Cutis

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.

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.

The world of telemedicine—especially teledermatology—had been a sleepy underutilized afterthought for most physicians until we were faced with a global pandemic the likes of which none of us had seen in our lifetimes. And just like that, teledermatology went from an afterthought to part of the “new normal.” Although those of us already practicing telemedicine knew of potential pitfalls and concerns, this great social experiment of throwing everyone into unexplored territory led to a great deal of frustration with technology and workflows that were not optimized for dermatology visits. The process is still changing, and the technical aspects of conducting teledermatology visits will no doubt improve, but what about the bigger question of reimbursement? Without adequate payments and financial models, the long-term future of telemedicine is uncertain, so an understanding of the current and likely future landscape of telemedicine reimbursement is critical.

Waivers During the Public Health Emergency

The declaration of a public health emergency (PHE)allowed for significant flexibility by the Centers for Medicare & Medicaid Services (CMS) during the coronavirus disease 2019 (COVID-19) pandemic. Importantly, the CMS was permitted to act quickly to allow telehealth to flourish during the worst of the pandemic and throughout the declared PHE, which has been extended several times already. Currently, the PHE is set to expire on April 20, 2021, but may be extended again if the pandemic is ongoing. The most important of these waivers was probably the removal of both the originating site and geographic requirements for telehealth services.¹ Prior to the COVID-19 PHE, a patient would have to travel to a doctor’s office, hospital, or skilled nursing facility to receive telehealth care (originating site requirement), and even then this was only allowed in defined rural areas of the country (geographic requirement). Both of these requirements were waived, allowing for any patient to receive telehealth services within their own homes. Concurrently, the requirement that patients must have an established relationship with the provider (ie, telehealth could not be used to provide care to new patients) also was waived.¹

In the spirit of expanding access to care and providing reasonable reimbursement for medical services, other changes were made for which the CMS should be commended. In acknowledging that many Medicare/Medicaid beneficiaries may not have access to devices that permit real-time, 2-way audio/video communication, which previously were necessary to qualify for a telehealth encounter, the CMS decided to cover telephone visits and provide reimbursement at the level of an established visit.¹ They also changed the billing structure to remove the place of service (POS) designation for telehealth (POS 02) and replace it with the normal physician’s office POS designation (usually POS 11), bringing back a telehealth modifier (modifier -95) in the process. The benefit of this change is solely to increase reimbursement for these services, as telehealth POS services generally are covered at lower facility rates, whereas POS 11 codes are reimbursed at the full level of a nonfacility physician’s office rate.

Finally, other waivers such as the Office of Civil Rights’ decision to waive HIPAA (Health Insurance Portability and Accountability Act) violations for telehealth platforms during the PHE allowed offices to take on telemedicine quickly without having to implement a new infrastructure.² Numerous codes were added to the list of covered services for telehealth, but these generally are not relevant for dermatologists. The CMS also allowed physicians’ offices to waive the patient responsibility/co-pay during the COVID-19 PHE, which previously was not allowed due to concerns about the anti-kickback statute.¹ These co-pay waivers were intended to remove another barrier to care for patients who were hesitant to participate in virtual visits. For the most part, the waiver of state licensing requirements is a bit less useful. As part of the CMS waiver, providers technically are allowed to see out-of-state Medicare/Medicaid beneficiaries, but state licensing laws are still in effect; thus, in the absence of a blanket state-level waiver (which some states enacted, modeled after the Uniform Emergency Volunteer Health Practitioner Act of 2006³), providers still cannot see most out-of-state patients from a legal and malpractice coverage standpoint.

An important flexibility during the COVID-19 PHE is one that often is underrecognized. The CMS has been clear about the ability to provide direct supervision for advanced practice providers (APPs) and residents via telehealth during the PHE, which allows for incident-to billing for APPs at remote sites given that the supervising physician is immediately available via an interactive, 2-way, live audio/video telecommunications method. It also allows for direct supervision of APPs and residents using such technology. For dermatology, which does not have a primary care waiver, an attending must still directly supervise each patient and see the patient via a live audio/video modality but does not have to be on-site to do so. This is a very interesting concept that, if extended, could truly impact practice management for the long-term.

Response From Commercial Insurance Carriers

Tracking along with the CMS waivers and flexibilities during the PHE, most commercial carriers quickly adopted similar policies to cover telehealth services. It should be noted that for most commercial insurance carriers, the coverage was already broader than Medicare/Medicaid coverage for telehealth prior to the PHE, so in many ways it is an extension of that concept and acceptance of telemedicine as a whole. What is sometimes confusing, though, is that various policies and requirements around billing exist; for example, while most carriers emulated the POS requirements that the CMS adopted, some carriers still stuck with the telemedicine POS but paid full in-office visit rates for those codes. Some carriers adopted higher reimbursement rates for telephone visits, similar to the CMS, while others instructed providers to just bill for the established office visit codes and allowed for telephone-only visits to qualify for these billing codes. Some carriers also waived co-pays for telehealth visits for their members (whether related to COVID-19 or not). It is beyond the scope of this article to delve into the specifics, which may vary not only by carrier but by region and plan. However, it is important to stay on top of one’s insurance carriers to find out what their latest directives are for billing for telehealth.

Postpandemic Teledermatology

What about the future of teledermatology? Although many dermatologists have adopted telehealth services out of necessity during the COVID-19 PHE, the jury is still out on the long-term forecast for telemedicine in dermatology. Concerns about liability/malpractice and technology issues abound, and for many, the headaches of teledermatology—such as trying to focus on a blurry photograph of a nevus that the patient is concerned about—make it unappealing. Some of these issues will be addressed by better technology, but the reimbursement structure must continue for teledermatology to remain in widespread use.

Currently, the biggest question facing telehealth is whether the waivers for originating site and geographic requirements will be able to continue. The CMS itself does not have the statutory authority to make these changes permanent and was only allowed to act due to a waiver under section 1135 of the Social Security Act during a PHE. It would take an act of Congress to change the law to allow for this specific expansion of telehealth services. A number of federal bills, including S 2741 (Creating Opportunities Now for Necessary and Effective Care Technologies [CONNECT] for Health Act of 2019) and S 4796 (Fair Care Act of 2020) from the Senate, contain such provisions, but none have been passed at the time of writing. There does seem to be broad support of the concept of expanding telemedicine access, such as noted by New York State Governor Andrew Cuomo in his 2021 State of the State address,⁴ but it remains to be seen when action will come.

Some regulations, such as the HIPAA waiver and the ability to waive co-pays, are not slated to continue after the pandemic. The ability to supervise residents via telehealth (real-time audio/video) has been made permanent, but only in rural areas. Direct supervision of APPs via telehealth will continue through the end of the calendar year of the PHE or the end of 2021, whichever comes later, but it remains to be seen whether remote supervision will continue. The CMS has stated in its comments that it is looking at this issue closely and may establish certain guardrails to ensure quality of care is maintained.¹ Telephone/audio-only visits also may come under further scrutiny, but research has supported the concept that patients who are more likely to gain access through audio-only modalities are older, Medicare/Medicaid (vs commercial), and Black (vs White) patients,⁵ so it would indeed introduce an unfair barrier to access if such coverage was rolled back.

Final Thoughts

Overall, we have made much progress in teledermatology. Once utilized by a small fraction of dermatologists, the vast majority of us turned to teledermatology to sustain our practices during the COVID-19 pandemic. Moving forward, there are 2 critical factors to consider: continued technological innovation and permanent coverage for telehealth reimbursement at in-office visit levels. With these challenges resolved, we can move forward and consider novel models that may be able to deliver dermatologic care to a broader patient population, thereby solving the critical issue of access to care for so many patients in need in our country.

The world of telemedicine—especially teledermatology—had been a sleepy underutilized afterthought for most physicians until we were faced with a global pandemic the likes of which none of us had seen in our lifetimes. And just like that, teledermatology went from an afterthought to part of the “new normal.” Although those of us already practicing telemedicine knew of potential pitfalls and concerns, this great social experiment of throwing everyone into unexplored territory led to a great deal of frustration with technology and workflows that were not optimized for dermatology visits. The process is still changing, and the technical aspects of conducting teledermatology visits will no doubt improve, but what about the bigger question of reimbursement? Without adequate payments and financial models, the long-term future of telemedicine is uncertain, so an understanding of the current and likely future landscape of telemedicine reimbursement is critical.

Waivers During the Public Health Emergency

The declaration of a public health emergency (PHE)allowed for significant flexibility by the Centers for Medicare & Medicaid Services (CMS) during the coronavirus disease 2019 (COVID-19) pandemic. Importantly, the CMS was permitted to act quickly to allow telehealth to flourish during the worst of the pandemic and throughout the declared PHE, which has been extended several times already. Currently, the PHE is set to expire on April 20, 2021, but may be extended again if the pandemic is ongoing. The most important of these waivers was probably the removal of both the originating site and geographic requirements for telehealth services.¹ Prior to the COVID-19 PHE, a patient would have to travel to a doctor’s office, hospital, or skilled nursing facility to receive telehealth care (originating site requirement), and even then this was only allowed in defined rural areas of the country (geographic requirement). Both of these requirements were waived, allowing for any patient to receive telehealth services within their own homes. Concurrently, the requirement that patients must have an established relationship with the provider (ie, telehealth could not be used to provide care to new patients) also was waived.¹

In the spirit of expanding access to care and providing reasonable reimbursement for medical services, other changes were made for which the CMS should be commended. In acknowledging that many Medicare/Medicaid beneficiaries may not have access to devices that permit real-time, 2-way audio/video communication, which previously were necessary to qualify for a telehealth encounter, the CMS decided to cover telephone visits and provide reimbursement at the level of an established visit.¹ They also changed the billing structure to remove the place of service (POS) designation for telehealth (POS 02) and replace it with the normal physician’s office POS designation (usually POS 11), bringing back a telehealth modifier (modifier -95) in the process. The benefit of this change is solely to increase reimbursement for these services, as telehealth POS services generally are covered at lower facility rates, whereas POS 11 codes are reimbursed at the full level of a nonfacility physician’s office rate.

Finally, other waivers such as the Office of Civil Rights’ decision to waive HIPAA (Health Insurance Portability and Accountability Act) violations for telehealth platforms during the PHE allowed offices to take on telemedicine quickly without having to implement a new infrastructure.² Numerous codes were added to the list of covered services for telehealth, but these generally are not relevant for dermatologists. The CMS also allowed physicians’ offices to waive the patient responsibility/co-pay during the COVID-19 PHE, which previously was not allowed due to concerns about the anti-kickback statute.¹ These co-pay waivers were intended to remove another barrier to care for patients who were hesitant to participate in virtual visits. For the most part, the waiver of state licensing requirements is a bit less useful. As part of the CMS waiver, providers technically are allowed to see out-of-state Medicare/Medicaid beneficiaries, but state licensing laws are still in effect; thus, in the absence of a blanket state-level waiver (which some states enacted, modeled after the Uniform Emergency Volunteer Health Practitioner Act of 2006³), providers still cannot see most out-of-state patients from a legal and malpractice coverage standpoint.

