.

Financial relationships between physicians and industry are prevalent and complex and may have implications for patient care. A 2007 study reported that 94% of 3167 physicians surveyed had established some form of paid relationship with companies in the pharmaceutical industry.¹ To facilitate increased transparency around these relationships, lawmakers passed the Physician Payments Sunshine Act in 2010, which requires pharmaceutical companies and device manufacturers to report all payments made to physicians.² Mandatory disclosures include meals, honoraria, travel expenses, grants, and ownership or investment interests greater than $10. The information is displayed publicly in the Open Payments database (OPD)(https://openpayments-data.cms.gov/), a platform run by the Centers for Medicare and Medicaid Services.

The OPD allows for in-depth analyses of industry payments made to physicians. Many medical specialties—including orthopedics,^3-5 plastic surgery,^6,7 ophthalmology,⁸ and gastroenterology⁹—have published extensive literature characterizing the nature of these payments and disparities in the distribution of payments based on sex, geographic distribution, and other factors. After the first full year of OPD data collection for dermatology in 2014, Feng et al¹⁰ examined the number, amount, and nature of industry payments to dermatologists, as well as their geographic distribution for that year. As a follow-up to this initial research, Schlager et al¹¹ characterized payments made to dermatologists for the year 2016 and found an increase in the total payments, mean payments, and number of dermatologists receiving payments compared with the 2014 data.

Our study aimed to characterize the last 5 years of available OPD data—from January 1, 2017, to December 31, 2021—to further explore trends in industry payments made to dermatologists. In particular, we examined the effects of the COVID-19 pandemic on payments as well as sex disparities and the distribution of industry payments.

Methods

We performed a retrospective analysis of the OPD for the general payment datasets from January 1, 2017, to December 31, 2021. The results were filtered to include only payments made to dermatologists, excluding physicians from other specialties, physician assistants, and other types of practitioners. Data for each physician were grouped by National Provider Identifier (NPI) for providers included in the set, allowing for analysis at the individual level. Data on sex were extracted from the National Plan & Provider Enumeration System’s monthly data dissemination for NPIs for July 2023 (when the study was conducted) and were joined to the OPD data using the NPI number reported for each physician. All data were extracted, transformed, and analyzed using R software (version 4.2.1). Figures and visualizations were produced using Microsoft Excel 2016.

Results

In 2017, a total of 358,884 payments were made by industry to dermatologists, accounting for nearly $58.0 million. The mean total value of payments received per dermatologist was $5231.74, and the mean payment amount was $161.49. In 2018, the total number of payments increased year-over-year by 5.5% (378,509 payments), the total value of payments received increased by 7.5% (approximately $62.3 million), and the mean total value of payments received per dermatologist increased by 5.3% ($5508.98). In 2019, the total number of payments increased by 3.0% (389,670 total payments), the total value of payments recieved increased by 13.2% (approximately $70.5 million), and the mean total value of payments received per dermatologist increased by 11.3% ($6133.45). All of these values decreased in 2020, likely due to COVID-19–related restrictions on travel and meetings (total number of payments, 208,470 [−46.5%]; total value of payments received, approximately $37.5 million [−46.9%], mean total value of payments received per dermatologist, $3757.27 [−38.7%]), but the mean payment amount remained stable at $179.47. In 2021, the total number of payments (295,808 [+41.9%]), total value of payments received (approximately $50.3 million [+34.4%]), and mean total value of payments received per dermatologist ($4707.88 [+25.3%]) all rebounded, but not to pre-2020 levels (Table 1). When looking at the geographic distribution of payments, the top 5 states receiving the highest total value of payments during the study period included California ($41.51 million), New York ($32.26 million), Florida ($21.38 million), Texas ($19.93 million), and Pennsylvania ($11.69 million).

