The Royal Swedish Academy of Sciences and the Crafoord Foundation in Lund has awarded Daniel Kastner, MD, PhD, its 2021 Crafoord Prize in Polyarthritis, “for establishing the concept of autoinflammatory diseases.” The prize, named after the donor Holger Crafoord because of his bout with severe rheumatoid arthritis toward the end of his life, is for 6 million Swedish kronor (approximately USD $700,000).

Dr. Kastner, scientific director at the U.S. National Human Genome Research Institute’s division of intramural research, received the award for identifying the mechanisms responsible for familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and other diagnoses within the group of autoinflammatory diseases.

“Dan Kastner is often called the father of autoinflammatory diseases, a title that he thoroughly deserves. His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases from which patients previously suffered enormously, sometimes leading to premature death,” Olle Kämpe, chair of the prize committee, said in a press announcement.

While the Crafoord Prize normally is awarded on a 3-year rotating basis for achievements in mathematics and astronomy, geosciences, and biosciences, the prize in polyarthritis is “only awarded when there has been scientific progress that motivates a prize,” according to the press release.

[email protected]

The Royal Swedish Academy of Sciences and the Crafoord Foundation in Lund has awarded Daniel Kastner, MD, PhD, its 2021 Crafoord Prize in Polyarthritis, “for establishing the concept of autoinflammatory diseases.” The prize, named after the donor Holger Crafoord because of his bout with severe rheumatoid arthritis toward the end of his life, is for 6 million Swedish kronor (approximately USD $700,000).

Dr. Kastner, scientific director at the U.S. National Human Genome Research Institute’s division of intramural research, received the award for identifying the mechanisms responsible for familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and other diagnoses within the group of autoinflammatory diseases.

“Dan Kastner is often called the father of autoinflammatory diseases, a title that he thoroughly deserves. His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases from which patients previously suffered enormously, sometimes leading to premature death,” Olle Kämpe, chair of the prize committee, said in a press announcement.

While the Crafoord Prize normally is awarded on a 3-year rotating basis for achievements in mathematics and astronomy, geosciences, and biosciences, the prize in polyarthritis is “only awarded when there has been scientific progress that motivates a prize,” according to the press release.

[email protected]

The Royal Swedish Academy of Sciences and the Crafoord Foundation in Lund has awarded Daniel Kastner, MD, PhD, its 2021 Crafoord Prize in Polyarthritis, “for establishing the concept of autoinflammatory diseases.” The prize, named after the donor Holger Crafoord because of his bout with severe rheumatoid arthritis toward the end of his life, is for 6 million Swedish kronor (approximately USD $700,000).

Dr. Kastner, scientific director at the U.S. National Human Genome Research Institute’s division of intramural research, received the award for identifying the mechanisms responsible for familial Mediterranean fever, tumor necrosis factor receptor–associated periodic syndrome, and other diagnoses within the group of autoinflammatory diseases.

“Dan Kastner is often called the father of autoinflammatory diseases, a title that he thoroughly deserves. His discoveries have taught us a great deal about the immune system and its functions, contributing to effective treatments that reduce the symptoms of diseases from which patients previously suffered enormously, sometimes leading to premature death,” Olle Kämpe, chair of the prize committee, said in a press announcement.

While the Crafoord Prize normally is awarded on a 3-year rotating basis for achievements in mathematics and astronomy, geosciences, and biosciences, the prize in polyarthritis is “only awarded when there has been scientific progress that motivates a prize,” according to the press release.

[email protected]

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

The pathogenesis of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not yet completely understood. Thus far, it is known to affect multiple organ systems, including gastrointestinal, neurological, and cardiovascular, with typical clinical symptoms of COVID-19 including fever, cough, myalgia, headache, anosmia, and diarrhea.¹ This multiorgan attack may be secondary to an exaggerated inflammatory reaction with vasculopathy and possibly a hypercoagulable state. Skin manifestations also are prevalent in COVID-19, and they often result in polymorphous presentations.² This article aims to summarize cutaneous clinical signs of COVID-19 so that dermatologists can promptly identify and manage COVID-19 and prevent its spread.

Methods

A PubMed search of articles indexed for MEDLINE was conducted on June 30, 2020. The literature included observational studies, case reports, and literature reviews from January 1, 2020, to June 30, 2020. Search terms included COVID-19, SARS-CoV-2, and coronavirus used in combination with cutaneous, skin, and dermatology. All of the resulting articles were then reviewed for relevance to the cutaneous manifestations of COVID-19. Only confirmed cases of COVID-19 infection were included in this review; suspected unconfirmed cases were excluded. Further exclusion criteria included articles that discussed dermatology in the time of COVID-19 that did not explicitly address its cutaneous manifestations. The remaining literature was evaluated to provide dermatologists and patients with a concise resource for the cutaneous signs and symptoms of COVID-19. Data extracted from the literature included geographic region, number of patients with skin findings, status of COVID-19 infection and timeline, and cutaneous signs. If a cutaneous sign was not given a clear diagnosis in the literature, the senior authors (A.L. and J.J.) assigned it to its most similar classification to aid in ease of understanding and clarity for the readers.

Results

A search of the key terms resulted in 75 articles published in the specified date range. After excluding overtly irrelevant articles and dermatologic conditions in the time of COVID-19 without confirmed SARS-CoV-2 infection, 25 articles ultimately met inclusion criteria. Relevant references from the articles also were explored for cutaneous dermatologic manifestations of COVID-19. Cutaneous manifestations that were repeatedly reported included chilblainlike lesions; acrocyanosis; urticaria; pityriasis rosea–like cutaneous eruption; erythema multiforme–like, vesiculopapular, and morbilliform eruptions; petechiae; livedo reticularis; and purpuric livedo reticularis (dermatologists may label this stellate purpura). Fewer but nonetheless notable cases of androgenic alopecia, periorbital dyschromia, and herpes zoster exacerbations also were documented. The Table summarizes the reported integumentary findings. The eTable groups the common findings and describes patient age, time to onset of cutaneous sign, and any prognostic significance as seen in the literature.

Chilblainlike Lesions and Acrocyanosis
Chilblainlike lesions are edematous eruptions of the fingers and toes. They usually do not scar and are described as erythematous to violaceous papules and macules with possible bullae on the digits. Skin biopsies demonstrate a histopathologic pattern of vacuolar interface dermatitis with necrotic keratinocytes and a thickened basement membrane. Lymphocytic infiltrate presents in a perieccrine distribution, occasionally with plasma cells. The dermatopathologic findings mimic those of chilblain lupus but lack dermal edema.³

These eruptions have been reported in cases of COVID-19 that more frequently affect children and young adults. They usually resolve over the course of viral infection, averaging within 14 days. Chilblainlike eruptions often are associated with pruritus or pain. They commonly are asymmetrical and appear more often on the toes than the fingers.⁴ In cases of COVID-19 that lack systemic symptoms, chilblainlike lesions have been seen on the dorsal fingers as the first presenting sign of infection.⁵

Acral erythema and chilblainlike lesions frequently have been associated with milder infection. Another positive prognostic indicator is the manifestation of these signs in younger individuals.³

Morbilliform Exanthem
The morbilliform exanthem associated with COVID-19 also typically presents in patients with milder disease. It often affects the buttocks, lower abdomen, and thighs, but spares the palms, soles, and mucosae.⁴ This skin sign, which may start out as a generalized morbilliform exanthem, has been seen to morph into macular hemorrhagic purpura on the legs. These cutaneous lesions typically spontaneously resolve.⁸

In a case report by Najarian,⁶ a morbilliform exanthem was seen on the legs, arms, and trunk of a patient who was otherwise asymptomatic but tested positive for COVID-19. The morbilliform exanthem then became confluent on the trunk. Notably, the patient reported pain of the hands and feet.⁶

Another case report described a patient with edematous annular plaques on the palms, neck, and upper extremities who presented solely with fever.⁷ The biopsy specimen was nonspecific but indicated a viral exanthem. Histopathology showed perivascular lymphocytic infiltrate, dermal edema and vacuoles, spongiosis, dyskeratotic basilar keratinocytes, and few neutrophils without eosinophils.⁷

Eczematous Eruption
A confluent eczematous eruption in the flexural areas, the antecubital fossae, and axillary folds has been found in COVID-19 patients.^21,22 An elderly patient with severe COVID-19 developed a squamous erythematous periumbilical patch 1 day after hospital admission. The cutaneous eruption rapidly progressed to digitate scaly plaques on the trunk, thighs, and flank. A biopsy specimen showed epidermal spongiosis, vesicles containing lymphocytes, and Langerhans cells. The upper dermis demonstrated a lymphohistiocytic infiltrate.²³

Pityriasis Rosea–Like Eruption
In Iran, a COVID-19–infected patient developed an erythematous papulosquamous eruption with a herald patch and trailing scales 3 days after viral symptoms, resembling that of pityriasis rosea.²⁴ Nests of Langerhans cells within the epidermis are seen in many viral exanthems, including cases of COVID-19 and pityriasis rosea.²⁵

Urticaria
According to a number of case reports, urticarial lesions have been the first presenting sign of COVID-19 infection, most resolving with antihistamines.^10,11 Some patients with more severe symptoms have had widespread urticaria. An urticarial exanthem appearing on the bilateral thighs and buttocks may be the initial sign of infection.^12,15 Pruritic erythematous plaques over the face and acral areas is another initial sign. Interestingly, pediatric patients have reported nonpruritic urticaria.⁹

Urticaria also has been seen as a late dermatologic sign of viral infection. After battling relentless viral infection for 1 month, a pruritic, confluent, ill-defined eruption appeared along a patient’s trunk, back, and proximal extremities. Histopathologic examination concluded a perivascular lymphocytic infiltrate and dilated vessels in the dermis. The urticaria resolved a week later, and the patient’s nasopharyngeal swab finally came back negative.¹³

Vesiculopapular Eruption
Vesicles mimicking those of chickenpox have been reported. A study of 375 confirmed cases of COVID-19 by Galván Casas et al¹² showed a 9% incidence of this vesicular eruption. A study by Sachdeva et al⁸ revealed vesicular eruptions in 25 of 72 patients. Pruritic papules and vesicles may resemble Grover disease. This cutaneous sign may be seen in the submammary folds, on the hips, or diffusely over the body.

Erythema Multiforme–Like Eruption
Targetoid lesions similar to those of erythema multiforme erupted in 2 of 27 patients with mild COVID-19 infection in a review by Wollina et al.⁴ In a study of 4 patients with erythema multiforme–like eruptions after COVID-19 symptoms resolved, 3 had palatal petechiae. Two of 4 patients had pseudovesicles in the center of the erythematous targetoid patches.²⁶ Targetoid lesions on the extremities have been reported in pediatric patients with COVID-19 infections. These patients often present without any typical viral symptoms but rather just a febrile exanthem or exanthem alone. Thus, to minimize spread of the virus, it is vital to recognize COVID-19 infection early in patients with a viral exanthem during the time of high COVID-19 incidence.⁴

Livedo Reticularis
In the United States, a case series reported 2 patients with transient livedo reticularis throughout the course of COVID-19 infection. The cutaneous eruption resembled erythema ab igne, but there was no history of exposure to heat.¹⁶

Stellate Purpura
In severe COVID-19 infection, a reticulated nonblanching purpura on the buttocks has been reported to demonstrate pauci-inflammatory vascular thrombosis, complement membrane attack complex deposition, and endothelial injury on dermatopathology. Stellate purpura on palmoplantar surfaces also has shown arterial thrombosis in the deep dermis due to complement deposition.¹⁷

Petechiae and Purpura
A morbilliform exanthem may develop into significant petechiae in the popliteal fossae, buttocks, and thighs. A punch biopsy specimen demonstrates a perivascular lymphocytic infiltrate with erythrocyte extravasation and papillary dermal edema with dyskeratotic cells.¹⁸ Purpura of the lower extremities may develop, with histopathology showing fibrinoid necrosis of small vessel walls, neutrophilic infiltrate with karyorrhexis, and granular complement deposition.¹⁹

In Thailand, a patient was misdiagnosed with dengue after presenting with petechiae and low platelet count.²⁰ Further progression of the viral illness resulted in respiratory symptoms. Subsequently, the patient tested positive for COVID-19. This case demonstrates that cutaneous signs of many sorts may be the first presenting signs of COVID-19, even prior to febrile symptoms.²⁰

Androgenic Alopecia
Studies have shown that androgens are related in the pathogenesis of COVID-19. Coronavirus disease 2019 uses a cellular co-receptor, TMPRSS2, which is androgen regulated.²⁷ In a study of 41 males with COVID-19, 29 had androgenic alopecia. However, this is only a correlation, and causation cannot be concluded here. It cannot be determined from this study whether androgenic alopecia is a risk factor, result of COVID-19, or confounder.²⁸

Exaggerated Herpes Zoster
Shors²⁹ reported a herpes zoster eruption in a patient who had symptoms of COVID-19 for 1 week. Further testing confirmed COVID-19 infection, and despite prompt treatment with valacyclovir, the eruption was slow to resolve. The patient then experienced severe postherpetic neuralgia for more than 4 weeks, even with treatment with gabapentin and lidocaine. It is hypothesized that because of the major inflammatory response caused by COVID-19, an exaggerated inflammation occurred in the dorsal root ganglion, resulting in relentless herpes zoster infection.²⁹

Mottled Skin
Born at term, a 15-day-old neonate presented with sepsis and mottling of the skin. The patient did not have any typical COVID-19 symptoms, such as diarrhea or cough, but tested positive for COVID-19.³⁰

Periorbital Dyschromia
Kalner and Vergilis³¹ reported 2 cases of periorbital dyschromia prior to any other COVID-19 infection symptoms. The discoloration improved with resolution of ensuing viral symptoms.³¹

Comment

Many dermatologic signs of COVID-19 have been identified. Their individual frequency and association with viral severity will become more apparent as more cases are reported. So far during this pandemic, common dermatologic manifestations have been polymorphic in clinical presentation.

