THE COMPARISON

A and B Axilla of a 65-year-old White man with erythrasma showing a well-demarcated erythematous plaque with fine scale (A). Wood lamp examination of the area showed characteristic bright coral red fluorescence (B).

C and D A well-demarcated, red-brown plaque with fine scale in the antecubital fossa of an obese Hispanic woman (C). Wood lamp examination revealed bright coral red fluorescence (D).

E Hypopigmented patches in the groin with pruritus in a Black man. He also had erythrasma between the toes.

Erythrasma is a skin condition caused by acute or chronic infection of the outermost layer of the epidermis (stratum corneum) with Corynebacterium minutissimum. It has a predilection for intertriginous regions such as the axillae, groin, and interdigital spaces of the toes. It can be associated with pruritus or can be asymptomatic.

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Erythrasma typically affects adults, with greater prevalence among those residing in shared living facilities, such as dormitories or nursing homes, or in humid climates.¹ It is a common disorder with an estimated prevalence of 17.6% of bacterial skin infections in elderly patients and 44% of diabetic interdigital toe space infections.^2,3

Key clinical features

Erythrasma can manifest as red-brown hyperpigmented plaques with fine scale and little central clearing (Figures A and C) or as a hypopigmented patch (Figure E) with a sharply marginated, hyperpigmented border in patients with skin of color. In the interdigital toe spaces, the skin often is white and macerated. These findings may appear in patients of all skin tones.

Worth noting

• Corynebacterium minutissimum produces coproporphyrin III, which glows fluorescent red under Wood lamp examination (Figures B and D). A recent shower or bath may remove the fluorescent coproporphyrins and cause a false-negative result. The interdigital space between the fourth and fifth toes is a common location for C minutissimum; thus clinicians should consider examining these areas with a Wood lamp.

• Associated risk factors include obesity, immunosuppression, diabetes mellitus, and excessive sweating.¹

• The differential diagnosis includes intertrigo, inverse psoriasis, confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome), acanthosis nigricans, seborrheic dermatitis, and tinea pedis when present in the interdigital toe spaces. Plaques occurring in circular patterns may be mistaken for tinea corporis or pityriasis rotunda.

• There is a high prevalence of erythrasma in patients with inverse psoriasis, and it may exacerbate psoriatic plaques.⁴

• Treatment options include application of topical clindamycin or erythromycin to the affected area.1 Some patients have responded to topical mupiricin.² For larger areas, a 1-g dose of clarithromycin⁵ or a 14-day course of erythromycin may be appropriate.1 Avoid prescribing clarithromycin to patients with preexisting heart disease due to its increased risk for cardiac events or death; consider other agents.

Health disparity highlight

Obesity, most prevalent in non-Hispanic Black adults (49.9%) and Hispanic adults (45.6%) followed by non- Hispanic White adults (41.4%),⁶ may cause velvety dark plaques on the neck called acanthosis nigricans. However, acute or chronic erythrasma also may cause hyperpigmentation of the body folds. Although the pathology of erythrasma is due to bacterial infection of the superficial layer of the stratum corneum, acanthosis nigricans is due to fibroblast proliferation and stimulation of epidermal keratinocytes likely from increased growth factors and insulinlike growth factor.⁷ If erythrasma is mistaken for acanthosis nigricans, the patient may be counseled inappropriately that the hyperpigmentation is something not easily resolved and subsequently left with an active treatable condition that adversely affects their quality of life.

THE COMPARISON

A and B Axilla of a 65-year-old White man with erythrasma showing a well-demarcated erythematous plaque with fine scale (A). Wood lamp examination of the area showed characteristic bright coral red fluorescence (B).

C and D A well-demarcated, red-brown plaque with fine scale in the antecubital fossa of an obese Hispanic woman (C). Wood lamp examination revealed bright coral red fluorescence (D).

E Hypopigmented patches in the groin with pruritus in a Black man. He also had erythrasma between the toes.

Erythrasma is a skin condition caused by acute or chronic infection of the outermost layer of the epidermis (stratum corneum) with Corynebacterium minutissimum. It has a predilection for intertriginous regions such as the axillae, groin, and interdigital spaces of the toes. It can be associated with pruritus or can be asymptomatic.

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Erythrasma typically affects adults, with greater prevalence among those residing in shared living facilities, such as dormitories or nursing homes, or in humid climates.¹ It is a common disorder with an estimated prevalence of 17.6% of bacterial skin infections in elderly patients and 44% of diabetic interdigital toe space infections.^2,3

Key clinical features

Erythrasma can manifest as red-brown hyperpigmented plaques with fine scale and little central clearing (Figures A and C) or as a hypopigmented patch (Figure E) with a sharply marginated, hyperpigmented border in patients with skin of color. In the interdigital toe spaces, the skin often is white and macerated. These findings may appear in patients of all skin tones.

Worth noting

• Corynebacterium minutissimum produces coproporphyrin III, which glows fluorescent red under Wood lamp examination (Figures B and D). A recent shower or bath may remove the fluorescent coproporphyrins and cause a false-negative result. The interdigital space between the fourth and fifth toes is a common location for C minutissimum; thus clinicians should consider examining these areas with a Wood lamp.

• Associated risk factors include obesity, immunosuppression, diabetes mellitus, and excessive sweating.¹

• The differential diagnosis includes intertrigo, inverse psoriasis, confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome), acanthosis nigricans, seborrheic dermatitis, and tinea pedis when present in the interdigital toe spaces. Plaques occurring in circular patterns may be mistaken for tinea corporis or pityriasis rotunda.

• There is a high prevalence of erythrasma in patients with inverse psoriasis, and it may exacerbate psoriatic plaques.⁴

• Treatment options include application of topical clindamycin or erythromycin to the affected area.1 Some patients have responded to topical mupiricin.² For larger areas, a 1-g dose of clarithromycin⁵ or a 14-day course of erythromycin may be appropriate.1 Avoid prescribing clarithromycin to patients with preexisting heart disease due to its increased risk for cardiac events or death; consider other agents.

Health disparity highlight

Obesity, most prevalent in non-Hispanic Black adults (49.9%) and Hispanic adults (45.6%) followed by non- Hispanic White adults (41.4%),⁶ may cause velvety dark plaques on the neck called acanthosis nigricans. However, acute or chronic erythrasma also may cause hyperpigmentation of the body folds. Although the pathology of erythrasma is due to bacterial infection of the superficial layer of the stratum corneum, acanthosis nigricans is due to fibroblast proliferation and stimulation of epidermal keratinocytes likely from increased growth factors and insulinlike growth factor.⁷ If erythrasma is mistaken for acanthosis nigricans, the patient may be counseled inappropriately that the hyperpigmentation is something not easily resolved and subsequently left with an active treatable condition that adversely affects their quality of life.

THE COMPARISON

A and B Axilla of a 65-year-old White man with erythrasma showing a well-demarcated erythematous plaque with fine scale (A). Wood lamp examination of the area showed characteristic bright coral red fluorescence (B).

C and D A well-demarcated, red-brown plaque with fine scale in the antecubital fossa of an obese Hispanic woman (C). Wood lamp examination revealed bright coral red fluorescence (D).

E Hypopigmented patches in the groin with pruritus in a Black man. He also had erythrasma between the toes.

Erythrasma is a skin condition caused by acute or chronic infection of the outermost layer of the epidermis (stratum corneum) with Corynebacterium minutissimum. It has a predilection for intertriginous regions such as the axillae, groin, and interdigital spaces of the toes. It can be associated with pruritus or can be asymptomatic.

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Erythrasma typically affects adults, with greater prevalence among those residing in shared living facilities, such as dormitories or nursing homes, or in humid climates.¹ It is a common disorder with an estimated prevalence of 17.6% of bacterial skin infections in elderly patients and 44% of diabetic interdigital toe space infections.^2,3

Key clinical features

Erythrasma can manifest as red-brown hyperpigmented plaques with fine scale and little central clearing (Figures A and C) or as a hypopigmented patch (Figure E) with a sharply marginated, hyperpigmented border in patients with skin of color. In the interdigital toe spaces, the skin often is white and macerated. These findings may appear in patients of all skin tones.

Worth noting

• Corynebacterium minutissimum produces coproporphyrin III, which glows fluorescent red under Wood lamp examination (Figures B and D). A recent shower or bath may remove the fluorescent coproporphyrins and cause a false-negative result. The interdigital space between the fourth and fifth toes is a common location for C minutissimum; thus clinicians should consider examining these areas with a Wood lamp.

• Associated risk factors include obesity, immunosuppression, diabetes mellitus, and excessive sweating.¹

• The differential diagnosis includes intertrigo, inverse psoriasis, confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome), acanthosis nigricans, seborrheic dermatitis, and tinea pedis when present in the interdigital toe spaces. Plaques occurring in circular patterns may be mistaken for tinea corporis or pityriasis rotunda.

• There is a high prevalence of erythrasma in patients with inverse psoriasis, and it may exacerbate psoriatic plaques.⁴

• Treatment options include application of topical clindamycin or erythromycin to the affected area.1 Some patients have responded to topical mupiricin.² For larger areas, a 1-g dose of clarithromycin⁵ or a 14-day course of erythromycin may be appropriate.1 Avoid prescribing clarithromycin to patients with preexisting heart disease due to its increased risk for cardiac events or death; consider other agents.

Health disparity highlight

Obesity, most prevalent in non-Hispanic Black adults (49.9%) and Hispanic adults (45.6%) followed by non- Hispanic White adults (41.4%),⁶ may cause velvety dark plaques on the neck called acanthosis nigricans. However, acute or chronic erythrasma also may cause hyperpigmentation of the body folds. Although the pathology of erythrasma is due to bacterial infection of the superficial layer of the stratum corneum, acanthosis nigricans is due to fibroblast proliferation and stimulation of epidermal keratinocytes likely from increased growth factors and insulinlike growth factor.⁷ If erythrasma is mistaken for acanthosis nigricans, the patient may be counseled inappropriately that the hyperpigmentation is something not easily resolved and subsequently left with an active treatable condition that adversely affects their quality of life.

A new meta-analysis of 884 studies evaluating 27 different types of antioxidant supplements has suggested that some of these micronutrients – including omega-3 fatty acids, folic acid, and coenzyme Q10 – may produce significant cardiovascular benefits.

Other antioxidant supplements that showed some evidence of reducing cardiovascular risk were omega-6 fatty acids, L-arginine, L-citrulline, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein, and quercetin.

No effect was seen with vitamin C, vitamin D, vitamin E, or selenium, and beta-carotene supplementation was linked to an increase in all-cause mortality in the analysis.

The study is published in the Journal of the American College of Cardiology and was also published online.

“Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” the authors, led by Peng An, PhD, China Agricultural University, Beijing, conclude.

“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” senior author Simin Liu, MD, professor of epidemiology and medicine at Brown University, Providence, R.I., said in an American College of Cardiology press release.

“The micronutrients identified require further validation in large, high-quality interventional trials to establish clinical efficacy to determine their long-term balance of risks and benefits,” the authors add.
 

Experts cautious

Experts in the field of cardiovascular risk and preventative medicine have urged caution in interpreting these results.

JoAnn Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital, Boston, told this news organization that she has concerns that some of the results in the meta-analysis may be inflated by publication bias and some are chance findings that haven’t been well replicated.

“Although this meta-analysis of micronutrients and cardiometabolic health was based on randomized clinical trials, the quality of randomized trials on this subject varies widely,” she noted.

“The study is informative, but the conclusions are only as good as the quality of the evidence. Some of the trials are limited by short duration, and included trials have a wide range of quality, dosing, inclusion criteria, imperfect blinding, and few of them focus on hard clinical events,” Dr. Manson said. “Also, with trials of this nature, the potential for publication bias warrants consideration, because many of the smaller trials with unfavorable or neutral results may remain unpublished or not even be submitted for publication.”   

However, she added, “despite these limitations, this is an important contribution to the literature on micronutrients and health – and goes a long way in separating the wheat from the chaff.”

Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic, was more critical of the meta-analysis.

“This study does not make sense. Some of the ‘micronutrients’ in this meta-analysis have undergone thorough testing in large randomized clinical trials that showed different results. I am skeptical whether any of the purported benefits of these supplements would be confirmed in a high-quality randomized controlled trial,” he said.

Dr. Nissen added that many of the included studies are low in quality. “I must quote [renowned cardiologist, Dr.] Franz Messerli: ‘A meta-analysis is like making bouillabaisse. ... One rotten fish can spoil the broth.’ This type of analysis does not override high-quality large, randomized trials.”

In the JACC paper, the study investigators note that the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for cardiovascular disease. A common feature of these dietary patterns is that they are low in saturated fat and sodium and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.

“To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” they note.

They therefore conducted the current systematic review and meta-analyses of all available randomized controlled trials investigating the effect of micronutrients with antioxidant properties on cardiovascular risk factors and events in diverse populations.

The meta-analysis included a total of 884 randomized trials evaluating 27 types of micronutrients among 883,627 participants.

Results showed that supplementation with n-3 fatty acids, n-6 fatty acids, L-arginine, L-citrulline, folic acid, magnesium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin had “moderate-to high-quality evidence” for reducing cardiovascular risk factors.

Specifically, n-3 fatty acid supplementation was linked to reduced rates of cardiovascular mortality (relative risk, 0.93), myocardial infarction (RR, 0.85), and coronary heart disease events (RR, 0.86). Folic acid supplementation was linked to a decreased stroke risk (RR, 0.84) and coenzyme Q10 was associated with a lower rate of all-cause mortality (RR, 0.68).

“The current study represents the first attempt in providing a comprehensive and most up-to-date evidence map that systematically assessed the quality and quantity of all randomized trials linking the effects of a wide variety of micronutrients on cardiovascular risk factors,” the authors say.

“The comprehensive evidence map presented here highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health, which may require cultural adaptations to apply globally,” they conclude.

Commenting on some of the specific beneficial findings, Dr. Manson said: “I do believe that the marine omega-3s confer heart benefits, but results are not consistent and vary by dose and formulation.”

However, she pointed out that, regarding folic acid, a previous meta-analysis including eight large randomized trials in more than 37,000 participants found no reduction in coronary events, stroke, or major cardiovascular events with folic acid supplementation, compared with placebo, “so the reported stroke benefit would need further confirmation.”

In an accompanying editorial, Juan Gormaz, PhD, University of Chile, and Rodrigo Carrasco, MD, Chilean Society of Cardiology and Cardiovascular Surgery, both in Santiago, state: “Given that the compounds with more pleiotropic properties produced the better outcomes, the antioxidant paradigm on cardiovascular prevention can be challenged. For example, inasmuch as n-3 fatty acids have antiplatelet and anti-inflammatory properties, they are too complex to enable attribution of the observed benefits solely to their antioxidant capacity.”

The editorialists note that from a research point of view, “although the current information opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, there is still a long way to go in terms of generating evidence.”

They add that the challenge now for some compounds is to begin establishing consensus in definitions of dose and combinations, as well as continue strengthening the evidence of effectiveness.

“Regarding routine clinical practice, these results begin to open spaces for the integration of new tools into the therapeutic arsenal aimed at cardiovascular prevention in selected populations, which could be easily accessible and, with specific exceptions, would present a low frequency of adverse effects,” they conclude.

This work was partly supported by the United States’ Fulbright Program and by the Beijing Advanced Innovation Center for Food Nutrition and Human Health, the National Natural Science Foundation of China, the Chinese Universities Scientific Fund, and the Beijing Municipal Natural Science Foundation.

Dr. Liu has received honoraria for scientific presentations or reviews at Johns Hopkins University, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, and the National Institutes of Health; he is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by Massachusetts General Hospital; he has received royalties from UpToDate and has received an honorarium from the American Society for Nutrition for his duties as Associate Editor. Co-author Jeffrey Mechanick, MD, has received honoraria from Abbott Nutrition for lectures and serves on the advisory boards of Aveta.Life, L-Nutra, and Twin Health. The other authors report no relevant financial relationships.

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

A new meta-analysis of 884 studies evaluating 27 different types of antioxidant supplements has suggested that some of these micronutrients – including omega-3 fatty acids, folic acid, and coenzyme Q10 – may produce significant cardiovascular benefits.

Other antioxidant supplements that showed some evidence of reducing cardiovascular risk were omega-6 fatty acids, L-arginine, L-citrulline, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein, and quercetin.

No effect was seen with vitamin C, vitamin D, vitamin E, or selenium, and beta-carotene supplementation was linked to an increase in all-cause mortality in the analysis.

The study is published in the Journal of the American College of Cardiology and was also published online.

“Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” the authors, led by Peng An, PhD, China Agricultural University, Beijing, conclude.

“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” senior author Simin Liu, MD, professor of epidemiology and medicine at Brown University, Providence, R.I., said in an American College of Cardiology press release.

“The micronutrients identified require further validation in large, high-quality interventional trials to establish clinical efficacy to determine their long-term balance of risks and benefits,” the authors add.
 

Experts cautious

Experts in the field of cardiovascular risk and preventative medicine have urged caution in interpreting these results.

JoAnn Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital, Boston, told this news organization that she has concerns that some of the results in the meta-analysis may be inflated by publication bias and some are chance findings that haven’t been well replicated.

“Although this meta-analysis of micronutrients and cardiometabolic health was based on randomized clinical trials, the quality of randomized trials on this subject varies widely,” she noted.

“The study is informative, but the conclusions are only as good as the quality of the evidence. Some of the trials are limited by short duration, and included trials have a wide range of quality, dosing, inclusion criteria, imperfect blinding, and few of them focus on hard clinical events,” Dr. Manson said. “Also, with trials of this nature, the potential for publication bias warrants consideration, because many of the smaller trials with unfavorable or neutral results may remain unpublished or not even be submitted for publication.”   

However, she added, “despite these limitations, this is an important contribution to the literature on micronutrients and health – and goes a long way in separating the wheat from the chaff.”

Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic, was more critical of the meta-analysis.

“This study does not make sense. Some of the ‘micronutrients’ in this meta-analysis have undergone thorough testing in large randomized clinical trials that showed different results. I am skeptical whether any of the purported benefits of these supplements would be confirmed in a high-quality randomized controlled trial,” he said.

Dr. Nissen added that many of the included studies are low in quality. “I must quote [renowned cardiologist, Dr.] Franz Messerli: ‘A meta-analysis is like making bouillabaisse. ... One rotten fish can spoil the broth.’ This type of analysis does not override high-quality large, randomized trials.”

In the JACC paper, the study investigators note that the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for cardiovascular disease. A common feature of these dietary patterns is that they are low in saturated fat and sodium and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.

“To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” they note.

They therefore conducted the current systematic review and meta-analyses of all available randomized controlled trials investigating the effect of micronutrients with antioxidant properties on cardiovascular risk factors and events in diverse populations.

The meta-analysis included a total of 884 randomized trials evaluating 27 types of micronutrients among 883,627 participants.

Results showed that supplementation with n-3 fatty acids, n-6 fatty acids, L-arginine, L-citrulline, folic acid, magnesium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin had “moderate-to high-quality evidence” for reducing cardiovascular risk factors.

Specifically, n-3 fatty acid supplementation was linked to reduced rates of cardiovascular mortality (relative risk, 0.93), myocardial infarction (RR, 0.85), and coronary heart disease events (RR, 0.86). Folic acid supplementation was linked to a decreased stroke risk (RR, 0.84) and coenzyme Q10 was associated with a lower rate of all-cause mortality (RR, 0.68).

“The current study represents the first attempt in providing a comprehensive and most up-to-date evidence map that systematically assessed the quality and quantity of all randomized trials linking the effects of a wide variety of micronutrients on cardiovascular risk factors,” the authors say.

“The comprehensive evidence map presented here highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health, which may require cultural adaptations to apply globally,” they conclude.

Commenting on some of the specific beneficial findings, Dr. Manson said: “I do believe that the marine omega-3s confer heart benefits, but results are not consistent and vary by dose and formulation.”

However, she pointed out that, regarding folic acid, a previous meta-analysis including eight large randomized trials in more than 37,000 participants found no reduction in coronary events, stroke, or major cardiovascular events with folic acid supplementation, compared with placebo, “so the reported stroke benefit would need further confirmation.”

In an accompanying editorial, Juan Gormaz, PhD, University of Chile, and Rodrigo Carrasco, MD, Chilean Society of Cardiology and Cardiovascular Surgery, both in Santiago, state: “Given that the compounds with more pleiotropic properties produced the better outcomes, the antioxidant paradigm on cardiovascular prevention can be challenged. For example, inasmuch as n-3 fatty acids have antiplatelet and anti-inflammatory properties, they are too complex to enable attribution of the observed benefits solely to their antioxidant capacity.”

The editorialists note that from a research point of view, “although the current information opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, there is still a long way to go in terms of generating evidence.”

They add that the challenge now for some compounds is to begin establishing consensus in definitions of dose and combinations, as well as continue strengthening the evidence of effectiveness.

“Regarding routine clinical practice, these results begin to open spaces for the integration of new tools into the therapeutic arsenal aimed at cardiovascular prevention in selected populations, which could be easily accessible and, with specific exceptions, would present a low frequency of adverse effects,” they conclude.

This work was partly supported by the United States’ Fulbright Program and by the Beijing Advanced Innovation Center for Food Nutrition and Human Health, the National Natural Science Foundation of China, the Chinese Universities Scientific Fund, and the Beijing Municipal Natural Science Foundation.

Dr. Liu has received honoraria for scientific presentations or reviews at Johns Hopkins University, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, and the National Institutes of Health; he is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by Massachusetts General Hospital; he has received royalties from UpToDate and has received an honorarium from the American Society for Nutrition for his duties as Associate Editor. Co-author Jeffrey Mechanick, MD, has received honoraria from Abbott Nutrition for lectures and serves on the advisory boards of Aveta.Life, L-Nutra, and Twin Health. The other authors report no relevant financial relationships.

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

A new meta-analysis of 884 studies evaluating 27 different types of antioxidant supplements has suggested that some of these micronutrients – including omega-3 fatty acids, folic acid, and coenzyme Q10 – may produce significant cardiovascular benefits.

Other antioxidant supplements that showed some evidence of reducing cardiovascular risk were omega-6 fatty acids, L-arginine, L-citrulline, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein, and quercetin.

No effect was seen with vitamin C, vitamin D, vitamin E, or selenium, and beta-carotene supplementation was linked to an increase in all-cause mortality in the analysis.

The study is published in the Journal of the American College of Cardiology and was also published online.

“Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” the authors, led by Peng An, PhD, China Agricultural University, Beijing, conclude.

“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” senior author Simin Liu, MD, professor of epidemiology and medicine at Brown University, Providence, R.I., said in an American College of Cardiology press release.

“The micronutrients identified require further validation in large, high-quality interventional trials to establish clinical efficacy to determine their long-term balance of risks and benefits,” the authors add.
 

Experts cautious

Experts in the field of cardiovascular risk and preventative medicine have urged caution in interpreting these results.

