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

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

Selecting a Systemic Nonbiologic Agent

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

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

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

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

Patient Comorbidities

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

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

Drug Contraindications

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

Pretreatment Screening

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

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

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

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

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

Monitoring During Active Treatment

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

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

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

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

Combination Therapy

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

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

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

Final Thoughts

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

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

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

Selecting a Systemic Nonbiologic Agent

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

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

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

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

Patient Comorbidities

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

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

Drug Contraindications

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

Pretreatment Screening

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

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

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

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

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

Monitoring During Active Treatment

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

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

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

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

Combination Therapy

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

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

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

Final Thoughts

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

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

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

Selecting a Systemic Nonbiologic Agent

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

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

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

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

Patient Comorbidities

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

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

Drug Contraindications

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

Pretreatment Screening

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

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

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

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

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

Monitoring During Active Treatment

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

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

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

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

Combination Therapy

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

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

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

Final Thoughts

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

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

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

Case Report

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

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

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

Comment

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

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

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

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

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

Conclusion

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

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

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

Case Report

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

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

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

Comment

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

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

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

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

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

Conclusion

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

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

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

Case Report

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

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

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

Comment

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

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

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

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

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

Conclusion

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

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

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

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

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

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

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

Case Report

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

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

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

Comment

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

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

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

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

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

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

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

Conclusion

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

Case Report

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

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

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

Comment

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

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

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

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

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

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

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

Conclusion

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

Case Report

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

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

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

Comment

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

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

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

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

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

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

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

Conclusion

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

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

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

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

Acanthosis Nigricans

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

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

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

Diabetic Dermopathy

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

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

Scleredema Diabeticorum

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

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

Ichthyosiform Skin Changes

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

Acrochordons

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

Keratosis Pilaris

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

Necrobiosis Lipoidica

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

Bullosis Diabeticorum

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

Generalized Granuloma Annulare

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

Final Thoughts

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

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

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

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

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

Acanthosis Nigricans

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

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

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

Diabetic Dermopathy

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

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

Scleredema Diabeticorum

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

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

Ichthyosiform Skin Changes

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

Acrochordons

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

Keratosis Pilaris

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

Necrobiosis Lipoidica

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

Bullosis Diabeticorum

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

Generalized Granuloma Annulare

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

Final Thoughts

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

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

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

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

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

Acanthosis Nigricans

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

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

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

Diabetic Dermopathy

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

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

Scleredema Diabeticorum

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

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

Ichthyosiform Skin Changes

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

Acrochordons

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

Keratosis Pilaris

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

Necrobiosis Lipoidica

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

Bullosis Diabeticorum

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

Generalized Granuloma Annulare

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

Final Thoughts

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

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

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.

Despite the high mortality rate for acquired hemophilia and the availability of suggested drug treatments, there are no randomized, controlled studies to inform doctors of the best therapies for their patients.

Immunoabsorption therapy (IA) is one such treatment that has been proposed as valid because of its ability to remove factor VIII clotting inhibitors from the bloodstream, but the data on its effectiveness are limited, according to Michael Esteves Pereira, of the Bern (Switzerland) University Hospital and the University of Bern, and colleagues.

In order to help answer the question of the benefits of IA for treating acquired hemophilia, the researchers performed a retrospective study assessing observational data as well as a systemic review and meta-analysis of published literature. They found evidence that the therapy was effective, but suggest that more confirmatory studies are needed, according to their report published online in Transfusion Medicine Reviews.

Data from the authors’ institution were available for 12 patients with acquired hemophilia treated since 2002. The median age was 76 years and four patients were women. The bleeding phenotype was extensive bruising and/or muscle hematomas in nine patients, gastrointestinal bleeding in two patients, and extensive bleeding after tooth extraction in one patient. Their data were added to the 10 published studies included in the literature review, resulting in a total of 118 patients.
 

Promising results

The author’s single institution analysis showed that IA treatment stopped bleeding in nine patients, while three patients did not respond. At 3 months, the median factor VIII increased to 80 IU/dL (considered complete remission) and the median inhibitor titer decreased to 0.15 BU/mL.