Onset of Skin Manifestations
The timeline of skin signs and COVID-19 symptoms varies from the first reported sign to weeks after symptom resolution. In the Region of Murcia, Spain, Pérez-Suárez et al¹⁴ collected data on cutaneous signs of patients with COVID-19. Of the patients studied, 9 had tests confirming COVID-19 infection. Truncal urticaria, sacral ulcers, acrocyanosis, and erythema multiforme were all reported in patients more than 2 weeks after symptom onset. One case of tinea infection also was reported 4 days after fever and respiratory symptoms began.¹⁴

Presentation
Coronavirus disease 2019 has affected the skin of both the central thorax and peripheral locations. In a study of 72 patients with cutaneous signs of COVID-19 by Sachdeva et al,⁸ a truncal distribution was most common, but 14 patients reported acral site involvement. Sachdeva et al⁸ reported urticarial reactions in 7 of 72 patients with cutaneous signs. A painful acral cyanosis was seen in 11 of 72 patients. Livedo reticularis presented in 2 patients, and only 1 patient had petechiae. Cutaneous signs were the first indicators of viral infection in 9 of 72 patients; 52 patients presented with respiratory symptoms first. All of the reported cutaneous signs spontaneously resolved within 10 days.⁸

Recalcati³² reviewed 88 patients with COVID-19, and 18 had cutaneous signs at initial onset of viral infection or during hospitalization. The most common integumentary sign reported in this study was erythema, followed by diffuse urticaria, and then a vesicular eruption resembling varicella infection.³²

Some less common phenomena have been identified in patients with COVID-19, including androgenic alopecia, exaggerated herpes zoster and postherpetic neuralgia, mottled skin, and periorbital dyschromia. Being aware of these complications may help in early treatment, diagnosis, and even prevention of viral spread.

Pathogenesis of Skin Manifestations
Few breakthroughs have been made in understanding the pathogenesis of skin manifestations of SARS-CoV-2. Acral ischemia may be a manifestation of COVID-19’s association with hypercoagulation. Increasing fibrinogen and prothrombin times lead to disseminated intravascular coagulation and microthrombi. These tiny blood clots then lodge in blood vessels and cause acral cyanosis and subsequent gangrene.² The proposed mechanism behind this clinical manifestation in younger populations is the hypercoagulable state that COVID-19 creates. Conversely, acral erythema and chilblainlike lesions in older patients are thought to be from acral ischemia as a response to insufficient type 1 interferons. This pathophysiologic mechanism is indicative of a worse prognosis due to the large role that type 1 interferons play in antiviral responses. Coronavirus disease 2019 similarly triggers type 1 interferons; thus, their efficacy positively correlates with good disease prognosis.³

Similarly, the pathogenesis for livedo reticularis in patients with COVID-19 can only be hypothesized. Infected patients are in a hypercoagulable state, and in these cases, it was uncertain whether this was due to a disseminated intravascular coagulation, cold agglutinins, cryofibrinogens, or lupus anticoagulant.¹⁶

Nonetheless, it can be difficult to separate the primary event between vasculopathy or vasculitis in larger vessel pathology specimens. Some of the studies’ pathology reports discuss a granulocytic infiltrate and red blood cell extravasation, which represent small vessel vasculitis. However, the gangrene and necrosing livedo represent vasculopathy events. A final conclusion about the pathogenesis cannot be made without further clinical and histopathologic evaluation.

Histopathology
Biopsy specimens of reported morbilliform eruptions have demonstrated thrombosed vessels with evidence of necrosis and granulocytic infiltrate.²⁵ Another biopsy specimen of a widespread erythematous exanthem demonstrated extravasated red blood cells and vessel wall damage similar to thrombophilic arteritis. Other reports of histopathology showed necrotic keratinocytes and lymphocytic satellitosis at the dermoepidermal junction, resembling Grover disease. These cases demonstrating necrosis suggest a strong cytokine reaction from the virus.²⁵ A concern with these biopsy findings is that morbilliform eruptions generally show dilated vessels with lymphocytes, and these biopsy findings are consistent with a cutaneous small vessel vasculitis. Additionally, histopathologic evaluation of purpuric eruptions has shown erythrocyte extravasation and granulocytic infiltrate indicative of a cutaneous small vessel vasculitis.

Although most reported cases of cutaneous signs of COVID-19 do not have histopathologic reports, Yao et al³³ conducted a dermatopathologic study that investigated the tissue in deceased patients who had COVID-19. This pathology showed hyaline thrombi within the small vessels of the skin, likely leading to the painful acral ischemia. Similarly, Yao et al³³ reported autopsies finding hyaline thrombi within the small vessels of the lungs. More research should be done to explore this pathogenesis as part of prognostic factors and virulence.

Conclusion

Cutaneous signs may be the first reported symptom of COVID-19 infection, and dermatologists should be prepared to identify them. This review may be used as a guide for physicians to quickly identify potential infection as well as further understand the pathogenesis related to COVID-19. Future research is necessary to determine the dermatologic pathogenesis, infectivity, and prevalence of cutaneous manifestations of COVID-19. It also will be important to explore if vasculopathic lesions predict more severe multisystem disease.

Office-based phototherapy practices have closed or are operating below capacity because of the coronavirus disease 2019 (COVID-19) pandemic.¹ Social distancing measures to reduce virus transmission are a significant driving factor.^1-3 In the age of biologics, other options requiring fewer patient visits are available, such as UVB phototherapy. UV phototherapy is considered first line when more than 10% of the body surface area is affected.⁴ Although phototherapy often is performed in the office, it also may be delivered at home.² Home-based phototherapy is safe, effective, and similar in cost to office-based phototherapy.⁴ Currently, there are limited COVID-19–specific guidelines for home-based phototherapy.

The risks and sequelae of COVID-19 are still being investigated, with cases varying by location. As such, local and national public health recommendations are evolving. Dermatologists must make individualized decisions about practice services, as local restrictions differ. As office-based phototherapy services may struggle to implement mitigation strategies, home-based phototherapy is an increasingly viable treatment option.^1,4,5 Patient benefits of home therapy include improved treatment compliance; greater patient satisfaction; reduced travel/waiting time; and reduced long-term cost, including co-pays, depending on insurance coverage.^2,4

We aim to provide recommendations on home-based phototherapy during the pandemic. Throughout the decision-making process, careful consideration of safety, risks, benefits, and treatment options for physicians, staff, and patients will be vital to the successful implementation of home-based phototherapy. Our recommendations are based on maximizing benefits and minimizing risks.

Considerations for Physicians

Physicians should take the following steps when assessing if home phototherapy is an option for each patient.^1,2,4

• Determine patient eligibility for phototherapy treatment if currently not on phototherapy

• Carefully review patient and provider requirements for home phototherapy supplier

• Review patient history of treatment compliance

• Determine insurance coverage and consider exclusion criteria

• Review prior treatments

• Provide education on side effects

• Provide education on signs of adequate treatment response

• Indicate the type of UV light and unit on the prescription

• Consider whether the patient is in the maintenance or initiation phase when providing recommendations

• Work with the supplier if the light therapy unit is denied by submitting an appeal or prescribing a different unit

• Follow up with telemedicine to assess treatment effectiveness and monitor for adverse effects

Considerations for Patients

Counsel patients to weigh the risks and benefits of home phototherapy prescription and usage.^1,2,4

• Evaluate cost

• Carefully review patient and provider requirements for home phototherapy supplier

• Ensure a complete understanding of treatment schedule

• Properly utilize protective equipment (eg, genital shields for men, eye shields for all)

• Avoid sharing phototherapy units with household members

• Disinfect and maintain units

• Maintain proper ventilation of spaces

• Maintain treatment log

• Attend follow-up

Treatment Alternatives

For patients with severe psoriasis, there are alternative treatments to office and home phototherapy. Biologics, immunosuppressive therapies, and other treatment options may be considered on a case-by-case basis.^3,4,6 Currently, recommendations for the risk of COVID-19 with biologics or systemic immunosuppressive therapies remains inconsistent and should be carefully considered when providing alternative treatments.^7-11

Final Thoughts

As restrictions are lifted according to local public health measures, prepandemic office phototherapy practices may resume operations. Home phototherapy is a practical and effective alternative for treatment of psoriasis when access to the office setting is limited.

Office-based phototherapy practices have closed or are operating below capacity because of the coronavirus disease 2019 (COVID-19) pandemic.¹ Social distancing measures to reduce virus transmission are a significant driving factor.^1-3 In the age of biologics, other options requiring fewer patient visits are available, such as UVB phototherapy. UV phototherapy is considered first line when more than 10% of the body surface area is affected.⁴ Although phototherapy often is performed in the office, it also may be delivered at home.² Home-based phototherapy is safe, effective, and similar in cost to office-based phototherapy.⁴ Currently, there are limited COVID-19–specific guidelines for home-based phototherapy.

The risks and sequelae of COVID-19 are still being investigated, with cases varying by location. As such, local and national public health recommendations are evolving. Dermatologists must make individualized decisions about practice services, as local restrictions differ. As office-based phototherapy services may struggle to implement mitigation strategies, home-based phototherapy is an increasingly viable treatment option.^1,4,5 Patient benefits of home therapy include improved treatment compliance; greater patient satisfaction; reduced travel/waiting time; and reduced long-term cost, including co-pays, depending on insurance coverage.^2,4

We aim to provide recommendations on home-based phototherapy during the pandemic. Throughout the decision-making process, careful consideration of safety, risks, benefits, and treatment options for physicians, staff, and patients will be vital to the successful implementation of home-based phototherapy. Our recommendations are based on maximizing benefits and minimizing risks.

Considerations for Physicians

Physicians should take the following steps when assessing if home phototherapy is an option for each patient.^1,2,4

• Determine patient eligibility for phototherapy treatment if currently not on phototherapy

• Carefully review patient and provider requirements for home phototherapy supplier

• Review patient history of treatment compliance

• Determine insurance coverage and consider exclusion criteria

• Review prior treatments

• Provide education on side effects

• Provide education on signs of adequate treatment response

• Indicate the type of UV light and unit on the prescription

• Consider whether the patient is in the maintenance or initiation phase when providing recommendations

• Work with the supplier if the light therapy unit is denied by submitting an appeal or prescribing a different unit

• Follow up with telemedicine to assess treatment effectiveness and monitor for adverse effects

Considerations for Patients

Counsel patients to weigh the risks and benefits of home phototherapy prescription and usage.^1,2,4

• Evaluate cost

• Carefully review patient and provider requirements for home phototherapy supplier

• Ensure a complete understanding of treatment schedule

• Properly utilize protective equipment (eg, genital shields for men, eye shields for all)

• Avoid sharing phototherapy units with household members

• Disinfect and maintain units

• Maintain proper ventilation of spaces

• Maintain treatment log

• Attend follow-up

Treatment Alternatives

For patients with severe psoriasis, there are alternative treatments to office and home phototherapy. Biologics, immunosuppressive therapies, and other treatment options may be considered on a case-by-case basis.^3,4,6 Currently, recommendations for the risk of COVID-19 with biologics or systemic immunosuppressive therapies remains inconsistent and should be carefully considered when providing alternative treatments.^7-11

Final Thoughts

As restrictions are lifted according to local public health measures, prepandemic office phototherapy practices may resume operations. Home phototherapy is a practical and effective alternative for treatment of psoriasis when access to the office setting is limited.

Office-based phototherapy practices have closed or are operating below capacity because of the coronavirus disease 2019 (COVID-19) pandemic.¹ Social distancing measures to reduce virus transmission are a significant driving factor.^1-3 In the age of biologics, other options requiring fewer patient visits are available, such as UVB phototherapy. UV phototherapy is considered first line when more than 10% of the body surface area is affected.⁴ Although phototherapy often is performed in the office, it also may be delivered at home.² Home-based phototherapy is safe, effective, and similar in cost to office-based phototherapy.⁴ Currently, there are limited COVID-19–specific guidelines for home-based phototherapy.

The risks and sequelae of COVID-19 are still being investigated, with cases varying by location. As such, local and national public health recommendations are evolving. Dermatologists must make individualized decisions about practice services, as local restrictions differ. As office-based phototherapy services may struggle to implement mitigation strategies, home-based phototherapy is an increasingly viable treatment option.^1,4,5 Patient benefits of home therapy include improved treatment compliance; greater patient satisfaction; reduced travel/waiting time; and reduced long-term cost, including co-pays, depending on insurance coverage.^2,4

We aim to provide recommendations on home-based phototherapy during the pandemic. Throughout the decision-making process, careful consideration of safety, risks, benefits, and treatment options for physicians, staff, and patients will be vital to the successful implementation of home-based phototherapy. Our recommendations are based on maximizing benefits and minimizing risks.

Considerations for Physicians

Physicians should take the following steps when assessing if home phototherapy is an option for each patient.^1,2,4

• Determine patient eligibility for phototherapy treatment if currently not on phototherapy

• Carefully review patient and provider requirements for home phototherapy supplier

• Review patient history of treatment compliance

• Determine insurance coverage and consider exclusion criteria

• Review prior treatments

• Provide education on side effects

• Provide education on signs of adequate treatment response

• Indicate the type of UV light and unit on the prescription

• Consider whether the patient is in the maintenance or initiation phase when providing recommendations

• Work with the supplier if the light therapy unit is denied by submitting an appeal or prescribing a different unit

• Follow up with telemedicine to assess treatment effectiveness and monitor for adverse effects

Considerations for Patients

Counsel patients to weigh the risks and benefits of home phototherapy prescription and usage.^1,2,4

• Evaluate cost

• Carefully review patient and provider requirements for home phototherapy supplier

• Ensure a complete understanding of treatment schedule

• Properly utilize protective equipment (eg, genital shields for men, eye shields for all)

• Avoid sharing phototherapy units with household members

• Disinfect and maintain units

• Maintain proper ventilation of spaces

• Maintain treatment log

• Attend follow-up

Treatment Alternatives

For patients with severe psoriasis, there are alternative treatments to office and home phototherapy. Biologics, immunosuppressive therapies, and other treatment options may be considered on a case-by-case basis.^3,4,6 Currently, recommendations for the risk of COVID-19 with biologics or systemic immunosuppressive therapies remains inconsistent and should be carefully considered when providing alternative treatments.^7-11

Final Thoughts

As restrictions are lifted according to local public health measures, prepandemic office phototherapy practices may resume operations. Home phototherapy is a practical and effective alternative for treatment of psoriasis when access to the office setting is limited.

The order Lepidoptera (phylum Arthropoda, class Hexapoda) is comprised of moths and butterflies.¹ Lepidopterism refers to a range of adverse medical conditions resulting from contact with these insects, typically during the caterpillar (larval) stage. It involves multiple pathologic mechanisms, including direct toxicity of venom and mechanical irritant effects.² Erucism has been defined as any reaction caused by contact with caterpillars or any reaction limited to the skin caused by contact with caterpillars, butterflies, or moths. Lepidopterism can mean any reaction to caterpillars or moths, referring only to reactions from contact with scales or hairs from adult moths or butterflies, or referring only to cases with systemic signs and symptoms (eg, rhinoconjunctival or asthmatic symptoms, angioedema and anaphylaxis, hemorrhagic diathesis) with or without cutaneous findings, resulting from contact with any lepidopteran source.¹ Strictly speaking, erucism should refer to any reaction from caterpillars and lepidopterism to reactions from moths or butterflies. Because reactions to both larval and adult lepidoptera can cause a variety of either cutaneous and/or systemic symptoms, classifying reactions into erucism or lepidopterism is only of academic interest.¹

We report a documented case of lepidopterism in a patient with acute cutaneous lesions following exposure to an adult-stage black butterfly (Hylesia nigricans).