JoAnn Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital, Boston, told this news organization that she has concerns that some of the results in the meta-analysis may be inflated by publication bias and some are chance findings that haven’t been well replicated.

“Although this meta-analysis of micronutrients and cardiometabolic health was based on randomized clinical trials, the quality of randomized trials on this subject varies widely,” she noted.

“The study is informative, but the conclusions are only as good as the quality of the evidence. Some of the trials are limited by short duration, and included trials have a wide range of quality, dosing, inclusion criteria, imperfect blinding, and few of them focus on hard clinical events,” Dr. Manson said. “Also, with trials of this nature, the potential for publication bias warrants consideration, because many of the smaller trials with unfavorable or neutral results may remain unpublished or not even be submitted for publication.”   

However, she added, “despite these limitations, this is an important contribution to the literature on micronutrients and health – and goes a long way in separating the wheat from the chaff.”

Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic, was more critical of the meta-analysis.

“This study does not make sense. Some of the ‘micronutrients’ in this meta-analysis have undergone thorough testing in large randomized clinical trials that showed different results. I am skeptical whether any of the purported benefits of these supplements would be confirmed in a high-quality randomized controlled trial,” he said.

Dr. Nissen added that many of the included studies are low in quality. “I must quote [renowned cardiologist, Dr.] Franz Messerli: ‘A meta-analysis is like making bouillabaisse. ... One rotten fish can spoil the broth.’ This type of analysis does not override high-quality large, randomized trials.”

In the JACC paper, the study investigators note that the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for cardiovascular disease. A common feature of these dietary patterns is that they are low in saturated fat and sodium and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.

“To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” they note.

They therefore conducted the current systematic review and meta-analyses of all available randomized controlled trials investigating the effect of micronutrients with antioxidant properties on cardiovascular risk factors and events in diverse populations.

The meta-analysis included a total of 884 randomized trials evaluating 27 types of micronutrients among 883,627 participants.

Results showed that supplementation with n-3 fatty acids, n-6 fatty acids, L-arginine, L-citrulline, folic acid, magnesium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin had “moderate-to high-quality evidence” for reducing cardiovascular risk factors.

Specifically, n-3 fatty acid supplementation was linked to reduced rates of cardiovascular mortality (relative risk, 0.93), myocardial infarction (RR, 0.85), and coronary heart disease events (RR, 0.86). Folic acid supplementation was linked to a decreased stroke risk (RR, 0.84) and coenzyme Q10 was associated with a lower rate of all-cause mortality (RR, 0.68).

“The current study represents the first attempt in providing a comprehensive and most up-to-date evidence map that systematically assessed the quality and quantity of all randomized trials linking the effects of a wide variety of micronutrients on cardiovascular risk factors,” the authors say.

“The comprehensive evidence map presented here highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health, which may require cultural adaptations to apply globally,” they conclude.

Commenting on some of the specific beneficial findings, Dr. Manson said: “I do believe that the marine omega-3s confer heart benefits, but results are not consistent and vary by dose and formulation.”

However, she pointed out that, regarding folic acid, a previous meta-analysis including eight large randomized trials in more than 37,000 participants found no reduction in coronary events, stroke, or major cardiovascular events with folic acid supplementation, compared with placebo, “so the reported stroke benefit would need further confirmation.”

In an accompanying editorial, Juan Gormaz, PhD, University of Chile, and Rodrigo Carrasco, MD, Chilean Society of Cardiology and Cardiovascular Surgery, both in Santiago, state: “Given that the compounds with more pleiotropic properties produced the better outcomes, the antioxidant paradigm on cardiovascular prevention can be challenged. For example, inasmuch as n-3 fatty acids have antiplatelet and anti-inflammatory properties, they are too complex to enable attribution of the observed benefits solely to their antioxidant capacity.”

The editorialists note that from a research point of view, “although the current information opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, there is still a long way to go in terms of generating evidence.”

They add that the challenge now for some compounds is to begin establishing consensus in definitions of dose and combinations, as well as continue strengthening the evidence of effectiveness.

“Regarding routine clinical practice, these results begin to open spaces for the integration of new tools into the therapeutic arsenal aimed at cardiovascular prevention in selected populations, which could be easily accessible and, with specific exceptions, would present a low frequency of adverse effects,” they conclude.

This work was partly supported by the United States’ Fulbright Program and by the Beijing Advanced Innovation Center for Food Nutrition and Human Health, the National Natural Science Foundation of China, the Chinese Universities Scientific Fund, and the Beijing Municipal Natural Science Foundation.

Dr. Liu has received honoraria for scientific presentations or reviews at Johns Hopkins University, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, and the National Institutes of Health; he is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by Massachusetts General Hospital; he has received royalties from UpToDate and has received an honorarium from the American Society for Nutrition for his duties as Associate Editor. Co-author Jeffrey Mechanick, MD, has received honoraria from Abbott Nutrition for lectures and serves on the advisory boards of Aveta.Life, L-Nutra, and Twin Health. The other authors report no relevant financial relationships.

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

The Diagnosis: Hybrid Schwannoma-Perineurioma

Hybrid nerve sheath tumors are rare entities that display features of more than one nerve sheath tumor such as neurofibromas, schwannomas, and perineuriomas.¹ These tumors often are found in the dermis or subcutaneous tissue of the extremities and abdomen²; however, cases of hybrid peripheral nerve sheath tumors have been reported in many anatomical locations without a gender predilection.³ The most common type of hybrid nerve sheath tumor is a schwannoma-perineurioma.^3,4 Histologically, they are well-circumscribed lesions composed of both spindled Schwann cells with plump nuclei and spindled perineural cells with more elongated thin nuclei.⁵ Although the Schwann cell component tends to predominate, the 2 cell populations interdigitate, making it challenging to definitively distinguish them by hematoxylin and eosin staining alone.4 However, immunohistochemical (IHC) staining can be used to help distinguish the 2 separate cell populations. Staining for S-100 and SRY-box transcription factor 10 (SOX-10) will be positive in the Schwann cell component, and staining for epithelial membrane antigen, Claudin-1, or glucose transporter-1 (Figure 1) will be positive in the perineural component. Other hybrid forms of benign nerve sheath tumors include neurofibroma-schwannoma and neurofibromaperineurioma.⁴ Neurofibroma-schwannomas usually have a schwannoma component containing Antoni A areas with palisading Verocay bodies. The neurofibroma cells typically have wavy elongated nuclei, fibroblasts, and mucinous myxoid material.³ Neurofibroma-perineurioma is the least common hybrid tumor. These hybrid tumors have a plexiform neurofibroma appearance with areas of perineural differentiation, which can be difficult to identify on routine histology and typically will require IHC staining to appreciate. The neurofibroma component will stain positive for S-100 and negative for markers of perineural differentiation, including epithelial membrane antigen, glucose transporter-1, and Claudin-1.³ Although schwannoma-perineuriomas are benign sporadic tumors not associated with neurofibromatosis, neurofibromaschwannomas are associated with neurofibromatosis types 1 and 2 (NF1 and NF2). Neurofibroma-perineurioma tumors usually are associated with only NF1.^3,6

Schwannomas typically present in middle-aged patients as tumors located on flexor surfaces.⁷ Although perineural cells can be seen at the periphery of a schwannoma forming a capsule, they do not interdigitate between the Schwann cells. Schwannomas are composed almost entirely of well-differentiated Schwann cells.^1,4,8 Schwannomas classically are well-circumscribed, encapsulated, biphasic lesions with alternating compact areas (Antoni A) and loosely arranged areas (Antoni B). The spindled cells occasionally may display nuclear palisading within the Antoni A areas, known as Verocay bodies (Figure 2). Antoni B areas are more disorganized and hypocellular with variable macrophage infiltrate.^1,4,8 The Schwann cells predominantly will have bland cytologic features, but scattered areas of degenerative nuclear atypia (also known as ancient change) may be present.⁴ Multiple schwannomas are associated with NF2 gene mutations and loss of merlin protein.8 There are different subtypes of schwannomas, including cellular and plexiform schwannomas.⁴ Because schwannomas are benign nerve sheath lesions, treatment typically consists of excision with careful dissection around the involved nerve.⁹

Neurofibromas are the most common peripheral nerve sheath tumors of the skin with no notable anatomic prediction, though one study found them to be more prevalent in the upper extremities.¹⁰ They typically present as sporadic solitary lesions, but multiple lesions may appear as superficial pedunculated growths that present in those aged 20 to 30 years.¹¹ Microscopically, neurofibromas typically are not well circumscribed and have an infiltrative growth pattern. Neurofibromas are composed of cytologically bland spindled Schwann cells with thin wavy nuclei in a variable myxoid stroma (Figure 3). In addition to Schwann cells, neurofibromas contain other cell components, including fibroblasts, mast cells, perineurial-like cells, and residual axons.⁴ Neurofibromas typically are located in the dermis but may extend into the subcutaneous tissue. Clinically, the overlying skin may show hyperpigmentation.8 Neurofibromas can be localized, diffuse, or plexiform, with the majority being localized. Diffuse neurofibromas clinically have a raised plaque appearance. Treatment is unnecessary because these lesions are benign.⁷

Desmoplastic melanoma (DM) is another diagnosis in the differential for this case. Patients with DM are older compared to non-DM melanoma patients, with a male predilection.¹² Desmoplastic melanomas are more likely to be located on the head and neck. In approximately one-third of cases, no in situ component will be identified, leading to confusion of the dermal lesion as a neural lesion or an area of scar formation. Microscopically, DM presents as a variable cellular infiltrative tumor composed of spindle cells with varying degrees of nuclear atypia. The spindled melanocytes are within a collagenous (desmoplastic) stroma (Figure 4).¹³ Desmoplastic melanoma has been described with a low mitotic index, leading to misdiagnosis with benign spindle cell neoplasms.¹⁴ The spindle cells should be positive for S-100 and SOX-10 with IHC staining. Unlike other melanomas, human melanoma black 45 and Melan-A often are negative or only focally positive. Treatment of DM is similar to non-DM in that wide local excision usually is employed. A systematic review evaluating sentinel lymph node biopsy (SLNB) recommended consideration of SLNB in mixed DM but not for pure DM, as rates of positive SLNB were much lower in the latter.¹⁵

Patients with malignant peripheral nerve sheath tumor (MPNST) usually present with an enlarging mass, pain, or neurologic symptoms. Most cases of MPNST are located on the trunk or extremities.¹⁶ Plexiform neurofibromas, especially in adults with NF1, have the potential to transform into an MPNST.⁴ In fact, MPNST is the most common malignancy in patients with NF1.¹⁷ Pediatric cancer survivors also are predisposed to MPNST, with a 40-fold increase in incidence compared to the general population.¹⁸ Transformation from schwannoma to MPNST is rare but has been reported.⁸ Histologically, spindle cells easily can be appreciated with a fasciculated growth pattern (Figure 5). Mitotic activity and tumor necrosis may be present. Diagnosis of these tumors historically has been challenging, though recent research has identified inactivation of polycomb repressive complex 2 in 70% to 90% of MPNSTs. Because of polycomb repressive complex 2 inactivation, there is loss of stone H3K27 trimethylation that can be capitalized on for MPNST diagnosis.¹⁹ Negative IHC staining for H3K27 trimethylation has been found to be highly specific for MPNST. Negative staining for different cytokeratin and melanoma markers can be helpful in differentiating it from carcinomas and melanoma. The only curative treatment for MPNST is complete excision, leaving patients with recurrent, refractory, and metastatic cases to be encouraged for enrollment in clinical trials. The 5-year survival rates for patients with MPNST reported in the literature range from 20% to 50%.²⁰

The Diagnosis: Hybrid Schwannoma-Perineurioma

Hybrid nerve sheath tumors are rare entities that display features of more than one nerve sheath tumor such as neurofibromas, schwannomas, and perineuriomas.¹ These tumors often are found in the dermis or subcutaneous tissue of the extremities and abdomen²; however, cases of hybrid peripheral nerve sheath tumors have been reported in many anatomical locations without a gender predilection.³ The most common type of hybrid nerve sheath tumor is a schwannoma-perineurioma.^3,4 Histologically, they are well-circumscribed lesions composed of both spindled Schwann cells with plump nuclei and spindled perineural cells with more elongated thin nuclei.⁵ Although the Schwann cell component tends to predominate, the 2 cell populations interdigitate, making it challenging to definitively distinguish them by hematoxylin and eosin staining alone.4 However, immunohistochemical (IHC) staining can be used to help distinguish the 2 separate cell populations. Staining for S-100 and SRY-box transcription factor 10 (SOX-10) will be positive in the Schwann cell component, and staining for epithelial membrane antigen, Claudin-1, or glucose transporter-1 (Figure 1) will be positive in the perineural component. Other hybrid forms of benign nerve sheath tumors include neurofibroma-schwannoma and neurofibromaperineurioma.⁴ Neurofibroma-schwannomas usually have a schwannoma component containing Antoni A areas with palisading Verocay bodies. The neurofibroma cells typically have wavy elongated nuclei, fibroblasts, and mucinous myxoid material.³ Neurofibroma-perineurioma is the least common hybrid tumor. These hybrid tumors have a plexiform neurofibroma appearance with areas of perineural differentiation, which can be difficult to identify on routine histology and typically will require IHC staining to appreciate. The neurofibroma component will stain positive for S-100 and negative for markers of perineural differentiation, including epithelial membrane antigen, glucose transporter-1, and Claudin-1.³ Although schwannoma-perineuriomas are benign sporadic tumors not associated with neurofibromatosis, neurofibromaschwannomas are associated with neurofibromatosis types 1 and 2 (NF1 and NF2). Neurofibroma-perineurioma tumors usually are associated with only NF1.^3,6

Schwannomas typically present in middle-aged patients as tumors located on flexor surfaces.⁷ Although perineural cells can be seen at the periphery of a schwannoma forming a capsule, they do not interdigitate between the Schwann cells. Schwannomas are composed almost entirely of well-differentiated Schwann cells.^1,4,8 Schwannomas classically are well-circumscribed, encapsulated, biphasic lesions with alternating compact areas (Antoni A) and loosely arranged areas (Antoni B). The spindled cells occasionally may display nuclear palisading within the Antoni A areas, known as Verocay bodies (Figure 2). Antoni B areas are more disorganized and hypocellular with variable macrophage infiltrate.^1,4,8 The Schwann cells predominantly will have bland cytologic features, but scattered areas of degenerative nuclear atypia (also known as ancient change) may be present.⁴ Multiple schwannomas are associated with NF2 gene mutations and loss of merlin protein.8 There are different subtypes of schwannomas, including cellular and plexiform schwannomas.⁴ Because schwannomas are benign nerve sheath lesions, treatment typically consists of excision with careful dissection around the involved nerve.⁹

Neurofibromas are the most common peripheral nerve sheath tumors of the skin with no notable anatomic prediction, though one study found them to be more prevalent in the upper extremities.¹⁰ They typically present as sporadic solitary lesions, but multiple lesions may appear as superficial pedunculated growths that present in those aged 20 to 30 years.¹¹ Microscopically, neurofibromas typically are not well circumscribed and have an infiltrative growth pattern. Neurofibromas are composed of cytologically bland spindled Schwann cells with thin wavy nuclei in a variable myxoid stroma (Figure 3). In addition to Schwann cells, neurofibromas contain other cell components, including fibroblasts, mast cells, perineurial-like cells, and residual axons.⁴ Neurofibromas typically are located in the dermis but may extend into the subcutaneous tissue. Clinically, the overlying skin may show hyperpigmentation.8 Neurofibromas can be localized, diffuse, or plexiform, with the majority being localized. Diffuse neurofibromas clinically have a raised plaque appearance. Treatment is unnecessary because these lesions are benign.⁷

Desmoplastic melanoma (DM) is another diagnosis in the differential for this case. Patients with DM are older compared to non-DM melanoma patients, with a male predilection.¹² Desmoplastic melanomas are more likely to be located on the head and neck. In approximately one-third of cases, no in situ component will be identified, leading to confusion of the dermal lesion as a neural lesion or an area of scar formation. Microscopically, DM presents as a variable cellular infiltrative tumor composed of spindle cells with varying degrees of nuclear atypia. The spindled melanocytes are within a collagenous (desmoplastic) stroma (Figure 4).¹³ Desmoplastic melanoma has been described with a low mitotic index, leading to misdiagnosis with benign spindle cell neoplasms.¹⁴ The spindle cells should be positive for S-100 and SOX-10 with IHC staining. Unlike other melanomas, human melanoma black 45 and Melan-A often are negative or only focally positive. Treatment of DM is similar to non-DM in that wide local excision usually is employed. A systematic review evaluating sentinel lymph node biopsy (SLNB) recommended consideration of SLNB in mixed DM but not for pure DM, as rates of positive SLNB were much lower in the latter.¹⁵

Patients with malignant peripheral nerve sheath tumor (MPNST) usually present with an enlarging mass, pain, or neurologic symptoms. Most cases of MPNST are located on the trunk or extremities.¹⁶ Plexiform neurofibromas, especially in adults with NF1, have the potential to transform into an MPNST.⁴ In fact, MPNST is the most common malignancy in patients with NF1.¹⁷ Pediatric cancer survivors also are predisposed to MPNST, with a 40-fold increase in incidence compared to the general population.¹⁸ Transformation from schwannoma to MPNST is rare but has been reported.⁸ Histologically, spindle cells easily can be appreciated with a fasciculated growth pattern (Figure 5). Mitotic activity and tumor necrosis may be present. Diagnosis of these tumors historically has been challenging, though recent research has identified inactivation of polycomb repressive complex 2 in 70% to 90% of MPNSTs. Because of polycomb repressive complex 2 inactivation, there is loss of stone H3K27 trimethylation that can be capitalized on for MPNST diagnosis.¹⁹ Negative IHC staining for H3K27 trimethylation has been found to be highly specific for MPNST. Negative staining for different cytokeratin and melanoma markers can be helpful in differentiating it from carcinomas and melanoma. The only curative treatment for MPNST is complete excision, leaving patients with recurrent, refractory, and metastatic cases to be encouraged for enrollment in clinical trials. The 5-year survival rates for patients with MPNST reported in the literature range from 20% to 50%.²⁰

The Diagnosis: Hybrid Schwannoma-Perineurioma

Hybrid nerve sheath tumors are rare entities that display features of more than one nerve sheath tumor such as neurofibromas, schwannomas, and perineuriomas.¹ These tumors often are found in the dermis or subcutaneous tissue of the extremities and abdomen²; however, cases of hybrid peripheral nerve sheath tumors have been reported in many anatomical locations without a gender predilection.³ The most common type of hybrid nerve sheath tumor is a schwannoma-perineurioma.^3,4 Histologically, they are well-circumscribed lesions composed of both spindled Schwann cells with plump nuclei and spindled perineural cells with more elongated thin nuclei.⁵ Although the Schwann cell component tends to predominate, the 2 cell populations interdigitate, making it challenging to definitively distinguish them by hematoxylin and eosin staining alone.4 However, immunohistochemical (IHC) staining can be used to help distinguish the 2 separate cell populations. Staining for S-100 and SRY-box transcription factor 10 (SOX-10) will be positive in the Schwann cell component, and staining for epithelial membrane antigen, Claudin-1, or glucose transporter-1 (Figure 1) will be positive in the perineural component. Other hybrid forms of benign nerve sheath tumors include neurofibroma-schwannoma and neurofibromaperineurioma.⁴ Neurofibroma-schwannomas usually have a schwannoma component containing Antoni A areas with palisading Verocay bodies. The neurofibroma cells typically have wavy elongated nuclei, fibroblasts, and mucinous myxoid material.³ Neurofibroma-perineurioma is the least common hybrid tumor. These hybrid tumors have a plexiform neurofibroma appearance with areas of perineural differentiation, which can be difficult to identify on routine histology and typically will require IHC staining to appreciate. The neurofibroma component will stain positive for S-100 and negative for markers of perineural differentiation, including epithelial membrane antigen, glucose transporter-1, and Claudin-1.³ Although schwannoma-perineuriomas are benign sporadic tumors not associated with neurofibromatosis, neurofibromaschwannomas are associated with neurofibromatosis types 1 and 2 (NF1 and NF2). Neurofibroma-perineurioma tumors usually are associated with only NF1.^3,6

Schwannomas typically present in middle-aged patients as tumors located on flexor surfaces.⁷ Although perineural cells can be seen at the periphery of a schwannoma forming a capsule, they do not interdigitate between the Schwann cells. Schwannomas are composed almost entirely of well-differentiated Schwann cells.^1,4,8 Schwannomas classically are well-circumscribed, encapsulated, biphasic lesions with alternating compact areas (Antoni A) and loosely arranged areas (Antoni B). The spindled cells occasionally may display nuclear palisading within the Antoni A areas, known as Verocay bodies (Figure 2). Antoni B areas are more disorganized and hypocellular with variable macrophage infiltrate.^1,4,8 The Schwann cells predominantly will have bland cytologic features, but scattered areas of degenerative nuclear atypia (also known as ancient change) may be present.⁴ Multiple schwannomas are associated with NF2 gene mutations and loss of merlin protein.8 There are different subtypes of schwannomas, including cellular and plexiform schwannomas.⁴ Because schwannomas are benign nerve sheath lesions, treatment typically consists of excision with careful dissection around the involved nerve.⁹

Neurofibromas are the most common peripheral nerve sheath tumors of the skin with no notable anatomic prediction, though one study found them to be more prevalent in the upper extremities.¹⁰ They typically present as sporadic solitary lesions, but multiple lesions may appear as superficial pedunculated growths that present in those aged 20 to 30 years.¹¹ Microscopically, neurofibromas typically are not well circumscribed and have an infiltrative growth pattern. Neurofibromas are composed of cytologically bland spindled Schwann cells with thin wavy nuclei in a variable myxoid stroma (Figure 3). In addition to Schwann cells, neurofibromas contain other cell components, including fibroblasts, mast cells, perineurial-like cells, and residual axons.⁴ Neurofibromas typically are located in the dermis but may extend into the subcutaneous tissue. Clinically, the overlying skin may show hyperpigmentation.8 Neurofibromas can be localized, diffuse, or plexiform, with the majority being localized. Diffuse neurofibromas clinically have a raised plaque appearance. Treatment is unnecessary because these lesions are benign.⁷

Desmoplastic melanoma (DM) is another diagnosis in the differential for this case. Patients with DM are older compared to non-DM melanoma patients, with a male predilection.¹² Desmoplastic melanomas are more likely to be located on the head and neck. In approximately one-third of cases, no in situ component will be identified, leading to confusion of the dermal lesion as a neural lesion or an area of scar formation. Microscopically, DM presents as a variable cellular infiltrative tumor composed of spindle cells with varying degrees of nuclear atypia. The spindled melanocytes are within a collagenous (desmoplastic) stroma (Figure 4).¹³ Desmoplastic melanoma has been described with a low mitotic index, leading to misdiagnosis with benign spindle cell neoplasms.¹⁴ The spindle cells should be positive for S-100 and SOX-10 with IHC staining. Unlike other melanomas, human melanoma black 45 and Melan-A often are negative or only focally positive. Treatment of DM is similar to non-DM in that wide local excision usually is employed. A systematic review evaluating sentinel lymph node biopsy (SLNB) recommended consideration of SLNB in mixed DM but not for pure DM, as rates of positive SLNB were much lower in the latter.¹⁵

Patients with malignant peripheral nerve sheath tumor (MPNST) usually present with an enlarging mass, pain, or neurologic symptoms. Most cases of MPNST are located on the trunk or extremities.¹⁶ Plexiform neurofibromas, especially in adults with NF1, have the potential to transform into an MPNST.⁴ In fact, MPNST is the most common malignancy in patients with NF1.¹⁷ Pediatric cancer survivors also are predisposed to MPNST, with a 40-fold increase in incidence compared to the general population.¹⁸ Transformation from schwannoma to MPNST is rare but has been reported.⁸ Histologically, spindle cells easily can be appreciated with a fasciculated growth pattern (Figure 5). Mitotic activity and tumor necrosis may be present. Diagnosis of these tumors historically has been challenging, though recent research has identified inactivation of polycomb repressive complex 2 in 70% to 90% of MPNSTs. Because of polycomb repressive complex 2 inactivation, there is loss of stone H3K27 trimethylation that can be capitalized on for MPNST diagnosis.¹⁹ Negative IHC staining for H3K27 trimethylation has been found to be highly specific for MPNST. Negative staining for different cytokeratin and melanoma markers can be helpful in differentiating it from carcinomas and melanoma. The only curative treatment for MPNST is complete excision, leaving patients with recurrent, refractory, and metastatic cases to be encouraged for enrollment in clinical trials. The 5-year survival rates for patients with MPNST reported in the literature range from 20% to 50%.²⁰

New research supports the benefit of maintaining a diet low in ultraprocessed foods (UPFs) to protect the aging brain.

Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), which included more than 10,000 people aged 35 and older, showed that higher intake of UPF was significantly associated with a faster rate of decline in executive and global cognitive function.

“These findings show that lifestyle choices, particularly high intake of ultraprocessed foods, can influence our cognitive health many years later,” coinvestigator Natalia Goncalves, PhD, University of São Paulo, Brazil, said in an interview.

The study was published online in JAMA Neurology.

The study’s findings were presented in August at the Alzheimer’s Association International Conference (AAIC) 2022 and were reported by this news organization at that time.
 

High sugar, salt, fat

The new results align with another recent study linking a diet high in UPFs to an increased risk for dementia.

UPFs are highly manipulated, are packed with added ingredients, including sugar, fat, and salt, and are low in protein and fiber. Examples of UPFs are soft drinks, chips, chocolate, candy, ice cream, sweetened breakfast cereals, packaged soups, chicken nuggets, hot dogs, and fries.

The ELSA-Brasil study comprised 10,775 adults (mean age, 50.6 years at baseline; 55% women; 53% White) who were evaluated in three waves approximately 4 years apart from 2008 to 2017.

Information on diet was obtained via food frequency questionnaires and included details regarding consumption of unprocessed foods, minimally processed foods, and UPFs.

Participants were grouped according to UPF consumption quartiles (lowest to highest). Cognitive performance was evaluated by use of a standardized battery of tests.

During median follow-up of 8 years, people who consumed more than 20% of daily calories from UPFs (quartiles 2-4) experienced a 28% faster rate of decline in global cognition (beta = –0.004; 95% confidence interval [CI], –0.006 to –0.001; P = .003) and a 25% faster rate of decline in executive function (beta = –0.003, 95% CI, –0.005 to 0.000; P = .01) compared to peers in quartile 1 who consumed less than 20% of daily calories from UPFs.

The researchers did not investigate individual groups of UPFs.

However, Dr. Goncalves noted that some studies have linked the consumption of sugar-sweetened beverages with lower cognitive performance, lower brain volume, and poorer memory performance. Another group of ultraprocessed foods, processed meats, has been associated with increased all-cause dementia and Alzheimer’s disease.

Other limitations include the fact that self-reported diet habits were assessed only at baseline using a food frequency questionnaire that was not designed to assess the degree of processing.

While analyses were adjusted for several sociodemographic and clinical confounders, the researchers said they could not exclude the possibility of residual confounding.

Also, since neuroimaging is not available in the ELSA-Brasil study, they were not able to investigate potential mechanisms that could explain the association between higher UPF consumption and cognitive decline.

Despite these limitations, the researchers said their findings suggest that “limiting UPF consumption, particularly in middle-aged adults, may be an efficient form to prevent cognitive decline.”
 

Weighing the evidence

Several experts weighed in on the results in a statement from the UK nonprofit organization, Science Media Centre.

Kevin McConway, PhD, with Open University, Milton Keynes, England, said it’s important to note that the study suggests “an association, a correlation, and that doesn’t necessarily mean that the cognitive decline was caused by eating more ultra-processed foods.”

He also noted that some types of cognitive decline that are associated with aging occurred in participants in all four quartiles, which were defined by the percentage of their daily energy that came from consuming UPFs.

“That’s hardly surprising – it’s a sad fact of life that pretty well all of us gradually lose some of our cognitive functions as we go through middle and older age,” Dr. McConway said.

“The study doesn’t establish that differences in speed of cognitive decline are caused by ultra-processed food consumption anyway. That’s because it’s an observational study. If the consumption of ultra-processed food causes the differences in rate of cognitive decline, then eating less of it might slow cognitive decline, but if the cause is something else, then that won’t happen,” Dr. McConway added.

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading, England, noted that UPFs have become a “fashionable term to explain associations between diet and ill health, and many studies have attempted to show associations.

“Most studies have been observational and had a key limitation: It is very difficult to determine ultra-processed food intake using methods that are not designed to do so, and so authors need to make a lot of assumptions. Bread and meat products are often classed as ‘ultra-processed,’ even though this is often wrong,” Dr. Kuhnle noted.

“The same applies to this study – the method used to measure ultra-processed food intake was not designed for that task and relied on assumptions. This makes it virtually impossible to draw any conclusions,” Dr. Kuhnle said.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, said the study does not change how we should try to eat to maintain good brain function and cognition.

“We should try to eat less foods which are high in added sugar, salt, and fat, which would include many of the foods classified as being ultra-processed, while eating more in terms of both quantity and variety of vegetables, fruit, nuts, seeds, and pulses, which are known to be beneficial for both our cognitive and overall health,” Dr. Mellor said.

The ELSA-Brasil study was supported by the Brazilian Ministry of Health, the Ministry of Science, Technology and Innovation, and the National Council for Scientific and Technological Development. The authors as well as Dr. McConway, Dr. Mellor, and Dr. Kuhnle have disclosed no relevant financial relationships.

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

New research supports the benefit of maintaining a diet low in ultraprocessed foods (UPFs) to protect the aging brain.

Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), which included more than 10,000 people aged 35 and older, showed that higher intake of UPF was significantly associated with a faster rate of decline in executive and global cognitive function.

“These findings show that lifestyle choices, particularly high intake of ultraprocessed foods, can influence our cognitive health many years later,” coinvestigator Natalia Goncalves, PhD, University of São Paulo, Brazil, said in an interview.

The study was published online in JAMA Neurology.

The study’s findings were presented in August at the Alzheimer’s Association International Conference (AAIC) 2022 and were reported by this news organization at that time.
 

High sugar, salt, fat

The new results align with another recent study linking a diet high in UPFs to an increased risk for dementia.

UPFs are highly manipulated, are packed with added ingredients, including sugar, fat, and salt, and are low in protein and fiber. Examples of UPFs are soft drinks, chips, chocolate, candy, ice cream, sweetened breakfast cereals, packaged soups, chicken nuggets, hot dogs, and fries.

The ELSA-Brasil study comprised 10,775 adults (mean age, 50.6 years at baseline; 55% women; 53% White) who were evaluated in three waves approximately 4 years apart from 2008 to 2017.

Information on diet was obtained via food frequency questionnaires and included details regarding consumption of unprocessed foods, minimally processed foods, and UPFs.

Participants were grouped according to UPF consumption quartiles (lowest to highest). Cognitive performance was evaluated by use of a standardized battery of tests.

During median follow-up of 8 years, people who consumed more than 20% of daily calories from UPFs (quartiles 2-4) experienced a 28% faster rate of decline in global cognition (beta = –0.004; 95% confidence interval [CI], –0.006 to –0.001; P = .003) and a 25% faster rate of decline in executive function (beta = –0.003, 95% CI, –0.005 to 0.000; P = .01) compared to peers in quartile 1 who consumed less than 20% of daily calories from UPFs.

The researchers did not investigate individual groups of UPFs.

However, Dr. Goncalves noted that some studies have linked the consumption of sugar-sweetened beverages with lower cognitive performance, lower brain volume, and poorer memory performance. Another group of ultraprocessed foods, processed meats, has been associated with increased all-cause dementia and Alzheimer’s disease.

Other limitations include the fact that self-reported diet habits were assessed only at baseline using a food frequency questionnaire that was not designed to assess the degree of processing.

While analyses were adjusted for several sociodemographic and clinical confounders, the researchers said they could not exclude the possibility of residual confounding.

Also, since neuroimaging is not available in the ELSA-Brasil study, they were not able to investigate potential mechanisms that could explain the association between higher UPF consumption and cognitive decline.

Despite these limitations, the researchers said their findings suggest that “limiting UPF consumption, particularly in middle-aged adults, may be an efficient form to prevent cognitive decline.”
 

Weighing the evidence

Several experts weighed in on the results in a statement from the UK nonprofit organization, Science Media Centre.

Kevin McConway, PhD, with Open University, Milton Keynes, England, said it’s important to note that the study suggests “an association, a correlation, and that doesn’t necessarily mean that the cognitive decline was caused by eating more ultra-processed foods.”

He also noted that some types of cognitive decline that are associated with aging occurred in participants in all four quartiles, which were defined by the percentage of their daily energy that came from consuming UPFs.

“That’s hardly surprising – it’s a sad fact of life that pretty well all of us gradually lose some of our cognitive functions as we go through middle and older age,” Dr. McConway said.

“The study doesn’t establish that differences in speed of cognitive decline are caused by ultra-processed food consumption anyway. That’s because it’s an observational study. If the consumption of ultra-processed food causes the differences in rate of cognitive decline, then eating less of it might slow cognitive decline, but if the cause is something else, then that won’t happen,” Dr. McConway added.

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading, England, noted that UPFs have become a “fashionable term to explain associations between diet and ill health, and many studies have attempted to show associations.

“Most studies have been observational and had a key limitation: It is very difficult to determine ultra-processed food intake using methods that are not designed to do so, and so authors need to make a lot of assumptions. Bread and meat products are often classed as ‘ultra-processed,’ even though this is often wrong,” Dr. Kuhnle noted.

“The same applies to this study – the method used to measure ultra-processed food intake was not designed for that task and relied on assumptions. This makes it virtually impossible to draw any conclusions,” Dr. Kuhnle said.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, said the study does not change how we should try to eat to maintain good brain function and cognition.

“We should try to eat less foods which are high in added sugar, salt, and fat, which would include many of the foods classified as being ultra-processed, while eating more in terms of both quantity and variety of vegetables, fruit, nuts, seeds, and pulses, which are known to be beneficial for both our cognitive and overall health,” Dr. Mellor said.

The ELSA-Brasil study was supported by the Brazilian Ministry of Health, the Ministry of Science, Technology and Innovation, and the National Council for Scientific and Technological Development. The authors as well as Dr. McConway, Dr. Mellor, and Dr. Kuhnle have disclosed no relevant financial relationships.

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

New research supports the benefit of maintaining a diet low in ultraprocessed foods (UPFs) to protect the aging brain.

Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), which included more than 10,000 people aged 35 and older, showed that higher intake of UPF was significantly associated with a faster rate of decline in executive and global cognitive function.

“These findings show that lifestyle choices, particularly high intake of ultraprocessed foods, can influence our cognitive health many years later,” coinvestigator Natalia Goncalves, PhD, University of São Paulo, Brazil, said in an interview.

The study was published online in JAMA Neurology.

The study’s findings were presented in August at the Alzheimer’s Association International Conference (AAIC) 2022 and were reported by this news organization at that time.
 

High sugar, salt, fat

The new results align with another recent study linking a diet high in UPFs to an increased risk for dementia.

UPFs are highly manipulated, are packed with added ingredients, including sugar, fat, and salt, and are low in protein and fiber. Examples of UPFs are soft drinks, chips, chocolate, candy, ice cream, sweetened breakfast cereals, packaged soups, chicken nuggets, hot dogs, and fries.

The ELSA-Brasil study comprised 10,775 adults (mean age, 50.6 years at baseline; 55% women; 53% White) who were evaluated in three waves approximately 4 years apart from 2008 to 2017.

Information on diet was obtained via food frequency questionnaires and included details regarding consumption of unprocessed foods, minimally processed foods, and UPFs.

Participants were grouped according to UPF consumption quartiles (lowest to highest). Cognitive performance was evaluated by use of a standardized battery of tests.

During median follow-up of 8 years, people who consumed more than 20% of daily calories from UPFs (quartiles 2-4) experienced a 28% faster rate of decline in global cognition (beta = –0.004; 95% confidence interval [CI], –0.006 to –0.001; P = .003) and a 25% faster rate of decline in executive function (beta = –0.003, 95% CI, –0.005 to 0.000; P = .01) compared to peers in quartile 1 who consumed less than 20% of daily calories from UPFs.

The researchers did not investigate individual groups of UPFs.

However, Dr. Goncalves noted that some studies have linked the consumption of sugar-sweetened beverages with lower cognitive performance, lower brain volume, and poorer memory performance. Another group of ultraprocessed foods, processed meats, has been associated with increased all-cause dementia and Alzheimer’s disease.

Other limitations include the fact that self-reported diet habits were assessed only at baseline using a food frequency questionnaire that was not designed to assess the degree of processing.

While analyses were adjusted for several sociodemographic and clinical confounders, the researchers said they could not exclude the possibility of residual confounding.

Also, since neuroimaging is not available in the ELSA-Brasil study, they were not able to investigate potential mechanisms that could explain the association between higher UPF consumption and cognitive decline.

Despite these limitations, the researchers said their findings suggest that “limiting UPF consumption, particularly in middle-aged adults, may be an efficient form to prevent cognitive decline.”
 

Weighing the evidence

Several experts weighed in on the results in a statement from the UK nonprofit organization, Science Media Centre.

Kevin McConway, PhD, with Open University, Milton Keynes, England, said it’s important to note that the study suggests “an association, a correlation, and that doesn’t necessarily mean that the cognitive decline was caused by eating more ultra-processed foods.”

He also noted that some types of cognitive decline that are associated with aging occurred in participants in all four quartiles, which were defined by the percentage of their daily energy that came from consuming UPFs.

“That’s hardly surprising – it’s a sad fact of life that pretty well all of us gradually lose some of our cognitive functions as we go through middle and older age,” Dr. McConway said.

“The study doesn’t establish that differences in speed of cognitive decline are caused by ultra-processed food consumption anyway. That’s because it’s an observational study. If the consumption of ultra-processed food causes the differences in rate of cognitive decline, then eating less of it might slow cognitive decline, but if the cause is something else, then that won’t happen,” Dr. McConway added.

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading, England, noted that UPFs have become a “fashionable term to explain associations between diet and ill health, and many studies have attempted to show associations.

“Most studies have been observational and had a key limitation: It is very difficult to determine ultra-processed food intake using methods that are not designed to do so, and so authors need to make a lot of assumptions. Bread and meat products are often classed as ‘ultra-processed,’ even though this is often wrong,” Dr. Kuhnle noted.

“The same applies to this study – the method used to measure ultra-processed food intake was not designed for that task and relied on assumptions. This makes it virtually impossible to draw any conclusions,” Dr. Kuhnle said.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, said the study does not change how we should try to eat to maintain good brain function and cognition.

“We should try to eat less foods which are high in added sugar, salt, and fat, which would include many of the foods classified as being ultra-processed, while eating more in terms of both quantity and variety of vegetables, fruit, nuts, seeds, and pulses, which are known to be beneficial for both our cognitive and overall health,” Dr. Mellor said.

The ELSA-Brasil study was supported by the Brazilian Ministry of Health, the Ministry of Science, Technology and Innovation, and the National Council for Scientific and Technological Development. The authors as well as Dr. McConway, Dr. Mellor, and Dr. Kuhnle have disclosed no relevant financial relationships.

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

Heart failure associated with illicit use of the psychostimulant methamphetamine (methHF) is increasing in the United States and around the world across racial, ethnic, and socioeconomic groups, a literature review indicates.

MethHF is associated with increased severity for HF, longer inpatient stay, and more readmissions, compared with non-MethHF, the data show.

Clinicians “need to consider methamphetamine as a potential etiology for heart failure and include a substance use history when evaluating patients. Treating methamphetamine use disorder improves heart failure outcomes,” first author Veena Manja, MD, PhD, with Stanford (Calif.) University, said in an interview.

The study was published online in the journal Heart.
 

Poor outcomes, ‘staggering’ costs

This “thoughtful” review is “important and necessary,” Jonathan Davis, MD, director of the heart failure program, Zuckerberg San Francisco General Hospital, wrote in an editorial in the journal.

Dr. Davis noted that patients with Meth HF are at increased risk for poor outcomes and death and the health care costs related to MethHF are “staggering.”

As an example, inpatient data for California show annual charges related to MethHF rose by 840% from 2008 to 2018, from $41.5 million to $390.2 million, compared with 82% for all HF, which rose from $3.5 billion to $6.8 billion.

Illicit use of methamphetamine – also known as “crystal meth,” “ice,” and “speed” – has been linked to hypertension, MI, stroke, aortic dissection, and sudden death. But until now, there was no comprehensive systematic review of published studies on MethHF.

“Our goal was to compile current knowledge on the topic, increase awareness of this condition and identify areas for future research,” Dr. Manja said.

The researchers reviewed 21 observational studies, mostly from the United States (14 from California), between 1997 and 2020. The mean age of adults with MethHF ranged in age from 35 to 60 and more than half were male (57%).

Illicit methamphetamine was inhaled, injected, swallowed, smoked, and snorted. The reported frequency ranged from daily to every other week, and the total monthly dose ranged from 0.35 g to 24.5 g.

The average duration of meth use before HF diagnosis was 5 years. However, 18% of users developed HF within 1 year of starting to use illicit methamphetamine. In some cases, HF was diagnosed after a single use.

The researchers also note that MethHF with preserved left ventricular ejection fraction, seen in up to 44% of cases, is a distinct entity that may progress to reduced LVEF with continued use.

MethHF is also associated with a greater likelihood of other substance abuse, PTSD, depression, and other heart and kidney disease.

Factors associated with improved MethHF outcomes include female sex, meth abstinence, and adherence to guideline-directed HF therapy.

Improvement in MethHF outcomes is possible even if abstinence is not consistent, a finding that lends support to harm reduction principles of “meeting patients where they are instead of insisting on complete abstinence,” the researchers said.
 

Large gaps in knowledge

They were unable to combine the results into a meta-analysis because of heterogeneity in study design, population, comparator, and outcome assessment. Also, the overall risk of bias is moderate because of the presence of confounders, selection bias and poor matching, and the overall certainty in the evidence is very low,.

No study evaluated the incidence or prevalence of HF among methamphetamine users and inconsistent history taking and testing in patients with HF impeded accurate MethHF prevalence assessment.

Several studies, however, document an increasing incidence of MethHF, particularly over the past decade.

One study from California reported a 585% increase in MethHF hospital admissions between 2008 and 2018. An analysis of the National Inpatient Survey found a 12-fold increase in annual MethHF hospitalizations between 2002 and 2014.

“The results of this systematic review highlight large gaps in our knowledge” of MethHF, Dr. Manja said in an interview.

“We need to understand the epidemiology, prevalence, factors that confer susceptibility to cardiovascular outcomes, and need research into treatment targeted toward this disease,” Dr. Manja added. “We should consider options to integrate substance use treatment in HF/cardiology/primary care clinics and design a multidisciplinary patient-centered approach.”

Dr. Davis agreed. This work “highlights that the standard of care academically and clinically must be a broad team across the care spectrum to simultaneously address methamphetamine use, heart failure, and social determinants of health.”

This research had no specific funding. Dr. Manja and Dr. Davis reported no relevant disclosures.

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

Heart failure associated with illicit use of the psychostimulant methamphetamine (methHF) is increasing in the United States and around the world across racial, ethnic, and socioeconomic groups, a literature review indicates.

MethHF is associated with increased severity for HF, longer inpatient stay, and more readmissions, compared with non-MethHF, the data show.

Clinicians “need to consider methamphetamine as a potential etiology for heart failure and include a substance use history when evaluating patients. Treating methamphetamine use disorder improves heart failure outcomes,” first author Veena Manja, MD, PhD, with Stanford (Calif.) University, said in an interview.

The study was published online in the journal Heart.
 

Poor outcomes, ‘staggering’ costs

This “thoughtful” review is “important and necessary,” Jonathan Davis, MD, director of the heart failure program, Zuckerberg San Francisco General Hospital, wrote in an editorial in the journal.

Dr. Davis noted that patients with Meth HF are at increased risk for poor outcomes and death and the health care costs related to MethHF are “staggering.”

As an example, inpatient data for California show annual charges related to MethHF rose by 840% from 2008 to 2018, from $41.5 million to $390.2 million, compared with 82% for all HF, which rose from $3.5 billion to $6.8 billion.

Illicit use of methamphetamine – also known as “crystal meth,” “ice,” and “speed” – has been linked to hypertension, MI, stroke, aortic dissection, and sudden death. But until now, there was no comprehensive systematic review of published studies on MethHF.

“Our goal was to compile current knowledge on the topic, increase awareness of this condition and identify areas for future research,” Dr. Manja said.

The researchers reviewed 21 observational studies, mostly from the United States (14 from California), between 1997 and 2020. The mean age of adults with MethHF ranged in age from 35 to 60 and more than half were male (57%).

Illicit methamphetamine was inhaled, injected, swallowed, smoked, and snorted. The reported frequency ranged from daily to every other week, and the total monthly dose ranged from 0.35 g to 24.5 g.

The average duration of meth use before HF diagnosis was 5 years. However, 18% of users developed HF within 1 year of starting to use illicit methamphetamine. In some cases, HF was diagnosed after a single use.

The researchers also note that MethHF with preserved left ventricular ejection fraction, seen in up to 44% of cases, is a distinct entity that may progress to reduced LVEF with continued use.

MethHF is also associated with a greater likelihood of other substance abuse, PTSD, depression, and other heart and kidney disease.

Factors associated with improved MethHF outcomes include female sex, meth abstinence, and adherence to guideline-directed HF therapy.

Improvement in MethHF outcomes is possible even if abstinence is not consistent, a finding that lends support to harm reduction principles of “meeting patients where they are instead of insisting on complete abstinence,” the researchers said.
 