The pooled proportion of the meta-analysis patients treated with IA who achieved factor VIII recovery defined as complete remission was 86% (95% confidence interval, 76%-94%). The pooled proportion of patients with a reduction of the inhibitor titer was 95% (95% CI, 83%-100%), while the pooled mortality was 7% (95% CI, 0%-18%). Sensitivity analyses did not reveal any significant differences in retrospective studies or in studies using different absorbing agents.

In addition, there were few reported side effects, most of which were considered mild, according to the researchers. These included nausea and vomiting, paresthesia, and mild hypotension. The authors did suggest that, as a central venous catheter is often used, patients were exposed to an added risk of bleeding and infection.

“At our institution, IA is considered on a case-by-case base rather than a strict cutoff level. Strong arguments are life-threatening bleeding complications, inhibitor titers 20 BU/mL or greater, or failed immunosuppressive treatment with corticosteroids and cyclophosphamide using an established dose regimen,” the researchers stated.

“Even though firm evidence is still lacking and the actual ‘added value’ of IA cannot be adequately assessed, we believe that IA might be a beneficial adjunctive treatment modality in some patients with acquired hemophilia. It was associated with a complete remission in the majority of patients, most of whom are at high risk of bleeding,” the researchers added.

The authors reported that they had no relevant disclosures.

[email protected]

Despite the high mortality rate for acquired hemophilia and the availability of suggested drug treatments, there are no randomized, controlled studies to inform doctors of the best therapies for their patients.

Immunoabsorption therapy (IA) is one such treatment that has been proposed as valid because of its ability to remove factor VIII clotting inhibitors from the bloodstream, but the data on its effectiveness are limited, according to Michael Esteves Pereira, of the Bern (Switzerland) University Hospital and the University of Bern, and colleagues.

In order to help answer the question of the benefits of IA for treating acquired hemophilia, the researchers performed a retrospective study assessing observational data as well as a systemic review and meta-analysis of published literature. They found evidence that the therapy was effective, but suggest that more confirmatory studies are needed, according to their report published online in Transfusion Medicine Reviews.

Data from the authors’ institution were available for 12 patients with acquired hemophilia treated since 2002. The median age was 76 years and four patients were women. The bleeding phenotype was extensive bruising and/or muscle hematomas in nine patients, gastrointestinal bleeding in two patients, and extensive bleeding after tooth extraction in one patient. Their data were added to the 10 published studies included in the literature review, resulting in a total of 118 patients.
 

Promising results

The author’s single institution analysis showed that IA treatment stopped bleeding in nine patients, while three patients did not respond. At 3 months, the median factor VIII increased to 80 IU/dL (considered complete remission) and the median inhibitor titer decreased to 0.15 BU/mL.

The pooled proportion of the meta-analysis patients treated with IA who achieved factor VIII recovery defined as complete remission was 86% (95% confidence interval, 76%-94%). The pooled proportion of patients with a reduction of the inhibitor titer was 95% (95% CI, 83%-100%), while the pooled mortality was 7% (95% CI, 0%-18%). Sensitivity analyses did not reveal any significant differences in retrospective studies or in studies using different absorbing agents.

In addition, there were few reported side effects, most of which were considered mild, according to the researchers. These included nausea and vomiting, paresthesia, and mild hypotension. The authors did suggest that, as a central venous catheter is often used, patients were exposed to an added risk of bleeding and infection.

“At our institution, IA is considered on a case-by-case base rather than a strict cutoff level. Strong arguments are life-threatening bleeding complications, inhibitor titers 20 BU/mL or greater, or failed immunosuppressive treatment with corticosteroids and cyclophosphamide using an established dose regimen,” the researchers stated.

“Even though firm evidence is still lacking and the actual ‘added value’ of IA cannot be adequately assessed, we believe that IA might be a beneficial adjunctive treatment modality in some patients with acquired hemophilia. It was associated with a complete remission in the majority of patients, most of whom are at high risk of bleeding,” the researchers added.

The authors reported that they had no relevant disclosures.

[email protected]

Despite the high mortality rate for acquired hemophilia and the availability of suggested drug treatments, there are no randomized, controlled studies to inform doctors of the best therapies for their patients.