An important flexibility during the COVID-19 PHE is one that often is underrecognized. The CMS has been clear about the ability to provide direct supervision for advanced practice providers (APPs) and residents via telehealth during the PHE, which allows for incident-to billing for APPs at remote sites given that the supervising physician is immediately available via an interactive, 2-way, live audio/video telecommunications method. It also allows for direct supervision of APPs and residents using such technology. For dermatology, which does not have a primary care waiver, an attending must still directly supervise each patient and see the patient via a live audio/video modality but does not have to be on-site to do so. This is a very interesting concept that, if extended, could truly impact practice management for the long-term.

Response From Commercial Insurance Carriers

Tracking along with the CMS waivers and flexibilities during the PHE, most commercial carriers quickly adopted similar policies to cover telehealth services. It should be noted that for most commercial insurance carriers, the coverage was already broader than Medicare/Medicaid coverage for telehealth prior to the PHE, so in many ways it is an extension of that concept and acceptance of telemedicine as a whole. What is sometimes confusing, though, is that various policies and requirements around billing exist; for example, while most carriers emulated the POS requirements that the CMS adopted, some carriers still stuck with the telemedicine POS but paid full in-office visit rates for those codes. Some carriers adopted higher reimbursement rates for telephone visits, similar to the CMS, while others instructed providers to just bill for the established office visit codes and allowed for telephone-only visits to qualify for these billing codes. Some carriers also waived co-pays for telehealth visits for their members (whether related to COVID-19 or not). It is beyond the scope of this article to delve into the specifics, which may vary not only by carrier but by region and plan. However, it is important to stay on top of one’s insurance carriers to find out what their latest directives are for billing for telehealth.

Postpandemic Teledermatology

What about the future of teledermatology? Although many dermatologists have adopted telehealth services out of necessity during the COVID-19 PHE, the jury is still out on the long-term forecast for telemedicine in dermatology. Concerns about liability/malpractice and technology issues abound, and for many, the headaches of teledermatology—such as trying to focus on a blurry photograph of a nevus that the patient is concerned about—make it unappealing. Some of these issues will be addressed by better technology, but the reimbursement structure must continue for teledermatology to remain in widespread use.

Currently, the biggest question facing telehealth is whether the waivers for originating site and geographic requirements will be able to continue. The CMS itself does not have the statutory authority to make these changes permanent and was only allowed to act due to a waiver under section 1135 of the Social Security Act during a PHE. It would take an act of Congress to change the law to allow for this specific expansion of telehealth services. A number of federal bills, including S 2741 (Creating Opportunities Now for Necessary and Effective Care Technologies [CONNECT] for Health Act of 2019) and S 4796 (Fair Care Act of 2020) from the Senate, contain such provisions, but none have been passed at the time of writing. There does seem to be broad support of the concept of expanding telemedicine access, such as noted by New York State Governor Andrew Cuomo in his 2021 State of the State address,⁴ but it remains to be seen when action will come.

Some regulations, such as the HIPAA waiver and the ability to waive co-pays, are not slated to continue after the pandemic. The ability to supervise residents via telehealth (real-time audio/video) has been made permanent, but only in rural areas. Direct supervision of APPs via telehealth will continue through the end of the calendar year of the PHE or the end of 2021, whichever comes later, but it remains to be seen whether remote supervision will continue. The CMS has stated in its comments that it is looking at this issue closely and may establish certain guardrails to ensure quality of care is maintained.¹ Telephone/audio-only visits also may come under further scrutiny, but research has supported the concept that patients who are more likely to gain access through audio-only modalities are older, Medicare/Medicaid (vs commercial), and Black (vs White) patients,⁵ so it would indeed introduce an unfair barrier to access if such coverage was rolled back.

Final Thoughts

Overall, we have made much progress in teledermatology. Once utilized by a small fraction of dermatologists, the vast majority of us turned to teledermatology to sustain our practices during the COVID-19 pandemic. Moving forward, there are 2 critical factors to consider: continued technological innovation and permanent coverage for telehealth reimbursement at in-office visit levels. With these challenges resolved, we can move forward and consider novel models that may be able to deliver dermatologic care to a broader patient population, thereby solving the critical issue of access to care for so many patients in need in our country.

The world of telemedicine—especially teledermatology—had been a sleepy underutilized afterthought for most physicians until we were faced with a global pandemic the likes of which none of us had seen in our lifetimes. And just like that, teledermatology went from an afterthought to part of the “new normal.” Although those of us already practicing telemedicine knew of potential pitfalls and concerns, this great social experiment of throwing everyone into unexplored territory led to a great deal of frustration with technology and workflows that were not optimized for dermatology visits. The process is still changing, and the technical aspects of conducting teledermatology visits will no doubt improve, but what about the bigger question of reimbursement? Without adequate payments and financial models, the long-term future of telemedicine is uncertain, so an understanding of the current and likely future landscape of telemedicine reimbursement is critical.

Waivers During the Public Health Emergency

The declaration of a public health emergency (PHE)allowed for significant flexibility by the Centers for Medicare & Medicaid Services (CMS) during the coronavirus disease 2019 (COVID-19) pandemic. Importantly, the CMS was permitted to act quickly to allow telehealth to flourish during the worst of the pandemic and throughout the declared PHE, which has been extended several times already. Currently, the PHE is set to expire on April 20, 2021, but may be extended again if the pandemic is ongoing. The most important of these waivers was probably the removal of both the originating site and geographic requirements for telehealth services.¹ Prior to the COVID-19 PHE, a patient would have to travel to a doctor’s office, hospital, or skilled nursing facility to receive telehealth care (originating site requirement), and even then this was only allowed in defined rural areas of the country (geographic requirement). Both of these requirements were waived, allowing for any patient to receive telehealth services within their own homes. Concurrently, the requirement that patients must have an established relationship with the provider (ie, telehealth could not be used to provide care to new patients) also was waived.¹

In the spirit of expanding access to care and providing reasonable reimbursement for medical services, other changes were made for which the CMS should be commended. In acknowledging that many Medicare/Medicaid beneficiaries may not have access to devices that permit real-time, 2-way audio/video communication, which previously were necessary to qualify for a telehealth encounter, the CMS decided to cover telephone visits and provide reimbursement at the level of an established visit.¹ They also changed the billing structure to remove the place of service (POS) designation for telehealth (POS 02) and replace it with the normal physician’s office POS designation (usually POS 11), bringing back a telehealth modifier (modifier -95) in the process. The benefit of this change is solely to increase reimbursement for these services, as telehealth POS services generally are covered at lower facility rates, whereas POS 11 codes are reimbursed at the full level of a nonfacility physician’s office rate.

Finally, other waivers such as the Office of Civil Rights’ decision to waive HIPAA (Health Insurance Portability and Accountability Act) violations for telehealth platforms during the PHE allowed offices to take on telemedicine quickly without having to implement a new infrastructure.² Numerous codes were added to the list of covered services for telehealth, but these generally are not relevant for dermatologists. The CMS also allowed physicians’ offices to waive the patient responsibility/co-pay during the COVID-19 PHE, which previously was not allowed due to concerns about the anti-kickback statute.¹ These co-pay waivers were intended to remove another barrier to care for patients who were hesitant to participate in virtual visits. For the most part, the waiver of state licensing requirements is a bit less useful. As part of the CMS waiver, providers technically are allowed to see out-of-state Medicare/Medicaid beneficiaries, but state licensing laws are still in effect; thus, in the absence of a blanket state-level waiver (which some states enacted, modeled after the Uniform Emergency Volunteer Health Practitioner Act of 2006³), providers still cannot see most out-of-state patients from a legal and malpractice coverage standpoint.

An important flexibility during the COVID-19 PHE is one that often is underrecognized. The CMS has been clear about the ability to provide direct supervision for advanced practice providers (APPs) and residents via telehealth during the PHE, which allows for incident-to billing for APPs at remote sites given that the supervising physician is immediately available via an interactive, 2-way, live audio/video telecommunications method. It also allows for direct supervision of APPs and residents using such technology. For dermatology, which does not have a primary care waiver, an attending must still directly supervise each patient and see the patient via a live audio/video modality but does not have to be on-site to do so. This is a very interesting concept that, if extended, could truly impact practice management for the long-term.

Response From Commercial Insurance Carriers

Tracking along with the CMS waivers and flexibilities during the PHE, most commercial carriers quickly adopted similar policies to cover telehealth services. It should be noted that for most commercial insurance carriers, the coverage was already broader than Medicare/Medicaid coverage for telehealth prior to the PHE, so in many ways it is an extension of that concept and acceptance of telemedicine as a whole. What is sometimes confusing, though, is that various policies and requirements around billing exist; for example, while most carriers emulated the POS requirements that the CMS adopted, some carriers still stuck with the telemedicine POS but paid full in-office visit rates for those codes. Some carriers adopted higher reimbursement rates for telephone visits, similar to the CMS, while others instructed providers to just bill for the established office visit codes and allowed for telephone-only visits to qualify for these billing codes. Some carriers also waived co-pays for telehealth visits for their members (whether related to COVID-19 or not). It is beyond the scope of this article to delve into the specifics, which may vary not only by carrier but by region and plan. However, it is important to stay on top of one’s insurance carriers to find out what their latest directives are for billing for telehealth.

Postpandemic Teledermatology

What about the future of teledermatology? Although many dermatologists have adopted telehealth services out of necessity during the COVID-19 PHE, the jury is still out on the long-term forecast for telemedicine in dermatology. Concerns about liability/malpractice and technology issues abound, and for many, the headaches of teledermatology—such as trying to focus on a blurry photograph of a nevus that the patient is concerned about—make it unappealing. Some of these issues will be addressed by better technology, but the reimbursement structure must continue for teledermatology to remain in widespread use.

Currently, the biggest question facing telehealth is whether the waivers for originating site and geographic requirements will be able to continue. The CMS itself does not have the statutory authority to make these changes permanent and was only allowed to act due to a waiver under section 1135 of the Social Security Act during a PHE. It would take an act of Congress to change the law to allow for this specific expansion of telehealth services. A number of federal bills, including S 2741 (Creating Opportunities Now for Necessary and Effective Care Technologies [CONNECT] for Health Act of 2019) and S 4796 (Fair Care Act of 2020) from the Senate, contain such provisions, but none have been passed at the time of writing. There does seem to be broad support of the concept of expanding telemedicine access, such as noted by New York State Governor Andrew Cuomo in his 2021 State of the State address,⁴ but it remains to be seen when action will come.

Some regulations, such as the HIPAA waiver and the ability to waive co-pays, are not slated to continue after the pandemic. The ability to supervise residents via telehealth (real-time audio/video) has been made permanent, but only in rural areas. Direct supervision of APPs via telehealth will continue through the end of the calendar year of the PHE or the end of 2021, whichever comes later, but it remains to be seen whether remote supervision will continue. The CMS has stated in its comments that it is looking at this issue closely and may establish certain guardrails to ensure quality of care is maintained.¹ Telephone/audio-only visits also may come under further scrutiny, but research has supported the concept that patients who are more likely to gain access through audio-only modalities are older, Medicare/Medicaid (vs commercial), and Black (vs White) patients,⁵ so it would indeed introduce an unfair barrier to access if such coverage was rolled back.