Case Report

A 21-year-old oil well worker presented with pruritic skin lesions on the right arm and flank of 3 hours’ duration. He reported that a black butterfly had perched on his arm while he was working and left a considerable number of small yellowish hairs on the skin, after which an intense pruritus and skin lesions began to develop. He denied other associated symptoms. Physical examination revealed numerous 1- to 2-mm, nonconfluent, erythematous and edematous papules on the right forearm, arm (Figure 1A), and flank. Some abrasions of the skin due to scratching and crusting were noted (Figure 1B). A skin biopsy from the right arm showed a superficial perivascular dermatitis with a mixed infiltrate of polymorphonuclear predominance with eosinophils (Figure 2A). Importantly, a structure resembling an urticating spicule was identified in the stratum corneum (Figure 2B); spicules are located on the abdomen of arthropods and are associated with an inflammatory response in human skin.

Based on the patient’s history of butterfly exposure, clinical presentation of the lesions, and histopathologic findings demonstrating the presence of the spicules, the diagnosis of lepidopterism was confirmed. The patient was treated with oral antihistamines and topical steroids for 1 week with complete resolution of the lesions.

Comment

Epidemiology of Envenomation
Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, such as dermatitis caused by contact with the skin (erucism or lepidopterism). Caterpillar envenomation is common, but this phenomenon rarely has been studied due to few reported cases, which hinders a complete understanding of the problem.³

The order Lepidoptera comprises 2 suborders: Rhopalocera, with adult specimens that fly during the daytime (butterflies), and Heterocera, which are largely nocturnal (moths). The stages of development include egg, larva (caterpillar), pupa (chrysalis), and adult (imago), constituting a holometabolic life cycle.⁴ Adult butterflies and moths represent the reproductive stage of lepidoptera.

The pathology of lepidopterism is attributed to contact with fluids such as hemolymph and secretions from the spicules, with histamine being identified as the main causative component.³ During the reproductive stage, female insects approach light sources and release clouds of bristles from their abdomens that can penetrate human skin and cause an irritating dermatitis.⁵ Lepidopterism can occur following contact with bristles from insects of the Hylesia genus (Saturniidae family), such as in our patient.^3,6 Epidemic outbreaks have been reported in several countries, mainly Argentina, Brazil, and Venezuela.⁵ The patient was located in Colombia, a country without any reported cases of lepidopterism from the black butterfly (H nigricans). Cutaneous reactions to lepidoptera insects come in many forms, most commonly presenting as a mild stinging reaction with a papular eruption, pruritic urticarial papules and plaques, or scaly erythematous papules and plaques in exposed areas.⁷

Histopathologic Findings
The histology of lepidoptera exposure is nonspecific, typically demonstrating epidermal edema, superficial perivascular lymphocytic infiltrate, and eosinophils. Epidermal necrosis and vasculitis rarely are seen. Embedded spines from Hylesia insects have been described.⁷ The histopathologic examination generally reveals a foreign body reaction in addition to granulomas.³

Therapy
The use of oral antihistamines is indicated for the control of pruritus, and topical treatment with cold compresses, baths, and corticosteroid creams is recommended.^3,8,9

Conclusion

We report the case of a patient with lepidopterism, a rare entity confirmed histologically with documentation of a spicule in the stratum corneum in the patient’s biopsy. Changes due to urbanization and industrialization have a closer relationship with various animal species that are pathogenic to humans; therefore, we encourage dermatologists to be aware of these diseases.

The order Lepidoptera (phylum Arthropoda, class Hexapoda) is comprised of moths and butterflies.¹ Lepidopterism refers to a range of adverse medical conditions resulting from contact with these insects, typically during the caterpillar (larval) stage. It involves multiple pathologic mechanisms, including direct toxicity of venom and mechanical irritant effects.² Erucism has been defined as any reaction caused by contact with caterpillars or any reaction limited to the skin caused by contact with caterpillars, butterflies, or moths. Lepidopterism can mean any reaction to caterpillars or moths, referring only to reactions from contact with scales or hairs from adult moths or butterflies, or referring only to cases with systemic signs and symptoms (eg, rhinoconjunctival or asthmatic symptoms, angioedema and anaphylaxis, hemorrhagic diathesis) with or without cutaneous findings, resulting from contact with any lepidopteran source.¹ Strictly speaking, erucism should refer to any reaction from caterpillars and lepidopterism to reactions from moths or butterflies. Because reactions to both larval and adult lepidoptera can cause a variety of either cutaneous and/or systemic symptoms, classifying reactions into erucism or lepidopterism is only of academic interest.¹

We report a documented case of lepidopterism in a patient with acute cutaneous lesions following exposure to an adult-stage black butterfly (Hylesia nigricans).

Case Report

A 21-year-old oil well worker presented with pruritic skin lesions on the right arm and flank of 3 hours’ duration. He reported that a black butterfly had perched on his arm while he was working and left a considerable number of small yellowish hairs on the skin, after which an intense pruritus and skin lesions began to develop. He denied other associated symptoms. Physical examination revealed numerous 1- to 2-mm, nonconfluent, erythematous and edematous papules on the right forearm, arm (Figure 1A), and flank. Some abrasions of the skin due to scratching and crusting were noted (Figure 1B). A skin biopsy from the right arm showed a superficial perivascular dermatitis with a mixed infiltrate of polymorphonuclear predominance with eosinophils (Figure 2A). Importantly, a structure resembling an urticating spicule was identified in the stratum corneum (Figure 2B); spicules are located on the abdomen of arthropods and are associated with an inflammatory response in human skin.

Based on the patient’s history of butterfly exposure, clinical presentation of the lesions, and histopathologic findings demonstrating the presence of the spicules, the diagnosis of lepidopterism was confirmed. The patient was treated with oral antihistamines and topical steroids for 1 week with complete resolution of the lesions.

Comment

Epidemiology of Envenomation
Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, such as dermatitis caused by contact with the skin (erucism or lepidopterism). Caterpillar envenomation is common, but this phenomenon rarely has been studied due to few reported cases, which hinders a complete understanding of the problem.³

The order Lepidoptera comprises 2 suborders: Rhopalocera, with adult specimens that fly during the daytime (butterflies), and Heterocera, which are largely nocturnal (moths). The stages of development include egg, larva (caterpillar), pupa (chrysalis), and adult (imago), constituting a holometabolic life cycle.⁴ Adult butterflies and moths represent the reproductive stage of lepidoptera.

The pathology of lepidopterism is attributed to contact with fluids such as hemolymph and secretions from the spicules, with histamine being identified as the main causative component.³ During the reproductive stage, female insects approach light sources and release clouds of bristles from their abdomens that can penetrate human skin and cause an irritating dermatitis.⁵ Lepidopterism can occur following contact with bristles from insects of the Hylesia genus (Saturniidae family), such as in our patient.^3,6 Epidemic outbreaks have been reported in several countries, mainly Argentina, Brazil, and Venezuela.⁵ The patient was located in Colombia, a country without any reported cases of lepidopterism from the black butterfly (H nigricans). Cutaneous reactions to lepidoptera insects come in many forms, most commonly presenting as a mild stinging reaction with a papular eruption, pruritic urticarial papules and plaques, or scaly erythematous papules and plaques in exposed areas.⁷

Histopathologic Findings
The histology of lepidoptera exposure is nonspecific, typically demonstrating epidermal edema, superficial perivascular lymphocytic infiltrate, and eosinophils. Epidermal necrosis and vasculitis rarely are seen. Embedded spines from Hylesia insects have been described.⁷ The histopathologic examination generally reveals a foreign body reaction in addition to granulomas.³

Therapy
The use of oral antihistamines is indicated for the control of pruritus, and topical treatment with cold compresses, baths, and corticosteroid creams is recommended.^3,8,9

Conclusion

We report the case of a patient with lepidopterism, a rare entity confirmed histologically with documentation of a spicule in the stratum corneum in the patient’s biopsy. Changes due to urbanization and industrialization have a closer relationship with various animal species that are pathogenic to humans; therefore, we encourage dermatologists to be aware of these diseases.

The order Lepidoptera (phylum Arthropoda, class Hexapoda) is comprised of moths and butterflies.¹ Lepidopterism refers to a range of adverse medical conditions resulting from contact with these insects, typically during the caterpillar (larval) stage. It involves multiple pathologic mechanisms, including direct toxicity of venom and mechanical irritant effects.² Erucism has been defined as any reaction caused by contact with caterpillars or any reaction limited to the skin caused by contact with caterpillars, butterflies, or moths. Lepidopterism can mean any reaction to caterpillars or moths, referring only to reactions from contact with scales or hairs from adult moths or butterflies, or referring only to cases with systemic signs and symptoms (eg, rhinoconjunctival or asthmatic symptoms, angioedema and anaphylaxis, hemorrhagic diathesis) with or without cutaneous findings, resulting from contact with any lepidopteran source.¹ Strictly speaking, erucism should refer to any reaction from caterpillars and lepidopterism to reactions from moths or butterflies. Because reactions to both larval and adult lepidoptera can cause a variety of either cutaneous and/or systemic symptoms, classifying reactions into erucism or lepidopterism is only of academic interest.¹

We report a documented case of lepidopterism in a patient with acute cutaneous lesions following exposure to an adult-stage black butterfly (Hylesia nigricans).

Case Report

A 21-year-old oil well worker presented with pruritic skin lesions on the right arm and flank of 3 hours’ duration. He reported that a black butterfly had perched on his arm while he was working and left a considerable number of small yellowish hairs on the skin, after which an intense pruritus and skin lesions began to develop. He denied other associated symptoms. Physical examination revealed numerous 1- to 2-mm, nonconfluent, erythematous and edematous papules on the right forearm, arm (Figure 1A), and flank. Some abrasions of the skin due to scratching and crusting were noted (Figure 1B). A skin biopsy from the right arm showed a superficial perivascular dermatitis with a mixed infiltrate of polymorphonuclear predominance with eosinophils (Figure 2A). Importantly, a structure resembling an urticating spicule was identified in the stratum corneum (Figure 2B); spicules are located on the abdomen of arthropods and are associated with an inflammatory response in human skin.

Based on the patient’s history of butterfly exposure, clinical presentation of the lesions, and histopathologic findings demonstrating the presence of the spicules, the diagnosis of lepidopterism was confirmed. The patient was treated with oral antihistamines and topical steroids for 1 week with complete resolution of the lesions.

Comment

Epidemiology of Envenomation
Although many tropical insects carry infectious diseases, cutaneous injury can occur by other mechanisms, such as dermatitis caused by contact with the skin (erucism or lepidopterism). Caterpillar envenomation is common, but this phenomenon rarely has been studied due to few reported cases, which hinders a complete understanding of the problem.³

The order Lepidoptera comprises 2 suborders: Rhopalocera, with adult specimens that fly during the daytime (butterflies), and Heterocera, which are largely nocturnal (moths). The stages of development include egg, larva (caterpillar), pupa (chrysalis), and adult (imago), constituting a holometabolic life cycle.⁴ Adult butterflies and moths represent the reproductive stage of lepidoptera.

The pathology of lepidopterism is attributed to contact with fluids such as hemolymph and secretions from the spicules, with histamine being identified as the main causative component.³ During the reproductive stage, female insects approach light sources and release clouds of bristles from their abdomens that can penetrate human skin and cause an irritating dermatitis.⁵ Lepidopterism can occur following contact with bristles from insects of the Hylesia genus (Saturniidae family), such as in our patient.^3,6 Epidemic outbreaks have been reported in several countries, mainly Argentina, Brazil, and Venezuela.⁵ The patient was located in Colombia, a country without any reported cases of lepidopterism from the black butterfly (H nigricans). Cutaneous reactions to lepidoptera insects come in many forms, most commonly presenting as a mild stinging reaction with a papular eruption, pruritic urticarial papules and plaques, or scaly erythematous papules and plaques in exposed areas.⁷

Histopathologic Findings
The histology of lepidoptera exposure is nonspecific, typically demonstrating epidermal edema, superficial perivascular lymphocytic infiltrate, and eosinophils. Epidermal necrosis and vasculitis rarely are seen. Embedded spines from Hylesia insects have been described.⁷ The histopathologic examination generally reveals a foreign body reaction in addition to granulomas.³

Therapy
The use of oral antihistamines is indicated for the control of pruritus, and topical treatment with cold compresses, baths, and corticosteroid creams is recommended.^3,8,9

Conclusion

We report the case of a patient with lepidopterism, a rare entity confirmed histologically with documentation of a spicule in the stratum corneum in the patient’s biopsy. Changes due to urbanization and industrialization have a closer relationship with various animal species that are pathogenic to humans; therefore, we encourage dermatologists to be aware of these diseases.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

Psoriasis is a chronic relapsing skin condition characterized by keratinocyte hyperproliferation and a chronic inflammatory cascade. Therefore, controlling inflammatory responses with systemic medications is beneficial in managing psoriatic lesions and their accompanying symptoms, especially in disease inadequately controlled by topicals. Ease of drug administration and treatment availability are benefits that systemic nonbiologic therapies may have over biologic therapies.

In 2020, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) published guidelines for managing psoriasis in adults with systemic nonbiologic therapies.¹ Dosing, efficacy, toxicity, drug-related interactions, and contraindications are addressed alongside evidence-based treatment recommendations. This review addresses current recommendations for systemic nonbiologics in psoriasis with a focus on the treatments approved by the US Food and Drug Administration (FDA): acitretin, apremilast, cyclosporine, and methotrexate (eTable). Fumaric acid esters and tofacitinib are FDA approved for psoriatic arthritis but not for plaque psoriasis. Additional long-term safety analyses of tofacitinib for plaque psoriasis were requested by the FDA. Dimethyl fumarate is approved by the European Medicines Agency for treatment of psoriasis and is among the first-line systemic treatments used in Germany.²

Selecting a Systemic Nonbiologic Agent

Methotrexate and apremilast have a strength level A recommendation for treating moderate to severe psoriasis in adults. However, methotrexate is less effective than biologic agents, including adalimumab and infliximab, for cutaneous psoriasis. Methotrexate is believed to improve psoriasis because of its direct immunosuppressive effect and inhibition of lymphoid cell proliferation. It typically is administered orally but can be administered subcutaneously for decreased gastrointestinal (GI) adverse effects. Compliance with close laboratory monitoring and lifestyle modifications, such as contraceptive use (because of teratogenicity) and alcohol cessation (because of the risk of liver damage) are essential in patients using methotrexate.