For each year from 2017 to 2021, more than 80% of payments made to dermatologists were less than $50. The majority (60.7%–75.8%) were in the $10 to $50 range. Between 4% and 5% of payments were more than $1000 for each year. Fewer than 10% of dermatologists received more than $5000 in total payments per year. Most dermatologists (33.3%–36.9%) received $100 to $500 per year. The distribution of payments stratified by number of payments made by amount and payment amount per dermatologist is further delineated in Table 2.

Comment

Benefits of Physician Relationships With Industry—The Physician Payments Sunshine Act increased transparency of industry payments to physicians by creating the OPD through which these relationships can be reported.¹² The effects of these relationships on treatment practices have been the subject of many studies in recent years. Some have suggested that industry ties may impact prescription patterns of endorsed medications.¹³ It also has been reported that the chance of a research study identifying a positive outcome for a particular treatment is higher when the study is funded by a pharmaceutical company compared to other sponsors.¹⁴ On the other hand, some researchers have argued that, when established and maintained in an ethical manner, industry-physician relationships may help practitioners stay updated on the newest treatment paradigms and benefit patient care.¹⁵ Industry relationships may help drive innovation of new products with direct input from frontline physicians who take care of the patients these products aim to help.

Limitations of the OPD—Critics of the OPD have argued that the reported data lack sufficient context and are not easily interpretable by most patients.¹⁶ In addition, many patients might not know about the existence of the database. Indeed, one national survey-based study showed that only 12% of 3542 respondents knew that this information was publicly available, and only 5% knew whether their own physician had received industry payments.¹⁷

Increased Payments From Industry—Our analysis builds on previously reported data in dermatology from 2014 to 2016.^10,11 We found that the trends of increasing numbers and dollar amounts of payments made by industry to dermatologists continued from 2017 to 2019, which may reflect the intended effects of the Physician Payments Sunshine Act, as more payments are being reported in a transparent manner. It also shows that relationships between industry and dermatologists have become more commonplace over time.

It is important to consider these trends in the context of overall Medicare expenditures and prescription volumes. Between 2008 and 2021, prescription volumes have been increasing at a rate of 1% to 4% per year, with 2020 being an exception as the volume decreased slightly from the year prior due to COVID-19 (−3%). Similarly, total Medicare and Medicaid expenditures have been growing at a rate of almost 5% per year.¹⁸ Based on our study results, it appears the total value of payments made between 2017 and 2021 increased at a rate that outpaced prescription volume and expenditures; however, it is difficult to draw conclusions about the relationship between payments made to dermatologists and spending without examining prescriptions specific to dermatologists in the OPD dataset. This relationship could be further explored in future studies.

COVID-19 Restrictions Impacted Payments in 2021—We hypothesize that COVID-19–related restrictions on traveling and in-person meetings led to a decrease in the number of payments, total payment amount, and mean total value of payments received per dermatologist. Notably, compensation for services other than consulting, including speaking fees, had the most precipitous decrease in total payment amount. On the other hand, honoraria and consulting fees were least impacted, as many dermatologists were still able to maintain relationships with industry on an advisory basis without traveling. From 2020 to 2021, the number of total payments and dollar amounts increased with easing of COVID-19 restrictions; however, they had not yet rebounded to 2019 levels during the study period. It will be interesting to continue monitoring these trends once data from future years become available.

Top-Compensated Dermatologists—Our study results also show that for all years from 2017 through 2021, the majority of industry payments were made to a small concentrated percentage of top-compensated dermatologists, which may reflect larger and more frequent payments to those identified by pharmaceutical companies as thought leaders and key opinion leaders in the field or those who are more willing to establish extensive ties with industry. Similarly skewed distributions in payments have been shown in other medical subspecialties including neurosurgery, plastic surgery, otolaryngology, and orthopedics.^4,6,19,20 It also is apparent that the majority of compensated dermatologists in the OPD maintain relatively small ties with industry. For every year from 2017 to 2021, more than half of compensated dermatologists received total payments of less than $500 per year, most of which stemmed from the food and beverage category. Interestingly, a prior study showed that patient perceptions of industry-physician ties may be more strongly impacted by the payment category than the amount.²¹ For example, respondents viewed payments for meals and lodging more negatively, as they were seen more as personal gifts without direct benefit to patients. Conversely, respondents held more positive views of physicians who received free drug samples, which were perceived as benefiting patients, as well as those receiving consulting fees, which were perceived as a signal of physician expertise. Notably, in the same study, physicians who received no payments from industry were seen as honest but also were viewed by some respondents as being inexperienced or uninformed about new treatments.²¹