Final Thoughts

Overall, we have made much progress in teledermatology. Once utilized by a small fraction of dermatologists, the vast majority of us turned to teledermatology to sustain our practices during the COVID-19 pandemic. Moving forward, there are 2 critical factors to consider: continued technological innovation and permanent coverage for telehealth reimbursement at in-office visit levels. With these challenges resolved, we can move forward and consider novel models that may be able to deliver dermatologic care to a broader patient population, thereby solving the critical issue of access to care for so many patients in need in our country.

In women, breast cancer is the leading cancer diagnosis and the second leading cause of cancer-related death,¹ as well as the most common malignancy to metastasize to the skin.² Cutaneous breast carcinoma may present as cutaneous metastasis or can occur secondary to direct tumor extension. Five percent to 10% of women with breast cancer will present clinically with metastatic cutaneous disease, most commonly as a recurrence of early-stage breast carcinoma.²

In a published meta-analysis that investigated the incidence of tumors most commonly found to metastasize to the skin, Krathen et al³ found that cutaneous metastases occurred in 24% of patients with breast cancer (N=1903). In 2 large retrospective studies from tumor registry data, breast cancer was found to be the most common tumor involving metastasis to the skin, and 3.5% of the breast cancer cases identified in the registry had cutaneous metastasis as the presenting sign (n=35) at time of diagnosis.⁴

We report an unusual presentation of cutaneous metastatic lobular breast carcinoma that involved diffuse cutaneous lesions and rapid progression from onset of the breast mass to development of clinically apparent metastatic skin lesions.

Case Report

A 59-year-old woman with an unremarkable medical history presented to our dermatology clinic for evaluation of new widespread lesions that developed over a period of months. The eruption was asymptomatic and consisted of numerous bumpy lesions that reportedly started on the patient’s neck and progressively spread to involve the trunk. Physical examination revealed multiple flesh-colored, firm nodules scattered across the upper back, neck, and chest (Figure 1). Bilateral cervical and axillary lymphadenopathy also was noted. Upon questioning regarding family history of malignancy, the patient reported that her brother had been diagnosed with colon cancer. Although she was not up to date on age-appropriate malignancy screenings, she did report having a diagnostic mammogram 1 year prior that revealed a suspicious lesion on the left breast. A repeat mammogram of the left breast 6 months later was read as unremarkable.

Two 3-mm representative punch biopsies were performed. Hematoxylin and eosin staining revealed a basket-weave stratum corneum with underlying epidermal atrophy. A relatively monomorphic epithelioid cell infiltrate extending from the superficial reticular dermis into the deep dermis and displaying an open chromatin pattern and pink cytoplasm was observed, as well as dermal collagen thickening. Linear, single-filing cells along with focal irregular nests and scattered cells were observed (Figure 2). Immunohistochemical staining was positive for cytokeratin 7 (Figure 3A), epithelial membrane antigen, and estrogen receptor (Figure 3B) along with gross cystic disease fluid protein 15; focal progesterone receptor positivity also was present. Cytokeratin 20, cytokeratin 5/6, carcinoembryonic antigen, p63, CDX2, paired box gene 8, thyroid transcription factor 1, and human epidermal growth factor receptor 2/neu stains were negative. Findings identified in both biopsies were consistent with metastatic cutaneous lobular breast carcinoma.

A complete blood cell count and complete metabolic panels were within normal limits, aside from a mildly elevated alkaline phosphatase level. Breast ultrasonography was unremarkable. Stereotactic breast magnetic resonance imaging (MRI) revealed a 9.4-cm mass in the upper outer quadrant of the right breast as well as enlarged lymph nodes 2.2 cm from the left axilla. A subsequent bone scan demonstrated focal activity in the left lateral fourth rib, left costochondral junction, and right anterolateral fifth rib—it was unclear whether these lesions were metastatic or secondary to trauma from a fall the patient reportedly had sustained 2 weeks prior. Lumbar MRI without gadolinium contrast revealed extensive abnormal heterogeneous signal intensity of osseous structures consistent with osseous metastasis.

Subsequent diagnostic bilateral breast ultrasonography and percutaneous left lymph node biopsy revealed pathology consistent with metastatic lobular breast carcinoma with near total effacement of the lymph node and extracapsular extension concordant with previous MRI findings. The mass in the upper outer quadrant of the right breast that previously was observed on MRI was not identifiable on this ultrasound. It was recommended that the patient pursue MRI-guided breast biopsy to have the breast lesion further characterized. She was referred to surgical oncology at a tertiary center for management; however, the patient was lost to follow-up, and there are no records available indicating the patient pursued any treatment. Although we were unable to confirm the patient’s breast lesion that previously was seen on MRI was the cause of the metastatic disease, the overall clinical picture supported metastatic lobular breast carcinoma.

Comment

Tumor metastasis to the skin accounts for approximately 2% of all skin cancers⁵ and typically is observed in advanced stages of cancer. In women, breast carcinoma is the most common type of cancer to exhibit this behavior.² Invasive ductal carcinoma represents the most common histologic subtype of breast cancer overall,^6,7 and breast adenocarcinomas, including lobular and ductal breast carcinomas, are the most common histologic subtypes to exhibit metastatic cutaneous lesions.⁸

Invasive lobular breast carcinoma represents approximately 10% of invasive breast cancer cases. Compared to invasive ductal carcinoma, there tends to be a delay in diagnosis often leading to larger tumor sizes relative to the former upon detection and with lymph node invasion. These findings may be explained by the greater difficulty of detecting invasive lobular carcinomas by mammography and clinical breast examination compared to invasive ductal carcinomas.^9-11 Additionally, invasive lobular carcinomas are more likely to be positive for estrogen and progesterone receptors compared to invasive ductal carcinomas,¹² which also was consistent in our case.

Cutaneous metastases of breast cancer most commonly are found on the anterior chest wall and can present as a wide spectrum of lesions, with nodules as the most common primary dermatologic manifestation.¹³ Cutaneous metastatic lesions commonly have been described as firm, mobile, round or oval, solitary or grouped nodules. The color of the nodules varies and may be flesh-colored, brown, blue, black, pink, and/or red-brown. The lesions often are asymptomatic but may ulcerate.²

In our case, the distribution of lesions was a unique aspect that is not typical of most cases of metastatic cutaneous breast carcinoma. The nodules appeared more scattered and involved multiple body regions, including the back, neck, and chest. Although cutaneous breast cancer metastases have been documented to extend to these body regions, a review of PubMed articles indexed for MEDLINE using the terms cutaneous metastatic lobular breast carcinoma, breast carcinoma, and metastatic breast cancer suggested that it is uncommon for these multiple areas to be simultaneously affected.^4,14 Rather, the more common clinical presentation of cutaneous metastatic breast carcinoma is as a solitary nodule or group of nodules localized to a single anatomic region.¹⁴

Another notable feature of our case was the rapid development of the cutaneous lesions relative to the primary tumor. This patient developed diffuse lesions over a period of several months, and given that her mammogram performed the previous year was negative for any abnormalities, one could suggest that the metastatic lesions developed less than a year from onset of the primary tumor. A previous study involving 41 patients with a known clinical primary visceral malignancy (ie, breast, lung, colon, esophageal, gastric, pancreatic, kidney, thyroid, prostate, or ovarian origin) found that it takes approximately 3 years on average for cutaneous metastases to develop from the onset of cancer diagnosis (range, 1–177 months).¹⁴ In the aforementioned study, 94% of patients had stage III or IV disease at time of skin metastasis, with the majority of those demonstrating stage IV disease. However, it also is possible that these breast tumors evaded detection or were too small to be identified on prior imaging.¹⁴ A review of our patient’s medical records did not indicate documentation of any visual or palpable breast changes prior to the onset of the clinically detected metastatic nodules.

Conclusion

Biopsy with immunohistochemical staining ultimately yielded the diagnosis of metastatic lobular breast carcinoma in our patient. Providers should be aware of the varying clinical presentations that may arise in the setting of cutaneous metastasis. When faced with lesions suspicious for cutaneous metastasis, biopsy is warranted to determine the correct diagnosis and ensure appropriate management. Upon diagnosis of cutaneous metastasis, prompt coordination with the primary care provider and appropriate referral to multidisciplinary teams is necessary. Clinical providers also should maintain a high index of suspicion when evaluating patients with cutaneous metastasis who have a history of normal malignancy screenings.

In women, breast cancer is the leading cancer diagnosis and the second leading cause of cancer-related death,¹ as well as the most common malignancy to metastasize to the skin.² Cutaneous breast carcinoma may present as cutaneous metastasis or can occur secondary to direct tumor extension. Five percent to 10% of women with breast cancer will present clinically with metastatic cutaneous disease, most commonly as a recurrence of early-stage breast carcinoma.²

In a published meta-analysis that investigated the incidence of tumors most commonly found to metastasize to the skin, Krathen et al³ found that cutaneous metastases occurred in 24% of patients with breast cancer (N=1903). In 2 large retrospective studies from tumor registry data, breast cancer was found to be the most common tumor involving metastasis to the skin, and 3.5% of the breast cancer cases identified in the registry had cutaneous metastasis as the presenting sign (n=35) at time of diagnosis.⁴

We report an unusual presentation of cutaneous metastatic lobular breast carcinoma that involved diffuse cutaneous lesions and rapid progression from onset of the breast mass to development of clinically apparent metastatic skin lesions.

Case Report

A 59-year-old woman with an unremarkable medical history presented to our dermatology clinic for evaluation of new widespread lesions that developed over a period of months. The eruption was asymptomatic and consisted of numerous bumpy lesions that reportedly started on the patient’s neck and progressively spread to involve the trunk. Physical examination revealed multiple flesh-colored, firm nodules scattered across the upper back, neck, and chest (Figure 1). Bilateral cervical and axillary lymphadenopathy also was noted. Upon questioning regarding family history of malignancy, the patient reported that her brother had been diagnosed with colon cancer. Although she was not up to date on age-appropriate malignancy screenings, she did report having a diagnostic mammogram 1 year prior that revealed a suspicious lesion on the left breast. A repeat mammogram of the left breast 6 months later was read as unremarkable.

Two 3-mm representative punch biopsies were performed. Hematoxylin and eosin staining revealed a basket-weave stratum corneum with underlying epidermal atrophy. A relatively monomorphic epithelioid cell infiltrate extending from the superficial reticular dermis into the deep dermis and displaying an open chromatin pattern and pink cytoplasm was observed, as well as dermal collagen thickening. Linear, single-filing cells along with focal irregular nests and scattered cells were observed (Figure 2). Immunohistochemical staining was positive for cytokeratin 7 (Figure 3A), epithelial membrane antigen, and estrogen receptor (Figure 3B) along with gross cystic disease fluid protein 15; focal progesterone receptor positivity also was present. Cytokeratin 20, cytokeratin 5/6, carcinoembryonic antigen, p63, CDX2, paired box gene 8, thyroid transcription factor 1, and human epidermal growth factor receptor 2/neu stains were negative. Findings identified in both biopsies were consistent with metastatic cutaneous lobular breast carcinoma.