Apremilast, the most recently FDA-approved oral systemic medication for psoriasis, inhibits phosphodiesterase 4, subsequently decreasing inflammatory responses involving helper T cells T_H1 and T_H17 as well as type 1 interferon pathways. Apremilast is particularly effective in treating psoriasis with scalp and palmoplantar involvement.³ Additionally, it has an encouraging safety profile and is favorable in patients with multiple comorbidities.

Among the 4 oral agents, cyclosporine has the quickest onset of effect and has a strength level A recommendation for treating severe and recalcitrant psoriasis. Because of its high-risk profile, it is recommended for short periods of time, acute flares, or during transitions to safer long-term treatment. Patients with multiple comorbidities should avoid cyclosporine as a treatment option.

Acitretin, an FDA-approved oral retinoid, is an optimal treatment option for immunosuppressed patients or patients with HIV on antiretroviral therapy because it is not immunosuppressive.⁴ Unlike cyclosporine, acitretin is less helpful for acute flares because it takes 3 to 6 months to reach peak therapeutic response for treating plaque psoriasis. Similar to cyclosporine, acitretin can be recommended for severe psoriatic variants of erythrodermic, generalized pustular, and palmoplantar psoriasis. Acitretin has been reported to be more effective and have a more rapid onset of action in erythrodermic and pustular psoriasis than in plaque psoriasis.⁵

Patient Comorbidities

Psoriatic arthritis (PsA) is a common comorbidity that affects treatment choice. Patients with coexisting PsA could be treated with apremilast, as it is approved for both psoriasis and PsA. In a phase 3 randomized, controlled trial, American College of Rheumatology (ACR) 20 response at weeks 16 and 52 was achieved by significantly more patients on apremilast at 20 mg twice daily (BID)(P=.0166) or 30 mg BID (P=.0001) than placebo.⁶ Although not FDA approved for PsA, methotrexate has been shown to improve concomitant PsA of the peripheral joints in patients with psoriasis. Furthermore, a trial of methotrexate has shown considerable improvements in PsA symptoms in patients with psoriasis—a 62.7% decrease in proportion of patients with dactylitis, 25.7% decrease in enthesitis, and improvements in ACR outcomes (ACR20 in 40.8%, ACR50 in 18.8%, and ACR70 in 8.6%, with 22.4% achieving minimal disease activity).⁷

Prior to starting a systemic medication for psoriasis, it is necessary to discuss effects on pregnancy and fertility. Pregnancy is an absolute contraindication for methotrexate and acitretin use because of the drugs’ teratogenicity. Fetal death and fetal abnormalities have been reported with methotrexate use in pregnant women.⁸ Bone, central nervous system, auditory, ocular, and cardiovascular fetal abnormalities have been reported with maternal acitretin use.⁹ Breastfeeding also is an absolute contraindication for methotrexate use, as methotrexate passes into breastmilk in small quantities. Patients taking acitretin also are strongly discouraged from nursing because of the long half-life (168 days) of etretinate, a reverse metabolism product of acitretin that is increased in the presence of alcohol. Women should wait 3 months after discontinuing methotrexate for complete drug clearance before conceiving compared to 3 years in women who have discontinued acitretin.^8,10 Men also are recommended to wait 3 months after discontinuing methotrexate before attempting to conceive, as its effect on male spermatogenesis and teratogenicity is unclear. Acitretin has no documented teratogenic effect in men. For women planning to become pregnant, apremilast and cyclosporine can be continued throughout pregnancy on an individual basis. The benefit of apremilast should be weighed against its potential risk to the fetus. There is no evidence of teratogenicity of apremilast at doses of 20 mg/kg daily.¹¹ Current research regarding cyclosporine use in pregnancy only exists in transplant patients and has revealed higher rates of prematurity and lower birth weight without teratogenic effects.^10,12 The risks and benefits of continuing cyclosporine while nursing should be evaluated, as cyclosporine (and ethanol-methanol components used in some formulations) is detectable in breast milk.

Drug Contraindications

Hypersensitivity to a specific systemic nonbiologic medication is a contraindication to its use and is an absolute contraindication for methotrexate. Other absolute contraindications to methotrexate are pregnancy and nursing, alcoholism, alcoholic liver disease, chronic liver disease, immunodeficiency, and cytopenia. Contraindications to acitretin include pregnancy, severely impaired liver and kidney function, and chronic abnormally elevated lipid levels. There are no additional contraindications for apremilast, but patients must be informed of the risk for depression before initiating therapy. Cyclosporine is contraindicated in patients with prior psoralen plus UVA (PUVA) treatment or radiation therapy, abnormal renal function, uncontrolled hypertension, uncontrolled and active infections, and a history of systemic malignancy. Live vaccines should be avoided in patients on cyclosporine, and caution is advised when cyclosporine is prescribed for patients with poorly controlled diabetes.

Pretreatment Screening

Because of drug interactions, a detailed medication history is essential prior to starting any systemic medication for psoriasis. Apremilast and cyclosporine are metabolized by cytochrome P450 and therefore are more susceptible to drug-related interactions. Cyclosporine use can affect levels of other medications that are metabolized by cytochrome P450, such as statins, calcium channel blockers, and warfarin. Similarly, acitretin’s metabolism is affected by drugs that interfere with cytochrome P450. Additionally, screening laboratory tests are needed before initiating systemic nonbiologic agents for psoriasis, with the exception of apremilast.

Prior to initiating methotrexate treatment, patients may require tuberculosis (TB), hepatitis B, and hepatitis C screening tests, depending on their risk factors. A baseline liver fibrosis assessment is recommended because of the potential of hepatotoxicity in patients receiving methotrexate. Noninvasive serology tests utilized to evaluate the presence of pre-existing liver disease include Fibrosis-4, FibroMeter, FibroSure, and Hepascore. Patients with impaired renal function have an increased predisposition to methotrexate-induced hematologic toxicity. Thus, it is necessary to administer a test dose of methotrexate in these patients followed by a complete blood cell count (CBC) 5 to 7 days later. An unremarkable CBC after the test dose suggests the absence of myelosuppression, and methotrexate dosage can be increased weekly. Patients on methotrexate also must receive folate supplementation to reduce the risk for adverse effects during treatment.

Patients considering cyclosporine must undergo screening for family and personal history of renal disease. Prior to initiating treatment, patients require 2 blood pressure measurements, hepatitis screening, TB screening, urinalysis, serum creatinine (Cr), blood urea nitrogen (BUN), CBC, potassium and magnesium levels, uric acid levels, lipid profile, bilirubin, and liver function tests (LFTs). A pregnancy test also is warranted for women of childbearing potential (WOCP).

Patients receiving acitretin should receive screening laboratory tests consisting of fasting cholesterol and triglycerides, CBC, renal function tests, LFTs, and a pregnancy test, if applicable.

After baseline evaluations, the selected oral systemic can be initiated using specific dosing regimens to ensure optimal drug efficacy and reduce incidence of adverse effects (eTable).

Monitoring During Active Treatment

Physicians need to counsel patients on potential adverse effects of their medications. Because of its relatively safe profile among the systemic nonbiologic agents, apremilast requires the least monitoring during treatment. There is no required routine laboratory monitoring for patients using apremilast, though testing may be pursued at the clinician’s discretion. However, weight should be regularly measured in patients on apremilast. In a phase 3 clinical trial of patients with psoriasis, 12% of patients on apremilast experienced a 5% to 10% weight loss compared to 5% of patients on placebo.^11,13 Thus, it is recommended that physicians consider discontinuing apremilast in patients with a weight loss of more than 5% from baseline, especially if it may lead to other unfavorable health effects. Because depression is reported among 1% of patients on apremilast, close monitoring for new or worsening symptoms of depression should be performed during treatment.^11,13 To avoid common GI side effects, apremilast is initiated at 10 mg/d and is increased by 10 mg/d over the first 5 days to a final dose of 30 mg BID. Elderly patients in particular should be cautioned about the risk of dehydration associated with GI side effects. Patients with severe renal impairment (Cr clearance, <30 mL/min) should use apremilast at a dosage of 30 mg once daily.

For patients on methotrexate, laboratory monitoring is essential after each dose increase. It also is important for physicians to obtain regular blood work to assess for hematologic abnormalities and hepatoxicity. Patients with risk factors such as renal insufficiency, increased age, hypoalbuminemia, alcohol abuse and alcoholic liver disease, and methotrexate dosing errors, as well as those prone to drug-related interactions, must be monitored closely for pancytopenia.^14,15 The protocol for screening for methotrexate-induced hepatotoxicity during treatment depends on patient risk factors. Risk factors for hepatoxicity include history of or current alcohol abuse, abnormal LFTs, personal or family history of liver disease, diabetes, obesity, use of other hepatotoxic drugs, and hyperlipidemia.¹⁶ In patients without blood work abnormalities, CBC and LFTs can be performed every 3 to 6 months. Patients with abnormally elevated LFTs require repeat blood work every 2 to 4 weeks. Persistent elevations in LFTs require further evaluation by a GI specialist. After a cumulative dose of 3.5 to 4 g, patients should receive a GI referral and further studies (such as vibration-controlled transient elastography or liver biopsy) to assess for liver fibrosis. Patients with signs of stage 3 liver fibrosis are recommended to discontinue methotrexate and switch to another medication for psoriasis. For patients with impaired renal function, periodic BUN and Cr monitoring are needed. Common adverse effects of methotrexate include diarrhea, nausea, and anorexia, which can be mitigated by taking methotrexate with food or lowering the dosage.⁸ Patients on methotrexate should be monitored for rare but potential risks of infection and reactivation of latent TB, hepatitis, and lymphoma. To reduce the incidence of methotrexate toxicity from drug interactions, a review of current medications at each follow-up visit is recommended.

Nephrotoxicity and hypertension are the most common adverse effects of cyclosporine. It is important to monitor BUN and Cr biweekly for the initial 3 months, then at monthly intervals if there are no persistent abnormalities. Patients also must receive monthly CBC, potassium and magnesium levels, uric acid levels, lipid panel, serum bilirubin, and LFTs to monitor for adverse effects.¹⁷ Physicians should obtain regular pregnancy tests in WOCP. Weekly monitoring of early-morning blood pressure is recommended for patients on cyclosporine to detect early cyclosporine-induced nephrotoxicity. Hypertension on 2 separate occasions warrants a reduction in cyclosporine dosage or an addition of a calcium channel blocker for blood pressure control. Dose reduction also should be performed in patients with an increase in Cr above baseline greater than 25%.¹⁷ If Cr level is persistently elevated or if blood pressure does not normalize to lower than 140/90 after dose reduction, cyclosporine should be immediately discontinued. Patients on cyclosporine for more than a year warrant an annual estimation of glomerular filtration rate because of irreversible kidney damage associated with long-term use. A systematic review of patients treated with cyclosporine for more than 2 years found that at least 50% of patients experienced a 30% increase in Cr above baseline.¹⁸

Patients taking acitretin should be monitored for hyperlipidemia, the most common laboratory abnormality seen in 25% to 50% of patients.¹⁹ Fasting lipid panel and LFTs should be performed monthly for the initial 3 months on acitretin, then at 3-month intervals. Lifestyle changes should be encouraged to reduce hyperlipidemia, and fibrates may be given to treat elevated triglyceride levels, the most common type of hyperlipidemia seen with acitretin. Acitretin-induced toxic hepatitis is a rare occurrence that warrants immediate discontinuation of the medication.²⁰ Monthly pregnancy tests must be performed in WOCP.

Combination Therapy

For apremilast, there is anecdotal evidence supporting its use in conjunction with phototherapy or biologics in some cases, but no high-quality data.²¹ On the other hand, using combination therapy with other systemic therapies can reduce adverse effects and decrease the amount of medication needed to achieve psoriasis clearance. Methotrexate used with etanercept, for example, has been more effective than methotrexate monotherapy in treating psoriasis, which has been attributed to a methotrexate-mediated reduction in the production of antidrug antibodies.^22,23

Methotrexate, cyclosporine, and acitretin have synergistic effects when used with phototherapy. Narrowband UVB (NB-UVB) phototherapy combined with methotrexate is more effective in clearing psoriasis than methotrexate or NB-UVB phototherapy alone. Similarly, acitretin and PUVA combination therapy is more effective than acitretin or PUVA phototherapy alone. Combination regimens of acitretin and broadband UVB phototherapy, acitretin and NB-UVB phototherapy, and acitretin and PUVA phototherapy also have been more effective than individual modalities alone. Combination therapy reduces the cumulative doses of both therapies and reduces the frequency and duration of phototherapy needed for psoriatic clearance.²⁴ In acitretin combination therapy with UVB phototherapy, the recommended regimen is 2 weeks of acitretin monotherapy followed by UVB phototherapy. For patients with an inadequate response to UVB phototherapy, the UVB dose can be reduced by 30% to 50%, and acitretin 25 mg/d can be added to phototherapy treatment. Acitretin-UVB combination therapy has been shown to reduce the risk of UVB-induced erythema seen in UVB monotherapy. Similarly, the risk of squamous cell carcinoma is reduced in acitretin-PUVA combination therapy compared to PUVA monotherapy.²⁵

The timing of phototherapy in combination with systemic nonbiologic agents is critical. Phototherapy used simultaneously with cyclosporine is contraindicated owing to increased risk of photocarcinogenesis, whereas phototherapy used in sequence with cyclosporine is well tolerated and effective. Furthermore, cyclosporine 3 mg/kg/d for 4 weeks followed by a rapid cyclosporine taper and initiation of NB-UVB phototherapy demonstrated resolution of psoriasis with fewer NB-UVB treatments and less UVB exposure than NB-UVB therapy alone.²⁶

Final Thoughts

The FDA-approved systemic nonbiologic agents are accessible and effective treatment options for adults with widespread or inadequately controlled psoriasis. Selecting the ideal therapy requires careful consideration of medication toxicity, contraindications, monitoring requirements, and patient comorbidities. The AAD-NPF guidelines guide dermatologists in prescribing systemic nonbiologic treatments in adults with psoriasis. Utilizing these recommendations in combination with clinician judgment will help patients achieve safe and optimal psoriasis clearance.