Large gaps in knowledge

They were unable to combine the results into a meta-analysis because of heterogeneity in study design, population, comparator, and outcome assessment. Also, the overall risk of bias is moderate because of the presence of confounders, selection bias and poor matching, and the overall certainty in the evidence is very low,.

No study evaluated the incidence or prevalence of HF among methamphetamine users and inconsistent history taking and testing in patients with HF impeded accurate MethHF prevalence assessment.

Several studies, however, document an increasing incidence of MethHF, particularly over the past decade.

One study from California reported a 585% increase in MethHF hospital admissions between 2008 and 2018. An analysis of the National Inpatient Survey found a 12-fold increase in annual MethHF hospitalizations between 2002 and 2014.

“The results of this systematic review highlight large gaps in our knowledge” of MethHF, Dr. Manja said in an interview.

“We need to understand the epidemiology, prevalence, factors that confer susceptibility to cardiovascular outcomes, and need research into treatment targeted toward this disease,” Dr. Manja added. “We should consider options to integrate substance use treatment in HF/cardiology/primary care clinics and design a multidisciplinary patient-centered approach.”

Dr. Davis agreed. This work “highlights that the standard of care academically and clinically must be a broad team across the care spectrum to simultaneously address methamphetamine use, heart failure, and social determinants of health.”

This research had no specific funding. Dr. Manja and Dr. Davis reported no relevant disclosures.

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

Heart failure associated with illicit use of the psychostimulant methamphetamine (methHF) is increasing in the United States and around the world across racial, ethnic, and socioeconomic groups, a literature review indicates.

MethHF is associated with increased severity for HF, longer inpatient stay, and more readmissions, compared with non-MethHF, the data show.

Clinicians “need to consider methamphetamine as a potential etiology for heart failure and include a substance use history when evaluating patients. Treating methamphetamine use disorder improves heart failure outcomes,” first author Veena Manja, MD, PhD, with Stanford (Calif.) University, said in an interview.

The study was published online in the journal Heart.
 

Poor outcomes, ‘staggering’ costs

This “thoughtful” review is “important and necessary,” Jonathan Davis, MD, director of the heart failure program, Zuckerberg San Francisco General Hospital, wrote in an editorial in the journal.

Dr. Davis noted that patients with Meth HF are at increased risk for poor outcomes and death and the health care costs related to MethHF are “staggering.”

As an example, inpatient data for California show annual charges related to MethHF rose by 840% from 2008 to 2018, from $41.5 million to $390.2 million, compared with 82% for all HF, which rose from $3.5 billion to $6.8 billion.

Illicit use of methamphetamine – also known as “crystal meth,” “ice,” and “speed” – has been linked to hypertension, MI, stroke, aortic dissection, and sudden death. But until now, there was no comprehensive systematic review of published studies on MethHF.

“Our goal was to compile current knowledge on the topic, increase awareness of this condition and identify areas for future research,” Dr. Manja said.

The researchers reviewed 21 observational studies, mostly from the United States (14 from California), between 1997 and 2020. The mean age of adults with MethHF ranged in age from 35 to 60 and more than half were male (57%).

Illicit methamphetamine was inhaled, injected, swallowed, smoked, and snorted. The reported frequency ranged from daily to every other week, and the total monthly dose ranged from 0.35 g to 24.5 g.

The average duration of meth use before HF diagnosis was 5 years. However, 18% of users developed HF within 1 year of starting to use illicit methamphetamine. In some cases, HF was diagnosed after a single use.

The researchers also note that MethHF with preserved left ventricular ejection fraction, seen in up to 44% of cases, is a distinct entity that may progress to reduced LVEF with continued use.

MethHF is also associated with a greater likelihood of other substance abuse, PTSD, depression, and other heart and kidney disease.

Factors associated with improved MethHF outcomes include female sex, meth abstinence, and adherence to guideline-directed HF therapy.

Improvement in MethHF outcomes is possible even if abstinence is not consistent, a finding that lends support to harm reduction principles of “meeting patients where they are instead of insisting on complete abstinence,” the researchers said.
 

Large gaps in knowledge

They were unable to combine the results into a meta-analysis because of heterogeneity in study design, population, comparator, and outcome assessment. Also, the overall risk of bias is moderate because of the presence of confounders, selection bias and poor matching, and the overall certainty in the evidence is very low,.

No study evaluated the incidence or prevalence of HF among methamphetamine users and inconsistent history taking and testing in patients with HF impeded accurate MethHF prevalence assessment.

Several studies, however, document an increasing incidence of MethHF, particularly over the past decade.

One study from California reported a 585% increase in MethHF hospital admissions between 2008 and 2018. An analysis of the National Inpatient Survey found a 12-fold increase in annual MethHF hospitalizations between 2002 and 2014.

“The results of this systematic review highlight large gaps in our knowledge” of MethHF, Dr. Manja said in an interview.

“We need to understand the epidemiology, prevalence, factors that confer susceptibility to cardiovascular outcomes, and need research into treatment targeted toward this disease,” Dr. Manja added. “We should consider options to integrate substance use treatment in HF/cardiology/primary care clinics and design a multidisciplinary patient-centered approach.”

Dr. Davis agreed. This work “highlights that the standard of care academically and clinically must be a broad team across the care spectrum to simultaneously address methamphetamine use, heart failure, and social determinants of health.”

This research had no specific funding. Dr. Manja and Dr. Davis reported no relevant disclosures.

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

A new type of wound dressing might change burn care for the better with one amazing property: dissolvability. Surgically debriding burn wounds can be tedious for doctors and excruciating for patients. To change that, bioengineers have created a new hydrogel formula that dissolves rapidly from wound sites, melting off in 6 minutes or less.

“The removal of dressings, with the current standard of care, is very hard and time-consuming. It becomes very painful for the patient. People are screaming, or they’re given a lot of opioids,” said senior author O. Berk Usta, PhD, of the Center for Engineering in Medicine and Surgery at Massachusetts General Hospital, Boston. “Those are the things we wanted to minimize: the pain and the time.”

Although beneficial for all patients, a short, painless bandage change would be a particular boon for younger patients. At the pediatric burns care center at Shriners Hospitals for Children (an MGH partner), researchers “observe a lot of children who go through therapy or treatment after burns,” said Dr. Usta. The team at MGH collaborated with scientists at Tufts University, Boston, with those patients in mind, setting out to create a new hydrogel that would transform burn wound care.
 

A better bandage

Hydrogels provide cooling relief to burn wounds and maintain a moist environment that can speed healing. There are currently hydrogel sheets and hydrogel-infused dressings, as well as gel that is applied directly to burn wounds before being covered with protective material. These dressings must be replaced frequently to prevent infections, but that can be unbearably painful and drawn out, as dressings often stick to wounds.

Mechanical debridement can be especially difficult for second-degree burn patients, whose wounds may still retain nerve endings. Debridement tends to also remove some healthy tissue and can damage newly formed tissue, slowing down healing.

“It can take up to 2, 3 hours, and it requires multiple people working on it,” said Dr. Usta.

The new hydrogel treatment can be applied directly to a wound and it forms a protective barrier around the site in 15 seconds. The hydrogel is then covered by a protective dressing until it needs to be changed.

“After you take off the protective covering, you add another solution, which dissolves the [hydrogel] dressing, so that it can be easily removed from the burn site,” Dr. Usta said.

The solution dissolves the hydrogel in 4-6 minutes.
 

Hybrid gels

Many hydrogels currently used for burn wounds feature physically cross-linked molecules. This makes them strong and capable of retaining moisture, but also difficult to dissolve. The researchers used a different approach.

“This is not physical cross-linking like the traditional approaches, but rather, softer covalent bonds between the different molecules. And that’s why, when you bring in another solution, the hydrogel dissolves away,” Dr. Usta said.

The new hydrogels rely on a supramolecular assembly: a network of synthetic polymers whose connections can be reversed more easily, meaning they can be dissolved quickly. Another standout feature of the new hydrogels is their hybrid composition, displaying characteristics of both liquids and solids. The polymers are knitted together into a mesh-like network that enables water retention, with the goal of maintaining the moist environment needed for wound healing.

The supramolecular assembly is also greener, Dr. Usta explained; traditional cross-linking approaches produce a lot of toxic by-products that could harm the environment.

And whereas traditional hydrogels can require a dozen chemistry steps to produce, the new hydrogels are ready after mixing two solutions, Dr. Usta explained. This makes them easy to prepare at bedside, ideal for treating large wounds in the ER or even on battlefields.

When tested in vitro, using skin cells, and in vivo, on mice, the new hydrogels were shown to be safe to use on wounds. Additional studies on mice, as well as large animals, will focus on safety and efficacy, and may be followed by human clinical trials, said Dr. Usta.

“The next phase of the project will be to look at whether these dressings will help wound healing by creating a moist environment,” said Dr. Usta.

The researchers are also exploring how to manufacture individual prewrapped hydrogels that could be applied in a clinical setting – or even in people’s homes. The consumer market is “another possibility,” said Dr. Usta, particularly among patients with “smaller, more superficial burns” or patients whose large burn wounds are still healing once they leave the hospital.

This research was supported by the National Institutes of Health, National Science Foundation, Massachusetts General Hospital Executive Committee on Research Interim Support Fund, and Shriners Hospitals.

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

A new type of wound dressing might change burn care for the better with one amazing property: dissolvability. Surgically debriding burn wounds can be tedious for doctors and excruciating for patients. To change that, bioengineers have created a new hydrogel formula that dissolves rapidly from wound sites, melting off in 6 minutes or less.

“The removal of dressings, with the current standard of care, is very hard and time-consuming. It becomes very painful for the patient. People are screaming, or they’re given a lot of opioids,” said senior author O. Berk Usta, PhD, of the Center for Engineering in Medicine and Surgery at Massachusetts General Hospital, Boston. “Those are the things we wanted to minimize: the pain and the time.”

Although beneficial for all patients, a short, painless bandage change would be a particular boon for younger patients. At the pediatric burns care center at Shriners Hospitals for Children (an MGH partner), researchers “observe a lot of children who go through therapy or treatment after burns,” said Dr. Usta. The team at MGH collaborated with scientists at Tufts University, Boston, with those patients in mind, setting out to create a new hydrogel that would transform burn wound care.
 

A better bandage

Hydrogels provide cooling relief to burn wounds and maintain a moist environment that can speed healing. There are currently hydrogel sheets and hydrogel-infused dressings, as well as gel that is applied directly to burn wounds before being covered with protective material. These dressings must be replaced frequently to prevent infections, but that can be unbearably painful and drawn out, as dressings often stick to wounds.

Mechanical debridement can be especially difficult for second-degree burn patients, whose wounds may still retain nerve endings. Debridement tends to also remove some healthy tissue and can damage newly formed tissue, slowing down healing.

“It can take up to 2, 3 hours, and it requires multiple people working on it,” said Dr. Usta.

The new hydrogel treatment can be applied directly to a wound and it forms a protective barrier around the site in 15 seconds. The hydrogel is then covered by a protective dressing until it needs to be changed.

“After you take off the protective covering, you add another solution, which dissolves the [hydrogel] dressing, so that it can be easily removed from the burn site,” Dr. Usta said.

The solution dissolves the hydrogel in 4-6 minutes.
 

Hybrid gels

Many hydrogels currently used for burn wounds feature physically cross-linked molecules. This makes them strong and capable of retaining moisture, but also difficult to dissolve. The researchers used a different approach.

“This is not physical cross-linking like the traditional approaches, but rather, softer covalent bonds between the different molecules. And that’s why, when you bring in another solution, the hydrogel dissolves away,” Dr. Usta said.

The new hydrogels rely on a supramolecular assembly: a network of synthetic polymers whose connections can be reversed more easily, meaning they can be dissolved quickly. Another standout feature of the new hydrogels is their hybrid composition, displaying characteristics of both liquids and solids. The polymers are knitted together into a mesh-like network that enables water retention, with the goal of maintaining the moist environment needed for wound healing.

The supramolecular assembly is also greener, Dr. Usta explained; traditional cross-linking approaches produce a lot of toxic by-products that could harm the environment.

And whereas traditional hydrogels can require a dozen chemistry steps to produce, the new hydrogels are ready after mixing two solutions, Dr. Usta explained. This makes them easy to prepare at bedside, ideal for treating large wounds in the ER or even on battlefields.

When tested in vitro, using skin cells, and in vivo, on mice, the new hydrogels were shown to be safe to use on wounds. Additional studies on mice, as well as large animals, will focus on safety and efficacy, and may be followed by human clinical trials, said Dr. Usta.

“The next phase of the project will be to look at whether these dressings will help wound healing by creating a moist environment,” said Dr. Usta.

The researchers are also exploring how to manufacture individual prewrapped hydrogels that could be applied in a clinical setting – or even in people’s homes. The consumer market is “another possibility,” said Dr. Usta, particularly among patients with “smaller, more superficial burns” or patients whose large burn wounds are still healing once they leave the hospital.

This research was supported by the National Institutes of Health, National Science Foundation, Massachusetts General Hospital Executive Committee on Research Interim Support Fund, and Shriners Hospitals.

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

A new type of wound dressing might change burn care for the better with one amazing property: dissolvability. Surgically debriding burn wounds can be tedious for doctors and excruciating for patients. To change that, bioengineers have created a new hydrogel formula that dissolves rapidly from wound sites, melting off in 6 minutes or less.

“The removal of dressings, with the current standard of care, is very hard and time-consuming. It becomes very painful for the patient. People are screaming, or they’re given a lot of opioids,” said senior author O. Berk Usta, PhD, of the Center for Engineering in Medicine and Surgery at Massachusetts General Hospital, Boston. “Those are the things we wanted to minimize: the pain and the time.”

Although beneficial for all patients, a short, painless bandage change would be a particular boon for younger patients. At the pediatric burns care center at Shriners Hospitals for Children (an MGH partner), researchers “observe a lot of children who go through therapy or treatment after burns,” said Dr. Usta. The team at MGH collaborated with scientists at Tufts University, Boston, with those patients in mind, setting out to create a new hydrogel that would transform burn wound care.
 

A better bandage

Hydrogels provide cooling relief to burn wounds and maintain a moist environment that can speed healing. There are currently hydrogel sheets and hydrogel-infused dressings, as well as gel that is applied directly to burn wounds before being covered with protective material. These dressings must be replaced frequently to prevent infections, but that can be unbearably painful and drawn out, as dressings often stick to wounds.

Mechanical debridement can be especially difficult for second-degree burn patients, whose wounds may still retain nerve endings. Debridement tends to also remove some healthy tissue and can damage newly formed tissue, slowing down healing.

“It can take up to 2, 3 hours, and it requires multiple people working on it,” said Dr. Usta.

The new hydrogel treatment can be applied directly to a wound and it forms a protective barrier around the site in 15 seconds. The hydrogel is then covered by a protective dressing until it needs to be changed.

“After you take off the protective covering, you add another solution, which dissolves the [hydrogel] dressing, so that it can be easily removed from the burn site,” Dr. Usta said.

The solution dissolves the hydrogel in 4-6 minutes.
 

Hybrid gels

Many hydrogels currently used for burn wounds feature physically cross-linked molecules. This makes them strong and capable of retaining moisture, but also difficult to dissolve. The researchers used a different approach.

“This is not physical cross-linking like the traditional approaches, but rather, softer covalent bonds between the different molecules. And that’s why, when you bring in another solution, the hydrogel dissolves away,” Dr. Usta said.

The new hydrogels rely on a supramolecular assembly: a network of synthetic polymers whose connections can be reversed more easily, meaning they can be dissolved quickly. Another standout feature of the new hydrogels is their hybrid composition, displaying characteristics of both liquids and solids. The polymers are knitted together into a mesh-like network that enables water retention, with the goal of maintaining the moist environment needed for wound healing.

The supramolecular assembly is also greener, Dr. Usta explained; traditional cross-linking approaches produce a lot of toxic by-products that could harm the environment.

And whereas traditional hydrogels can require a dozen chemistry steps to produce, the new hydrogels are ready after mixing two solutions, Dr. Usta explained. This makes them easy to prepare at bedside, ideal for treating large wounds in the ER or even on battlefields.

When tested in vitro, using skin cells, and in vivo, on mice, the new hydrogels were shown to be safe to use on wounds. Additional studies on mice, as well as large animals, will focus on safety and efficacy, and may be followed by human clinical trials, said Dr. Usta.

“The next phase of the project will be to look at whether these dressings will help wound healing by creating a moist environment,” said Dr. Usta.

The researchers are also exploring how to manufacture individual prewrapped hydrogels that could be applied in a clinical setting – or even in people’s homes. The consumer market is “another possibility,” said Dr. Usta, particularly among patients with “smaller, more superficial burns” or patients whose large burn wounds are still healing once they leave the hospital.

This research was supported by the National Institutes of Health, National Science Foundation, Massachusetts General Hospital Executive Committee on Research Interim Support Fund, and Shriners Hospitals.

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

Dr Anca Askanase, director of the Lupus Center at Columbia University Medical Center, highlights the latest research on systemic lupus erythematosus (SLE) and lupus nephritis from the American College of Rheumatology (ACR) 2022.  

Dr Askanase first discusses a small study using autologous chimeric antigen receptor T-cell (CAR-T) therapy, which is approved for use in several blood cancers, as an alternative for patients with refractory SLE. Five patients received CAR-T cells, and all achieved sustained, drug-free remission. 

Next, Dr Askanase highlights a phase 2B study evaluating the tyrosine kinase 2 inhibitor deucravacitinib in patients with SLE. In early results, patients taking deucravacitinib showed a statistically meaningful response in disease activity compared with placebo.   

She then summarizes her presentation on oral cenerimod. The phase 2, 12-week study demonstrated that cenerimod reduced total lymphocyte count compared with placebo in SLE patients.  

Next, Dr Askanase details the long-term extension of the TULIP trials. Researchers found that anifrolumab has a favorable benefit-risk profile when compared with placebo and is therefore a possible long-term treatment option for patients with moderate to severe SLE.   

Finally, Dr Askanase discusses the positive findings from the phase 3 AURORA 1 and AURORA 2 studies, which sought to determine whether the addition of voclosporin to mycophenolate mofetil and low-dose steroids could maintain the reduction in proteinuria in patients with lupus nephritis. 

--

Anca Askanase, MD, MPH, Professor of Medicine, Director, Lupus Center, Department of Rheumatology, Columbia University Medical Center, New York, New York 

Anca Askanase, MD, MPH, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; Bristol Myers Squibb; Celgene; Eli Lilly; GSK; Idorsia; Janssen; Pfizer 

Received income in an amount equal to or greater than $250 from: AstraZeneca; Bristol Myers Squibb; Celgene; Eli Lilly; GSK; Idorsia; Janssen; Pfizer 

Dr Anca Askanase, director of the Lupus Center at Columbia University Medical Center, highlights the latest research on systemic lupus erythematosus (SLE) and lupus nephritis from the American College of Rheumatology (ACR) 2022.  

Dr Askanase first discusses a small study using autologous chimeric antigen receptor T-cell (CAR-T) therapy, which is approved for use in several blood cancers, as an alternative for patients with refractory SLE. Five patients received CAR-T cells, and all achieved sustained, drug-free remission. 

Next, Dr Askanase highlights a phase 2B study evaluating the tyrosine kinase 2 inhibitor deucravacitinib in patients with SLE. In early results, patients taking deucravacitinib showed a statistically meaningful response in disease activity compared with placebo.   

She then summarizes her presentation on oral cenerimod. The phase 2, 12-week study demonstrated that cenerimod reduced total lymphocyte count compared with placebo in SLE patients.  

Next, Dr Askanase details the long-term extension of the TULIP trials. Researchers found that anifrolumab has a favorable benefit-risk profile when compared with placebo and is therefore a possible long-term treatment option for patients with moderate to severe SLE.   

Finally, Dr Askanase discusses the positive findings from the phase 3 AURORA 1 and AURORA 2 studies, which sought to determine whether the addition of voclosporin to mycophenolate mofetil and low-dose steroids could maintain the reduction in proteinuria in patients with lupus nephritis. 

--

Anca Askanase, MD, MPH, Professor of Medicine, Director, Lupus Center, Department of Rheumatology, Columbia University Medical Center, New York, New York 

Anca Askanase, MD, MPH, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; Bristol Myers Squibb; Celgene; Eli Lilly; GSK; Idorsia; Janssen; Pfizer 

Received income in an amount equal to or greater than $250 from: AstraZeneca; Bristol Myers Squibb; Celgene; Eli Lilly; GSK; Idorsia; Janssen; Pfizer 

Dr Anca Askanase, director of the Lupus Center at Columbia University Medical Center, highlights the latest research on systemic lupus erythematosus (SLE) and lupus nephritis from the American College of Rheumatology (ACR) 2022.  

Dr Askanase first discusses a small study using autologous chimeric antigen receptor T-cell (CAR-T) therapy, which is approved for use in several blood cancers, as an alternative for patients with refractory SLE. Five patients received CAR-T cells, and all achieved sustained, drug-free remission. 

Next, Dr Askanase highlights a phase 2B study evaluating the tyrosine kinase 2 inhibitor deucravacitinib in patients with SLE. In early results, patients taking deucravacitinib showed a statistically meaningful response in disease activity compared with placebo.   

She then summarizes her presentation on oral cenerimod. The phase 2, 12-week study demonstrated that cenerimod reduced total lymphocyte count compared with placebo in SLE patients.  

Next, Dr Askanase details the long-term extension of the TULIP trials. Researchers found that anifrolumab has a favorable benefit-risk profile when compared with placebo and is therefore a possible long-term treatment option for patients with moderate to severe SLE.   

Finally, Dr Askanase discusses the positive findings from the phase 3 AURORA 1 and AURORA 2 studies, which sought to determine whether the addition of voclosporin to mycophenolate mofetil and low-dose steroids could maintain the reduction in proteinuria in patients with lupus nephritis. 

--

Anca Askanase, MD, MPH, Professor of Medicine, Director, Lupus Center, Department of Rheumatology, Columbia University Medical Center, New York, New York 

Anca Askanase, MD, MPH, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; Bristol Myers Squibb; Celgene; Eli Lilly; GSK; Idorsia; Janssen; Pfizer 

Received income in an amount equal to or greater than $250 from: AstraZeneca; Bristol Myers Squibb; Celgene; Eli Lilly; GSK; Idorsia; Janssen; Pfizer 

The atopic dermatitis (AD) therapeutic landscape is changing considerably with the advent of Janus kinase (JAK) inhibitors. Several JAK inhibitors recently have been approved by the US Food and Drug Administration, building off years of foundational research aimed at elucidating the downstream effects of the JAK–signal transducer and activator of transcription (STAT) pathway and its role in AD pathogenesis. Agents within this promising new class of drugs have performed well vs placebo in phase 2 and 3 clinical trials. This article reviews relevant trial efficacy and safety data of several JAK inhibitors as well as the implications of the use of these medications in AD patients, with specific considerations unique to active-duty military personnel.