A complete blood cell count and complete metabolic panels were within normal limits, aside from a mildly elevated alkaline phosphatase level. Breast ultrasonography was unremarkable. Stereotactic breast magnetic resonance imaging (MRI) revealed a 9.4-cm mass in the upper outer quadrant of the right breast as well as enlarged lymph nodes 2.2 cm from the left axilla. A subsequent bone scan demonstrated focal activity in the left lateral fourth rib, left costochondral junction, and right anterolateral fifth rib—it was unclear whether these lesions were metastatic or secondary to trauma from a fall the patient reportedly had sustained 2 weeks prior. Lumbar MRI without gadolinium contrast revealed extensive abnormal heterogeneous signal intensity of osseous structures consistent with osseous metastasis.

Subsequent diagnostic bilateral breast ultrasonography and percutaneous left lymph node biopsy revealed pathology consistent with metastatic lobular breast carcinoma with near total effacement of the lymph node and extracapsular extension concordant with previous MRI findings. The mass in the upper outer quadrant of the right breast that previously was observed on MRI was not identifiable on this ultrasound. It was recommended that the patient pursue MRI-guided breast biopsy to have the breast lesion further characterized. She was referred to surgical oncology at a tertiary center for management; however, the patient was lost to follow-up, and there are no records available indicating the patient pursued any treatment. Although we were unable to confirm the patient’s breast lesion that previously was seen on MRI was the cause of the metastatic disease, the overall clinical picture supported metastatic lobular breast carcinoma.

Comment

Tumor metastasis to the skin accounts for approximately 2% of all skin cancers⁵ and typically is observed in advanced stages of cancer. In women, breast carcinoma is the most common type of cancer to exhibit this behavior.² Invasive ductal carcinoma represents the most common histologic subtype of breast cancer overall,^6,7 and breast adenocarcinomas, including lobular and ductal breast carcinomas, are the most common histologic subtypes to exhibit metastatic cutaneous lesions.⁸

Invasive lobular breast carcinoma represents approximately 10% of invasive breast cancer cases. Compared to invasive ductal carcinoma, there tends to be a delay in diagnosis often leading to larger tumor sizes relative to the former upon detection and with lymph node invasion. These findings may be explained by the greater difficulty of detecting invasive lobular carcinomas by mammography and clinical breast examination compared to invasive ductal carcinomas.^9-11 Additionally, invasive lobular carcinomas are more likely to be positive for estrogen and progesterone receptors compared to invasive ductal carcinomas,¹² which also was consistent in our case.

Cutaneous metastases of breast cancer most commonly are found on the anterior chest wall and can present as a wide spectrum of lesions, with nodules as the most common primary dermatologic manifestation.¹³ Cutaneous metastatic lesions commonly have been described as firm, mobile, round or oval, solitary or grouped nodules. The color of the nodules varies and may be flesh-colored, brown, blue, black, pink, and/or red-brown. The lesions often are asymptomatic but may ulcerate.²

In our case, the distribution of lesions was a unique aspect that is not typical of most cases of metastatic cutaneous breast carcinoma. The nodules appeared more scattered and involved multiple body regions, including the back, neck, and chest. Although cutaneous breast cancer metastases have been documented to extend to these body regions, a review of PubMed articles indexed for MEDLINE using the terms cutaneous metastatic lobular breast carcinoma, breast carcinoma, and metastatic breast cancer suggested that it is uncommon for these multiple areas to be simultaneously affected.^4,14 Rather, the more common clinical presentation of cutaneous metastatic breast carcinoma is as a solitary nodule or group of nodules localized to a single anatomic region.¹⁴

Another notable feature of our case was the rapid development of the cutaneous lesions relative to the primary tumor. This patient developed diffuse lesions over a period of several months, and given that her mammogram performed the previous year was negative for any abnormalities, one could suggest that the metastatic lesions developed less than a year from onset of the primary tumor. A previous study involving 41 patients with a known clinical primary visceral malignancy (ie, breast, lung, colon, esophageal, gastric, pancreatic, kidney, thyroid, prostate, or ovarian origin) found that it takes approximately 3 years on average for cutaneous metastases to develop from the onset of cancer diagnosis (range, 1–177 months).¹⁴ In the aforementioned study, 94% of patients had stage III or IV disease at time of skin metastasis, with the majority of those demonstrating stage IV disease. However, it also is possible that these breast tumors evaded detection or were too small to be identified on prior imaging.¹⁴ A review of our patient’s medical records did not indicate documentation of any visual or palpable breast changes prior to the onset of the clinically detected metastatic nodules.

Conclusion

Biopsy with immunohistochemical staining ultimately yielded the diagnosis of metastatic lobular breast carcinoma in our patient. Providers should be aware of the varying clinical presentations that may arise in the setting of cutaneous metastasis. When faced with lesions suspicious for cutaneous metastasis, biopsy is warranted to determine the correct diagnosis and ensure appropriate management. Upon diagnosis of cutaneous metastasis, prompt coordination with the primary care provider and appropriate referral to multidisciplinary teams is necessary. Clinical providers also should maintain a high index of suspicion when evaluating patients with cutaneous metastasis who have a history of normal malignancy screenings.

In women, breast cancer is the leading cancer diagnosis and the second leading cause of cancer-related death,¹ as well as the most common malignancy to metastasize to the skin.² Cutaneous breast carcinoma may present as cutaneous metastasis or can occur secondary to direct tumor extension. Five percent to 10% of women with breast cancer will present clinically with metastatic cutaneous disease, most commonly as a recurrence of early-stage breast carcinoma.²

In a published meta-analysis that investigated the incidence of tumors most commonly found to metastasize to the skin, Krathen et al³ found that cutaneous metastases occurred in 24% of patients with breast cancer (N=1903). In 2 large retrospective studies from tumor registry data, breast cancer was found to be the most common tumor involving metastasis to the skin, and 3.5% of the breast cancer cases identified in the registry had cutaneous metastasis as the presenting sign (n=35) at time of diagnosis.⁴

We report an unusual presentation of cutaneous metastatic lobular breast carcinoma that involved diffuse cutaneous lesions and rapid progression from onset of the breast mass to development of clinically apparent metastatic skin lesions.

Case Report

A 59-year-old woman with an unremarkable medical history presented to our dermatology clinic for evaluation of new widespread lesions that developed over a period of months. The eruption was asymptomatic and consisted of numerous bumpy lesions that reportedly started on the patient’s neck and progressively spread to involve the trunk. Physical examination revealed multiple flesh-colored, firm nodules scattered across the upper back, neck, and chest (Figure 1). Bilateral cervical and axillary lymphadenopathy also was noted. Upon questioning regarding family history of malignancy, the patient reported that her brother had been diagnosed with colon cancer. Although she was not up to date on age-appropriate malignancy screenings, she did report having a diagnostic mammogram 1 year prior that revealed a suspicious lesion on the left breast. A repeat mammogram of the left breast 6 months later was read as unremarkable.

Two 3-mm representative punch biopsies were performed. Hematoxylin and eosin staining revealed a basket-weave stratum corneum with underlying epidermal atrophy. A relatively monomorphic epithelioid cell infiltrate extending from the superficial reticular dermis into the deep dermis and displaying an open chromatin pattern and pink cytoplasm was observed, as well as dermal collagen thickening. Linear, single-filing cells along with focal irregular nests and scattered cells were observed (Figure 2). Immunohistochemical staining was positive for cytokeratin 7 (Figure 3A), epithelial membrane antigen, and estrogen receptor (Figure 3B) along with gross cystic disease fluid protein 15; focal progesterone receptor positivity also was present. Cytokeratin 20, cytokeratin 5/6, carcinoembryonic antigen, p63, CDX2, paired box gene 8, thyroid transcription factor 1, and human epidermal growth factor receptor 2/neu stains were negative. Findings identified in both biopsies were consistent with metastatic cutaneous lobular breast carcinoma.

A complete blood cell count and complete metabolic panels were within normal limits, aside from a mildly elevated alkaline phosphatase level. Breast ultrasonography was unremarkable. Stereotactic breast magnetic resonance imaging (MRI) revealed a 9.4-cm mass in the upper outer quadrant of the right breast as well as enlarged lymph nodes 2.2 cm from the left axilla. A subsequent bone scan demonstrated focal activity in the left lateral fourth rib, left costochondral junction, and right anterolateral fifth rib—it was unclear whether these lesions were metastatic or secondary to trauma from a fall the patient reportedly had sustained 2 weeks prior. Lumbar MRI without gadolinium contrast revealed extensive abnormal heterogeneous signal intensity of osseous structures consistent with osseous metastasis.

Subsequent diagnostic bilateral breast ultrasonography and percutaneous left lymph node biopsy revealed pathology consistent with metastatic lobular breast carcinoma with near total effacement of the lymph node and extracapsular extension concordant with previous MRI findings. The mass in the upper outer quadrant of the right breast that previously was observed on MRI was not identifiable on this ultrasound. It was recommended that the patient pursue MRI-guided breast biopsy to have the breast lesion further characterized. She was referred to surgical oncology at a tertiary center for management; however, the patient was lost to follow-up, and there are no records available indicating the patient pursued any treatment. Although we were unable to confirm the patient’s breast lesion that previously was seen on MRI was the cause of the metastatic disease, the overall clinical picture supported metastatic lobular breast carcinoma.

Comment

Tumor metastasis to the skin accounts for approximately 2% of all skin cancers⁵ and typically is observed in advanced stages of cancer. In women, breast carcinoma is the most common type of cancer to exhibit this behavior.² Invasive ductal carcinoma represents the most common histologic subtype of breast cancer overall,^6,7 and breast adenocarcinomas, including lobular and ductal breast carcinomas, are the most common histologic subtypes to exhibit metastatic cutaneous lesions.⁸

Invasive lobular breast carcinoma represents approximately 10% of invasive breast cancer cases. Compared to invasive ductal carcinoma, there tends to be a delay in diagnosis often leading to larger tumor sizes relative to the former upon detection and with lymph node invasion. These findings may be explained by the greater difficulty of detecting invasive lobular carcinomas by mammography and clinical breast examination compared to invasive ductal carcinomas.^9-11 Additionally, invasive lobular carcinomas are more likely to be positive for estrogen and progesterone receptors compared to invasive ductal carcinomas,¹² which also was consistent in our case.

Cutaneous metastases of breast cancer most commonly are found on the anterior chest wall and can present as a wide spectrum of lesions, with nodules as the most common primary dermatologic manifestation.¹³ Cutaneous metastatic lesions commonly have been described as firm, mobile, round or oval, solitary or grouped nodules. The color of the nodules varies and may be flesh-colored, brown, blue, black, pink, and/or red-brown. The lesions often are asymptomatic but may ulcerate.²

In our case, the distribution of lesions was a unique aspect that is not typical of most cases of metastatic cutaneous breast carcinoma. The nodules appeared more scattered and involved multiple body regions, including the back, neck, and chest. Although cutaneous breast cancer metastases have been documented to extend to these body regions, a review of PubMed articles indexed for MEDLINE using the terms cutaneous metastatic lobular breast carcinoma, breast carcinoma, and metastatic breast cancer suggested that it is uncommon for these multiple areas to be simultaneously affected.^4,14 Rather, the more common clinical presentation of cutaneous metastatic breast carcinoma is as a solitary nodule or group of nodules localized to a single anatomic region.¹⁴

Another notable feature of our case was the rapid development of the cutaneous lesions relative to the primary tumor. This patient developed diffuse lesions over a period of several months, and given that her mammogram performed the previous year was negative for any abnormalities, one could suggest that the metastatic lesions developed less than a year from onset of the primary tumor. A previous study involving 41 patients with a known clinical primary visceral malignancy (ie, breast, lung, colon, esophageal, gastric, pancreatic, kidney, thyroid, prostate, or ovarian origin) found that it takes approximately 3 years on average for cutaneous metastases to develop from the onset of cancer diagnosis (range, 1–177 months).¹⁴ In the aforementioned study, 94% of patients had stage III or IV disease at time of skin metastasis, with the majority of those demonstrating stage IV disease. However, it also is possible that these breast tumors evaded detection or were too small to be identified on prior imaging.¹⁴ A review of our patient’s medical records did not indicate documentation of any visual or palpable breast changes prior to the onset of the clinically detected metastatic nodules.