The contribution and public perception of dermatologists who conduct investigator-initiated research utilizing other types of funding (eg, government grants) also are important to consider but were not directly assessed within the scope of the current study.

Sex Disparities in Compensation—Multiple studies in the literature have demonstrated that sex inequities exist across medical specialties.^22,23 In dermatology, although women make up slightly more than 50% of board-certified dermatologists, they continue to be underrepresented compared with men in leadership positions, academic rank, research funding, and lectureships at national meetings.^24-27 In survey-based studies specifically examining gender-based physician compensation, male dermatologists were found to earn higher salaries than their female counterparts in both private practice and academic settings, even after adjusting for work hours, practice characteristics, and academic rank.^28,29

Our study contributes to the growing body of evidence suggesting that sex inequities also may exist with regard to financial payments from industry. Our results showed that, although the number of male and female dermatologists with industry relationships was similar each year, the number of payments made and total payment amount were both significantly (P<.001) higher for male dermatologists from 2017 through 2021. In 2021, the mean payment amount ($201.57 for male dermatologists; $117.73 for female dermatologists) and mean total amount of payments received ($6172.89 and $2957.79, respectively) also were significantly higher for male compared with female dermatologists (P<.001). The cause of this disparity likely is multifactorial and warrants additional studies in the future. One hypothesis in the existing literature is that male physicians may be more inclined to seek out relationships with industry; it also is possible that disparities in research funding, academic rank, and speaking opportunities at national conferences detailed previously may contribute to inequities in industry payments as companies seek out perceived leaders in the field.³⁰

Limitations and Future Directions—Several important limitations of our study warrant further consideration. As with any database study, the accuracy of the results presented and the conclusions drawn are highly dependent on the precision of the available data, which is reliant on transparent documentation by pharmaceutical companies and physicians. There are no independent methods of verifying the information reported. There have been reports in the literature questioning the utility of the OPD data and risk for misinterpretation.^16,31 Furthermore, the OPD only includes companies whose products are covered by government-sponsored programs, such as Medicare and Medicaid, and therefore does not encompass the totality of industry-dermatologist relationships. We also focused specifically on board-certified dermatologists and did not analyze the extent of industry relationships involving residents, nurses, physician assistants, and other critical members of health care teams that may impact patient care. Differences between academic and private practice payments also could not be examined using the OPD but could present an interesting area for future studies.

Despite these limitations, our study was extensive, using the publicly available OPD to analyze trends and disparities in financial relationships between dermatologists and industry partners from 2017 through 2021. Notably, these findings are not intended to provide judgment or seek to tease out financial relationships that are beneficial for patient care from those that are not; rather, they are intended only to lend additional transparency, provoke thought, and encourage future studies and discussion surrounding this important topic.

Conclusion

Financial relationships between dermatologists and industry are complex and are becoming more prevalent, as shown in our study. These relationships may be critical to facilitate novel patient-centered research and growth in the field of dermatology; however, they also have the potential to be seen as bias in patient care. Transparent reporting of these relationships is an important step in future research regarding the effects of different payment types and serves as the basis for further understanding industry-dermatologist relationships as well as any inequities that exist in the distribution of payments. We encourage all dermatologists to review their public profiles in the OPD. Physicians have the opportunity to review all payment data reported by companies and challenge the accuracy of the data if necessary.