Background on JAK Inhibitors

The hematopoietin superfamily of cytokine receptors encompasses a broad group that includes receptors for immune (eg, IL-2, IL-4, IFN-γ), hematopoietic (eg, erythropoietin, thrombopoietin, granulocyte-macrophage colony-stimulating factor), and nonimmune (eg, prolactin, leptin, growth hormone) cytokines. These cytokines signal via the JAK-STAT pathway. The hematopoietin family of cytokine receptors lacks intrinsic enzymatic activity, and as a result, they rely on JAK enzymes to transmit their signals intracellularly after cytokine binding to the receptor.¹ Janus, of Roman mythology, was the god of doorways and archways and was commonly depicted with 2 heads. Janus kinases were named for their 2 “faces,” the kinase domain with its adjacent regulatory kinaselike domains.² The binding of a cytokine to its receptor triggers engagement of the receptor by JAKs, leading to phosphorylation of both the JAKs and the receptor. Subsequent recruitment and phosphorylation of STAT proteins occurs. Following STAT phosphorylation, the STAT proteins dissociate, dimerize, and translocate to the nucleus, where they enact changes in cell behavior through transcriptional effects.¹

Humans possess only 4 JAKs. Janus kinase 1, JAK2, and tyrosine kinase 2 are widely expressed, whereas JAK3 expression is largely limited to immune cells. Thus, there is notable overlap in the use of the 4 JAKs among the relatively larger number of various cytokines that utilize them to propagate intracellular signaling.¹ Janus kinase 1 is important for signaling of receptors activated by a variety of interleukins, as well as IFN-α, IFN-β, and IFN-γ. Janus kinase 2 is important for signaling for the hormonelike cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5. Janus kinase 3 is important for hematopoietic cell proliferation and function.¹

JAK Inhibitors and Atopic Dermatitis

Topical treatments, including corticosteroids and calcineurin inhibitors, are considered the standard-of-care therapy for most patients with AD; however, their clinical benefit often is limited by their anatomic use restrictions and local adverse events, including skin atrophy, striae, and application-site reactions such as stinging and burning.³ As a result, long-term application of these drugs, particularly in sensitive areas, is not recommended owing to safety/tolerability issues.³ Systemic immunomodulatory medications are indicated for patients with AD who do not achieve adequate disease control with topical treatments and/or phototherapy or for patients with severely impaired quality of life.⁴

Janus kinase inhibitors have several key benefits over biologics: oral and topical bioavailability, predictable pharmacokinetics, nonimmunogenicity, and dosing flexibility.⁴ Janus kinase 1 is central to the cell signaling of many cytokines involved in the pathogenesis of AD that comprise the T-helper lymphocytes type 2 axis: IL-4, IL-13, and thymic stromal lymphopoietin. Janus kinase signaling also may mediate itch responses by acting directly on sensory nerve fibers. Consequently, the substantial reduction in pruritus seen in many studies of JAK inhibitors is thought to be in part due to the effects on sensory nerve fibers in the skin and the blockade of early itch signaling in response to IL-4, IL-13, and IL-31.⁵

Abrocitinib is a JAK1 inhibitor with a similar side effect profile to upadacitinib. Both agents were approved by the FDA for the treatment of refractory moderate to severe AD on January 14, 2022.⁶ These are second-generation (also referred to as selective) oral JAK inhibitors with much greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2, thereby reducing the risk for hematopoietic effects associated with JAK2 inhibition. The approval of abrocitinib stemmed from the phase 3 clinical trial JAK1 Atopic Dermatitis Efficacy and Safety (JADE)-MONO-1 (N=387),⁷ its replicate trial JADE-MONO-2 (N=391),⁸ and the JADE COMPARE trial.⁹ The JADE-MONO trials were multicenter, double-blind, placebo-controlled studies that enrolled patients 12 years and older with moderate to severe AD.^7,8 Treatment groups consisted of 100-mg and 200-mg doses and were evaluated with the placebo group for their ability to achieve an investigator global assessment (IGA) score of 0 or 1 and eczema area and severity index 75 (EASI-75) at 12 weeks.^7,8 Sixty-three percent of patients in the 200-mg group, 40% in the 100-mg group, and 12% in the placebo group reached the EASI-75 end point, and the differences in these response rates were statistically significant vs placebo (100 mg: 27.9% [95% CI, 17.4-38.3], P<.0001; 200 mg: 51.0% [95% CI, 40.5-61.5], P<.0001). Notably, 44% of patients using the 200-mg dose achieved almost complete or complete resolution of AD (IGA responders, improvement of ≥2 and IGA score of 0 or 1 at 12 weeks).⁷ In JADE-MONO-2, EASI-75 also was achieved significantly more frequently in the treatment groups compared with the placebo group at 12 weeks (200 mg: 61.0%; 100 mg: 44.5%; placebo: 10.4%; P<.001 vs placebo).⁸ Adjunctive therapy with topical corticosteroids was prohibited in both studies. A dose-dependent decrease in platelets was seen in both trials, as in the phase 2 trial that preceded them.¹⁰

The primary end point of the JADE COMPARE trial was to evaluate the efficacy of abrocitinib as compared with placebo at 12 weeks in adult patients with moderate to severe AD and in the setting of concomitant topical corticosteroid therapy.⁹ One of several secondary end points of this study compared the ability of dupilumab vs abrocitinib and placebo treatment groups to achieve itch reduction at 2 weeks, defined as 4-point improvement or more from baseline in the score on the Peak Pruritus Numerical Rating Scale (NRS), a well‐defined, reliable, sensitive, and valid scale for evaluating worst itch intensity in adults with moderate to severe AD.^9,11 The primary end point was the same as in the other phase 3 studies and was met in the JADE COMPARE trial by all treatment arms. An EASI-75 was seen in 70.3% of patients treated with 200 mg of abrocitinib, 58.7% in the 100-mg abrocitinib group, 58.1% in the dupilumab group, and 27.1% in the placebo group (P<.001 for both abrocitinib doses vs placebo). Only the 200-mg dose of abrocitinib demonstrated superior itch response at week 2 compared with dupilumab (22.1% response rate difference [95% CI, 13.5-30.7; P<.001]). Both abrocitinib groups failed to demonstrate significant differences compared with dupilumab with respect to other secondary end points to include IGA response and EASI-75 at week 16.⁹

The most frequently reported treatment-associated adverse events were nausea, nasopharyngitis, upper respiratory tract infection, and headache, and the percentages were similar among trial groups.⁹ Acne was more frequently reported in the abrocitinib groups compared with placebo and the dupilumab group, and conjunctivitis was more frequently reported in the dupilumab group. Herpesvirus cutaneous infections were rare in the abrocitinib groups, as were other serious infections. No deaths, major adverse cardiovascular events (MACEs), or venous thromboembolic events (VTEs) occurred during the trial. Dose-dependent increases in creatinine phosphokinase were seen in the abrocitinib groups, whereas dose-dependent decreases were seen in platelet counts, with no patient demonstrating a platelet count below 75,000/mm³ during the study.⁹ Low-density lipoprotein cholesterol levels and high-density lipoprotein cholesterol levels increased in a dose-dependent manner as well, but the ratios of low-density lipoprotein to high-density lipoprotein were unchanged.⁹ The results of a phase 3, 92-week extension study, JADE EXTEND, were recently published and demonstrated a role for abrocitinib as a treatment for patients with moderate to severe AD, regardless of prior dupilumab response status.¹²

Upadacitinib, another selective JAK1 inhibitor, was approved following data from 2 replicate double-blind, phase 3, randomized, controlled trials—Measure Up 1 and Measure Up 2.¹³ Results demonstrated that monotherapy with once-daily upadacitinib 15 mg or 30 mg is an effective and well-tolerated treatment option for patients with moderate to severe AD vs placebo. All coprimary end points at week 16 were achieved in the upadacitinib groups in both trials. Acne, upper respiratory tract infections, nasopharyngitis, headache, and increase in serum creatinine phosphokinase levels were the most frequently reported adverse events. Rates of herpes zoster infection in upadacitinib groups were low.¹³

In the subsequent phase 3 AD Up trial, researchers evaluated the safety and efficacy of combination therapy with topical corticosteroids in patients aged 12 to 75 years.¹⁴ Upadacitinib groups again achieved the identical coprimary end points that were present in the Measure Up trials¹³ as well as all key secondary end points.¹⁴ Additionally, significant differences in secondary end points, such as a 4-point improvement in the Worst Pruritus NRS vs placebo, were noticed in both upadacitinib treatment groups as early as 1 week into the study (P<.0001), with maintenance of the effect through to week 16 (P<.0001).¹⁴ AD Up was followed by the Heads Up trial, a 24-week, phase 3, multicenter, double-blind, randomized, controlled trial comparing safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate to severe AD.¹⁵ At week 16, a higher percentage of patients in the upadacitinib group achieved EASI-75 vs the dupilumab group (71.0% vs 61.1%, respectively; P=.006). The difference noted at week 2 was even more impressive, with 43.7% of patients in the upadacitinib treatment group achieving EASI-75 compared with 17.4% in the dupilumab group (P<.001). No new safety-related events were registered compared with the already available data for both drugs.¹⁵

Ruxolitinib (RUX) is a topical JAK1 and JAK2 inhibitor that was FDA approved in September 2021 for the treatment of AD.¹⁶ In a phase 2 clinical trial of 307 adult patients with 3% to 20% body surface area (BSA) affected with AD, significant reductions in itch NRS scores were observed within 36 hours after the first application of RUX cream 1.5% twice daily (-1.8 vs -0.2, P<.0001).¹⁷ These decreases were noted within the first 2 weeks of treatment for all the RUX cream regimens and were sustained through to week 8, the end of the double-blind period. At 4 weeks, change in itch from baseline was significantly reduced in the RUX 1.5% twice-daily group compared with the triamcinolone ointment 0.1% group (−4 vs −2.5, P=.003). During the open-label treatment period from 8 to 12 weeks, all patients who switched to RUX cream 1.5% twice daily noted further reductions in itch, and those who continued it demonstrated additional improvement.¹⁷

The recent FDA approval was further backed by positive phase 3 trial data from the TRuE-AD1 and TRuE-AD2 studies.¹⁸ Patients in these trials were aged 12 years and older and had AD for 2 or more years with an IGA score of 2 or 3 and 3% to 20% affected BSA. Patients were randomized to twice-daily RUX cream 0.75%, RUX cream 1.5%, or vehicle cream, and the primary end point was an IGA score of 0 or 1 and an improvement of 2 or more points from baseline at week 8. Significantly more patients achieved IGA treatment success with RUX cream 0.75% (TRuE-AD1, 50.0%; TRuE-AD2, 39.0%) and RUX cream 1.5% (TRuE-AD1, 53.8%; TRuE-AD2, 51.3%) vs vehicle (TRuE-AD1, 15.1%; TRuE-AD2, 7.6%; P<.0001) at week 8. The RUX groups experienced dramatically reduced itch compared with vehicle, with a mean reduction of approximately 3 points on the NRS at 8 weeks. Additionally, statistically significant itch reductions vs vehicle were reported within 12 hours of first application of RUX cream 1.5% (P<.05). Application-site reactions including stinging and burning occurred in less than 1% of patients, and none were considered clinically significant. Mean plasma concentrations of RUX were monitored during the phase 2 and 3 AD studies and did not lead to any clinically meaningful changes in hematologic parameters. The low bioavailability following topical application of RUX cream (6% in the TRuE-AD studies) allows for a targeted delivery of the active drug to lesional skin while reducing the safety issues associated with oral administration of JAK inhibitors.¹⁸

Baricitinib is a predominantly JAK1 and JAK2 inhibitor that was the first JAK inhibitor to be approved for the treatment of moderate to severe AD in the European Union and Japan.¹⁹ Although the FDA’s decision on baricitinib has lagged behind market competitors, in 2 phase 3 clinical trials, BREEZE-AD1 and BREEZE-AD2, baricitinib demonstrated benefit over placebo on clinically important measures of disease severity. The primary end point—the proportion of patients achieving an IGA score of 0 or 1 with an improvement of 2 or more points from baseline at week 16—was met by both tested doses of baricitinib (2 mg and 4 mg) vs placebo in BREEZE-AD1 (2 mg, P≤.05; 4 mg, P≤.001) and BREEZE-AD2 (2 mg, P≤.05; 4 mg, P≤.001). In addition, baricitinib 4 mg consistently demonstrated significant benefit over placebo on other clinically important measures of disease severity at week 16 to include itch (BREEZE-AD1 and BREEZE-AD2, P≤.001), sleep disturbance (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001), and skin pain (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001). Nasopharyngitis, upper respiratory tract infections, creatine phosphokinase elevations, and headaches were the most frequently reported adverse events. During the 16-week treatment period in these trials, no deaths, MACEs, or VTEs occurred.¹⁹ Similar results were seen in a long-term extension study, BREEZE-AD3.²⁰ The combination of baricitinib and topical corticosteroids were evaluated in 2 additional phase 3 trials, BREEZE-AD4²¹ and BREEZE-AD7.²² Although only baricitinib 4 mg met the primary end point of EASI-75 at week 16 in both trials, both dosing regimens plus topical corticosteroids demonstrated notable reduction in multiple clinical and quality-of-life indices prior to week 2 when compared with placebo plus topical corticosteroids.^22,23

AD in Military Service Members

Atopic dermatitis is a common condition in the general population, with a prevalence of 7.3% (95% CI, 5.9-8.8) in a recent study of American adults.²⁴ Historically, the burden of AD that would be expected among active-duty military service members given the prevalence among the general population has not been observed, in part because of the disqualifying nature of AD for enlistment.²⁵ The Department of Defense Instruction 6130.03, Volume 1, Medical Standards for Military Service: Appointment, Enlistment, or Induction stipulates that a history of AD or eczema after the twelfth birthday or history of residual or recurrent lesions in characteristic areas (ie, face, neck, antecubital or popliteal fossae, occasionally wrists and hands) is disqualifying.²⁶ Specific military services possess additional standards that further define limits within the aforementioned Department of Defense instruction.²⁵ Additionally, there are service-specific policies in place that mandate medical evaluation boards to determine fitness for continued service in the event the condition interferes with the member’s ability to perform their duties. Insection 4.2 of the U.S. Navy Aeromedical Reference and Waiver Guide, further restrictions for aviation personnel are delineated: “Depending on the location of lesions, there can be interference with the wearing of flight gear. The symptoms, particularly itching, can be distracting in flight. Patients with atopic dermatitis are more susceptible to contact dermatitis due to irritants found in a military environment.” Ultimately, the document stipulates that symptom severity and the requirement for therapy will determine the aeromedical disposition. It specifically states that “[p]atients controlled on topical therapy over small areas and patients who are asymptomatic on stable doses of loratadine (Claritin) OR fexofenadine (Allegra) may be considered for waiver,” and “intermittent use of topical steroids over a limited area is compatible with waiver.”²⁷ It follows that limited use of topical JAK inhibitors, such as RUX, would be compatible with a waiver, given the favorable side effect profile and requirement for use in patients with 20% or lower affected BSA.¹⁶ This is just one example of duty-specific and service-specific medical standards that exist that could impact the use of both topical and oral JAK inhibitors.

Use of oral JAK inhibitors in active-duty service members is less ideal for multiple reasons. A large randomized safety clinical trial of patients with rheumatoid arthritis who received tofacitinib and methotrexate was required by the FDA to evaluate the risk of MACEs, malignancy, and infections associated with JAK inhibitor treatment. Data from this trial showed a dose-dependent increased risk for MACEs, all-cause mortality, and thrombosis at both doses of tofacitinib compared with tumor necrosis factor inhibitors and a non–dose-dependent increased risk for malignancy excluding nonmelanoma skin cancer.²⁸ In contrast to the MACE and VTE data from patients with diseases other than AD treated with JAK inhibitors, there has been only 1 patient who developed a pulmonary embolism while being treated with baricitinib 4 mg.^22,29 Downstream effects from the above study were label recommendations to reserve the medicines for patients who had an inadequate response or intolerance to 1 or more tumor necrosis factor blockers and to carefully consider risks vs benefits in patients, in particular current or prior smokers, those with other cardiovascular risk factors or a history of VTE, and those with a malignancy history other than already treated nonmelanoma skin cancer.²⁸

There are consistent observations of laboratory abnormalities with JAK inhibitors, as discussed above, to include creatine phosphokinase elevation and cytopenias.³⁰ Although existing data demonstrate that cytopenias are less of a concern in the AD population compared with the rheumatoid arthritis population, baseline and periodic laboratory monitoring are still recommended. In general, pretreatment laboratory assessment prior to initiating an oral JAK inhibitor should consist of a complete blood cell count with differential, complete metabolic panel, tuberculosis screening, chronic hepatitis panel, HIV screening, and a fasting lipid panel.² The feasibility of obtaining these laboratory measurements in an operational setting or sea-going platform is limited, but many deployed locations and naval vessels possess the laboratory capability to perform a complete blood cell count and complete metabolic panel. Overall tolerability of oral JAK inhibitors in the treatment of AD appears favorable based on studies that were mostly 16 weeks in duration. Few recent longer-term studies have confirmed this side effect profile, but additional studies are needed.

Final Thoughts

Janus kinase inhibitors are a promising therapeutic class with multiple recently FDA-approved agents for the treatment of moderate to severe AD, with new agents on the horizon. Available efficacy data are promising and balanced by a favorable safety profile in clinical trials to date. The oral and topical bioavailability of JAK inhibitors makes them attractive alternatives to existing therapies. The rapidity of itch reduction and AD improvement demonstrated in multiple trials has the potential to decrease the length of limited-duty assignments, potentially returning treated service members to full-duty status more expeditiously. Other applications include use of these medications in scenarios where injectable medications are either unavailable or unsupported.

In the active-duty population, both the condition and/or the treatment may be duty limiting. Service members with AD who require more than topical treatment may require a medical evaluation board to determine if they are still fit to serve. The deployed environment routinely exacerbates AD and exposes service members to infections and environments where immunosuppression can create more risks than in the general population. Nonbiologic medications, which do not require refrigeration, are an exciting option for our patients with AD, including those actively serving or considering serving in the military. However, all factors in any patient’s life should be considered. Therefore, it is important for the nonmilitary dermatologist to work with local military physicians and the patient to determine the optimal treatment regimen to result in the best possible outcome.

The atopic dermatitis (AD) therapeutic landscape is changing considerably with the advent of Janus kinase (JAK) inhibitors. Several JAK inhibitors recently have been approved by the US Food and Drug Administration, building off years of foundational research aimed at elucidating the downstream effects of the JAK–signal transducer and activator of transcription (STAT) pathway and its role in AD pathogenesis. Agents within this promising new class of drugs have performed well vs placebo in phase 2 and 3 clinical trials. This article reviews relevant trial efficacy and safety data of several JAK inhibitors as well as the implications of the use of these medications in AD patients, with specific considerations unique to active-duty military personnel.

Background on JAK Inhibitors

The hematopoietin superfamily of cytokine receptors encompasses a broad group that includes receptors for immune (eg, IL-2, IL-4, IFN-γ), hematopoietic (eg, erythropoietin, thrombopoietin, granulocyte-macrophage colony-stimulating factor), and nonimmune (eg, prolactin, leptin, growth hormone) cytokines. These cytokines signal via the JAK-STAT pathway. The hematopoietin family of cytokine receptors lacks intrinsic enzymatic activity, and as a result, they rely on JAK enzymes to transmit their signals intracellularly after cytokine binding to the receptor.¹ Janus, of Roman mythology, was the god of doorways and archways and was commonly depicted with 2 heads. Janus kinases were named for their 2 “faces,” the kinase domain with its adjacent regulatory kinaselike domains.² The binding of a cytokine to its receptor triggers engagement of the receptor by JAKs, leading to phosphorylation of both the JAKs and the receptor. Subsequent recruitment and phosphorylation of STAT proteins occurs. Following STAT phosphorylation, the STAT proteins dissociate, dimerize, and translocate to the nucleus, where they enact changes in cell behavior through transcriptional effects.¹

Humans possess only 4 JAKs. Janus kinase 1, JAK2, and tyrosine kinase 2 are widely expressed, whereas JAK3 expression is largely limited to immune cells. Thus, there is notable overlap in the use of the 4 JAKs among the relatively larger number of various cytokines that utilize them to propagate intracellular signaling.¹ Janus kinase 1 is important for signaling of receptors activated by a variety of interleukins, as well as IFN-α, IFN-β, and IFN-γ. Janus kinase 2 is important for signaling for the hormonelike cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5. Janus kinase 3 is important for hematopoietic cell proliferation and function.¹

JAK Inhibitors and Atopic Dermatitis

Topical treatments, including corticosteroids and calcineurin inhibitors, are considered the standard-of-care therapy for most patients with AD; however, their clinical benefit often is limited by their anatomic use restrictions and local adverse events, including skin atrophy, striae, and application-site reactions such as stinging and burning.³ As a result, long-term application of these drugs, particularly in sensitive areas, is not recommended owing to safety/tolerability issues.³ Systemic immunomodulatory medications are indicated for patients with AD who do not achieve adequate disease control with topical treatments and/or phototherapy or for patients with severely impaired quality of life.⁴

Janus kinase inhibitors have several key benefits over biologics: oral and topical bioavailability, predictable pharmacokinetics, nonimmunogenicity, and dosing flexibility.⁴ Janus kinase 1 is central to the cell signaling of many cytokines involved in the pathogenesis of AD that comprise the T-helper lymphocytes type 2 axis: IL-4, IL-13, and thymic stromal lymphopoietin. Janus kinase signaling also may mediate itch responses by acting directly on sensory nerve fibers. Consequently, the substantial reduction in pruritus seen in many studies of JAK inhibitors is thought to be in part due to the effects on sensory nerve fibers in the skin and the blockade of early itch signaling in response to IL-4, IL-13, and IL-31.⁵

Abrocitinib is a JAK1 inhibitor with a similar side effect profile to upadacitinib. Both agents were approved by the FDA for the treatment of refractory moderate to severe AD on January 14, 2022.⁶ These are second-generation (also referred to as selective) oral JAK inhibitors with much greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2, thereby reducing the risk for hematopoietic effects associated with JAK2 inhibition. The approval of abrocitinib stemmed from the phase 3 clinical trial JAK1 Atopic Dermatitis Efficacy and Safety (JADE)-MONO-1 (N=387),⁷ its replicate trial JADE-MONO-2 (N=391),⁸ and the JADE COMPARE trial.⁹ The JADE-MONO trials were multicenter, double-blind, placebo-controlled studies that enrolled patients 12 years and older with moderate to severe AD.^7,8 Treatment groups consisted of 100-mg and 200-mg doses and were evaluated with the placebo group for their ability to achieve an investigator global assessment (IGA) score of 0 or 1 and eczema area and severity index 75 (EASI-75) at 12 weeks.^7,8 Sixty-three percent of patients in the 200-mg group, 40% in the 100-mg group, and 12% in the placebo group reached the EASI-75 end point, and the differences in these response rates were statistically significant vs placebo (100 mg: 27.9% [95% CI, 17.4-38.3], P<.0001; 200 mg: 51.0% [95% CI, 40.5-61.5], P<.0001). Notably, 44% of patients using the 200-mg dose achieved almost complete or complete resolution of AD (IGA responders, improvement of ≥2 and IGA score of 0 or 1 at 12 weeks).⁷ In JADE-MONO-2, EASI-75 also was achieved significantly more frequently in the treatment groups compared with the placebo group at 12 weeks (200 mg: 61.0%; 100 mg: 44.5%; placebo: 10.4%; P<.001 vs placebo).⁸ Adjunctive therapy with topical corticosteroids was prohibited in both studies. A dose-dependent decrease in platelets was seen in both trials, as in the phase 2 trial that preceded them.¹⁰