Conclusion

Biopsy with immunohistochemical staining ultimately yielded the diagnosis of metastatic lobular breast carcinoma in our patient. Providers should be aware of the varying clinical presentations that may arise in the setting of cutaneous metastasis. When faced with lesions suspicious for cutaneous metastasis, biopsy is warranted to determine the correct diagnosis and ensure appropriate management. Upon diagnosis of cutaneous metastasis, prompt coordination with the primary care provider and appropriate referral to multidisciplinary teams is necessary. Clinical providers also should maintain a high index of suspicion when evaluating patients with cutaneous metastasis who have a history of normal malignancy screenings.

The Diagnosis: Bazex‐Dupré‐Christol Syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) is a rare X-linked dominant genodermatosis characterized by a triad of hypotrichosis, follicular atrophoderma, and multiple basal cell carcinomas (BCCs). Since first being described in 1964,¹ there have been fewer than 200 reported cases of BDCS.² Although a causative gene has not yet been identified, the mutation has been mapped to an 11.4-Mb interval in the Xq25-27.1 region of the X chromosome.³

Classically, congenital hypotrichosis is the first observed symptom and can present shortly after birth.⁴ It typically is widespread, though sometimes it may be confined to the eyebrows, eyelashes, and scalp. Follicular atrophoderma, which occurs due to a laxation and deepening of the follicular ostia, is seen in 80% of cases and typically presents in early childhood as depressions lacking hair.² It commonly is found on the face, extensor surfaces of the elbows and knees, and dorsal aspects of the hands and feet. Physical examination of our patient revealed follicular atrophoderma on both the dorsal surfaces of the hands and the extensor surfaces of the elbows. Hair shaft anomalies including pili torti, pili bifurcati, and trichorrhexis nodosa are infrequently observed symptoms of BDCS.²

Basal cell carcinoma often manifests in the second or third decades of life, though there are reports of BCC developing in BDCS patients as young as 3 years. Basal cell carcinoma typically arises on sun-exposed areas, especially the face, neck, and chest. These lesions can be pigmented or nonpigmented and range from 2 to 20 mm in diameter.⁴ Our patient presented with a BCC on the forehead (Figure 1). Histopathologic evaluation showed a proliferation of basaloid cells with peripheral palisading (Figure 2), confirming the diagnosis of BCC.

Milia, which are not considered part of the classic BDCS triad, are seen in 70% of cases.² They commonly are found on the face and often diminish with age. Milia may precede the formation of follicular atrophoderma and BCC. Hypohidrosis most commonly occurs on the forehead but can be widespread.² Other less commonly observed features include epidermal cysts, hyperpigmentation of the face, and trichoepitheliomas.⁴ The management of BDCS involves frequent clinical examinations, BCC treatment, genetic counseling, and photoprotection.^2,4

Nevoid BCC syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an autosomal-dominant disease characterized by multiple nevoid BCCs, macrocephaly with a large forehead, cleft lip or palate, jaw keratocysts, palmar and plantar pits, and calcification of the falx cerebri.⁵ Nevoid BCC syndrome is caused by a mutation in the PTCH1 gene in the hedgehog signaling pathway.⁶ The absence of common symptoms of NBCCS including macrocephaly, palmar or plantar pits, and cleft lip or palate, as well as negative genetic testing, suggested that our patient did not have NBCCS.

Rombo syndrome shares features with BDCS. Similar to BDCS, symptoms of Rombo syndrome include follicular atrophy, milialike papules, and BCC. Patients with Rombo syndrome typically present with atrophoderma vermiculatum on the cheeks and forehead in childhood.⁷ This atrophoderma presents with a pitted atrophic appearance in a reticular pattern on sun-exposed areas. Other distinguishing features from BDCS include cyanotic redness of sun-exposed skin and telangiectatic vessels.⁸

Multiple hereditary infundibulocystic BCC is another rare genodermatosis that is characterized by the presence of multiple infundibulocystic BCCs on the face and genitals. Infundibulocystic BCC is a well-differentiated subtype of BCC characterized by buds and cords of basaloid cells with scant stroma. Multiple hereditary infundibulocystic BCC is inherited in an autosomal-dominant fashion and has been linked to ^SUFU mutation in the sonic hedgehog pathway.⁹

Rothmund-Thomson syndrome is an autosomalrecessive disorder characterized by sparse hair, skeletal and dental abnormalities, and a high risk for developing keratinocyte carcinomas. It is differentiated from BDCS clinically by the presence of erythema, edema, and blistering, resulting in poikiloderma, plantar hyperkeratotic lesions, and bone defects.¹⁰

The Diagnosis: Bazex‐Dupré‐Christol Syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) is a rare X-linked dominant genodermatosis characterized by a triad of hypotrichosis, follicular atrophoderma, and multiple basal cell carcinomas (BCCs). Since first being described in 1964,¹ there have been fewer than 200 reported cases of BDCS.² Although a causative gene has not yet been identified, the mutation has been mapped to an 11.4-Mb interval in the Xq25-27.1 region of the X chromosome.³

Classically, congenital hypotrichosis is the first observed symptom and can present shortly after birth.⁴ It typically is widespread, though sometimes it may be confined to the eyebrows, eyelashes, and scalp. Follicular atrophoderma, which occurs due to a laxation and deepening of the follicular ostia, is seen in 80% of cases and typically presents in early childhood as depressions lacking hair.² It commonly is found on the face, extensor surfaces of the elbows and knees, and dorsal aspects of the hands and feet. Physical examination of our patient revealed follicular atrophoderma on both the dorsal surfaces of the hands and the extensor surfaces of the elbows. Hair shaft anomalies including pili torti, pili bifurcati, and trichorrhexis nodosa are infrequently observed symptoms of BDCS.²

Basal cell carcinoma often manifests in the second or third decades of life, though there are reports of BCC developing in BDCS patients as young as 3 years. Basal cell carcinoma typically arises on sun-exposed areas, especially the face, neck, and chest. These lesions can be pigmented or nonpigmented and range from 2 to 20 mm in diameter.⁴ Our patient presented with a BCC on the forehead (Figure 1). Histopathologic evaluation showed a proliferation of basaloid cells with peripheral palisading (Figure 2), confirming the diagnosis of BCC.

Milia, which are not considered part of the classic BDCS triad, are seen in 70% of cases.² They commonly are found on the face and often diminish with age. Milia may precede the formation of follicular atrophoderma and BCC. Hypohidrosis most commonly occurs on the forehead but can be widespread.² Other less commonly observed features include epidermal cysts, hyperpigmentation of the face, and trichoepitheliomas.⁴ The management of BDCS involves frequent clinical examinations, BCC treatment, genetic counseling, and photoprotection.^2,4

Nevoid BCC syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an autosomal-dominant disease characterized by multiple nevoid BCCs, macrocephaly with a large forehead, cleft lip or palate, jaw keratocysts, palmar and plantar pits, and calcification of the falx cerebri.⁵ Nevoid BCC syndrome is caused by a mutation in the PTCH1 gene in the hedgehog signaling pathway.⁶ The absence of common symptoms of NBCCS including macrocephaly, palmar or plantar pits, and cleft lip or palate, as well as negative genetic testing, suggested that our patient did not have NBCCS.

Rombo syndrome shares features with BDCS. Similar to BDCS, symptoms of Rombo syndrome include follicular atrophy, milialike papules, and BCC. Patients with Rombo syndrome typically present with atrophoderma vermiculatum on the cheeks and forehead in childhood.⁷ This atrophoderma presents with a pitted atrophic appearance in a reticular pattern on sun-exposed areas. Other distinguishing features from BDCS include cyanotic redness of sun-exposed skin and telangiectatic vessels.⁸

Multiple hereditary infundibulocystic BCC is another rare genodermatosis that is characterized by the presence of multiple infundibulocystic BCCs on the face and genitals. Infundibulocystic BCC is a well-differentiated subtype of BCC characterized by buds and cords of basaloid cells with scant stroma. Multiple hereditary infundibulocystic BCC is inherited in an autosomal-dominant fashion and has been linked to ^SUFU mutation in the sonic hedgehog pathway.⁹

Rothmund-Thomson syndrome is an autosomalrecessive disorder characterized by sparse hair, skeletal and dental abnormalities, and a high risk for developing keratinocyte carcinomas. It is differentiated from BDCS clinically by the presence of erythema, edema, and blistering, resulting in poikiloderma, plantar hyperkeratotic lesions, and bone defects.¹⁰

The Diagnosis: Bazex‐Dupré‐Christol Syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) is a rare X-linked dominant genodermatosis characterized by a triad of hypotrichosis, follicular atrophoderma, and multiple basal cell carcinomas (BCCs). Since first being described in 1964,¹ there have been fewer than 200 reported cases of BDCS.² Although a causative gene has not yet been identified, the mutation has been mapped to an 11.4-Mb interval in the Xq25-27.1 region of the X chromosome.³

Classically, congenital hypotrichosis is the first observed symptom and can present shortly after birth.⁴ It typically is widespread, though sometimes it may be confined to the eyebrows, eyelashes, and scalp. Follicular atrophoderma, which occurs due to a laxation and deepening of the follicular ostia, is seen in 80% of cases and typically presents in early childhood as depressions lacking hair.² It commonly is found on the face, extensor surfaces of the elbows and knees, and dorsal aspects of the hands and feet. Physical examination of our patient revealed follicular atrophoderma on both the dorsal surfaces of the hands and the extensor surfaces of the elbows. Hair shaft anomalies including pili torti, pili bifurcati, and trichorrhexis nodosa are infrequently observed symptoms of BDCS.²

Basal cell carcinoma often manifests in the second or third decades of life, though there are reports of BCC developing in BDCS patients as young as 3 years. Basal cell carcinoma typically arises on sun-exposed areas, especially the face, neck, and chest. These lesions can be pigmented or nonpigmented and range from 2 to 20 mm in diameter.⁴ Our patient presented with a BCC on the forehead (Figure 1). Histopathologic evaluation showed a proliferation of basaloid cells with peripheral palisading (Figure 2), confirming the diagnosis of BCC.