The treatment landscape for psoriasis has evolved rapidly over the last decade. Biologic therapies have demonstrated robust efficacy and acceptable safety profiles among many patients with moderate to severe plaque psoriasis. However, the use of biologics among immunocompromised patients with psoriasis rarely is discussed in the literature. As new biologics for psoriasis are being developed, a critical gap exists in the literature regarding the safety and efficacy of these medications in immunocompromised patients. Per American Academy of Dermatology–National Psoriasis Foundation guidelines, caution should be exercised when using biologics in patients with immunocompromising conditions.¹ In organ transplant recipients, the potential risks of combining systemic medications used for organ transplantation and biologic treatments for psoriasis are unknown.²

In the posttransplant period, the immunosuppressive regimens for transplantation likely will improve psoriasis. However, patients with organ transplant and psoriasis still experience flares that can be challenging to treat.³ Prior treatment modalities to prevent psoriasis flares in organ transplant recipients have relied largely on topical therapies, posttransplant immunosuppressive medications (eg, cyclosporine, tacrolimus, mycophenolate mofetil) that prevent graft rejection, and systemic corticosteroids. We report a case of a 50-year-old man with a recent history of liver transplantation who presented with severe plaque psoriasis and psoriatic arthritis.

Case Report

A 50-year-old man presented to the dermatology clinic with moderate to severe plaque psoriasis and psoriatic arthritis that had been present for 15 years. His plaque psoriasis covered approximately 40% of the body surface area, including the scalp, trunk, arms, and legs. In addition, he had diffuse joint pain in the hands and feet; a radiograph revealed active psoriatic arthritis involving the joints of the fingers and toes.

One year prior to presentation to our dermatology clinic, the patient underwent an an orthotopic liver transplant for history of Child-Pugh class C liver cirrhosis secondary to untreated hepatitis C virus (HCV) and alcohol use that was complicated by hepatocellular carcinoma. He acquired a high-risk donor liver that was HCV positive with HCV genotype 1a. Starting 2 months after the transplant, he underwent 12 weeks of treatment for HCV with glecaprevir-pibrentasvir. Once his HCV treatment course was completed, he achieved a sustained virologic response with an undetectable viral load. To prevent transplant rejection, he was on chronic immunosuppression with tacrolimus, a calcineurin inhibitor, and mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase whose action leads to decreased proliferation of T cells and B cells.

The patient’s psoriasis initially was treated with triamcinolone acetonide ointment 0.1% applied twice daily to the psoriasis lesions for 1 year by another dermatologist. However, his psoriasis progressed to involve 40% of the body surface area. Following our evaluation 1 year posttransplant, the patient was started on subcutaneous brodalumab 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter. Approximately 10 weeks after initiation of brodalumab, the patient’s psoriasis was completely clear, and he was asymptomatic from psoriatic arthritis. The patient’s improvement persisted at 6 months, and his liver enzymes, including alkaline phosphatase, total bilirubin, alanine transaminase, and aspartate transaminase, continued to be within reference range. To date, there has been no evidence of posttransplant complications such as graft-vs-host disease, serious infections, or skin cancers.

Comment

Increased Risk for Infection and Malignancies in Transplant Patients
Transplant patients are on immunosuppressive regimens that increase their risk for infection and malignancies. For example, high doses of immunosuppresants predispose these patients to reactivation of viral infections, including BK and JC viruses.⁴ In addition, the incidence of squamous cell carcinoma is 65- to 250-fold higher in transplant patients compared to the general population.⁵ The risk for Merkel cell carcinoma is increased after solid organ transplantation compared to the general population.⁶ Importantly, transplant patients have a higher mortality from skin cancers than other types of cancers, including breast and colon cancer.⁷

Psoriasis in Organ Transplant Recipients
Psoriasis is a chronic, immune-mediated, inflammatory disease with a prevalence of approximately 3% in the United States.⁸ Approximately one-third of patients with psoriasis develop psoriatic arthritis.⁹ Organ transplant recipients with psoriasis and psoriatic arthritis represent a unique patient population whereby their use of chronic immunosuppressive medications to prevent graft rejection may put them at risk for developing infections and malignancies.

Special Considerations for Brodalumab
Brodalumab is an immunomodulatory biologic that binds to and inhibits IL-17RA, thereby inhibiting the actions of IL-17A, F, E, and C.² The blockade of IL-17RA by brodalumab has been shown to result in reversal of psoriatic phenotype and gene expression patterns.¹⁰ Brodalumab was chosen as the treatment in our patient because it has a rapid onset of action, sustained efficacy, and an acceptable safety profile.¹¹ Brodalumab is well tolerated, with approximately 60% of patients achieving clearance long-term.¹² Candidal infections can occur in patients with brodalumab, but the rates are low and they are reversible with antifungal treatment.¹³ The increased mucocutaneous candidal infections are consistent with medications whose mechanism of action is IL-17 inhibition.^14,15 The most common adverse reactions found were nasopharyngitis and headache.¹⁶ The causal link between brodalumab and suicidality has not been established.¹⁷

The use of brodalumab for psoriasis in organ transplant recipients has not been previously reported in the literature. A few case reports have been published on the successful use of etanercept and ixekizumab as biologic treatment options for psoriasis in transplant patients.^18-23 In addition to choosing an appropriate biologic for psoriasis in transplant patients, transplant providers may evaluate the choice of immunosuppression regimen for the organ transplant in the context of psoriasis. In a retrospective analysis of liver transplant patients with psoriasis, Foroncewicz et al³ found cyclosporine, which was used as an antirejection immunosuppressive agent in the posttransplant period, to be more effective than tacrolimus in treating recurrent psoriasis in liver transplant recipients.

Our case illustrates one example of the successful use of brodalumab in a patient with a solid organ transplant. Our patient’s psoriasis and symptoms of psoriatic arthritis greatly improved after initiation of brodalumab. In the posttransplant period, the patient did not develop graft-vs-host disease, infections, malignancies, depression, or suicidal ideation while taking brodalumab.

Conclusion

It is important that the patient, dermatology team, and transplant team work together to navigate the challenges and relatively unknown landscape of psoriasis treatment in organ transplant recipients. As the number of organ transplant recipients continues to increase, this issue will become more clinically relevant. Case reports and future prospective studies will continue to inform us regarding the role of biologics in psoriasis treatment posttransplantation.

The treatment landscape for psoriasis has evolved rapidly over the last decade. Biologic therapies have demonstrated robust efficacy and acceptable safety profiles among many patients with moderate to severe plaque psoriasis. However, the use of biologics among immunocompromised patients with psoriasis rarely is discussed in the literature. As new biologics for psoriasis are being developed, a critical gap exists in the literature regarding the safety and efficacy of these medications in immunocompromised patients. Per American Academy of Dermatology–National Psoriasis Foundation guidelines, caution should be exercised when using biologics in patients with immunocompromising conditions.¹ In organ transplant recipients, the potential risks of combining systemic medications used for organ transplantation and biologic treatments for psoriasis are unknown.²

In the posttransplant period, the immunosuppressive regimens for transplantation likely will improve psoriasis. However, patients with organ transplant and psoriasis still experience flares that can be challenging to treat.³ Prior treatment modalities to prevent psoriasis flares in organ transplant recipients have relied largely on topical therapies, posttransplant immunosuppressive medications (eg, cyclosporine, tacrolimus, mycophenolate mofetil) that prevent graft rejection, and systemic corticosteroids. We report a case of a 50-year-old man with a recent history of liver transplantation who presented with severe plaque psoriasis and psoriatic arthritis.

Case Report

A 50-year-old man presented to the dermatology clinic with moderate to severe plaque psoriasis and psoriatic arthritis that had been present for 15 years. His plaque psoriasis covered approximately 40% of the body surface area, including the scalp, trunk, arms, and legs. In addition, he had diffuse joint pain in the hands and feet; a radiograph revealed active psoriatic arthritis involving the joints of the fingers and toes.

One year prior to presentation to our dermatology clinic, the patient underwent an an orthotopic liver transplant for history of Child-Pugh class C liver cirrhosis secondary to untreated hepatitis C virus (HCV) and alcohol use that was complicated by hepatocellular carcinoma. He acquired a high-risk donor liver that was HCV positive with HCV genotype 1a. Starting 2 months after the transplant, he underwent 12 weeks of treatment for HCV with glecaprevir-pibrentasvir. Once his HCV treatment course was completed, he achieved a sustained virologic response with an undetectable viral load. To prevent transplant rejection, he was on chronic immunosuppression with tacrolimus, a calcineurin inhibitor, and mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase whose action leads to decreased proliferation of T cells and B cells.

The patient’s psoriasis initially was treated with triamcinolone acetonide ointment 0.1% applied twice daily to the psoriasis lesions for 1 year by another dermatologist. However, his psoriasis progressed to involve 40% of the body surface area. Following our evaluation 1 year posttransplant, the patient was started on subcutaneous brodalumab 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter. Approximately 10 weeks after initiation of brodalumab, the patient’s psoriasis was completely clear, and he was asymptomatic from psoriatic arthritis. The patient’s improvement persisted at 6 months, and his liver enzymes, including alkaline phosphatase, total bilirubin, alanine transaminase, and aspartate transaminase, continued to be within reference range. To date, there has been no evidence of posttransplant complications such as graft-vs-host disease, serious infections, or skin cancers.

Comment

Increased Risk for Infection and Malignancies in Transplant Patients
Transplant patients are on immunosuppressive regimens that increase their risk for infection and malignancies. For example, high doses of immunosuppresants predispose these patients to reactivation of viral infections, including BK and JC viruses.⁴ In addition, the incidence of squamous cell carcinoma is 65- to 250-fold higher in transplant patients compared to the general population.⁵ The risk for Merkel cell carcinoma is increased after solid organ transplantation compared to the general population.⁶ Importantly, transplant patients have a higher mortality from skin cancers than other types of cancers, including breast and colon cancer.⁷

Psoriasis in Organ Transplant Recipients
Psoriasis is a chronic, immune-mediated, inflammatory disease with a prevalence of approximately 3% in the United States.⁸ Approximately one-third of patients with psoriasis develop psoriatic arthritis.⁹ Organ transplant recipients with psoriasis and psoriatic arthritis represent a unique patient population whereby their use of chronic immunosuppressive medications to prevent graft rejection may put them at risk for developing infections and malignancies.

Special Considerations for Brodalumab
Brodalumab is an immunomodulatory biologic that binds to and inhibits IL-17RA, thereby inhibiting the actions of IL-17A, F, E, and C.² The blockade of IL-17RA by brodalumab has been shown to result in reversal of psoriatic phenotype and gene expression patterns.¹⁰ Brodalumab was chosen as the treatment in our patient because it has a rapid onset of action, sustained efficacy, and an acceptable safety profile.¹¹ Brodalumab is well tolerated, with approximately 60% of patients achieving clearance long-term.¹² Candidal infections can occur in patients with brodalumab, but the rates are low and they are reversible with antifungal treatment.¹³ The increased mucocutaneous candidal infections are consistent with medications whose mechanism of action is IL-17 inhibition.^14,15 The most common adverse reactions found were nasopharyngitis and headache.¹⁶ The causal link between brodalumab and suicidality has not been established.¹⁷

The use of brodalumab for psoriasis in organ transplant recipients has not been previously reported in the literature. A few case reports have been published on the successful use of etanercept and ixekizumab as biologic treatment options for psoriasis in transplant patients.^18-23 In addition to choosing an appropriate biologic for psoriasis in transplant patients, transplant providers may evaluate the choice of immunosuppression regimen for the organ transplant in the context of psoriasis. In a retrospective analysis of liver transplant patients with psoriasis, Foroncewicz et al³ found cyclosporine, which was used as an antirejection immunosuppressive agent in the posttransplant period, to be more effective than tacrolimus in treating recurrent psoriasis in liver transplant recipients.

Our case illustrates one example of the successful use of brodalumab in a patient with a solid organ transplant. Our patient’s psoriasis and symptoms of psoriatic arthritis greatly improved after initiation of brodalumab. In the posttransplant period, the patient did not develop graft-vs-host disease, infections, malignancies, depression, or suicidal ideation while taking brodalumab.

Conclusion

It is important that the patient, dermatology team, and transplant team work together to navigate the challenges and relatively unknown landscape of psoriasis treatment in organ transplant recipients. As the number of organ transplant recipients continues to increase, this issue will become more clinically relevant. Case reports and future prospective studies will continue to inform us regarding the role of biologics in psoriasis treatment posttransplantation.

The treatment landscape for psoriasis has evolved rapidly over the last decade. Biologic therapies have demonstrated robust efficacy and acceptable safety profiles among many patients with moderate to severe plaque psoriasis. However, the use of biologics among immunocompromised patients with psoriasis rarely is discussed in the literature. As new biologics for psoriasis are being developed, a critical gap exists in the literature regarding the safety and efficacy of these medications in immunocompromised patients. Per American Academy of Dermatology–National Psoriasis Foundation guidelines, caution should be exercised when using biologics in patients with immunocompromising conditions.¹ In organ transplant recipients, the potential risks of combining systemic medications used for organ transplantation and biologic treatments for psoriasis are unknown.²

In the posttransplant period, the immunosuppressive regimens for transplantation likely will improve psoriasis. However, patients with organ transplant and psoriasis still experience flares that can be challenging to treat.³ Prior treatment modalities to prevent psoriasis flares in organ transplant recipients have relied largely on topical therapies, posttransplant immunosuppressive medications (eg, cyclosporine, tacrolimus, mycophenolate mofetil) that prevent graft rejection, and systemic corticosteroids. We report a case of a 50-year-old man with a recent history of liver transplantation who presented with severe plaque psoriasis and psoriatic arthritis.

Case Report

A 50-year-old man presented to the dermatology clinic with moderate to severe plaque psoriasis and psoriatic arthritis that had been present for 15 years. His plaque psoriasis covered approximately 40% of the body surface area, including the scalp, trunk, arms, and legs. In addition, he had diffuse joint pain in the hands and feet; a radiograph revealed active psoriatic arthritis involving the joints of the fingers and toes.

One year prior to presentation to our dermatology clinic, the patient underwent an an orthotopic liver transplant for history of Child-Pugh class C liver cirrhosis secondary to untreated hepatitis C virus (HCV) and alcohol use that was complicated by hepatocellular carcinoma. He acquired a high-risk donor liver that was HCV positive with HCV genotype 1a. Starting 2 months after the transplant, he underwent 12 weeks of treatment for HCV with glecaprevir-pibrentasvir. Once his HCV treatment course was completed, he achieved a sustained virologic response with an undetectable viral load. To prevent transplant rejection, he was on chronic immunosuppression with tacrolimus, a calcineurin inhibitor, and mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase whose action leads to decreased proliferation of T cells and B cells.