The primary end point of the JADE COMPARE trial was to evaluate the efficacy of abrocitinib as compared with placebo at 12 weeks in adult patients with moderate to severe AD and in the setting of concomitant topical corticosteroid therapy.⁹ One of several secondary end points of this study compared the ability of dupilumab vs abrocitinib and placebo treatment groups to achieve itch reduction at 2 weeks, defined as 4-point improvement or more from baseline in the score on the Peak Pruritus Numerical Rating Scale (NRS), a well‐defined, reliable, sensitive, and valid scale for evaluating worst itch intensity in adults with moderate to severe AD.^9,11 The primary end point was the same as in the other phase 3 studies and was met in the JADE COMPARE trial by all treatment arms. An EASI-75 was seen in 70.3% of patients treated with 200 mg of abrocitinib, 58.7% in the 100-mg abrocitinib group, 58.1% in the dupilumab group, and 27.1% in the placebo group (P<.001 for both abrocitinib doses vs placebo). Only the 200-mg dose of abrocitinib demonstrated superior itch response at week 2 compared with dupilumab (22.1% response rate difference [95% CI, 13.5-30.7; P<.001]). Both abrocitinib groups failed to demonstrate significant differences compared with dupilumab with respect to other secondary end points to include IGA response and EASI-75 at week 16.⁹

The most frequently reported treatment-associated adverse events were nausea, nasopharyngitis, upper respiratory tract infection, and headache, and the percentages were similar among trial groups.⁹ Acne was more frequently reported in the abrocitinib groups compared with placebo and the dupilumab group, and conjunctivitis was more frequently reported in the dupilumab group. Herpesvirus cutaneous infections were rare in the abrocitinib groups, as were other serious infections. No deaths, major adverse cardiovascular events (MACEs), or venous thromboembolic events (VTEs) occurred during the trial. Dose-dependent increases in creatinine phosphokinase were seen in the abrocitinib groups, whereas dose-dependent decreases were seen in platelet counts, with no patient demonstrating a platelet count below 75,000/mm³ during the study.⁹ Low-density lipoprotein cholesterol levels and high-density lipoprotein cholesterol levels increased in a dose-dependent manner as well, but the ratios of low-density lipoprotein to high-density lipoprotein were unchanged.⁹ The results of a phase 3, 92-week extension study, JADE EXTEND, were recently published and demonstrated a role for abrocitinib as a treatment for patients with moderate to severe AD, regardless of prior dupilumab response status.¹²

Upadacitinib, another selective JAK1 inhibitor, was approved following data from 2 replicate double-blind, phase 3, randomized, controlled trials—Measure Up 1 and Measure Up 2.¹³ Results demonstrated that monotherapy with once-daily upadacitinib 15 mg or 30 mg is an effective and well-tolerated treatment option for patients with moderate to severe AD vs placebo. All coprimary end points at week 16 were achieved in the upadacitinib groups in both trials. Acne, upper respiratory tract infections, nasopharyngitis, headache, and increase in serum creatinine phosphokinase levels were the most frequently reported adverse events. Rates of herpes zoster infection in upadacitinib groups were low.¹³

In the subsequent phase 3 AD Up trial, researchers evaluated the safety and efficacy of combination therapy with topical corticosteroids in patients aged 12 to 75 years.¹⁴ Upadacitinib groups again achieved the identical coprimary end points that were present in the Measure Up trials¹³ as well as all key secondary end points.¹⁴ Additionally, significant differences in secondary end points, such as a 4-point improvement in the Worst Pruritus NRS vs placebo, were noticed in both upadacitinib treatment groups as early as 1 week into the study (P<.0001), with maintenance of the effect through to week 16 (P<.0001).¹⁴ AD Up was followed by the Heads Up trial, a 24-week, phase 3, multicenter, double-blind, randomized, controlled trial comparing safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate to severe AD.¹⁵ At week 16, a higher percentage of patients in the upadacitinib group achieved EASI-75 vs the dupilumab group (71.0% vs 61.1%, respectively; P=.006). The difference noted at week 2 was even more impressive, with 43.7% of patients in the upadacitinib treatment group achieving EASI-75 compared with 17.4% in the dupilumab group (P<.001). No new safety-related events were registered compared with the already available data for both drugs.¹⁵

Ruxolitinib (RUX) is a topical JAK1 and JAK2 inhibitor that was FDA approved in September 2021 for the treatment of AD.¹⁶ In a phase 2 clinical trial of 307 adult patients with 3% to 20% body surface area (BSA) affected with AD, significant reductions in itch NRS scores were observed within 36 hours after the first application of RUX cream 1.5% twice daily (-1.8 vs -0.2, P<.0001).¹⁷ These decreases were noted within the first 2 weeks of treatment for all the RUX cream regimens and were sustained through to week 8, the end of the double-blind period. At 4 weeks, change in itch from baseline was significantly reduced in the RUX 1.5% twice-daily group compared with the triamcinolone ointment 0.1% group (−4 vs −2.5, P=.003). During the open-label treatment period from 8 to 12 weeks, all patients who switched to RUX cream 1.5% twice daily noted further reductions in itch, and those who continued it demonstrated additional improvement.¹⁷

The recent FDA approval was further backed by positive phase 3 trial data from the TRuE-AD1 and TRuE-AD2 studies.¹⁸ Patients in these trials were aged 12 years and older and had AD for 2 or more years with an IGA score of 2 or 3 and 3% to 20% affected BSA. Patients were randomized to twice-daily RUX cream 0.75%, RUX cream 1.5%, or vehicle cream, and the primary end point was an IGA score of 0 or 1 and an improvement of 2 or more points from baseline at week 8. Significantly more patients achieved IGA treatment success with RUX cream 0.75% (TRuE-AD1, 50.0%; TRuE-AD2, 39.0%) and RUX cream 1.5% (TRuE-AD1, 53.8%; TRuE-AD2, 51.3%) vs vehicle (TRuE-AD1, 15.1%; TRuE-AD2, 7.6%; P<.0001) at week 8. The RUX groups experienced dramatically reduced itch compared with vehicle, with a mean reduction of approximately 3 points on the NRS at 8 weeks. Additionally, statistically significant itch reductions vs vehicle were reported within 12 hours of first application of RUX cream 1.5% (P<.05). Application-site reactions including stinging and burning occurred in less than 1% of patients, and none were considered clinically significant. Mean plasma concentrations of RUX were monitored during the phase 2 and 3 AD studies and did not lead to any clinically meaningful changes in hematologic parameters. The low bioavailability following topical application of RUX cream (6% in the TRuE-AD studies) allows for a targeted delivery of the active drug to lesional skin while reducing the safety issues associated with oral administration of JAK inhibitors.¹⁸

Baricitinib is a predominantly JAK1 and JAK2 inhibitor that was the first JAK inhibitor to be approved for the treatment of moderate to severe AD in the European Union and Japan.¹⁹ Although the FDA’s decision on baricitinib has lagged behind market competitors, in 2 phase 3 clinical trials, BREEZE-AD1 and BREEZE-AD2, baricitinib demonstrated benefit over placebo on clinically important measures of disease severity. The primary end point—the proportion of patients achieving an IGA score of 0 or 1 with an improvement of 2 or more points from baseline at week 16—was met by both tested doses of baricitinib (2 mg and 4 mg) vs placebo in BREEZE-AD1 (2 mg, P≤.05; 4 mg, P≤.001) and BREEZE-AD2 (2 mg, P≤.05; 4 mg, P≤.001). In addition, baricitinib 4 mg consistently demonstrated significant benefit over placebo on other clinically important measures of disease severity at week 16 to include itch (BREEZE-AD1 and BREEZE-AD2, P≤.001), sleep disturbance (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001), and skin pain (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001). Nasopharyngitis, upper respiratory tract infections, creatine phosphokinase elevations, and headaches were the most frequently reported adverse events. During the 16-week treatment period in these trials, no deaths, MACEs, or VTEs occurred.¹⁹ Similar results were seen in a long-term extension study, BREEZE-AD3.²⁰ The combination of baricitinib and topical corticosteroids were evaluated in 2 additional phase 3 trials, BREEZE-AD4²¹ and BREEZE-AD7.²² Although only baricitinib 4 mg met the primary end point of EASI-75 at week 16 in both trials, both dosing regimens plus topical corticosteroids demonstrated notable reduction in multiple clinical and quality-of-life indices prior to week 2 when compared with placebo plus topical corticosteroids.^22,23

AD in Military Service Members

Atopic dermatitis is a common condition in the general population, with a prevalence of 7.3% (95% CI, 5.9-8.8) in a recent study of American adults.²⁴ Historically, the burden of AD that would be expected among active-duty military service members given the prevalence among the general population has not been observed, in part because of the disqualifying nature of AD for enlistment.²⁵ The Department of Defense Instruction 6130.03, Volume 1, Medical Standards for Military Service: Appointment, Enlistment, or Induction stipulates that a history of AD or eczema after the twelfth birthday or history of residual or recurrent lesions in characteristic areas (ie, face, neck, antecubital or popliteal fossae, occasionally wrists and hands) is disqualifying.²⁶ Specific military services possess additional standards that further define limits within the aforementioned Department of Defense instruction.²⁵ Additionally, there are service-specific policies in place that mandate medical evaluation boards to determine fitness for continued service in the event the condition interferes with the member’s ability to perform their duties. Insection 4.2 of the U.S. Navy Aeromedical Reference and Waiver Guide, further restrictions for aviation personnel are delineated: “Depending on the location of lesions, there can be interference with the wearing of flight gear. The symptoms, particularly itching, can be distracting in flight. Patients with atopic dermatitis are more susceptible to contact dermatitis due to irritants found in a military environment.” Ultimately, the document stipulates that symptom severity and the requirement for therapy will determine the aeromedical disposition. It specifically states that “[p]atients controlled on topical therapy over small areas and patients who are asymptomatic on stable doses of loratadine (Claritin) OR fexofenadine (Allegra) may be considered for waiver,” and “intermittent use of topical steroids over a limited area is compatible with waiver.”²⁷ It follows that limited use of topical JAK inhibitors, such as RUX, would be compatible with a waiver, given the favorable side effect profile and requirement for use in patients with 20% or lower affected BSA.¹⁶ This is just one example of duty-specific and service-specific medical standards that exist that could impact the use of both topical and oral JAK inhibitors.

Use of oral JAK inhibitors in active-duty service members is less ideal for multiple reasons. A large randomized safety clinical trial of patients with rheumatoid arthritis who received tofacitinib and methotrexate was required by the FDA to evaluate the risk of MACEs, malignancy, and infections associated with JAK inhibitor treatment. Data from this trial showed a dose-dependent increased risk for MACEs, all-cause mortality, and thrombosis at both doses of tofacitinib compared with tumor necrosis factor inhibitors and a non–dose-dependent increased risk for malignancy excluding nonmelanoma skin cancer.²⁸ In contrast to the MACE and VTE data from patients with diseases other than AD treated with JAK inhibitors, there has been only 1 patient who developed a pulmonary embolism while being treated with baricitinib 4 mg.^22,29 Downstream effects from the above study were label recommendations to reserve the medicines for patients who had an inadequate response or intolerance to 1 or more tumor necrosis factor blockers and to carefully consider risks vs benefits in patients, in particular current or prior smokers, those with other cardiovascular risk factors or a history of VTE, and those with a malignancy history other than already treated nonmelanoma skin cancer.²⁸

There are consistent observations of laboratory abnormalities with JAK inhibitors, as discussed above, to include creatine phosphokinase elevation and cytopenias.³⁰ Although existing data demonstrate that cytopenias are less of a concern in the AD population compared with the rheumatoid arthritis population, baseline and periodic laboratory monitoring are still recommended. In general, pretreatment laboratory assessment prior to initiating an oral JAK inhibitor should consist of a complete blood cell count with differential, complete metabolic panel, tuberculosis screening, chronic hepatitis panel, HIV screening, and a fasting lipid panel.² The feasibility of obtaining these laboratory measurements in an operational setting or sea-going platform is limited, but many deployed locations and naval vessels possess the laboratory capability to perform a complete blood cell count and complete metabolic panel. Overall tolerability of oral JAK inhibitors in the treatment of AD appears favorable based on studies that were mostly 16 weeks in duration. Few recent longer-term studies have confirmed this side effect profile, but additional studies are needed.

Final Thoughts

Janus kinase inhibitors are a promising therapeutic class with multiple recently FDA-approved agents for the treatment of moderate to severe AD, with new agents on the horizon. Available efficacy data are promising and balanced by a favorable safety profile in clinical trials to date. The oral and topical bioavailability of JAK inhibitors makes them attractive alternatives to existing therapies. The rapidity of itch reduction and AD improvement demonstrated in multiple trials has the potential to decrease the length of limited-duty assignments, potentially returning treated service members to full-duty status more expeditiously. Other applications include use of these medications in scenarios where injectable medications are either unavailable or unsupported.

In the active-duty population, both the condition and/or the treatment may be duty limiting. Service members with AD who require more than topical treatment may require a medical evaluation board to determine if they are still fit to serve. The deployed environment routinely exacerbates AD and exposes service members to infections and environments where immunosuppression can create more risks than in the general population. Nonbiologic medications, which do not require refrigeration, are an exciting option for our patients with AD, including those actively serving or considering serving in the military. However, all factors in any patient’s life should be considered. Therefore, it is important for the nonmilitary dermatologist to work with local military physicians and the patient to determine the optimal treatment regimen to result in the best possible outcome.

The atopic dermatitis (AD) therapeutic landscape is changing considerably with the advent of Janus kinase (JAK) inhibitors. Several JAK inhibitors recently have been approved by the US Food and Drug Administration, building off years of foundational research aimed at elucidating the downstream effects of the JAK–signal transducer and activator of transcription (STAT) pathway and its role in AD pathogenesis. Agents within this promising new class of drugs have performed well vs placebo in phase 2 and 3 clinical trials. This article reviews relevant trial efficacy and safety data of several JAK inhibitors as well as the implications of the use of these medications in AD patients, with specific considerations unique to active-duty military personnel.

Background on JAK Inhibitors

The hematopoietin superfamily of cytokine receptors encompasses a broad group that includes receptors for immune (eg, IL-2, IL-4, IFN-γ), hematopoietic (eg, erythropoietin, thrombopoietin, granulocyte-macrophage colony-stimulating factor), and nonimmune (eg, prolactin, leptin, growth hormone) cytokines. These cytokines signal via the JAK-STAT pathway. The hematopoietin family of cytokine receptors lacks intrinsic enzymatic activity, and as a result, they rely on JAK enzymes to transmit their signals intracellularly after cytokine binding to the receptor.¹ Janus, of Roman mythology, was the god of doorways and archways and was commonly depicted with 2 heads. Janus kinases were named for their 2 “faces,” the kinase domain with its adjacent regulatory kinaselike domains.² The binding of a cytokine to its receptor triggers engagement of the receptor by JAKs, leading to phosphorylation of both the JAKs and the receptor. Subsequent recruitment and phosphorylation of STAT proteins occurs. Following STAT phosphorylation, the STAT proteins dissociate, dimerize, and translocate to the nucleus, where they enact changes in cell behavior through transcriptional effects.¹

Humans possess only 4 JAKs. Janus kinase 1, JAK2, and tyrosine kinase 2 are widely expressed, whereas JAK3 expression is largely limited to immune cells. Thus, there is notable overlap in the use of the 4 JAKs among the relatively larger number of various cytokines that utilize them to propagate intracellular signaling.¹ Janus kinase 1 is important for signaling of receptors activated by a variety of interleukins, as well as IFN-α, IFN-β, and IFN-γ. Janus kinase 2 is important for signaling for the hormonelike cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5. Janus kinase 3 is important for hematopoietic cell proliferation and function.¹

JAK Inhibitors and Atopic Dermatitis

Topical treatments, including corticosteroids and calcineurin inhibitors, are considered the standard-of-care therapy for most patients with AD; however, their clinical benefit often is limited by their anatomic use restrictions and local adverse events, including skin atrophy, striae, and application-site reactions such as stinging and burning.³ As a result, long-term application of these drugs, particularly in sensitive areas, is not recommended owing to safety/tolerability issues.³ Systemic immunomodulatory medications are indicated for patients with AD who do not achieve adequate disease control with topical treatments and/or phototherapy or for patients with severely impaired quality of life.⁴

Janus kinase inhibitors have several key benefits over biologics: oral and topical bioavailability, predictable pharmacokinetics, nonimmunogenicity, and dosing flexibility.⁴ Janus kinase 1 is central to the cell signaling of many cytokines involved in the pathogenesis of AD that comprise the T-helper lymphocytes type 2 axis: IL-4, IL-13, and thymic stromal lymphopoietin. Janus kinase signaling also may mediate itch responses by acting directly on sensory nerve fibers. Consequently, the substantial reduction in pruritus seen in many studies of JAK inhibitors is thought to be in part due to the effects on sensory nerve fibers in the skin and the blockade of early itch signaling in response to IL-4, IL-13, and IL-31.⁵

Abrocitinib is a JAK1 inhibitor with a similar side effect profile to upadacitinib. Both agents were approved by the FDA for the treatment of refractory moderate to severe AD on January 14, 2022.⁶ These are second-generation (also referred to as selective) oral JAK inhibitors with much greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2, thereby reducing the risk for hematopoietic effects associated with JAK2 inhibition. The approval of abrocitinib stemmed from the phase 3 clinical trial JAK1 Atopic Dermatitis Efficacy and Safety (JADE)-MONO-1 (N=387),⁷ its replicate trial JADE-MONO-2 (N=391),⁸ and the JADE COMPARE trial.⁹ The JADE-MONO trials were multicenter, double-blind, placebo-controlled studies that enrolled patients 12 years and older with moderate to severe AD.^7,8 Treatment groups consisted of 100-mg and 200-mg doses and were evaluated with the placebo group for their ability to achieve an investigator global assessment (IGA) score of 0 or 1 and eczema area and severity index 75 (EASI-75) at 12 weeks.^7,8 Sixty-three percent of patients in the 200-mg group, 40% in the 100-mg group, and 12% in the placebo group reached the EASI-75 end point, and the differences in these response rates were statistically significant vs placebo (100 mg: 27.9% [95% CI, 17.4-38.3], P<.0001; 200 mg: 51.0% [95% CI, 40.5-61.5], P<.0001). Notably, 44% of patients using the 200-mg dose achieved almost complete or complete resolution of AD (IGA responders, improvement of ≥2 and IGA score of 0 or 1 at 12 weeks).⁷ In JADE-MONO-2, EASI-75 also was achieved significantly more frequently in the treatment groups compared with the placebo group at 12 weeks (200 mg: 61.0%; 100 mg: 44.5%; placebo: 10.4%; P<.001 vs placebo).⁸ Adjunctive therapy with topical corticosteroids was prohibited in both studies. A dose-dependent decrease in platelets was seen in both trials, as in the phase 2 trial that preceded them.¹⁰

The primary end point of the JADE COMPARE trial was to evaluate the efficacy of abrocitinib as compared with placebo at 12 weeks in adult patients with moderate to severe AD and in the setting of concomitant topical corticosteroid therapy.⁹ One of several secondary end points of this study compared the ability of dupilumab vs abrocitinib and placebo treatment groups to achieve itch reduction at 2 weeks, defined as 4-point improvement or more from baseline in the score on the Peak Pruritus Numerical Rating Scale (NRS), a well‐defined, reliable, sensitive, and valid scale for evaluating worst itch intensity in adults with moderate to severe AD.^9,11 The primary end point was the same as in the other phase 3 studies and was met in the JADE COMPARE trial by all treatment arms. An EASI-75 was seen in 70.3% of patients treated with 200 mg of abrocitinib, 58.7% in the 100-mg abrocitinib group, 58.1% in the dupilumab group, and 27.1% in the placebo group (P<.001 for both abrocitinib doses vs placebo). Only the 200-mg dose of abrocitinib demonstrated superior itch response at week 2 compared with dupilumab (22.1% response rate difference [95% CI, 13.5-30.7; P<.001]). Both abrocitinib groups failed to demonstrate significant differences compared with dupilumab with respect to other secondary end points to include IGA response and EASI-75 at week 16.⁹

The most frequently reported treatment-associated adverse events were nausea, nasopharyngitis, upper respiratory tract infection, and headache, and the percentages were similar among trial groups.⁹ Acne was more frequently reported in the abrocitinib groups compared with placebo and the dupilumab group, and conjunctivitis was more frequently reported in the dupilumab group. Herpesvirus cutaneous infections were rare in the abrocitinib groups, as were other serious infections. No deaths, major adverse cardiovascular events (MACEs), or venous thromboembolic events (VTEs) occurred during the trial. Dose-dependent increases in creatinine phosphokinase were seen in the abrocitinib groups, whereas dose-dependent decreases were seen in platelet counts, with no patient demonstrating a platelet count below 75,000/mm³ during the study.⁹ Low-density lipoprotein cholesterol levels and high-density lipoprotein cholesterol levels increased in a dose-dependent manner as well, but the ratios of low-density lipoprotein to high-density lipoprotein were unchanged.⁹ The results of a phase 3, 92-week extension study, JADE EXTEND, were recently published and demonstrated a role for abrocitinib as a treatment for patients with moderate to severe AD, regardless of prior dupilumab response status.¹²

Upadacitinib, another selective JAK1 inhibitor, was approved following data from 2 replicate double-blind, phase 3, randomized, controlled trials—Measure Up 1 and Measure Up 2.¹³ Results demonstrated that monotherapy with once-daily upadacitinib 15 mg or 30 mg is an effective and well-tolerated treatment option for patients with moderate to severe AD vs placebo. All coprimary end points at week 16 were achieved in the upadacitinib groups in both trials. Acne, upper respiratory tract infections, nasopharyngitis, headache, and increase in serum creatinine phosphokinase levels were the most frequently reported adverse events. Rates of herpes zoster infection in upadacitinib groups were low.¹³