Milia, which are not considered part of the classic BDCS triad, are seen in 70% of cases.² They commonly are found on the face and often diminish with age. Milia may precede the formation of follicular atrophoderma and BCC. Hypohidrosis most commonly occurs on the forehead but can be widespread.² Other less commonly observed features include epidermal cysts, hyperpigmentation of the face, and trichoepitheliomas.⁴ The management of BDCS involves frequent clinical examinations, BCC treatment, genetic counseling, and photoprotection.^2,4

Nevoid BCC syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an autosomal-dominant disease characterized by multiple nevoid BCCs, macrocephaly with a large forehead, cleft lip or palate, jaw keratocysts, palmar and plantar pits, and calcification of the falx cerebri.⁵ Nevoid BCC syndrome is caused by a mutation in the PTCH1 gene in the hedgehog signaling pathway.⁶ The absence of common symptoms of NBCCS including macrocephaly, palmar or plantar pits, and cleft lip or palate, as well as negative genetic testing, suggested that our patient did not have NBCCS.

Rombo syndrome shares features with BDCS. Similar to BDCS, symptoms of Rombo syndrome include follicular atrophy, milialike papules, and BCC. Patients with Rombo syndrome typically present with atrophoderma vermiculatum on the cheeks and forehead in childhood.⁷ This atrophoderma presents with a pitted atrophic appearance in a reticular pattern on sun-exposed areas. Other distinguishing features from BDCS include cyanotic redness of sun-exposed skin and telangiectatic vessels.⁸

Multiple hereditary infundibulocystic BCC is another rare genodermatosis that is characterized by the presence of multiple infundibulocystic BCCs on the face and genitals. Infundibulocystic BCC is a well-differentiated subtype of BCC characterized by buds and cords of basaloid cells with scant stroma. Multiple hereditary infundibulocystic BCC is inherited in an autosomal-dominant fashion and has been linked to ^SUFU mutation in the sonic hedgehog pathway.⁹

Rothmund-Thomson syndrome is an autosomalrecessive disorder characterized by sparse hair, skeletal and dental abnormalities, and a high risk for developing keratinocyte carcinomas. It is differentiated from BDCS clinically by the presence of erythema, edema, and blistering, resulting in poikiloderma, plantar hyperkeratotic lesions, and bone defects.¹⁰

As the dermatology admissions cycle restarts, I reflect back on my journey as a Black woman applying to dermatology. Before deciding, I internally questioned, “Is dermatology right for me?” There were not many faces that looked like mine within the field. After committing to dermatology, I asked dermatologists—almost any who would spare a few minutes to talk to me—how to get into this specialty and be successful when applying. I spoke to advisors and friends at my home department, emailed dermatologists far and wide, approached conference lecturers after their presentations, sought out advice from current residents, and asked prior applicants what they thought was important to match into dermatology. There had been too many unmatched students before me who had achieved good grades and aced US Medical Licensing Examination Step 1. The equation for success was missing a variable.

Mentorship

One weekend, I attended a conference for patients with skin of color. I talked to a student who had taken a year off (retroactively after not matching in prior years). She told me that the biggest key to matching was mentorship; forming a strong relationship with a clinician or investigator who had seen how well you perform in clinic or during research was paramount. Having a collaborator or instructor write you a letter of recommendation and make calls on your behalf could be the difference between matching or taking another year off. More often than any other aspect of the application, it is a lack of mentorship that many students of color do not have access to when pursuing a highly competitive specialty such as dermatology.^1,2 In such a small field, applicants need someone to vouch for them—to speak on their behalf compassionately, invite them to collaborate on research projects, and inform them of conference opportunities to present their work.

Representation in Dermatology

We are told that you can accomplish anything with hard work and grit; however, without the platform to show how effectively you have worked, your efforts may never be seen. The diversity statistics for dermatology are clear and disheartening. Although 13% of Americans are Black, only 3% of all dermatologists are Black.^2,3 Just over 4% of dermatologists are Hispanic compared with 16% of the general population. The Association of American Medical Colleges reported that the overall 2015 medical school acceptance rate was 41%.⁴ White (44%), Asian (42%), and Hispanic or Latino (42%) applicants all had similar acceptance rates; however, only one-third of Black applicants were accepted. At graduation in 2015, White individuals were 51% of matriculants. Medical graduates were only 6% Black.⁴ What percentage of these 6% Black graduates thought about applying into dermatology? How many had someone to encourage them to pursue the specialty or a mentor who they could ask about the nuances and strategy to be a competitive applicant?

In addition to discrimination, social psychologists have described stereotype threat, a risk for minorities that occurs when negative stereotypes associated with an individual’s group status become relevant after perceived cues.⁵ Therefore, some students of color might avoid competitive specialties such as dermatology because of this internalized lack of confidence in their own abilities and performance thinking, “I’ll never be good enough to match into dermatology.” I have seen this discouraging perception when classmates doubt their own talent and achievements, which is a variation of imposter syndrome—when an individual doubts their abilities and may have an internal fear of eventually being exposed as a fraud.

After several publications received press coverage on the lack of diversity in dermatology applicant selection,^3,6,7 I looked around at my interview group composed of 25 to 40 interviewees and on average saw 2 to 3 Black applicants around the room. We always found a way during the packed interview day to find time to introduce ourselves. I almost always left with a new friend who shared feelings of anxiety, uncertainty, hope, and gratefulness from being the few Black people in the room. Bootstrapping might have helped us to make it into medical school, pass shelf examinations, and even get a great Step 1 score. However, the addition of mentorship—or better yet, sponsorship—helped to get us an interview in this competitive field. The impact of mentorship has been especially true for research, which has shown that students often gravitate toward mentors who look like them.⁸ However, the reality is that many Black and Hispanic students may be at a disadvantage for finding mentors in this way given that there are less than 10% of dermatologists who identify as individuals with skin of color. During the process of applying to dermatology, my greatest advocates were ethnically and racially diverse. The proverb is that it takes a village to raise a child; this reality extends to the medical student’s ability to thrive, not only in residency but also in the residency application process. My sponsors have been as different as their advice and perspectives, which helped me to think about the varied ways I viewed myself as an applicant and shaped what I looked for in residency.

Final Thoughts

Now that I have been a resident in the Department of Dermatology at the Warren Alpert Medical School of Brown University, I excitedly look for opportunities to mentor medical students and help create equity in the application process. Dermatology needs to increase the representation of minority applicants. Efforts to encourage minority medical students include joining the National Medical Association dermatology section through the Student National Medical Association, membership in the Skin of Color Society, getting involved with the Dermatology Interest Group at more medical schools, and awareness of medical student–friendly dermatology conferences. In addition, I was able to establish lifelong mentorship through the American Academy of Dermatology’s Minority Diversity Mentorship Program. One important component is an enhanced effort to increase the number of financial scholarships for away rotations (post–coronavirus disease 2019 pandemic) or application expenses geared to help underrepresented minorities. To truly increase diversity in dermatology, perhaps we need more physicians and residents willing to encourage students of color that dermatology is achievable.

As the dermatology admissions cycle restarts, I reflect back on my journey as a Black woman applying to dermatology. Before deciding, I internally questioned, “Is dermatology right for me?” There were not many faces that looked like mine within the field. After committing to dermatology, I asked dermatologists—almost any who would spare a few minutes to talk to me—how to get into this specialty and be successful when applying. I spoke to advisors and friends at my home department, emailed dermatologists far and wide, approached conference lecturers after their presentations, sought out advice from current residents, and asked prior applicants what they thought was important to match into dermatology. There had been too many unmatched students before me who had achieved good grades and aced US Medical Licensing Examination Step 1. The equation for success was missing a variable.

Mentorship

One weekend, I attended a conference for patients with skin of color. I talked to a student who had taken a year off (retroactively after not matching in prior years). She told me that the biggest key to matching was mentorship; forming a strong relationship with a clinician or investigator who had seen how well you perform in clinic or during research was paramount. Having a collaborator or instructor write you a letter of recommendation and make calls on your behalf could be the difference between matching or taking another year off. More often than any other aspect of the application, it is a lack of mentorship that many students of color do not have access to when pursuing a highly competitive specialty such as dermatology.^1,2 In such a small field, applicants need someone to vouch for them—to speak on their behalf compassionately, invite them to collaborate on research projects, and inform them of conference opportunities to present their work.

Representation in Dermatology

We are told that you can accomplish anything with hard work and grit; however, without the platform to show how effectively you have worked, your efforts may never be seen. The diversity statistics for dermatology are clear and disheartening. Although 13% of Americans are Black, only 3% of all dermatologists are Black.^2,3 Just over 4% of dermatologists are Hispanic compared with 16% of the general population. The Association of American Medical Colleges reported that the overall 2015 medical school acceptance rate was 41%.⁴ White (44%), Asian (42%), and Hispanic or Latino (42%) applicants all had similar acceptance rates; however, only one-third of Black applicants were accepted. At graduation in 2015, White individuals were 51% of matriculants. Medical graduates were only 6% Black.⁴ What percentage of these 6% Black graduates thought about applying into dermatology? How many had someone to encourage them to pursue the specialty or a mentor who they could ask about the nuances and strategy to be a competitive applicant?

In addition to discrimination, social psychologists have described stereotype threat, a risk for minorities that occurs when negative stereotypes associated with an individual’s group status become relevant after perceived cues.⁵ Therefore, some students of color might avoid competitive specialties such as dermatology because of this internalized lack of confidence in their own abilities and performance thinking, “I’ll never be good enough to match into dermatology.” I have seen this discouraging perception when classmates doubt their own talent and achievements, which is a variation of imposter syndrome—when an individual doubts their abilities and may have an internal fear of eventually being exposed as a fraud.

After several publications received press coverage on the lack of diversity in dermatology applicant selection,^3,6,7 I looked around at my interview group composed of 25 to 40 interviewees and on average saw 2 to 3 Black applicants around the room. We always found a way during the packed interview day to find time to introduce ourselves. I almost always left with a new friend who shared feelings of anxiety, uncertainty, hope, and gratefulness from being the few Black people in the room. Bootstrapping might have helped us to make it into medical school, pass shelf examinations, and even get a great Step 1 score. However, the addition of mentorship—or better yet, sponsorship—helped to get us an interview in this competitive field. The impact of mentorship has been especially true for research, which has shown that students often gravitate toward mentors who look like them.⁸ However, the reality is that many Black and Hispanic students may be at a disadvantage for finding mentors in this way given that there are less than 10% of dermatologists who identify as individuals with skin of color. During the process of applying to dermatology, my greatest advocates were ethnically and racially diverse. The proverb is that it takes a village to raise a child; this reality extends to the medical student’s ability to thrive, not only in residency but also in the residency application process. My sponsors have been as different as their advice and perspectives, which helped me to think about the varied ways I viewed myself as an applicant and shaped what I looked for in residency.

Final Thoughts

Now that I have been a resident in the Department of Dermatology at the Warren Alpert Medical School of Brown University, I excitedly look for opportunities to mentor medical students and help create equity in the application process. Dermatology needs to increase the representation of minority applicants. Efforts to encourage minority medical students include joining the National Medical Association dermatology section through the Student National Medical Association, membership in the Skin of Color Society, getting involved with the Dermatology Interest Group at more medical schools, and awareness of medical student–friendly dermatology conferences. In addition, I was able to establish lifelong mentorship through the American Academy of Dermatology’s Minority Diversity Mentorship Program. One important component is an enhanced effort to increase the number of financial scholarships for away rotations (post–coronavirus disease 2019 pandemic) or application expenses geared to help underrepresented minorities. To truly increase diversity in dermatology, perhaps we need more physicians and residents willing to encourage students of color that dermatology is achievable.