Immunoabsorption therapy (IA) is one such treatment that has been proposed as valid because of its ability to remove factor VIII clotting inhibitors from the bloodstream, but the data on its effectiveness are limited, according to Michael Esteves Pereira, of the Bern (Switzerland) University Hospital and the University of Bern, and colleagues.

In order to help answer the question of the benefits of IA for treating acquired hemophilia, the researchers performed a retrospective study assessing observational data as well as a systemic review and meta-analysis of published literature. They found evidence that the therapy was effective, but suggest that more confirmatory studies are needed, according to their report published online in Transfusion Medicine Reviews.

Data from the authors’ institution were available for 12 patients with acquired hemophilia treated since 2002. The median age was 76 years and four patients were women. The bleeding phenotype was extensive bruising and/or muscle hematomas in nine patients, gastrointestinal bleeding in two patients, and extensive bleeding after tooth extraction in one patient. Their data were added to the 10 published studies included in the literature review, resulting in a total of 118 patients.
 

Promising results

The author’s single institution analysis showed that IA treatment stopped bleeding in nine patients, while three patients did not respond. At 3 months, the median factor VIII increased to 80 IU/dL (considered complete remission) and the median inhibitor titer decreased to 0.15 BU/mL.

The pooled proportion of the meta-analysis patients treated with IA who achieved factor VIII recovery defined as complete remission was 86% (95% confidence interval, 76%-94%). The pooled proportion of patients with a reduction of the inhibitor titer was 95% (95% CI, 83%-100%), while the pooled mortality was 7% (95% CI, 0%-18%). Sensitivity analyses did not reveal any significant differences in retrospective studies or in studies using different absorbing agents.

In addition, there were few reported side effects, most of which were considered mild, according to the researchers. These included nausea and vomiting, paresthesia, and mild hypotension. The authors did suggest that, as a central venous catheter is often used, patients were exposed to an added risk of bleeding and infection.

“At our institution, IA is considered on a case-by-case base rather than a strict cutoff level. Strong arguments are life-threatening bleeding complications, inhibitor titers 20 BU/mL or greater, or failed immunosuppressive treatment with corticosteroids and cyclophosphamide using an established dose regimen,” the researchers stated.

“Even though firm evidence is still lacking and the actual ‘added value’ of IA cannot be adequately assessed, we believe that IA might be a beneficial adjunctive treatment modality in some patients with acquired hemophilia. It was associated with a complete remission in the majority of patients, most of whom are at high risk of bleeding,” the researchers added.

The authors reported that they had no relevant disclosures.

[email protected]

Areas with active cannabis dispensaries have seen a decrease in opioid-related mortalities, recent research has shown.

“Our findings suggest that higher storefront cannabis dispensary counts are associated with reduced opioid related mortality rates at the county level,” wrote Greta Hsu, PhD, professor of management, University of California, Davis, and Balázs Kovács, PhD, associate professor of organizational behavior, Yale University, New Haven, Conn. “This association holds for both medical and recreational dispensaries, and appears particularly strong for deaths associated with synthetic (nonmethadone) opioids, which include the highly potent synthetic opioid fentanyl and its analogs.”

Results ‘may be even stronger’ than reported

Christopher G. Fichtner, MD, clinical professor of psychiatry and neuroscience at the University of California, Riverside, said in an interview that the evidence for using cannabis as an opioid substitution for pain management has not been balanced, but noted “the bulk of it suggests that there is some harm reduction benefit by having liberalized access to cannabis.”

Courtesy Dr. Christopher Fichtner

One strength of the study by Dr. Hsu and Dr. Kovács was how they were able to examine implementation of legalization of medical or recreational cannabis, rather than simply a change in the law, he said.

“By looking at dispensary count, it’s actually looking at a better measure of on-the-ground implementation than just change in policy,” Dr. Fichtner explained. “You’re looking at what was actually accomplished in terms of making cannabis legally available.”

The choice to evaluate storefront dispensaries only and not include delivery services in their data, “probably makes it a relatively conservative estimate. I think that would be a strength, that their findings may be even stronger than what it is they’re reporting,” Dr. Fichtner said.