The patient’s psoriasis initially was treated with triamcinolone acetonide ointment 0.1% applied twice daily to the psoriasis lesions for 1 year by another dermatologist. However, his psoriasis progressed to involve 40% of the body surface area. Following our evaluation 1 year posttransplant, the patient was started on subcutaneous brodalumab 210 mg at weeks 0, 1, and 2, then every 2 weeks thereafter. Approximately 10 weeks after initiation of brodalumab, the patient’s psoriasis was completely clear, and he was asymptomatic from psoriatic arthritis. The patient’s improvement persisted at 6 months, and his liver enzymes, including alkaline phosphatase, total bilirubin, alanine transaminase, and aspartate transaminase, continued to be within reference range. To date, there has been no evidence of posttransplant complications such as graft-vs-host disease, serious infections, or skin cancers.

Comment

Increased Risk for Infection and Malignancies in Transplant Patients
Transplant patients are on immunosuppressive regimens that increase their risk for infection and malignancies. For example, high doses of immunosuppresants predispose these patients to reactivation of viral infections, including BK and JC viruses.⁴ In addition, the incidence of squamous cell carcinoma is 65- to 250-fold higher in transplant patients compared to the general population.⁵ The risk for Merkel cell carcinoma is increased after solid organ transplantation compared to the general population.⁶ Importantly, transplant patients have a higher mortality from skin cancers than other types of cancers, including breast and colon cancer.⁷

Psoriasis in Organ Transplant Recipients
Psoriasis is a chronic, immune-mediated, inflammatory disease with a prevalence of approximately 3% in the United States.⁸ Approximately one-third of patients with psoriasis develop psoriatic arthritis.⁹ Organ transplant recipients with psoriasis and psoriatic arthritis represent a unique patient population whereby their use of chronic immunosuppressive medications to prevent graft rejection may put them at risk for developing infections and malignancies.

Special Considerations for Brodalumab
Brodalumab is an immunomodulatory biologic that binds to and inhibits IL-17RA, thereby inhibiting the actions of IL-17A, F, E, and C.² The blockade of IL-17RA by brodalumab has been shown to result in reversal of psoriatic phenotype and gene expression patterns.¹⁰ Brodalumab was chosen as the treatment in our patient because it has a rapid onset of action, sustained efficacy, and an acceptable safety profile.¹¹ Brodalumab is well tolerated, with approximately 60% of patients achieving clearance long-term.¹² Candidal infections can occur in patients with brodalumab, but the rates are low and they are reversible with antifungal treatment.¹³ The increased mucocutaneous candidal infections are consistent with medications whose mechanism of action is IL-17 inhibition.^14,15 The most common adverse reactions found were nasopharyngitis and headache.¹⁶ The causal link between brodalumab and suicidality has not been established.¹⁷

The use of brodalumab for psoriasis in organ transplant recipients has not been previously reported in the literature. A few case reports have been published on the successful use of etanercept and ixekizumab as biologic treatment options for psoriasis in transplant patients.^18-23 In addition to choosing an appropriate biologic for psoriasis in transplant patients, transplant providers may evaluate the choice of immunosuppression regimen for the organ transplant in the context of psoriasis. In a retrospective analysis of liver transplant patients with psoriasis, Foroncewicz et al³ found cyclosporine, which was used as an antirejection immunosuppressive agent in the posttransplant period, to be more effective than tacrolimus in treating recurrent psoriasis in liver transplant recipients.

Our case illustrates one example of the successful use of brodalumab in a patient with a solid organ transplant. Our patient’s psoriasis and symptoms of psoriatic arthritis greatly improved after initiation of brodalumab. In the posttransplant period, the patient did not develop graft-vs-host disease, infections, malignancies, depression, or suicidal ideation while taking brodalumab.

Conclusion

It is important that the patient, dermatology team, and transplant team work together to navigate the challenges and relatively unknown landscape of psoriasis treatment in organ transplant recipients. As the number of organ transplant recipients continues to increase, this issue will become more clinically relevant. Case reports and future prospective studies will continue to inform us regarding the role of biologics in psoriasis treatment posttransplantation.

The incidence of autoimmune hepatitis (AIH) may be rising, according to a prospective population-based study conducted in New Zealand.

From 2008 to 2016, the rising incidence of AIH led to a 40% increase in point prevalence, reported lead author Mehul Lamba, MD, of Christchurch (New Zealand) Hospital and colleagues.

The incidence of autoimmune hepatitis (AIH) may be rising, according to a prospective population-based study conducted in New Zealand.

From 2008 to 2016, the rising incidence of AIH led to a 40% increase in point prevalence, reported lead author Mehul Lamba, MD, of Christchurch (New Zealand) Hospital and colleagues.

The incidence of autoimmune hepatitis (AIH) may be rising, according to a prospective population-based study conducted in New Zealand.

From 2008 to 2016, the rising incidence of AIH led to a 40% increase in point prevalence, reported lead author Mehul Lamba, MD, of Christchurch (New Zealand) Hospital and colleagues.

Case Report

An 80-year-old man with a history of hypertension and coronary artery disease presented to the dermatology clinic with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the abdomen, back, and leg (Figure 1). He reported that these “growths” appeared 20 years prior to presentation, shortly after coronary artery bypass surgery with a saphenous vein graft. The patient initially was given a diagnosis of verruca vulgaris and then biopsy-proven psoriasis later that year. At that time, he refused systemic treatment and was treated instead with triamcinolone acetonide ointment, with periodic surgical removal of bothersome lesions.

At the current presentation, physical examination revealed many hyperkeratotic, yellow-gray, verrucous nodules overlying scaly, erythematous, sharply demarcated plaques, exclusively on the left side of the body, including the left side of the abdomen, back, and leg. The differential diagnosis included linear psoriasis and inflammatory linear verrucous epidermal nevus (ILVEN).

Skin biopsy showed irregular psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and papillomatosis, with convergence of the rete ridges, known as buttressing (Figure 2A). There were tortuous dilated blood vessels in the dermal papillae, epidermal neutrophils at the tip of the suprapapillary plates, and Munro microabscesses in the stratum corneum (Figure 2B). Koilocytes were absent, and periodic acid–Schiff staining was negative. Taken together, clinical and histologic features led to a diagnosis of unilateral verrucous psoriasis.

Comment

Presentation and Histology
Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. It typically arises in patients with established psoriasis but can occur de novo.

Histologic features of verrucous psoriasis include epidermal hyperplasia with acanthosis, papillomatosis, and epidermal buttressing.¹ It has been hypothesized that notable hyperkeratosis observed in these lesions is induced by repeat trauma to the extremities in patients with established psoriasis or by anoxia from conditions that predispose to poor circulation, such as diabetes mellitus and pulmonary disease.^1,2

Pathogenesis
Most reported cases of verrucous psoriasis arose atop pre-existing psoriasis lesions.^3,4 The relevance of our patient’s verrucous psoriasis to his prior coronary artery bypass surgery with saphenous vein graft is unknown; however, the distribution of lesions, timing of psoriasis onset in relation to the surgical procedure, and recent data proposing a role for neuropeptide responses to nerve injury in the development of psoriasis, taken together, provide an argument for a role for surgical trauma in the development of our patient’s condition.

Treatment
Although verrucous psoriasis presents both diagnostic and therapeutic challenges, there are some reports of improvement with topical or intralesional corticosteroids in combination with keratolytics,³ coal tar,⁵ and oral methotrexate.⁶ In addition, there are rare reports of successful treatment with biologics. A case report showed successful resolution with adalimumab,⁴ and a case of erythrodermic verrucous psoriasis showed moderate improvement with ustekinumab after other failed treatments.⁷

Differential Diagnosis
Psoriasis typically presents in a symmetric distribution, with rare reported cases of unilateral distribution. Two cases of unilateral psoriasis arising after a surgical procedure have been reported, one after mastectomy and the other after neurosurgery.^8,9 Other cases of unilateral psoriasis are reported to have arisen in adolescents and young adults idiopathically.

A case of linear psoriasis arising in the distribution of the sciatic nerve in a patient with radiculopathy implicated tumor necrosis factor α, neuropeptides, and nerve growth factor released in response to compression as possible etiologic agents.¹⁰ However, none of the reported cases of linear psoriasis, or reported cases of unilateral psoriasis, exhibited verrucous features clinically or histologically. In our patient, distribution of the lesions appeared less typically blaschkoid than in linear psoriasis, and the presence of exophytic wartlike growths throughout the lesions was not characteristic of linear psoriasis.

Late-adulthood onset in this patient in addition to the absence of typical histologic features of ILVEN, including alternating orthokeratosis and parakeratosis,¹¹ make a diagnosis of ILVEN less likely; ILVEN can be distinguished from linear psoriasis based on later age of onset and responsiveness to antipsoriatic therapy of linear psoriasis.¹²

Conclusion

We describe a unique presentation of an already rare variant of psoriasis that can be difficult to diagnose clinically. The unilateral distribution of lesions in this patient can create further diagnostic confusion with other entities, such as ILVEN and linear psoriasis, though it can be distinguished from those diseases based on histologic features. Our aim is that this report improves recognition of this unusual presentation of verrucous psoriasis in clinical settings and decreases delays in diagnosis and treatment.

Case Report

An 80-year-old man with a history of hypertension and coronary artery disease presented to the dermatology clinic with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the abdomen, back, and leg (Figure 1). He reported that these “growths” appeared 20 years prior to presentation, shortly after coronary artery bypass surgery with a saphenous vein graft. The patient initially was given a diagnosis of verruca vulgaris and then biopsy-proven psoriasis later that year. At that time, he refused systemic treatment and was treated instead with triamcinolone acetonide ointment, with periodic surgical removal of bothersome lesions.

At the current presentation, physical examination revealed many hyperkeratotic, yellow-gray, verrucous nodules overlying scaly, erythematous, sharply demarcated plaques, exclusively on the left side of the body, including the left side of the abdomen, back, and leg. The differential diagnosis included linear psoriasis and inflammatory linear verrucous epidermal nevus (ILVEN).

Skin biopsy showed irregular psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and papillomatosis, with convergence of the rete ridges, known as buttressing (Figure 2A). There were tortuous dilated blood vessels in the dermal papillae, epidermal neutrophils at the tip of the suprapapillary plates, and Munro microabscesses in the stratum corneum (Figure 2B). Koilocytes were absent, and periodic acid–Schiff staining was negative. Taken together, clinical and histologic features led to a diagnosis of unilateral verrucous psoriasis.

Comment

Presentation and Histology
Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. It typically arises in patients with established psoriasis but can occur de novo.

Histologic features of verrucous psoriasis include epidermal hyperplasia with acanthosis, papillomatosis, and epidermal buttressing.¹ It has been hypothesized that notable hyperkeratosis observed in these lesions is induced by repeat trauma to the extremities in patients with established psoriasis or by anoxia from conditions that predispose to poor circulation, such as diabetes mellitus and pulmonary disease.^1,2

Pathogenesis
Most reported cases of verrucous psoriasis arose atop pre-existing psoriasis lesions.^3,4 The relevance of our patient’s verrucous psoriasis to his prior coronary artery bypass surgery with saphenous vein graft is unknown; however, the distribution of lesions, timing of psoriasis onset in relation to the surgical procedure, and recent data proposing a role for neuropeptide responses to nerve injury in the development of psoriasis, taken together, provide an argument for a role for surgical trauma in the development of our patient’s condition.

Treatment
Although verrucous psoriasis presents both diagnostic and therapeutic challenges, there are some reports of improvement with topical or intralesional corticosteroids in combination with keratolytics,³ coal tar,⁵ and oral methotrexate.⁶ In addition, there are rare reports of successful treatment with biologics. A case report showed successful resolution with adalimumab,⁴ and a case of erythrodermic verrucous psoriasis showed moderate improvement with ustekinumab after other failed treatments.⁷

Differential Diagnosis
Psoriasis typically presents in a symmetric distribution, with rare reported cases of unilateral distribution. Two cases of unilateral psoriasis arising after a surgical procedure have been reported, one after mastectomy and the other after neurosurgery.^8,9 Other cases of unilateral psoriasis are reported to have arisen in adolescents and young adults idiopathically.

A case of linear psoriasis arising in the distribution of the sciatic nerve in a patient with radiculopathy implicated tumor necrosis factor α, neuropeptides, and nerve growth factor released in response to compression as possible etiologic agents.¹⁰ However, none of the reported cases of linear psoriasis, or reported cases of unilateral psoriasis, exhibited verrucous features clinically or histologically. In our patient, distribution of the lesions appeared less typically blaschkoid than in linear psoriasis, and the presence of exophytic wartlike growths throughout the lesions was not characteristic of linear psoriasis.

Late-adulthood onset in this patient in addition to the absence of typical histologic features of ILVEN, including alternating orthokeratosis and parakeratosis,¹¹ make a diagnosis of ILVEN less likely; ILVEN can be distinguished from linear psoriasis based on later age of onset and responsiveness to antipsoriatic therapy of linear psoriasis.¹²

Conclusion

We describe a unique presentation of an already rare variant of psoriasis that can be difficult to diagnose clinically. The unilateral distribution of lesions in this patient can create further diagnostic confusion with other entities, such as ILVEN and linear psoriasis, though it can be distinguished from those diseases based on histologic features. Our aim is that this report improves recognition of this unusual presentation of verrucous psoriasis in clinical settings and decreases delays in diagnosis and treatment.

Case Report

An 80-year-old man with a history of hypertension and coronary artery disease presented to the dermatology clinic with a rash characterized by multiple asymptomatic plaques with overlying verrucous nodules on the left side of the abdomen, back, and leg (Figure 1). He reported that these “growths” appeared 20 years prior to presentation, shortly after coronary artery bypass surgery with a saphenous vein graft. The patient initially was given a diagnosis of verruca vulgaris and then biopsy-proven psoriasis later that year. At that time, he refused systemic treatment and was treated instead with triamcinolone acetonide ointment, with periodic surgical removal of bothersome lesions.

At the current presentation, physical examination revealed many hyperkeratotic, yellow-gray, verrucous nodules overlying scaly, erythematous, sharply demarcated plaques, exclusively on the left side of the body, including the left side of the abdomen, back, and leg. The differential diagnosis included linear psoriasis and inflammatory linear verrucous epidermal nevus (ILVEN).