As the dermatology admissions cycle restarts, I reflect back on my journey as a Black woman applying to dermatology. Before deciding, I internally questioned, “Is dermatology right for me?” There were not many faces that looked like mine within the field. After committing to dermatology, I asked dermatologists—almost any who would spare a few minutes to talk to me—how to get into this specialty and be successful when applying. I spoke to advisors and friends at my home department, emailed dermatologists far and wide, approached conference lecturers after their presentations, sought out advice from current residents, and asked prior applicants what they thought was important to match into dermatology. There had been too many unmatched students before me who had achieved good grades and aced US Medical Licensing Examination Step 1. The equation for success was missing a variable.

Mentorship

One weekend, I attended a conference for patients with skin of color. I talked to a student who had taken a year off (retroactively after not matching in prior years). She told me that the biggest key to matching was mentorship; forming a strong relationship with a clinician or investigator who had seen how well you perform in clinic or during research was paramount. Having a collaborator or instructor write you a letter of recommendation and make calls on your behalf could be the difference between matching or taking another year off. More often than any other aspect of the application, it is a lack of mentorship that many students of color do not have access to when pursuing a highly competitive specialty such as dermatology.^1,2 In such a small field, applicants need someone to vouch for them—to speak on their behalf compassionately, invite them to collaborate on research projects, and inform them of conference opportunities to present their work.

Representation in Dermatology

We are told that you can accomplish anything with hard work and grit; however, without the platform to show how effectively you have worked, your efforts may never be seen. The diversity statistics for dermatology are clear and disheartening. Although 13% of Americans are Black, only 3% of all dermatologists are Black.^2,3 Just over 4% of dermatologists are Hispanic compared with 16% of the general population. The Association of American Medical Colleges reported that the overall 2015 medical school acceptance rate was 41%.⁴ White (44%), Asian (42%), and Hispanic or Latino (42%) applicants all had similar acceptance rates; however, only one-third of Black applicants were accepted. At graduation in 2015, White individuals were 51% of matriculants. Medical graduates were only 6% Black.⁴ What percentage of these 6% Black graduates thought about applying into dermatology? How many had someone to encourage them to pursue the specialty or a mentor who they could ask about the nuances and strategy to be a competitive applicant?

In addition to discrimination, social psychologists have described stereotype threat, a risk for minorities that occurs when negative stereotypes associated with an individual’s group status become relevant after perceived cues.⁵ Therefore, some students of color might avoid competitive specialties such as dermatology because of this internalized lack of confidence in their own abilities and performance thinking, “I’ll never be good enough to match into dermatology.” I have seen this discouraging perception when classmates doubt their own talent and achievements, which is a variation of imposter syndrome—when an individual doubts their abilities and may have an internal fear of eventually being exposed as a fraud.

After several publications received press coverage on the lack of diversity in dermatology applicant selection,^3,6,7 I looked around at my interview group composed of 25 to 40 interviewees and on average saw 2 to 3 Black applicants around the room. We always found a way during the packed interview day to find time to introduce ourselves. I almost always left with a new friend who shared feelings of anxiety, uncertainty, hope, and gratefulness from being the few Black people in the room. Bootstrapping might have helped us to make it into medical school, pass shelf examinations, and even get a great Step 1 score. However, the addition of mentorship—or better yet, sponsorship—helped to get us an interview in this competitive field. The impact of mentorship has been especially true for research, which has shown that students often gravitate toward mentors who look like them.⁸ However, the reality is that many Black and Hispanic students may be at a disadvantage for finding mentors in this way given that there are less than 10% of dermatologists who identify as individuals with skin of color. During the process of applying to dermatology, my greatest advocates were ethnically and racially diverse. The proverb is that it takes a village to raise a child; this reality extends to the medical student’s ability to thrive, not only in residency but also in the residency application process. My sponsors have been as different as their advice and perspectives, which helped me to think about the varied ways I viewed myself as an applicant and shaped what I looked for in residency.

Final Thoughts

Now that I have been a resident in the Department of Dermatology at the Warren Alpert Medical School of Brown University, I excitedly look for opportunities to mentor medical students and help create equity in the application process. Dermatology needs to increase the representation of minority applicants. Efforts to encourage minority medical students include joining the National Medical Association dermatology section through the Student National Medical Association, membership in the Skin of Color Society, getting involved with the Dermatology Interest Group at more medical schools, and awareness of medical student–friendly dermatology conferences. In addition, I was able to establish lifelong mentorship through the American Academy of Dermatology’s Minority Diversity Mentorship Program. One important component is an enhanced effort to increase the number of financial scholarships for away rotations (post–coronavirus disease 2019 pandemic) or application expenses geared to help underrepresented minorities. To truly increase diversity in dermatology, perhaps we need more physicians and residents willing to encourage students of color that dermatology is achievable.

Men have unique dermatologic needs yet are significantly less likely than women to visit a dermatologist’s office.¹ Male patients might have preconceived notions about the nature of dermatology visits and necessary areas of the body to be examined: For example, male patients might associate the genital examination with a urologist and not expect a dermatologist to complete such a seemingly private examination.²

Genital examinations are currently underperformed: Only one-quarter of dermatologists report examining a male patient’s genitals at most or all visits.³ In this commentary, we discuss the importance of genital examinations in men’s dermatology, specific issues that can arise, and strategies to enhance the quality and frequency of genital examinations in male patients.

Invaluable Aspect of Care

Thorough inspection of a male patient’s genital region is an important part of conducting a total-body skin examination (TBSE) for routine surveillance and evaluation of genital dermatoses. Sexually transmitted infections, warts, and other common lesions can be missed in diagnosis without careful inspection of the genital region. Additionally, scrotal malignancies, such as primary and metastatic melanoma and basal cell carcinoma, though rare, might be overlooked until symptoms become severe.^4,5

There is no substitute for a physical examination but, in certain circumstances, it might be appropriate for a dermatologist to ask a patient if he has concerning lesions on his genitals. However, patients often are unsure of worrisome signs, and areas of the perineum might not be easily visible to a patient. Genital inspection during the physical examination allows for a teachable moment, during which the dermatologist can educate the patient about benign lesions and variants, such as pearly penile papules, seborrheic keratoses, and sebaceous cysts.⁶ These lesions might not require intervention but should be monitored for atypical features or infection.⁶

Also, the dermatologist might incidentally discover transmissible lesions, such as condylomata caused by human papillomavirus, which has been shown to be present in approximately 50% of men in the United States⁷—many of whom are unaware. Inflammatory dermatoses, such as psoriasis, often affect the genitals and go unnoticed; prompt intervention can decrease the likelihood of complications.⁶

Protocol for Genital Examinations

To examine the genitals, all surfaces of the penis, scrotum, and perineum should be evaluated, with anatomic and pathologic variants noted. The patient or physician should stretch the penis, maneuvering it in multiple directions so that all aspects can be examined. In uncircumcised men, the foreskin should be retracted so that the head of the penis can be examined, followed by replacement of the foreskin by the patient.⁸ The scrotum also should be examined and lifted to fully view the perineum.

Providers should not grasp the penis with the whole hand but use the thumb and first finger to hold the head of the penis to maneuver it.⁸ Similarly, using the back of the hand and fingers to manipulate the genitals establishes boundaries and sets a clinical tone for the examination.

Unintentional Erection
Unique to the male dermatologic examination is the unintentional patient erection; a physician might be unsure of how to approach such a potentially awkward situation. An erection is not always an indication of sexual arousal; rather, it can reflect an autonomic reflex in response to physical stimulation. Erections occur commonly in health care settings, especially if the genitals are being manipulated.⁹

Generally, the course of action here depends on the patient’s response.¹⁰ For patients who appear unbothered, it might be appropriate to ignore the erection and proceed with the examination, especially if the physician is not actively examining the genital region. If the patient appears embarrassed, the physician can say “This is completely normal” or “Random erections are common” to normalize the situation. Joking or laughing should be avoided. For a patient who appears upset, the physician can step outside the room for a brief period to give the patient privacy, then re-enter and ask him if he is comfortable continuing with the examination.

When a patient develops an erection, the physician might become uncomfortable and, consciously or subconsciously, increase the pace of the examination, which is a natural tendency, but expediency at the expense of comprehensive care is inappropriate.

Examiner’s Body Language and Tone
Throughout the genital examination, the physician should be mindful of their comments and body language to avoid exacerbating patient vulnerability. Using anatomic terms, rather than colloquial ones, to describe the genitalia is advised to prevent misunderstanding and maintain a professional clinical environment. Providers should be prepared to explain anatomic terms because some patients are not familiar with medical terminology.

Presence of a Chaperone
Involving a chaperone, as recommended by the American Medical Association, might make a patient more comfortable and alleviate potential misunderstanding. Still, physicians should be aware that some patients might feel uncomfortable with a chaperone, interpreting their presence as an expectation of impropriety.¹¹ Universal offering of a chaperone to all patients, regardless of the gender of the physician, as well as appropriate signage in the clinical environment, normalizes chaperone invitation and use.

Other Helpful Considerations
Various strategies in the male genital examination can increase patient and physician comfort and improve care:

• The patient should be offered a gown before a TBSE or any skin examination during which the genitals will be examined.
• The patient should be allowed to keep his shorts or underwear on to avoid the feeling of being naked, which can provoke anxiety. Prior to beginning the examination, disclose that it will include “under the covered areas.”
• Ask the patient for permission to conduct the examination, enumerate the steps, and provide a rationale for a genital examination. These steps help gain cooperation, alleviate anticipation, and prevent surprise.
• To increase the patient’s comfort level, he can be asked whether he prefers to be examined supine or standing.
• Consider allowing the patient, himself, to expose and manipulate his genitals during the examination to increase his involvement and sense of autonomy.
• For genital examinations, patients often prefer that the examiner be a physician of the same gender. Accommodating a patient’s request regarding the examiner’s gender might not always be possible, but the medical practice should make an honest attempt to oblige.

Lastly, providers should be cognizant of the needs of male sexual and gender minority populations (ie, gay, bisexual, transgender/gender diverse, queer or questioning, intersex, and asexual persons). For example, transgender women might retain male anatomy or have surgical alteration of the genital region that also requires evaluation. In such patient populations, the genital examination is equally important to evaluate for dermatologic conditions that require treatment.

Final Thoughts

The male genital examination is an important component of the TBSE, as dermatologists can recognize lesions before symptoms present. Robust educational methods for trainees and practitioners in dermatology are lacking, and development of curricula might be beneficial to increase comfort in performing the genital examination. Still, use of the procedures described in this commentary can normalize the men’s genital examination, optimize the physical examination, and improve men’s overall dermatologic health.

Men have unique dermatologic needs yet are significantly less likely than women to visit a dermatologist’s office.¹ Male patients might have preconceived notions about the nature of dermatology visits and necessary areas of the body to be examined: For example, male patients might associate the genital examination with a urologist and not expect a dermatologist to complete such a seemingly private examination.²

Genital examinations are currently underperformed: Only one-quarter of dermatologists report examining a male patient’s genitals at most or all visits.³ In this commentary, we discuss the importance of genital examinations in men’s dermatology, specific issues that can arise, and strategies to enhance the quality and frequency of genital examinations in male patients.