In the subsequent phase 3 AD Up trial, researchers evaluated the safety and efficacy of combination therapy with topical corticosteroids in patients aged 12 to 75 years.¹⁴ Upadacitinib groups again achieved the identical coprimary end points that were present in the Measure Up trials¹³ as well as all key secondary end points.¹⁴ Additionally, significant differences in secondary end points, such as a 4-point improvement in the Worst Pruritus NRS vs placebo, were noticed in both upadacitinib treatment groups as early as 1 week into the study (P<.0001), with maintenance of the effect through to week 16 (P<.0001).¹⁴ AD Up was followed by the Heads Up trial, a 24-week, phase 3, multicenter, double-blind, randomized, controlled trial comparing safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate to severe AD.¹⁵ At week 16, a higher percentage of patients in the upadacitinib group achieved EASI-75 vs the dupilumab group (71.0% vs 61.1%, respectively; P=.006). The difference noted at week 2 was even more impressive, with 43.7% of patients in the upadacitinib treatment group achieving EASI-75 compared with 17.4% in the dupilumab group (P<.001). No new safety-related events were registered compared with the already available data for both drugs.¹⁵

Ruxolitinib (RUX) is a topical JAK1 and JAK2 inhibitor that was FDA approved in September 2021 for the treatment of AD.¹⁶ In a phase 2 clinical trial of 307 adult patients with 3% to 20% body surface area (BSA) affected with AD, significant reductions in itch NRS scores were observed within 36 hours after the first application of RUX cream 1.5% twice daily (-1.8 vs -0.2, P<.0001).¹⁷ These decreases were noted within the first 2 weeks of treatment for all the RUX cream regimens and were sustained through to week 8, the end of the double-blind period. At 4 weeks, change in itch from baseline was significantly reduced in the RUX 1.5% twice-daily group compared with the triamcinolone ointment 0.1% group (−4 vs −2.5, P=.003). During the open-label treatment period from 8 to 12 weeks, all patients who switched to RUX cream 1.5% twice daily noted further reductions in itch, and those who continued it demonstrated additional improvement.¹⁷

The recent FDA approval was further backed by positive phase 3 trial data from the TRuE-AD1 and TRuE-AD2 studies.¹⁸ Patients in these trials were aged 12 years and older and had AD for 2 or more years with an IGA score of 2 or 3 and 3% to 20% affected BSA. Patients were randomized to twice-daily RUX cream 0.75%, RUX cream 1.5%, or vehicle cream, and the primary end point was an IGA score of 0 or 1 and an improvement of 2 or more points from baseline at week 8. Significantly more patients achieved IGA treatment success with RUX cream 0.75% (TRuE-AD1, 50.0%; TRuE-AD2, 39.0%) and RUX cream 1.5% (TRuE-AD1, 53.8%; TRuE-AD2, 51.3%) vs vehicle (TRuE-AD1, 15.1%; TRuE-AD2, 7.6%; P<.0001) at week 8. The RUX groups experienced dramatically reduced itch compared with vehicle, with a mean reduction of approximately 3 points on the NRS at 8 weeks. Additionally, statistically significant itch reductions vs vehicle were reported within 12 hours of first application of RUX cream 1.5% (P<.05). Application-site reactions including stinging and burning occurred in less than 1% of patients, and none were considered clinically significant. Mean plasma concentrations of RUX were monitored during the phase 2 and 3 AD studies and did not lead to any clinically meaningful changes in hematologic parameters. The low bioavailability following topical application of RUX cream (6% in the TRuE-AD studies) allows for a targeted delivery of the active drug to lesional skin while reducing the safety issues associated with oral administration of JAK inhibitors.¹⁸

Baricitinib is a predominantly JAK1 and JAK2 inhibitor that was the first JAK inhibitor to be approved for the treatment of moderate to severe AD in the European Union and Japan.¹⁹ Although the FDA’s decision on baricitinib has lagged behind market competitors, in 2 phase 3 clinical trials, BREEZE-AD1 and BREEZE-AD2, baricitinib demonstrated benefit over placebo on clinically important measures of disease severity. The primary end point—the proportion of patients achieving an IGA score of 0 or 1 with an improvement of 2 or more points from baseline at week 16—was met by both tested doses of baricitinib (2 mg and 4 mg) vs placebo in BREEZE-AD1 (2 mg, P≤.05; 4 mg, P≤.001) and BREEZE-AD2 (2 mg, P≤.05; 4 mg, P≤.001). In addition, baricitinib 4 mg consistently demonstrated significant benefit over placebo on other clinically important measures of disease severity at week 16 to include itch (BREEZE-AD1 and BREEZE-AD2, P≤.001), sleep disturbance (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001), and skin pain (BREEZE-AD1, P≤.01; BREEZE-AD2, P≤.001). Nasopharyngitis, upper respiratory tract infections, creatine phosphokinase elevations, and headaches were the most frequently reported adverse events. During the 16-week treatment period in these trials, no deaths, MACEs, or VTEs occurred.¹⁹ Similar results were seen in a long-term extension study, BREEZE-AD3.²⁰ The combination of baricitinib and topical corticosteroids were evaluated in 2 additional phase 3 trials, BREEZE-AD4²¹ and BREEZE-AD7.²² Although only baricitinib 4 mg met the primary end point of EASI-75 at week 16 in both trials, both dosing regimens plus topical corticosteroids demonstrated notable reduction in multiple clinical and quality-of-life indices prior to week 2 when compared with placebo plus topical corticosteroids.^22,23

AD in Military Service Members

Atopic dermatitis is a common condition in the general population, with a prevalence of 7.3% (95% CI, 5.9-8.8) in a recent study of American adults.²⁴ Historically, the burden of AD that would be expected among active-duty military service members given the prevalence among the general population has not been observed, in part because of the disqualifying nature of AD for enlistment.²⁵ The Department of Defense Instruction 6130.03, Volume 1, Medical Standards for Military Service: Appointment, Enlistment, or Induction stipulates that a history of AD or eczema after the twelfth birthday or history of residual or recurrent lesions in characteristic areas (ie, face, neck, antecubital or popliteal fossae, occasionally wrists and hands) is disqualifying.²⁶ Specific military services possess additional standards that further define limits within the aforementioned Department of Defense instruction.²⁵ Additionally, there are service-specific policies in place that mandate medical evaluation boards to determine fitness for continued service in the event the condition interferes with the member’s ability to perform their duties. Insection 4.2 of the U.S. Navy Aeromedical Reference and Waiver Guide, further restrictions for aviation personnel are delineated: “Depending on the location of lesions, there can be interference with the wearing of flight gear. The symptoms, particularly itching, can be distracting in flight. Patients with atopic dermatitis are more susceptible to contact dermatitis due to irritants found in a military environment.” Ultimately, the document stipulates that symptom severity and the requirement for therapy will determine the aeromedical disposition. It specifically states that “[p]atients controlled on topical therapy over small areas and patients who are asymptomatic on stable doses of loratadine (Claritin) OR fexofenadine (Allegra) may be considered for waiver,” and “intermittent use of topical steroids over a limited area is compatible with waiver.”²⁷ It follows that limited use of topical JAK inhibitors, such as RUX, would be compatible with a waiver, given the favorable side effect profile and requirement for use in patients with 20% or lower affected BSA.¹⁶ This is just one example of duty-specific and service-specific medical standards that exist that could impact the use of both topical and oral JAK inhibitors.

Use of oral JAK inhibitors in active-duty service members is less ideal for multiple reasons. A large randomized safety clinical trial of patients with rheumatoid arthritis who received tofacitinib and methotrexate was required by the FDA to evaluate the risk of MACEs, malignancy, and infections associated with JAK inhibitor treatment. Data from this trial showed a dose-dependent increased risk for MACEs, all-cause mortality, and thrombosis at both doses of tofacitinib compared with tumor necrosis factor inhibitors and a non–dose-dependent increased risk for malignancy excluding nonmelanoma skin cancer.²⁸ In contrast to the MACE and VTE data from patients with diseases other than AD treated with JAK inhibitors, there has been only 1 patient who developed a pulmonary embolism while being treated with baricitinib 4 mg.^22,29 Downstream effects from the above study were label recommendations to reserve the medicines for patients who had an inadequate response or intolerance to 1 or more tumor necrosis factor blockers and to carefully consider risks vs benefits in patients, in particular current or prior smokers, those with other cardiovascular risk factors or a history of VTE, and those with a malignancy history other than already treated nonmelanoma skin cancer.²⁸

There are consistent observations of laboratory abnormalities with JAK inhibitors, as discussed above, to include creatine phosphokinase elevation and cytopenias.³⁰ Although existing data demonstrate that cytopenias are less of a concern in the AD population compared with the rheumatoid arthritis population, baseline and periodic laboratory monitoring are still recommended. In general, pretreatment laboratory assessment prior to initiating an oral JAK inhibitor should consist of a complete blood cell count with differential, complete metabolic panel, tuberculosis screening, chronic hepatitis panel, HIV screening, and a fasting lipid panel.² The feasibility of obtaining these laboratory measurements in an operational setting or sea-going platform is limited, but many deployed locations and naval vessels possess the laboratory capability to perform a complete blood cell count and complete metabolic panel. Overall tolerability of oral JAK inhibitors in the treatment of AD appears favorable based on studies that were mostly 16 weeks in duration. Few recent longer-term studies have confirmed this side effect profile, but additional studies are needed.

Final Thoughts

Janus kinase inhibitors are a promising therapeutic class with multiple recently FDA-approved agents for the treatment of moderate to severe AD, with new agents on the horizon. Available efficacy data are promising and balanced by a favorable safety profile in clinical trials to date. The oral and topical bioavailability of JAK inhibitors makes them attractive alternatives to existing therapies. The rapidity of itch reduction and AD improvement demonstrated in multiple trials has the potential to decrease the length of limited-duty assignments, potentially returning treated service members to full-duty status more expeditiously. Other applications include use of these medications in scenarios where injectable medications are either unavailable or unsupported.

In the active-duty population, both the condition and/or the treatment may be duty limiting. Service members with AD who require more than topical treatment may require a medical evaluation board to determine if they are still fit to serve. The deployed environment routinely exacerbates AD and exposes service members to infections and environments where immunosuppression can create more risks than in the general population. Nonbiologic medications, which do not require refrigeration, are an exciting option for our patients with AD, including those actively serving or considering serving in the military. However, all factors in any patient’s life should be considered. Therefore, it is important for the nonmilitary dermatologist to work with local military physicians and the patient to determine the optimal treatment regimen to result in the best possible outcome.

New Year, New Codes: A Win-Win for Digital Pathology

In July 2022, the American Medical Association CPT (Current Procedural Terminology) Editorial Panel released 13 new digital pathology add-on Category III codes for 2023 that the College of American Pathologists successfully advocated for inclusion.¹ These codes are for reporting additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis (Table). They go into effect on January 1, 2023.

Although there is no additional compensation with the new Category III codes, dermatopathology laboratories will be able to report when they have made a diagnosis using digital pathology. The new CPT codes will provide payers with data they need to directly understand the utilization and increased value of digital pathology, which will bring dermatopathology laboratories one step closer to receiving additional reimbursement for digital interpretation.

The adoption of digital pathology has been accelerating in the United States but still lags behind many European countries where reimbursement for digital pathology has been established for many years. Many of the barriers to digital pathology have improved—cloud storage is more affordable, scanners have a higher throughput, digital pathology platforms have improved, and the US Food and Drug Administration has granted approvals for digital pathology. Digital pathology allows for more efficient workflow, which results in increased productivity and a reduction in turnaround times. It also allows for a wide spectrum of clinical applications and more innovation as well as research and educational applications.

The new Category III codes cannot be reported solely for archival purposes (eg, after the Category I service has already been performed and reported), solely for educational purposes (eg, when services are not used for individual patient reporting), solely for developing a database for training or validation of artificial intelligence algorithms, and solely for clinical conference presentations (eg, tumor board interdisciplinary conferences).

The new codes are a major victory for the adoption and future compensation for digital pathology.

New Year, New Cuts: Proposed 2023 Medicare Policy and Payment Changes for Dermatologists

The United States Spent $3.8 Trillion on Health Care in 2019: Where Did It Go?—In 2019, approximately $3.8 trillion was spent on health care in the United States (Figure 1). Physician services accounted for approximately 15% of total health care spending.²

Medicare Payments for Physician Services—Medicare payments for physician services are determined by a relative value unit (RVU) multiplied by a conversion factor (CF). Relative value units were set up in 1992 by what is now the Centers for Medicare & Medicaid Services, and they calculated the time it took a physician to complete a task or RVU and multiplied it by $32.00 (CF).³

Thirty years later—in 2022—the CF is $34.61. If the CF had increased with inflation, it would be $59.00. If the Proposed Rule is adopted, the 2023 fee schedule payment formula would decrease by 4.4% (to $33.08) relative to that of the 2022 fee schedule ($34.61), which is a decrease of 8.2% since 2019 ($36.04). This decrease is due to expiration of the 3% increase to Medicare fee schedule payments for 2022 required by the Protecting Medicare and American Farmers from Sequester Cuts Act and the required budget neutrality adjustment required by changes in RVUs. Medicare physician payment has declined 22% from 2001 to 2022 (Figure 2).^4,5

The adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index; (2) expenditure target “performance adjustment”; and (3) miscellaneous adjustments, including those for “budget neutrality” required by law.

Medicare Physician Payments Compared With Other Provider Types and Inflation—The proposed Medicare physician payment policy is unsustainable for outpatient dermatologists. Practice overhead has increased markedly since 1992. Other service providers, such as those in skilled nursing facilities and hospitals (Figure 3), have received favorable payment increases compared with practice cost inflation and the Consumer Price Index.^3-6 Flat reimbursement affects all physicians who accept insurance, as even private insurers base their reimbursement on Medicare.

In addition, there are other issues resulting in decreased physician payments when evaluation and management services are reported with same-day procedures using modifier −25 as well as preserving or finding alternative strategies for 10- and 90-day global period payments for medical procedures. When Medicare cuts physician payments, dermatologists find it difficult to own and operate their own practices, resulting in health market consolidation, limited competition, increased health care costs, limited patient access to care, and decreased quality of health care.

Medicare Payment Reform—Medicare payment reform is necessary to stop annual payment cuts and create a stable predictable payment system that ensures patient access to quality, value-based care. Medicare physician payment reform needs to happen at a national level. The American Academy of Dermatology Association (AADA) is working with the House of Medicine and the medical specialty community to develop specific proposals, such as “Characteristics of a Rational Medicare Physician Payment System,” to reform Medicare’s payment system.⁷ Advocacy groups, including the AADA, have been working to mitigate the proposed 2023 cuts by engaging with Congress and urging them to act before these changes go into effect on January 1, 2023.

Make Advocacy Your New Year’s Resolution: AADA’s Top Advocacy Priorities

The AADA’s top priority is Medicare payment policies.³ In addition, the AADA is working on drug access and cost by cutting the bureaucratic red tape caused by prior authorization (PA) and step therapy policies. The AADA collaborates with manufacturers, the health care community, policymakers, private payers, pharmacists, pharmacy benefit managers, and patients to minimize and/or eliminate barriers that patients face in accessing needed medications. Specifically, the AADA advocates for legislation that limits obstacles associated with health insurance step therapy requirements, streamlines PA, and prohibits mid-year formulary changes.⁸

Step therapy requires that patients first try a medication specified by the insurance company; the therapy must fail before the patient is placed on the medication originally prescribed by the provider. Regarding PA, the AADA tries to ensure that determinations are standardized, requires the speed of determinations to be quantified and minimized, and ensures that PA and appeals policies do not unduly burden physicians or patients in accessing optimal drug therapy.⁸

Another advocacy priority is telehealth. The AADA is advocating for legislation on expansion of telehealth in underserved areas and modifications to state licensure requirements, liability issues, and reimbursement for store-and-forward technology. The AADA is involved in protecting scope of practice, truth in advertising, and access to specialty care, as well as monitoring legislation and regulation concerning the potential environmental impact of sunscreen ingredients, indoor tanning restrictions, and skin cancer prevention.⁸

Advocacy Matters and Makes a Difference—It is important to learn about and support advocacy priorities and efforts and join forces to protect your practice. The AADA advocacy priorities are to protect the value of dermatology services, mobilize dermatologists for political action, ensure dermatologists can participate in new payment models, and strengthen the profession.⁹ Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves. All of us are in it together, and a collaborative collective voice can make a difference. Take action, join the AADA, and contact Congress today to stop Medicare payment cuts (https://takeaction.aad.org/).

New Year, New Codes: A Win-Win for Digital Pathology

In July 2022, the American Medical Association CPT (Current Procedural Terminology) Editorial Panel released 13 new digital pathology add-on Category III codes for 2023 that the College of American Pathologists successfully advocated for inclusion.¹ These codes are for reporting additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis (Table). They go into effect on January 1, 2023.

Although there is no additional compensation with the new Category III codes, dermatopathology laboratories will be able to report when they have made a diagnosis using digital pathology. The new CPT codes will provide payers with data they need to directly understand the utilization and increased value of digital pathology, which will bring dermatopathology laboratories one step closer to receiving additional reimbursement for digital interpretation.

The adoption of digital pathology has been accelerating in the United States but still lags behind many European countries where reimbursement for digital pathology has been established for many years. Many of the barriers to digital pathology have improved—cloud storage is more affordable, scanners have a higher throughput, digital pathology platforms have improved, and the US Food and Drug Administration has granted approvals for digital pathology. Digital pathology allows for more efficient workflow, which results in increased productivity and a reduction in turnaround times. It also allows for a wide spectrum of clinical applications and more innovation as well as research and educational applications.

The new Category III codes cannot be reported solely for archival purposes (eg, after the Category I service has already been performed and reported), solely for educational purposes (eg, when services are not used for individual patient reporting), solely for developing a database for training or validation of artificial intelligence algorithms, and solely for clinical conference presentations (eg, tumor board interdisciplinary conferences).

The new codes are a major victory for the adoption and future compensation for digital pathology.

New Year, New Cuts: Proposed 2023 Medicare Policy and Payment Changes for Dermatologists

The United States Spent $3.8 Trillion on Health Care in 2019: Where Did It Go?—In 2019, approximately $3.8 trillion was spent on health care in the United States (Figure 1). Physician services accounted for approximately 15% of total health care spending.²

Medicare Payments for Physician Services—Medicare payments for physician services are determined by a relative value unit (RVU) multiplied by a conversion factor (CF). Relative value units were set up in 1992 by what is now the Centers for Medicare & Medicaid Services, and they calculated the time it took a physician to complete a task or RVU and multiplied it by $32.00 (CF).³

Thirty years later—in 2022—the CF is $34.61. If the CF had increased with inflation, it would be $59.00. If the Proposed Rule is adopted, the 2023 fee schedule payment formula would decrease by 4.4% (to $33.08) relative to that of the 2022 fee schedule ($34.61), which is a decrease of 8.2% since 2019 ($36.04). This decrease is due to expiration of the 3% increase to Medicare fee schedule payments for 2022 required by the Protecting Medicare and American Farmers from Sequester Cuts Act and the required budget neutrality adjustment required by changes in RVUs. Medicare physician payment has declined 22% from 2001 to 2022 (Figure 2).^4,5

The adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index; (2) expenditure target “performance adjustment”; and (3) miscellaneous adjustments, including those for “budget neutrality” required by law.

Medicare Physician Payments Compared With Other Provider Types and Inflation—The proposed Medicare physician payment policy is unsustainable for outpatient dermatologists. Practice overhead has increased markedly since 1992. Other service providers, such as those in skilled nursing facilities and hospitals (Figure 3), have received favorable payment increases compared with practice cost inflation and the Consumer Price Index.^3-6 Flat reimbursement affects all physicians who accept insurance, as even private insurers base their reimbursement on Medicare.

In addition, there are other issues resulting in decreased physician payments when evaluation and management services are reported with same-day procedures using modifier −25 as well as preserving or finding alternative strategies for 10- and 90-day global period payments for medical procedures. When Medicare cuts physician payments, dermatologists find it difficult to own and operate their own practices, resulting in health market consolidation, limited competition, increased health care costs, limited patient access to care, and decreased quality of health care.

Medicare Payment Reform—Medicare payment reform is necessary to stop annual payment cuts and create a stable predictable payment system that ensures patient access to quality, value-based care. Medicare physician payment reform needs to happen at a national level. The American Academy of Dermatology Association (AADA) is working with the House of Medicine and the medical specialty community to develop specific proposals, such as “Characteristics of a Rational Medicare Physician Payment System,” to reform Medicare’s payment system.⁷ Advocacy groups, including the AADA, have been working to mitigate the proposed 2023 cuts by engaging with Congress and urging them to act before these changes go into effect on January 1, 2023.

Make Advocacy Your New Year’s Resolution: AADA’s Top Advocacy Priorities

The AADA’s top priority is Medicare payment policies.³ In addition, the AADA is working on drug access and cost by cutting the bureaucratic red tape caused by prior authorization (PA) and step therapy policies. The AADA collaborates with manufacturers, the health care community, policymakers, private payers, pharmacists, pharmacy benefit managers, and patients to minimize and/or eliminate barriers that patients face in accessing needed medications. Specifically, the AADA advocates for legislation that limits obstacles associated with health insurance step therapy requirements, streamlines PA, and prohibits mid-year formulary changes.⁸

Step therapy requires that patients first try a medication specified by the insurance company; the therapy must fail before the patient is placed on the medication originally prescribed by the provider. Regarding PA, the AADA tries to ensure that determinations are standardized, requires the speed of determinations to be quantified and minimized, and ensures that PA and appeals policies do not unduly burden physicians or patients in accessing optimal drug therapy.⁸

Another advocacy priority is telehealth. The AADA is advocating for legislation on expansion of telehealth in underserved areas and modifications to state licensure requirements, liability issues, and reimbursement for store-and-forward technology. The AADA is involved in protecting scope of practice, truth in advertising, and access to specialty care, as well as monitoring legislation and regulation concerning the potential environmental impact of sunscreen ingredients, indoor tanning restrictions, and skin cancer prevention.⁸

Advocacy Matters and Makes a Difference—It is important to learn about and support advocacy priorities and efforts and join forces to protect your practice. The AADA advocacy priorities are to protect the value of dermatology services, mobilize dermatologists for political action, ensure dermatologists can participate in new payment models, and strengthen the profession.⁹ Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves. All of us are in it together, and a collaborative collective voice can make a difference. Take action, join the AADA, and contact Congress today to stop Medicare payment cuts (https://takeaction.aad.org/).

New Year, New Codes: A Win-Win for Digital Pathology

In July 2022, the American Medical Association CPT (Current Procedural Terminology) Editorial Panel released 13 new digital pathology add-on Category III codes for 2023 that the College of American Pathologists successfully advocated for inclusion.¹ These codes are for reporting additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis (Table). They go into effect on January 1, 2023.

Although there is no additional compensation with the new Category III codes, dermatopathology laboratories will be able to report when they have made a diagnosis using digital pathology. The new CPT codes will provide payers with data they need to directly understand the utilization and increased value of digital pathology, which will bring dermatopathology laboratories one step closer to receiving additional reimbursement for digital interpretation.