Skin biopsy showed irregular psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and papillomatosis, with convergence of the rete ridges, known as buttressing (Figure 2A). There were tortuous dilated blood vessels in the dermal papillae, epidermal neutrophils at the tip of the suprapapillary plates, and Munro microabscesses in the stratum corneum (Figure 2B). Koilocytes were absent, and periodic acid–Schiff staining was negative. Taken together, clinical and histologic features led to a diagnosis of unilateral verrucous psoriasis.

Comment

Presentation and Histology
Verrucous psoriasis is a variant of psoriasis that presents with wartlike clinical features and overlapping histologic features of verruca and psoriasis. It typically arises in patients with established psoriasis but can occur de novo.

Histologic features of verrucous psoriasis include epidermal hyperplasia with acanthosis, papillomatosis, and epidermal buttressing.¹ It has been hypothesized that notable hyperkeratosis observed in these lesions is induced by repeat trauma to the extremities in patients with established psoriasis or by anoxia from conditions that predispose to poor circulation, such as diabetes mellitus and pulmonary disease.^1,2

Pathogenesis
Most reported cases of verrucous psoriasis arose atop pre-existing psoriasis lesions.^3,4 The relevance of our patient’s verrucous psoriasis to his prior coronary artery bypass surgery with saphenous vein graft is unknown; however, the distribution of lesions, timing of psoriasis onset in relation to the surgical procedure, and recent data proposing a role for neuropeptide responses to nerve injury in the development of psoriasis, taken together, provide an argument for a role for surgical trauma in the development of our patient’s condition.

Treatment
Although verrucous psoriasis presents both diagnostic and therapeutic challenges, there are some reports of improvement with topical or intralesional corticosteroids in combination with keratolytics,³ coal tar,⁵ and oral methotrexate.⁶ In addition, there are rare reports of successful treatment with biologics. A case report showed successful resolution with adalimumab,⁴ and a case of erythrodermic verrucous psoriasis showed moderate improvement with ustekinumab after other failed treatments.⁷

Differential Diagnosis
Psoriasis typically presents in a symmetric distribution, with rare reported cases of unilateral distribution. Two cases of unilateral psoriasis arising after a surgical procedure have been reported, one after mastectomy and the other after neurosurgery.^8,9 Other cases of unilateral psoriasis are reported to have arisen in adolescents and young adults idiopathically.

A case of linear psoriasis arising in the distribution of the sciatic nerve in a patient with radiculopathy implicated tumor necrosis factor α, neuropeptides, and nerve growth factor released in response to compression as possible etiologic agents.¹⁰ However, none of the reported cases of linear psoriasis, or reported cases of unilateral psoriasis, exhibited verrucous features clinically or histologically. In our patient, distribution of the lesions appeared less typically blaschkoid than in linear psoriasis, and the presence of exophytic wartlike growths throughout the lesions was not characteristic of linear psoriasis.

Late-adulthood onset in this patient in addition to the absence of typical histologic features of ILVEN, including alternating orthokeratosis and parakeratosis,¹¹ make a diagnosis of ILVEN less likely; ILVEN can be distinguished from linear psoriasis based on later age of onset and responsiveness to antipsoriatic therapy of linear psoriasis.¹²

Conclusion

We describe a unique presentation of an already rare variant of psoriasis that can be difficult to diagnose clinically. The unilateral distribution of lesions in this patient can create further diagnostic confusion with other entities, such as ILVEN and linear psoriasis, though it can be distinguished from those diseases based on histologic features. Our aim is that this report improves recognition of this unusual presentation of verrucous psoriasis in clinical settings and decreases delays in diagnosis and treatment.

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.^1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.^4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.^7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.^7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.⁷ Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.⁷ These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.^8-10

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.^11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.^11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.^14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.^11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.^11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.^19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.^20,22

The pathogenesis of DD remains uncertain, but one proposed mechanism is through microvascular damage caused by hyperglycemia-induced, nonenzymatic glycation, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.^20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.²⁴ Subcutaneous nerve ischemia and degeneration secondary to diabetic neuropathy also have been postulated as causative.^20,23 Given the lack of effective therapies and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including diabetic nephropathy, retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.^19,20

Scleredema Diabeticorum

Scleredema diabeticorum (SD) refers to the slowly progressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.^25-27 Although SD generally is asymptomatic, some individuals may experience restricted mobility and decreased sensation in affected areas.^25,27,28 The diagnosis of SD frequently is missed or ignored clinically. Biopsy can provide diagnostic confirmation of this entity, as histopathology reveals a thickened reticular dermis with an accumulation of collagen and adjacent mucinous infiltrate with no edema or sclerosis.^28,29

Although the pathogenesis of SD is not well established, it is theorized that the binding of advanced glycation end products (AGEs) to collagen fibers impairs proper cross-linking and degradation by collagenase.^29-31 It is well known that hyperglycemic conditions can promote endogenous formation of AGEs, which occur when reducing sugar molecules become glycated through a nonenzymatic reaction.^30-32 The Western diet also is high in preformed AGEs, which are created primarily through certain high-heat cooking methods such as frying and grilling.^31,32 Hyperglycemia-induced stimulation of fibroblasts also has been proposed as a driver of increased collagen deposition observed histologically in SD.^28,29,33 Treatment of SD can be difficult, as there are no consistently reported therapies, and even improvement in glycemic control does not appear to reverse this condition.²⁹ Case reports have demonstrated some efficacy with various phototherapeutic modalities, including psoralen plus UVA and narrowband UVB phototherapy.^34-36

Ichthyosiform Skin Changes

Ichthyosiform skin changes refer to areas of xerosis and scaling that classically present on the anterior distal lower extremities. Although ichthyosiform alterations have been associated with numerous systemic diseases, they often represent an early finding in diabetic patients.^27,37 The development of ichthyosiform skin changes has been linked to the formation and accumulation of AGEs, which can cause defective cell adhesion in the stratum corneum.^37,38 Treatment with topical emollients and keratolytics may prove beneficial for the skin but do not improve the underlying systemic condition.³⁹

Acrochordons

Acrochordons (skin tags) are common benign fibroepithelial polyps that classically present on the face, neck, and trunk. The underlying mechanism responsible for the development of acrochordons is uncertain, but the association with insulin resistance and impaired carbohydrate metabolism is well validated.^40-46 Several large cross-sectional and case-control studies have reported rates of T2DM ranging from 23% to 72% in patients with acrochordons.^41,42,47 The pathophysiology may involve an increase in tissue and epidermal growth factors driven by elevated serum insulin levels, stimulation of IGF-1 receptors, and a localized proliferation of cutaneous tissue in elastin-poor areas.^45,48,49 Interestingly, the quantity of acrochordons has been positively correlated with fasting blood glucose levels. Additionally, the presence of 30 or more acrochordons was found to increase the risk of developing T2DM.⁴¹ Therefore, the presence and number of acrochordons may serve as a convenient indicator of systemic glycemic control and insulin resistance. Screening for T2DM is warranted in individuals without a prior diagnosis who present with multiple acrochordons.

Keratosis Pilaris

Keratosis pilaris (KP) is a benign skin condition characterized by pink-red, erythematous, monomorphic, follicular papules often seen on the extensor arms, thighs, buttocks, and cheeks. Keratosis pilaris is exceedingly common in the general population but occurs more frequently and with more extensive involvement in those with atopic dermatitis and T2DM.^27,50,51 The mechanism underlying the hyperkeratosis and inflammatory change observed in KP is not well understood and is likely multifactorial.^52,53 Hyperandrogenism, as a consequence of hyperinsulinemia, may play an important role in KP, as elevated circulating androgens are known drivers of keratinocyte proliferation of the pilosebaceous unit of hair follicles.^52,54 Support for this theory includes the clinical exaggeration of KP frequently encountered around puberty when androgen levels peak.^55,56 Moreover, one study found a higher incidence of KP among adolescent patients with type 1 diabetes mellitus than among healthy age-matched controls.²⁷ The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG laser. Numerous topical modalities have been employed to treat KP but exhibit limited efficacy, including mineral oil, tacrolimus, azelaic acid, and salicylic acid, among others.⁵⁷

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a chronic granulomatous skin condition of unknown origin that presents with well-demarcated, yellow-brown, atrophic patches and plaques often found exclusively on the shins. There is a strong association with type 1 diabetes mellitus, with reported rates ranging from 11% to 65% in patients with NL.^58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.⁶¹ Nevertheless, NL is a rare entity that affects less than 1% of the diabetic population.⁶⁰ Given its correlation with diabetes, it has been postulated that the pathogenesis of NL is due to microvascular ischemic changes resulting from prolonged hyperglycemia.⁶⁰ However, studies revealing an increase in blood flow to NL lesions suggest that the condition may instead be attributed to an inflammatory process.⁶² Despite the disfiguring appearance, the lesions of NL often are asymptomatic. Pain or pruritus may develop secondary to ulceration, which occurs in approximately one-third of patients. Although many treatment options have been attempted—including topical and intralesional corticosteroids, immunomodulators, platelet inhibitors, and phototherapy—efficacy is limited.⁶⁰

Bullosis Diabeticorum

Bullosis diabeticorum (BD) is the abrupt onset of noninflammatory vesicles and bullae developing in the setting of diabetes. The prevalence of BD in the diabetic population ranges from 0.16% to 0.5%.^63-66 Bullosis diabeticorum occasionally has been reported to occur prior to the onset of diabetes, warranting screening hemoglobin A_1c in patients without an established diagnosis of diabetes.⁶⁷ Bullae most commonly present over the acral surfaces, but the lower extremities also are routinely affected. Bullae typically are large and painless, contain clear fluid, and may progress from tense to flaccid over the course of several days. Although histologic analysis reveals nonspecific findings, biopsy may be useful in excluding other bullous disorders. Because BD is a benign condition that spontaneously resolves over several weeks, treatment rarely is pursued.^63,64

Generalized Granuloma Annulare

Generalized granuloma annulare (GA) is an idiopathic inflammatory cutaneous disorder characterized by pink-red, arciform and annular, nonscaly, beaded papules and plaques. Granuloma annulare can be localized or generalized with perforating, patch, and palmoplantar variants. Although the pathogenesis is poorly understood, some studies have demonstrated a correlation between GA and type 1 diabetes mellitus.^68-71 Generalized GA appears to be most strongly associated with diabetes, and approximately 10% to 15% of cases occur in this population.^70,72 Because GA has been reported to precede the diagnosis of diabetes, patients with generalized or recurrent localized GA should be screened for persistent hyperglycemia with a hemoglobin A_1c test.^71,73 Although some GA is self-resolving, treatment options for persevering GA include topical and intralesional steroids, isotretinoin, dapsone, tacrolimus, antimalarials, biologic medications, and psoralen plus UVA therapy.⁷⁴

Final Thoughts

Mechanistic links between common cutaneous conditions and persistent hyperglycemic and hyperinsulinemic states are slowly emerging. Hyperglycemia promotes nonenzymatic glycation of the vascular endothelium as well as formation of AGEs that impair cross-linking of collagen in the skin. The consequent microangiopathic damage may lead to cutaneous conditions such as DD, NL, and BD. In addition to microvascular compromise, impaired collagen cross-linking may result in ichthyosiform skin changes and SD. Hyperinsulinemia causes increased circulating levels of IGF-1, which leads to the overactivation of IGF-1 receptors present on fibroblasts and keratinocytes. This aberrant IGF-1 signaling drives cellular hyperproliferation and differentiation, which may be responsible for cutaneous findings such as AN, KP, and/or acrochordons. An insulin-dependent increase in IGF-1 and androgenic signaling may have implications for hormonally driven inflammatory skin disorders such as acne vulgaris and hidradenitis suppurativa, warranting further investigation.

Physicians should be aware of these dermatologic manifestations and their proposed underlying pathophysiologic mechanisms related to impaired glucose tolerance and insulin resistance. A diagnosis of T2DM is not a prerequisite for metabolic disturbance, and the skin may serve as the first clue to underlying systemic disease. Early identification of these cutaneous conditions may lead to timely patient counseling, lifestyle modification, and/or medical management, preventing the long-term sequelae associated with metabolic disorders.

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.^1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.^4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.^7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.^7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.⁷ Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.⁷ These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.^8-10

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.^11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.^11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.^14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.^11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.^11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.^19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.^20,22

The pathogenesis of DD remains uncertain, but one proposed mechanism is through microvascular damage caused by hyperglycemia-induced, nonenzymatic glycation, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.^20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.²⁴ Subcutaneous nerve ischemia and degeneration secondary to diabetic neuropathy also have been postulated as causative.^20,23 Given the lack of effective therapies and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including diabetic nephropathy, retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.^19,20

Scleredema Diabeticorum

Scleredema diabeticorum (SD) refers to the slowly progressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.^25-27 Although SD generally is asymptomatic, some individuals may experience restricted mobility and decreased sensation in affected areas.^25,27,28 The diagnosis of SD frequently is missed or ignored clinically. Biopsy can provide diagnostic confirmation of this entity, as histopathology reveals a thickened reticular dermis with an accumulation of collagen and adjacent mucinous infiltrate with no edema or sclerosis.^28,29

Although the pathogenesis of SD is not well established, it is theorized that the binding of advanced glycation end products (AGEs) to collagen fibers impairs proper cross-linking and degradation by collagenase.^29-31 It is well known that hyperglycemic conditions can promote endogenous formation of AGEs, which occur when reducing sugar molecules become glycated through a nonenzymatic reaction.^30-32 The Western diet also is high in preformed AGEs, which are created primarily through certain high-heat cooking methods such as frying and grilling.^31,32 Hyperglycemia-induced stimulation of fibroblasts also has been proposed as a driver of increased collagen deposition observed histologically in SD.^28,29,33 Treatment of SD can be difficult, as there are no consistently reported therapies, and even improvement in glycemic control does not appear to reverse this condition.²⁹ Case reports have demonstrated some efficacy with various phototherapeutic modalities, including psoralen plus UVA and narrowband UVB phototherapy.^34-36

Ichthyosiform Skin Changes

Ichthyosiform skin changes refer to areas of xerosis and scaling that classically present on the anterior distal lower extremities. Although ichthyosiform alterations have been associated with numerous systemic diseases, they often represent an early finding in diabetic patients.^27,37 The development of ichthyosiform skin changes has been linked to the formation and accumulation of AGEs, which can cause defective cell adhesion in the stratum corneum.^37,38 Treatment with topical emollients and keratolytics may prove beneficial for the skin but do not improve the underlying systemic condition.³⁹

Acrochordons

Acrochordons (skin tags) are common benign fibroepithelial polyps that classically present on the face, neck, and trunk. The underlying mechanism responsible for the development of acrochordons is uncertain, but the association with insulin resistance and impaired carbohydrate metabolism is well validated.^40-46 Several large cross-sectional and case-control studies have reported rates of T2DM ranging from 23% to 72% in patients with acrochordons.^41,42,47 The pathophysiology may involve an increase in tissue and epidermal growth factors driven by elevated serum insulin levels, stimulation of IGF-1 receptors, and a localized proliferation of cutaneous tissue in elastin-poor areas.^45,48,49 Interestingly, the quantity of acrochordons has been positively correlated with fasting blood glucose levels. Additionally, the presence of 30 or more acrochordons was found to increase the risk of developing T2DM.⁴¹ Therefore, the presence and number of acrochordons may serve as a convenient indicator of systemic glycemic control and insulin resistance. Screening for T2DM is warranted in individuals without a prior diagnosis who present with multiple acrochordons.