Invaluable Aspect of Care

Thorough inspection of a male patient’s genital region is an important part of conducting a total-body skin examination (TBSE) for routine surveillance and evaluation of genital dermatoses. Sexually transmitted infections, warts, and other common lesions can be missed in diagnosis without careful inspection of the genital region. Additionally, scrotal malignancies, such as primary and metastatic melanoma and basal cell carcinoma, though rare, might be overlooked until symptoms become severe.^4,5

There is no substitute for a physical examination but, in certain circumstances, it might be appropriate for a dermatologist to ask a patient if he has concerning lesions on his genitals. However, patients often are unsure of worrisome signs, and areas of the perineum might not be easily visible to a patient. Genital inspection during the physical examination allows for a teachable moment, during which the dermatologist can educate the patient about benign lesions and variants, such as pearly penile papules, seborrheic keratoses, and sebaceous cysts.⁶ These lesions might not require intervention but should be monitored for atypical features or infection.⁶

Also, the dermatologist might incidentally discover transmissible lesions, such as condylomata caused by human papillomavirus, which has been shown to be present in approximately 50% of men in the United States⁷—many of whom are unaware. Inflammatory dermatoses, such as psoriasis, often affect the genitals and go unnoticed; prompt intervention can decrease the likelihood of complications.⁶

Protocol for Genital Examinations

To examine the genitals, all surfaces of the penis, scrotum, and perineum should be evaluated, with anatomic and pathologic variants noted. The patient or physician should stretch the penis, maneuvering it in multiple directions so that all aspects can be examined. In uncircumcised men, the foreskin should be retracted so that the head of the penis can be examined, followed by replacement of the foreskin by the patient.⁸ The scrotum also should be examined and lifted to fully view the perineum.

Providers should not grasp the penis with the whole hand but use the thumb and first finger to hold the head of the penis to maneuver it.⁸ Similarly, using the back of the hand and fingers to manipulate the genitals establishes boundaries and sets a clinical tone for the examination.

Unintentional Erection
Unique to the male dermatologic examination is the unintentional patient erection; a physician might be unsure of how to approach such a potentially awkward situation. An erection is not always an indication of sexual arousal; rather, it can reflect an autonomic reflex in response to physical stimulation. Erections occur commonly in health care settings, especially if the genitals are being manipulated.⁹

Generally, the course of action here depends on the patient’s response.¹⁰ For patients who appear unbothered, it might be appropriate to ignore the erection and proceed with the examination, especially if the physician is not actively examining the genital region. If the patient appears embarrassed, the physician can say “This is completely normal” or “Random erections are common” to normalize the situation. Joking or laughing should be avoided. For a patient who appears upset, the physician can step outside the room for a brief period to give the patient privacy, then re-enter and ask him if he is comfortable continuing with the examination.

When a patient develops an erection, the physician might become uncomfortable and, consciously or subconsciously, increase the pace of the examination, which is a natural tendency, but expediency at the expense of comprehensive care is inappropriate.

Examiner’s Body Language and Tone
Throughout the genital examination, the physician should be mindful of their comments and body language to avoid exacerbating patient vulnerability. Using anatomic terms, rather than colloquial ones, to describe the genitalia is advised to prevent misunderstanding and maintain a professional clinical environment. Providers should be prepared to explain anatomic terms because some patients are not familiar with medical terminology.

Presence of a Chaperone
Involving a chaperone, as recommended by the American Medical Association, might make a patient more comfortable and alleviate potential misunderstanding. Still, physicians should be aware that some patients might feel uncomfortable with a chaperone, interpreting their presence as an expectation of impropriety.¹¹ Universal offering of a chaperone to all patients, regardless of the gender of the physician, as well as appropriate signage in the clinical environment, normalizes chaperone invitation and use.

Other Helpful Considerations
Various strategies in the male genital examination can increase patient and physician comfort and improve care:

• The patient should be offered a gown before a TBSE or any skin examination during which the genitals will be examined.
• The patient should be allowed to keep his shorts or underwear on to avoid the feeling of being naked, which can provoke anxiety. Prior to beginning the examination, disclose that it will include “under the covered areas.”
• Ask the patient for permission to conduct the examination, enumerate the steps, and provide a rationale for a genital examination. These steps help gain cooperation, alleviate anticipation, and prevent surprise.
• To increase the patient’s comfort level, he can be asked whether he prefers to be examined supine or standing.
• Consider allowing the patient, himself, to expose and manipulate his genitals during the examination to increase his involvement and sense of autonomy.
• For genital examinations, patients often prefer that the examiner be a physician of the same gender. Accommodating a patient’s request regarding the examiner’s gender might not always be possible, but the medical practice should make an honest attempt to oblige.

Lastly, providers should be cognizant of the needs of male sexual and gender minority populations (ie, gay, bisexual, transgender/gender diverse, queer or questioning, intersex, and asexual persons). For example, transgender women might retain male anatomy or have surgical alteration of the genital region that also requires evaluation. In such patient populations, the genital examination is equally important to evaluate for dermatologic conditions that require treatment.

Final Thoughts

The male genital examination is an important component of the TBSE, as dermatologists can recognize lesions before symptoms present. Robust educational methods for trainees and practitioners in dermatology are lacking, and development of curricula might be beneficial to increase comfort in performing the genital examination. Still, use of the procedures described in this commentary can normalize the men’s genital examination, optimize the physical examination, and improve men’s overall dermatologic health.

Men have unique dermatologic needs yet are significantly less likely than women to visit a dermatologist’s office.¹ Male patients might have preconceived notions about the nature of dermatology visits and necessary areas of the body to be examined: For example, male patients might associate the genital examination with a urologist and not expect a dermatologist to complete such a seemingly private examination.²

Genital examinations are currently underperformed: Only one-quarter of dermatologists report examining a male patient’s genitals at most or all visits.³ In this commentary, we discuss the importance of genital examinations in men’s dermatology, specific issues that can arise, and strategies to enhance the quality and frequency of genital examinations in male patients.

Invaluable Aspect of Care

Thorough inspection of a male patient’s genital region is an important part of conducting a total-body skin examination (TBSE) for routine surveillance and evaluation of genital dermatoses. Sexually transmitted infections, warts, and other common lesions can be missed in diagnosis without careful inspection of the genital region. Additionally, scrotal malignancies, such as primary and metastatic melanoma and basal cell carcinoma, though rare, might be overlooked until symptoms become severe.^4,5

There is no substitute for a physical examination but, in certain circumstances, it might be appropriate for a dermatologist to ask a patient if he has concerning lesions on his genitals. However, patients often are unsure of worrisome signs, and areas of the perineum might not be easily visible to a patient. Genital inspection during the physical examination allows for a teachable moment, during which the dermatologist can educate the patient about benign lesions and variants, such as pearly penile papules, seborrheic keratoses, and sebaceous cysts.⁶ These lesions might not require intervention but should be monitored for atypical features or infection.⁶

Also, the dermatologist might incidentally discover transmissible lesions, such as condylomata caused by human papillomavirus, which has been shown to be present in approximately 50% of men in the United States⁷—many of whom are unaware. Inflammatory dermatoses, such as psoriasis, often affect the genitals and go unnoticed; prompt intervention can decrease the likelihood of complications.⁶

Protocol for Genital Examinations

To examine the genitals, all surfaces of the penis, scrotum, and perineum should be evaluated, with anatomic and pathologic variants noted. The patient or physician should stretch the penis, maneuvering it in multiple directions so that all aspects can be examined. In uncircumcised men, the foreskin should be retracted so that the head of the penis can be examined, followed by replacement of the foreskin by the patient.⁸ The scrotum also should be examined and lifted to fully view the perineum.

Providers should not grasp the penis with the whole hand but use the thumb and first finger to hold the head of the penis to maneuver it.⁸ Similarly, using the back of the hand and fingers to manipulate the genitals establishes boundaries and sets a clinical tone for the examination.

Unintentional Erection
Unique to the male dermatologic examination is the unintentional patient erection; a physician might be unsure of how to approach such a potentially awkward situation. An erection is not always an indication of sexual arousal; rather, it can reflect an autonomic reflex in response to physical stimulation. Erections occur commonly in health care settings, especially if the genitals are being manipulated.⁹

Generally, the course of action here depends on the patient’s response.¹⁰ For patients who appear unbothered, it might be appropriate to ignore the erection and proceed with the examination, especially if the physician is not actively examining the genital region. If the patient appears embarrassed, the physician can say “This is completely normal” or “Random erections are common” to normalize the situation. Joking or laughing should be avoided. For a patient who appears upset, the physician can step outside the room for a brief period to give the patient privacy, then re-enter and ask him if he is comfortable continuing with the examination.

When a patient develops an erection, the physician might become uncomfortable and, consciously or subconsciously, increase the pace of the examination, which is a natural tendency, but expediency at the expense of comprehensive care is inappropriate.

Examiner’s Body Language and Tone
Throughout the genital examination, the physician should be mindful of their comments and body language to avoid exacerbating patient vulnerability. Using anatomic terms, rather than colloquial ones, to describe the genitalia is advised to prevent misunderstanding and maintain a professional clinical environment. Providers should be prepared to explain anatomic terms because some patients are not familiar with medical terminology.

Presence of a Chaperone
Involving a chaperone, as recommended by the American Medical Association, might make a patient more comfortable and alleviate potential misunderstanding. Still, physicians should be aware that some patients might feel uncomfortable with a chaperone, interpreting their presence as an expectation of impropriety.¹¹ Universal offering of a chaperone to all patients, regardless of the gender of the physician, as well as appropriate signage in the clinical environment, normalizes chaperone invitation and use.

Other Helpful Considerations
Various strategies in the male genital examination can increase patient and physician comfort and improve care:

• The patient should be offered a gown before a TBSE or any skin examination during which the genitals will be examined.
• The patient should be allowed to keep his shorts or underwear on to avoid the feeling of being naked, which can provoke anxiety. Prior to beginning the examination, disclose that it will include “under the covered areas.”
• Ask the patient for permission to conduct the examination, enumerate the steps, and provide a rationale for a genital examination. These steps help gain cooperation, alleviate anticipation, and prevent surprise.
• To increase the patient’s comfort level, he can be asked whether he prefers to be examined supine or standing.
• Consider allowing the patient, himself, to expose and manipulate his genitals during the examination to increase his involvement and sense of autonomy.
• For genital examinations, patients often prefer that the examiner be a physician of the same gender. Accommodating a patient’s request regarding the examiner’s gender might not always be possible, but the medical practice should make an honest attempt to oblige.

Lastly, providers should be cognizant of the needs of male sexual and gender minority populations (ie, gay, bisexual, transgender/gender diverse, queer or questioning, intersex, and asexual persons). For example, transgender women might retain male anatomy or have surgical alteration of the genital region that also requires evaluation. In such patient populations, the genital examination is equally important to evaluate for dermatologic conditions that require treatment.

Final Thoughts

The male genital examination is an important component of the TBSE, as dermatologists can recognize lesions before symptoms present. Robust educational methods for trainees and practitioners in dermatology are lacking, and development of curricula might be beneficial to increase comfort in performing the genital examination. Still, use of the procedures described in this commentary can normalize the men’s genital examination, optimize the physical examination, and improve men’s overall dermatologic health.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.