The adoption of digital pathology has been accelerating in the United States but still lags behind many European countries where reimbursement for digital pathology has been established for many years. Many of the barriers to digital pathology have improved—cloud storage is more affordable, scanners have a higher throughput, digital pathology platforms have improved, and the US Food and Drug Administration has granted approvals for digital pathology. Digital pathology allows for more efficient workflow, which results in increased productivity and a reduction in turnaround times. It also allows for a wide spectrum of clinical applications and more innovation as well as research and educational applications.

The new Category III codes cannot be reported solely for archival purposes (eg, after the Category I service has already been performed and reported), solely for educational purposes (eg, when services are not used for individual patient reporting), solely for developing a database for training or validation of artificial intelligence algorithms, and solely for clinical conference presentations (eg, tumor board interdisciplinary conferences).

The new codes are a major victory for the adoption and future compensation for digital pathology.

New Year, New Cuts: Proposed 2023 Medicare Policy and Payment Changes for Dermatologists

The United States Spent $3.8 Trillion on Health Care in 2019: Where Did It Go?—In 2019, approximately $3.8 trillion was spent on health care in the United States (Figure 1). Physician services accounted for approximately 15% of total health care spending.²

Medicare Payments for Physician Services—Medicare payments for physician services are determined by a relative value unit (RVU) multiplied by a conversion factor (CF). Relative value units were set up in 1992 by what is now the Centers for Medicare & Medicaid Services, and they calculated the time it took a physician to complete a task or RVU and multiplied it by $32.00 (CF).³

Thirty years later—in 2022—the CF is $34.61. If the CF had increased with inflation, it would be $59.00. If the Proposed Rule is adopted, the 2023 fee schedule payment formula would decrease by 4.4% (to $33.08) relative to that of the 2022 fee schedule ($34.61), which is a decrease of 8.2% since 2019 ($36.04). This decrease is due to expiration of the 3% increase to Medicare fee schedule payments for 2022 required by the Protecting Medicare and American Farmers from Sequester Cuts Act and the required budget neutrality adjustment required by changes in RVUs. Medicare physician payment has declined 22% from 2001 to 2022 (Figure 2).^4,5

The adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index; (2) expenditure target “performance adjustment”; and (3) miscellaneous adjustments, including those for “budget neutrality” required by law.

Medicare Physician Payments Compared With Other Provider Types and Inflation—The proposed Medicare physician payment policy is unsustainable for outpatient dermatologists. Practice overhead has increased markedly since 1992. Other service providers, such as those in skilled nursing facilities and hospitals (Figure 3), have received favorable payment increases compared with practice cost inflation and the Consumer Price Index.^3-6 Flat reimbursement affects all physicians who accept insurance, as even private insurers base their reimbursement on Medicare.

In addition, there are other issues resulting in decreased physician payments when evaluation and management services are reported with same-day procedures using modifier −25 as well as preserving or finding alternative strategies for 10- and 90-day global period payments for medical procedures. When Medicare cuts physician payments, dermatologists find it difficult to own and operate their own practices, resulting in health market consolidation, limited competition, increased health care costs, limited patient access to care, and decreased quality of health care.

Medicare Payment Reform—Medicare payment reform is necessary to stop annual payment cuts and create a stable predictable payment system that ensures patient access to quality, value-based care. Medicare physician payment reform needs to happen at a national level. The American Academy of Dermatology Association (AADA) is working with the House of Medicine and the medical specialty community to develop specific proposals, such as “Characteristics of a Rational Medicare Physician Payment System,” to reform Medicare’s payment system.⁷ Advocacy groups, including the AADA, have been working to mitigate the proposed 2023 cuts by engaging with Congress and urging them to act before these changes go into effect on January 1, 2023.

Make Advocacy Your New Year’s Resolution: AADA’s Top Advocacy Priorities

The AADA’s top priority is Medicare payment policies.³ In addition, the AADA is working on drug access and cost by cutting the bureaucratic red tape caused by prior authorization (PA) and step therapy policies. The AADA collaborates with manufacturers, the health care community, policymakers, private payers, pharmacists, pharmacy benefit managers, and patients to minimize and/or eliminate barriers that patients face in accessing needed medications. Specifically, the AADA advocates for legislation that limits obstacles associated with health insurance step therapy requirements, streamlines PA, and prohibits mid-year formulary changes.⁸

Step therapy requires that patients first try a medication specified by the insurance company; the therapy must fail before the patient is placed on the medication originally prescribed by the provider. Regarding PA, the AADA tries to ensure that determinations are standardized, requires the speed of determinations to be quantified and minimized, and ensures that PA and appeals policies do not unduly burden physicians or patients in accessing optimal drug therapy.⁸

Another advocacy priority is telehealth. The AADA is advocating for legislation on expansion of telehealth in underserved areas and modifications to state licensure requirements, liability issues, and reimbursement for store-and-forward technology. The AADA is involved in protecting scope of practice, truth in advertising, and access to specialty care, as well as monitoring legislation and regulation concerning the potential environmental impact of sunscreen ingredients, indoor tanning restrictions, and skin cancer prevention.⁸

Advocacy Matters and Makes a Difference—It is important to learn about and support advocacy priorities and efforts and join forces to protect your practice. The AADA advocacy priorities are to protect the value of dermatology services, mobilize dermatologists for political action, ensure dermatologists can participate in new payment models, and strengthen the profession.⁹ Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves. All of us are in it together, and a collaborative collective voice can make a difference. Take action, join the AADA, and contact Congress today to stop Medicare payment cuts (https://takeaction.aad.org/).

The residents of our program asked me to serve as their commencement speaker in June. Since I was retiring from my position as department chair, this touching honor seemed a fitting capstone for my career. It gave me the opportunity to reflect on the enormity of the changes that have occurred between my graduation from residency in 1983 and the current time, which is marked by disruption from the digital revolution and the COVID-19 pandemic. Throughout this 40-year period, there were times of external global turmoil, economic instability, significant changes in the business of medicine, stressful changes in documentation of competency and certification, and the difficult transition to electronic medical records. Another epidemic—AIDS—changed surgical practices. During my residency, we did biopsies without wearing gloves or masks. Gloves were added to protect the person doing the procedure as well as to prevent spread of disease to other patients, not to reduce the infection rate for the patient undergoing the procedure. Of course, change in the last 40 years also occurred outside of work and included various familial stresses. The irritations of daily life easily mounted up to being overwhelming. However, I had gone to work every day for 40 years, seeking to do my best for my patients and my colleagues and the staff with whom I worked, sometimes feeling successful and sometimes feeling incompetent. Some days went smoothly, and some days were filled with challenges that I could not begin to imagine how I would solve. I have a habit of seeing problems rather than successes, which creates its own difficulties. I did, however, grab opportunities that continually improved my practice of medicine and allowed me to serve in several professional positions as well as in leadership positions of multiple professional societies. As I prepared the commencement address, I realized that the totality of my career was very satisfying.

The Merriam-Webster dictionary definition of satisfying is “producing pleasure or contentment by providing what is needed or wanted.”¹ My use of the word means that my career over the long term has pleased me—maybe not some of the people I reported to, but rather me.

My approach to my career can be summarized in 3 words: purpose, serendipity, and curiosity.

The first element is purpose. Job satisfaction generally is associated with work being aligned with values, an appreciation that you are accomplishing the purpose with which you set out on your journey. It is not associated with every day being wonderful and problem free or every task being completed without setbacks or complications. The reality of working is not that every moment brings pure happiness or that every task fulfills a passion. How does a person ensure that the days add up to be satisfying? Start with values. Why did you decide to pursue medical school? Some may have chosen it for economic security, but there are many ways to achieve economic security. Maybe being a physician feeds into the family lore, but families generally have broad ranges of acceptable careers. Maybe it appealed scientifically, but a PhD in biology also fulfills that interest. Maybe it is that you noticed respect for physicians in the community when you were growing up, but that is changing and does not represent an internal value anyway. Consider your values carefully, write them down, and keep them at the forefront of the day. Go back to them consciously any time you have a rough day and understand why you are doing what you are doing. When you are 55 years old and going through your umpteenth change in reimbursement process, go back to the day you decided on medicine as a career. Focus on your values as the grounding for your purpose. Also note that purpose is different than goals. Some goals will be reached, and some will not. Goals change with external realities and/ or internal factors. Purpose and values remain the same if we have thoughtfully identified them.

The second element is serendipity. Serendipity often is thought of as luck, as karma, as being in the right place at the right time. It feels random, and at first glance it appears that purpose and serendipity are complete opposites and do not intersect. Serendipity is, however, not just luck. It is an ability to distinguish events and observations in meaningful ways. It is a close relative of creativity and benefits from sloppiness, playfulness, tinkering, and discussion. It cannot exist in a vacuum. History is replete with serendipitous discoveries. It is thought that James Watson and Francis Crick would never have been able to elucidate the nature of DNA without sharing offices with people with whom they argued daily. In fact, figuring out the DNA structure was not even the main focus of their laboratories. It was just a side angle that several people loved to think about. Appreciating serendipity by being truly open to opportunities that are out on the wings brings experiences that are deeply rewarding even if not planned. I had no idea at all, no plan, no goal of serving as president of the American Academy of Dermatology or as Department Chair, and yet these happened. These experiences have allowed me to work on my purpose as I have defined it. How can you harness serendipity in your own life? My philosophy may be somewhat simple, but I think if you show up every day doing the best job you can at the tasks on hand, doors will appear, at odd intervals and in odd directions. You must be open enough and in tune with your purpose to an extent that you can sense the direction in which to turn and what doorways through which to walk.

The third element is curiosity. One definition is that curiosity is the motivation to learn new information. Another definition is that curiosity is a special form of information seeking distinguished by the fact that it is internally motivated. We are all familiar with intellectual curiosity. For example, a patient has a basal cell carcinoma on the upper back. What does the literature say about the cure rates of various treatments for that particular tumor? In addition, we can be curious about other things as well. Is it a really small tumor? How was it found and why is the patient anxious? Why does it make me irritated that the patient is worried about such a small, easily treated tumor? Or is it a large neglected tumor? Why was it not treated before? Why does it make me sad that it is so large? Why does it annoy me that I have a difficult situation to manage? Being able to define an emotional reaction by being curious about its presence helps us manage destructive responses and promote more positive outcomes. This curiosity is related to emotional intelligence and is mindfully harnessed by effective leaders. Curiosity will get you through tough days when your office team is stressed and the tough years that are complicated by professional and personal challenges.

Curiosity also will help you identify your purpose and harness serendipity, and so we come full circle with our 3 elements: purpose, serendipity, and curiosity.

My wish for all of you is that when you are at the tail end of your career, you will look back and say, “This has been a great ride.” I am very grateful that I can acknowledge this for myself. I have been so fortunate to have found dermatology, where I can go to work every day making a difference for patients in a stimulating environment with good colleagues. One of my values is to try and make life better in some way for everyone around me, even if it is just a smile at the start of the workday. As I look back, this value has allowed me to meet interesting people, hear fascinating stories, make good friends, and have enduring relationships. I have held onto fellow travelers, and we have supported each other through tough times as well as celebrated together the good times.

Nurturing a satisfying career includes these essential fundamentals. First, accept the reality of constant change. Second, develop productive relationships with fellow travelers. And third and most importantly, go forth with purpose, serendipity, and curiosity.

The residents of our program asked me to serve as their commencement speaker in June. Since I was retiring from my position as department chair, this touching honor seemed a fitting capstone for my career. It gave me the opportunity to reflect on the enormity of the changes that have occurred between my graduation from residency in 1983 and the current time, which is marked by disruption from the digital revolution and the COVID-19 pandemic. Throughout this 40-year period, there were times of external global turmoil, economic instability, significant changes in the business of medicine, stressful changes in documentation of competency and certification, and the difficult transition to electronic medical records. Another epidemic—AIDS—changed surgical practices. During my residency, we did biopsies without wearing gloves or masks. Gloves were added to protect the person doing the procedure as well as to prevent spread of disease to other patients, not to reduce the infection rate for the patient undergoing the procedure. Of course, change in the last 40 years also occurred outside of work and included various familial stresses. The irritations of daily life easily mounted up to being overwhelming. However, I had gone to work every day for 40 years, seeking to do my best for my patients and my colleagues and the staff with whom I worked, sometimes feeling successful and sometimes feeling incompetent. Some days went smoothly, and some days were filled with challenges that I could not begin to imagine how I would solve. I have a habit of seeing problems rather than successes, which creates its own difficulties. I did, however, grab opportunities that continually improved my practice of medicine and allowed me to serve in several professional positions as well as in leadership positions of multiple professional societies. As I prepared the commencement address, I realized that the totality of my career was very satisfying.

The Merriam-Webster dictionary definition of satisfying is “producing pleasure or contentment by providing what is needed or wanted.”¹ My use of the word means that my career over the long term has pleased me—maybe not some of the people I reported to, but rather me.

My approach to my career can be summarized in 3 words: purpose, serendipity, and curiosity.

The first element is purpose. Job satisfaction generally is associated with work being aligned with values, an appreciation that you are accomplishing the purpose with which you set out on your journey. It is not associated with every day being wonderful and problem free or every task being completed without setbacks or complications. The reality of working is not that every moment brings pure happiness or that every task fulfills a passion. How does a person ensure that the days add up to be satisfying? Start with values. Why did you decide to pursue medical school? Some may have chosen it for economic security, but there are many ways to achieve economic security. Maybe being a physician feeds into the family lore, but families generally have broad ranges of acceptable careers. Maybe it appealed scientifically, but a PhD in biology also fulfills that interest. Maybe it is that you noticed respect for physicians in the community when you were growing up, but that is changing and does not represent an internal value anyway. Consider your values carefully, write them down, and keep them at the forefront of the day. Go back to them consciously any time you have a rough day and understand why you are doing what you are doing. When you are 55 years old and going through your umpteenth change in reimbursement process, go back to the day you decided on medicine as a career. Focus on your values as the grounding for your purpose. Also note that purpose is different than goals. Some goals will be reached, and some will not. Goals change with external realities and/ or internal factors. Purpose and values remain the same if we have thoughtfully identified them.

The second element is serendipity. Serendipity often is thought of as luck, as karma, as being in the right place at the right time. It feels random, and at first glance it appears that purpose and serendipity are complete opposites and do not intersect. Serendipity is, however, not just luck. It is an ability to distinguish events and observations in meaningful ways. It is a close relative of creativity and benefits from sloppiness, playfulness, tinkering, and discussion. It cannot exist in a vacuum. History is replete with serendipitous discoveries. It is thought that James Watson and Francis Crick would never have been able to elucidate the nature of DNA without sharing offices with people with whom they argued daily. In fact, figuring out the DNA structure was not even the main focus of their laboratories. It was just a side angle that several people loved to think about. Appreciating serendipity by being truly open to opportunities that are out on the wings brings experiences that are deeply rewarding even if not planned. I had no idea at all, no plan, no goal of serving as president of the American Academy of Dermatology or as Department Chair, and yet these happened. These experiences have allowed me to work on my purpose as I have defined it. How can you harness serendipity in your own life? My philosophy may be somewhat simple, but I think if you show up every day doing the best job you can at the tasks on hand, doors will appear, at odd intervals and in odd directions. You must be open enough and in tune with your purpose to an extent that you can sense the direction in which to turn and what doorways through which to walk.

The third element is curiosity. One definition is that curiosity is the motivation to learn new information. Another definition is that curiosity is a special form of information seeking distinguished by the fact that it is internally motivated. We are all familiar with intellectual curiosity. For example, a patient has a basal cell carcinoma on the upper back. What does the literature say about the cure rates of various treatments for that particular tumor? In addition, we can be curious about other things as well. Is it a really small tumor? How was it found and why is the patient anxious? Why does it make me irritated that the patient is worried about such a small, easily treated tumor? Or is it a large neglected tumor? Why was it not treated before? Why does it make me sad that it is so large? Why does it annoy me that I have a difficult situation to manage? Being able to define an emotional reaction by being curious about its presence helps us manage destructive responses and promote more positive outcomes. This curiosity is related to emotional intelligence and is mindfully harnessed by effective leaders. Curiosity will get you through tough days when your office team is stressed and the tough years that are complicated by professional and personal challenges.

Curiosity also will help you identify your purpose and harness serendipity, and so we come full circle with our 3 elements: purpose, serendipity, and curiosity.

My wish for all of you is that when you are at the tail end of your career, you will look back and say, “This has been a great ride.” I am very grateful that I can acknowledge this for myself. I have been so fortunate to have found dermatology, where I can go to work every day making a difference for patients in a stimulating environment with good colleagues. One of my values is to try and make life better in some way for everyone around me, even if it is just a smile at the start of the workday. As I look back, this value has allowed me to meet interesting people, hear fascinating stories, make good friends, and have enduring relationships. I have held onto fellow travelers, and we have supported each other through tough times as well as celebrated together the good times.

Nurturing a satisfying career includes these essential fundamentals. First, accept the reality of constant change. Second, develop productive relationships with fellow travelers. And third and most importantly, go forth with purpose, serendipity, and curiosity.

The residents of our program asked me to serve as their commencement speaker in June. Since I was retiring from my position as department chair, this touching honor seemed a fitting capstone for my career. It gave me the opportunity to reflect on the enormity of the changes that have occurred between my graduation from residency in 1983 and the current time, which is marked by disruption from the digital revolution and the COVID-19 pandemic. Throughout this 40-year period, there were times of external global turmoil, economic instability, significant changes in the business of medicine, stressful changes in documentation of competency and certification, and the difficult transition to electronic medical records. Another epidemic—AIDS—changed surgical practices. During my residency, we did biopsies without wearing gloves or masks. Gloves were added to protect the person doing the procedure as well as to prevent spread of disease to other patients, not to reduce the infection rate for the patient undergoing the procedure. Of course, change in the last 40 years also occurred outside of work and included various familial stresses. The irritations of daily life easily mounted up to being overwhelming. However, I had gone to work every day for 40 years, seeking to do my best for my patients and my colleagues and the staff with whom I worked, sometimes feeling successful and sometimes feeling incompetent. Some days went smoothly, and some days were filled with challenges that I could not begin to imagine how I would solve. I have a habit of seeing problems rather than successes, which creates its own difficulties. I did, however, grab opportunities that continually improved my practice of medicine and allowed me to serve in several professional positions as well as in leadership positions of multiple professional societies. As I prepared the commencement address, I realized that the totality of my career was very satisfying.

The Merriam-Webster dictionary definition of satisfying is “producing pleasure or contentment by providing what is needed or wanted.”¹ My use of the word means that my career over the long term has pleased me—maybe not some of the people I reported to, but rather me.

My approach to my career can be summarized in 3 words: purpose, serendipity, and curiosity.

The first element is purpose. Job satisfaction generally is associated with work being aligned with values, an appreciation that you are accomplishing the purpose with which you set out on your journey. It is not associated with every day being wonderful and problem free or every task being completed without setbacks or complications. The reality of working is not that every moment brings pure happiness or that every task fulfills a passion. How does a person ensure that the days add up to be satisfying? Start with values. Why did you decide to pursue medical school? Some may have chosen it for economic security, but there are many ways to achieve economic security. Maybe being a physician feeds into the family lore, but families generally have broad ranges of acceptable careers. Maybe it appealed scientifically, but a PhD in biology also fulfills that interest. Maybe it is that you noticed respect for physicians in the community when you were growing up, but that is changing and does not represent an internal value anyway. Consider your values carefully, write them down, and keep them at the forefront of the day. Go back to them consciously any time you have a rough day and understand why you are doing what you are doing. When you are 55 years old and going through your umpteenth change in reimbursement process, go back to the day you decided on medicine as a career. Focus on your values as the grounding for your purpose. Also note that purpose is different than goals. Some goals will be reached, and some will not. Goals change with external realities and/ or internal factors. Purpose and values remain the same if we have thoughtfully identified them.

The second element is serendipity. Serendipity often is thought of as luck, as karma, as being in the right place at the right time. It feels random, and at first glance it appears that purpose and serendipity are complete opposites and do not intersect. Serendipity is, however, not just luck. It is an ability to distinguish events and observations in meaningful ways. It is a close relative of creativity and benefits from sloppiness, playfulness, tinkering, and discussion. It cannot exist in a vacuum. History is replete with serendipitous discoveries. It is thought that James Watson and Francis Crick would never have been able to elucidate the nature of DNA without sharing offices with people with whom they argued daily. In fact, figuring out the DNA structure was not even the main focus of their laboratories. It was just a side angle that several people loved to think about. Appreciating serendipity by being truly open to opportunities that are out on the wings brings experiences that are deeply rewarding even if not planned. I had no idea at all, no plan, no goal of serving as president of the American Academy of Dermatology or as Department Chair, and yet these happened. These experiences have allowed me to work on my purpose as I have defined it. How can you harness serendipity in your own life? My philosophy may be somewhat simple, but I think if you show up every day doing the best job you can at the tasks on hand, doors will appear, at odd intervals and in odd directions. You must be open enough and in tune with your purpose to an extent that you can sense the direction in which to turn and what doorways through which to walk.

The third element is curiosity. One definition is that curiosity is the motivation to learn new information. Another definition is that curiosity is a special form of information seeking distinguished by the fact that it is internally motivated. We are all familiar with intellectual curiosity. For example, a patient has a basal cell carcinoma on the upper back. What does the literature say about the cure rates of various treatments for that particular tumor? In addition, we can be curious about other things as well. Is it a really small tumor? How was it found and why is the patient anxious? Why does it make me irritated that the patient is worried about such a small, easily treated tumor? Or is it a large neglected tumor? Why was it not treated before? Why does it make me sad that it is so large? Why does it annoy me that I have a difficult situation to manage? Being able to define an emotional reaction by being curious about its presence helps us manage destructive responses and promote more positive outcomes. This curiosity is related to emotional intelligence and is mindfully harnessed by effective leaders. Curiosity will get you through tough days when your office team is stressed and the tough years that are complicated by professional and personal challenges.

Curiosity also will help you identify your purpose and harness serendipity, and so we come full circle with our 3 elements: purpose, serendipity, and curiosity.

My wish for all of you is that when you are at the tail end of your career, you will look back and say, “This has been a great ride.” I am very grateful that I can acknowledge this for myself. I have been so fortunate to have found dermatology, where I can go to work every day making a difference for patients in a stimulating environment with good colleagues. One of my values is to try and make life better in some way for everyone around me, even if it is just a smile at the start of the workday. As I look back, this value has allowed me to meet interesting people, hear fascinating stories, make good friends, and have enduring relationships. I have held onto fellow travelers, and we have supported each other through tough times as well as celebrated together the good times.

Nurturing a satisfying career includes these essential fundamentals. First, accept the reality of constant change. Second, develop productive relationships with fellow travelers. And third and most importantly, go forth with purpose, serendipity, and curiosity.