Keratosis Pilaris

Keratosis pilaris (KP) is a benign skin condition characterized by pink-red, erythematous, monomorphic, follicular papules often seen on the extensor arms, thighs, buttocks, and cheeks. Keratosis pilaris is exceedingly common in the general population but occurs more frequently and with more extensive involvement in those with atopic dermatitis and T2DM.^27,50,51 The mechanism underlying the hyperkeratosis and inflammatory change observed in KP is not well understood and is likely multifactorial.^52,53 Hyperandrogenism, as a consequence of hyperinsulinemia, may play an important role in KP, as elevated circulating androgens are known drivers of keratinocyte proliferation of the pilosebaceous unit of hair follicles.^52,54 Support for this theory includes the clinical exaggeration of KP frequently encountered around puberty when androgen levels peak.^55,56 Moreover, one study found a higher incidence of KP among adolescent patients with type 1 diabetes mellitus than among healthy age-matched controls.²⁷ The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG laser. Numerous topical modalities have been employed to treat KP but exhibit limited efficacy, including mineral oil, tacrolimus, azelaic acid, and salicylic acid, among others.⁵⁷

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a chronic granulomatous skin condition of unknown origin that presents with well-demarcated, yellow-brown, atrophic patches and plaques often found exclusively on the shins. There is a strong association with type 1 diabetes mellitus, with reported rates ranging from 11% to 65% in patients with NL.^58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.⁶¹ Nevertheless, NL is a rare entity that affects less than 1% of the diabetic population.⁶⁰ Given its correlation with diabetes, it has been postulated that the pathogenesis of NL is due to microvascular ischemic changes resulting from prolonged hyperglycemia.⁶⁰ However, studies revealing an increase in blood flow to NL lesions suggest that the condition may instead be attributed to an inflammatory process.⁶² Despite the disfiguring appearance, the lesions of NL often are asymptomatic. Pain or pruritus may develop secondary to ulceration, which occurs in approximately one-third of patients. Although many treatment options have been attempted—including topical and intralesional corticosteroids, immunomodulators, platelet inhibitors, and phototherapy—efficacy is limited.⁶⁰

Bullosis Diabeticorum

Bullosis diabeticorum (BD) is the abrupt onset of noninflammatory vesicles and bullae developing in the setting of diabetes. The prevalence of BD in the diabetic population ranges from 0.16% to 0.5%.^63-66 Bullosis diabeticorum occasionally has been reported to occur prior to the onset of diabetes, warranting screening hemoglobin A_1c in patients without an established diagnosis of diabetes.⁶⁷ Bullae most commonly present over the acral surfaces, but the lower extremities also are routinely affected. Bullae typically are large and painless, contain clear fluid, and may progress from tense to flaccid over the course of several days. Although histologic analysis reveals nonspecific findings, biopsy may be useful in excluding other bullous disorders. Because BD is a benign condition that spontaneously resolves over several weeks, treatment rarely is pursued.^63,64

Generalized Granuloma Annulare

Generalized granuloma annulare (GA) is an idiopathic inflammatory cutaneous disorder characterized by pink-red, arciform and annular, nonscaly, beaded papules and plaques. Granuloma annulare can be localized or generalized with perforating, patch, and palmoplantar variants. Although the pathogenesis is poorly understood, some studies have demonstrated a correlation between GA and type 1 diabetes mellitus.^68-71 Generalized GA appears to be most strongly associated with diabetes, and approximately 10% to 15% of cases occur in this population.^70,72 Because GA has been reported to precede the diagnosis of diabetes, patients with generalized or recurrent localized GA should be screened for persistent hyperglycemia with a hemoglobin A_1c test.^71,73 Although some GA is self-resolving, treatment options for persevering GA include topical and intralesional steroids, isotretinoin, dapsone, tacrolimus, antimalarials, biologic medications, and psoralen plus UVA therapy.⁷⁴

Final Thoughts

Mechanistic links between common cutaneous conditions and persistent hyperglycemic and hyperinsulinemic states are slowly emerging. Hyperglycemia promotes nonenzymatic glycation of the vascular endothelium as well as formation of AGEs that impair cross-linking of collagen in the skin. The consequent microangiopathic damage may lead to cutaneous conditions such as DD, NL, and BD. In addition to microvascular compromise, impaired collagen cross-linking may result in ichthyosiform skin changes and SD. Hyperinsulinemia causes increased circulating levels of IGF-1, which leads to the overactivation of IGF-1 receptors present on fibroblasts and keratinocytes. This aberrant IGF-1 signaling drives cellular hyperproliferation and differentiation, which may be responsible for cutaneous findings such as AN, KP, and/or acrochordons. An insulin-dependent increase in IGF-1 and androgenic signaling may have implications for hormonally driven inflammatory skin disorders such as acne vulgaris and hidradenitis suppurativa, warranting further investigation.

Physicians should be aware of these dermatologic manifestations and their proposed underlying pathophysiologic mechanisms related to impaired glucose tolerance and insulin resistance. A diagnosis of T2DM is not a prerequisite for metabolic disturbance, and the skin may serve as the first clue to underlying systemic disease. Early identification of these cutaneous conditions may lead to timely patient counseling, lifestyle modification, and/or medical management, preventing the long-term sequelae associated with metabolic disorders.

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.^1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.^4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.^7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.^7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.⁷ Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.⁷ These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.^8-10

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.^11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.^11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.^14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.^11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.^11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.^19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.^20,22

The pathogenesis of DD remains uncertain, but one proposed mechanism is through microvascular damage caused by hyperglycemia-induced, nonenzymatic glycation, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.^20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.²⁴ Subcutaneous nerve ischemia and degeneration secondary to diabetic neuropathy also have been postulated as causative.^20,23 Given the lack of effective therapies and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including diabetic nephropathy, retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.^19,20

Scleredema Diabeticorum

Scleredema diabeticorum (SD) refers to the slowly progressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.^25-27 Although SD generally is asymptomatic, some individuals may experience restricted mobility and decreased sensation in affected areas.^25,27,28 The diagnosis of SD frequently is missed or ignored clinically. Biopsy can provide diagnostic confirmation of this entity, as histopathology reveals a thickened reticular dermis with an accumulation of collagen and adjacent mucinous infiltrate with no edema or sclerosis.^28,29

Although the pathogenesis of SD is not well established, it is theorized that the binding of advanced glycation end products (AGEs) to collagen fibers impairs proper cross-linking and degradation by collagenase.^29-31 It is well known that hyperglycemic conditions can promote endogenous formation of AGEs, which occur when reducing sugar molecules become glycated through a nonenzymatic reaction.^30-32 The Western diet also is high in preformed AGEs, which are created primarily through certain high-heat cooking methods such as frying and grilling.^31,32 Hyperglycemia-induced stimulation of fibroblasts also has been proposed as a driver of increased collagen deposition observed histologically in SD.^28,29,33 Treatment of SD can be difficult, as there are no consistently reported therapies, and even improvement in glycemic control does not appear to reverse this condition.²⁹ Case reports have demonstrated some efficacy with various phototherapeutic modalities, including psoralen plus UVA and narrowband UVB phototherapy.^34-36

Ichthyosiform Skin Changes

Ichthyosiform skin changes refer to areas of xerosis and scaling that classically present on the anterior distal lower extremities. Although ichthyosiform alterations have been associated with numerous systemic diseases, they often represent an early finding in diabetic patients.^27,37 The development of ichthyosiform skin changes has been linked to the formation and accumulation of AGEs, which can cause defective cell adhesion in the stratum corneum.^37,38 Treatment with topical emollients and keratolytics may prove beneficial for the skin but do not improve the underlying systemic condition.³⁹

Acrochordons

Acrochordons (skin tags) are common benign fibroepithelial polyps that classically present on the face, neck, and trunk. The underlying mechanism responsible for the development of acrochordons is uncertain, but the association with insulin resistance and impaired carbohydrate metabolism is well validated.^40-46 Several large cross-sectional and case-control studies have reported rates of T2DM ranging from 23% to 72% in patients with acrochordons.^41,42,47 The pathophysiology may involve an increase in tissue and epidermal growth factors driven by elevated serum insulin levels, stimulation of IGF-1 receptors, and a localized proliferation of cutaneous tissue in elastin-poor areas.^45,48,49 Interestingly, the quantity of acrochordons has been positively correlated with fasting blood glucose levels. Additionally, the presence of 30 or more acrochordons was found to increase the risk of developing T2DM.⁴¹ Therefore, the presence and number of acrochordons may serve as a convenient indicator of systemic glycemic control and insulin resistance. Screening for T2DM is warranted in individuals without a prior diagnosis who present with multiple acrochordons.

Keratosis Pilaris

Keratosis pilaris (KP) is a benign skin condition characterized by pink-red, erythematous, monomorphic, follicular papules often seen on the extensor arms, thighs, buttocks, and cheeks. Keratosis pilaris is exceedingly common in the general population but occurs more frequently and with more extensive involvement in those with atopic dermatitis and T2DM.^27,50,51 The mechanism underlying the hyperkeratosis and inflammatory change observed in KP is not well understood and is likely multifactorial.^52,53 Hyperandrogenism, as a consequence of hyperinsulinemia, may play an important role in KP, as elevated circulating androgens are known drivers of keratinocyte proliferation of the pilosebaceous unit of hair follicles.^52,54 Support for this theory includes the clinical exaggeration of KP frequently encountered around puberty when androgen levels peak.^55,56 Moreover, one study found a higher incidence of KP among adolescent patients with type 1 diabetes mellitus than among healthy age-matched controls.²⁷ The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG laser. Numerous topical modalities have been employed to treat KP but exhibit limited efficacy, including mineral oil, tacrolimus, azelaic acid, and salicylic acid, among others.⁵⁷

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a chronic granulomatous skin condition of unknown origin that presents with well-demarcated, yellow-brown, atrophic patches and plaques often found exclusively on the shins. There is a strong association with type 1 diabetes mellitus, with reported rates ranging from 11% to 65% in patients with NL.^58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.⁶¹ Nevertheless, NL is a rare entity that affects less than 1% of the diabetic population.⁶⁰ Given its correlation with diabetes, it has been postulated that the pathogenesis of NL is due to microvascular ischemic changes resulting from prolonged hyperglycemia.⁶⁰ However, studies revealing an increase in blood flow to NL lesions suggest that the condition may instead be attributed to an inflammatory process.⁶² Despite the disfiguring appearance, the lesions of NL often are asymptomatic. Pain or pruritus may develop secondary to ulceration, which occurs in approximately one-third of patients. Although many treatment options have been attempted—including topical and intralesional corticosteroids, immunomodulators, platelet inhibitors, and phototherapy—efficacy is limited.⁶⁰

Bullosis Diabeticorum

Bullosis diabeticorum (BD) is the abrupt onset of noninflammatory vesicles and bullae developing in the setting of diabetes. The prevalence of BD in the diabetic population ranges from 0.16% to 0.5%.^63-66 Bullosis diabeticorum occasionally has been reported to occur prior to the onset of diabetes, warranting screening hemoglobin A_1c in patients without an established diagnosis of diabetes.⁶⁷ Bullae most commonly present over the acral surfaces, but the lower extremities also are routinely affected. Bullae typically are large and painless, contain clear fluid, and may progress from tense to flaccid over the course of several days. Although histologic analysis reveals nonspecific findings, biopsy may be useful in excluding other bullous disorders. Because BD is a benign condition that spontaneously resolves over several weeks, treatment rarely is pursued.^63,64

Generalized Granuloma Annulare

Generalized granuloma annulare (GA) is an idiopathic inflammatory cutaneous disorder characterized by pink-red, arciform and annular, nonscaly, beaded papules and plaques. Granuloma annulare can be localized or generalized with perforating, patch, and palmoplantar variants. Although the pathogenesis is poorly understood, some studies have demonstrated a correlation between GA and type 1 diabetes mellitus.^68-71 Generalized GA appears to be most strongly associated with diabetes, and approximately 10% to 15% of cases occur in this population.^70,72 Because GA has been reported to precede the diagnosis of diabetes, patients with generalized or recurrent localized GA should be screened for persistent hyperglycemia with a hemoglobin A_1c test.^71,73 Although some GA is self-resolving, treatment options for persevering GA include topical and intralesional steroids, isotretinoin, dapsone, tacrolimus, antimalarials, biologic medications, and psoralen plus UVA therapy.⁷⁴

Final Thoughts

Mechanistic links between common cutaneous conditions and persistent hyperglycemic and hyperinsulinemic states are slowly emerging. Hyperglycemia promotes nonenzymatic glycation of the vascular endothelium as well as formation of AGEs that impair cross-linking of collagen in the skin. The consequent microangiopathic damage may lead to cutaneous conditions such as DD, NL, and BD. In addition to microvascular compromise, impaired collagen cross-linking may result in ichthyosiform skin changes and SD. Hyperinsulinemia causes increased circulating levels of IGF-1, which leads to the overactivation of IGF-1 receptors present on fibroblasts and keratinocytes. This aberrant IGF-1 signaling drives cellular hyperproliferation and differentiation, which may be responsible for cutaneous findings such as AN, KP, and/or acrochordons. An insulin-dependent increase in IGF-1 and androgenic signaling may have implications for hormonally driven inflammatory skin disorders such as acne vulgaris and hidradenitis suppurativa, warranting further investigation.

Physicians should be aware of these dermatologic manifestations and their proposed underlying pathophysiologic mechanisms related to impaired glucose tolerance and insulin resistance. A diagnosis of T2DM is not a prerequisite for metabolic disturbance, and the skin may serve as the first clue to underlying systemic disease. Early identification of these cutaneous conditions may lead to timely patient counseling, lifestyle modification, and/or medical management, preventing the long-term sequelae associated with metabolic disorders.