“I do think, if anything, the paper is relatively tentative about advancing its conclusions, which I think is a weakness in a lot of these studies,” he added. In 2017, the National Academy of Sciences released a report that found evidence cannabis or cannabinoids can significantly reduce pain symptoms. In that report, “one of their strongest conclusions is that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective management of chronic pain,” Dr. Fichtner said.

He said that digging deeper into what kinds of pain cannabis can treat is one area for future research. “Certainly, it seems that it’s unlikely that cannabis is going to be good for every kind of pain,” he said. “What kinds of pain is it better for than others? Is it some benefit for many kinds of pain, or only a few types of pain?”

The authors reported no relevant financial disclosures. Dr. Fichtner is the author of a book on cannabis policy in the United States, but reported no other financial disclosures.
 

Areas with active cannabis dispensaries have seen a decrease in opioid-related mortalities, recent research has shown.

“Our findings suggest that higher storefront cannabis dispensary counts are associated with reduced opioid related mortality rates at the county level,” wrote Greta Hsu, PhD, professor of management, University of California, Davis, and Balázs Kovács, PhD, associate professor of organizational behavior, Yale University, New Haven, Conn. “This association holds for both medical and recreational dispensaries, and appears particularly strong for deaths associated with synthetic (nonmethadone) opioids, which include the highly potent synthetic opioid fentanyl and its analogs.”

Results ‘may be even stronger’ than reported

Christopher G. Fichtner, MD, clinical professor of psychiatry and neuroscience at the University of California, Riverside, said in an interview that the evidence for using cannabis as an opioid substitution for pain management has not been balanced, but noted “the bulk of it suggests that there is some harm reduction benefit by having liberalized access to cannabis.”

Courtesy Dr. Christopher Fichtner

One strength of the study by Dr. Hsu and Dr. Kovács was how they were able to examine implementation of legalization of medical or recreational cannabis, rather than simply a change in the law, he said.

“By looking at dispensary count, it’s actually looking at a better measure of on-the-ground implementation than just change in policy,” Dr. Fichtner explained. “You’re looking at what was actually accomplished in terms of making cannabis legally available.”

The choice to evaluate storefront dispensaries only and not include delivery services in their data, “probably makes it a relatively conservative estimate. I think that would be a strength, that their findings may be even stronger than what it is they’re reporting,” Dr. Fichtner said.

“I do think, if anything, the paper is relatively tentative about advancing its conclusions, which I think is a weakness in a lot of these studies,” he added. In 2017, the National Academy of Sciences released a report that found evidence cannabis or cannabinoids can significantly reduce pain symptoms. In that report, “one of their strongest conclusions is that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective management of chronic pain,” Dr. Fichtner said.

He said that digging deeper into what kinds of pain cannabis can treat is one area for future research. “Certainly, it seems that it’s unlikely that cannabis is going to be good for every kind of pain,” he said. “What kinds of pain is it better for than others? Is it some benefit for many kinds of pain, or only a few types of pain?”

The authors reported no relevant financial disclosures. Dr. Fichtner is the author of a book on cannabis policy in the United States, but reported no other financial disclosures.
 

Areas with active cannabis dispensaries have seen a decrease in opioid-related mortalities, recent research has shown.

“Our findings suggest that higher storefront cannabis dispensary counts are associated with reduced opioid related mortality rates at the county level,” wrote Greta Hsu, PhD, professor of management, University of California, Davis, and Balázs Kovács, PhD, associate professor of organizational behavior, Yale University, New Haven, Conn. “This association holds for both medical and recreational dispensaries, and appears particularly strong for deaths associated with synthetic (nonmethadone) opioids, which include the highly potent synthetic opioid fentanyl and its analogs.”

Results ‘may be even stronger’ than reported

Christopher G. Fichtner, MD, clinical professor of psychiatry and neuroscience at the University of California, Riverside, said in an interview that the evidence for using cannabis as an opioid substitution for pain management has not been balanced, but noted “the bulk of it suggests that there is some harm reduction benefit by having liberalized access to cannabis.”

Courtesy Dr. Christopher Fichtner

One strength of the study by Dr. Hsu and Dr. Kovács was how they were able to examine implementation of legalization of medical or recreational cannabis, rather than simply a change in the law, he said.

“By looking at dispensary count, it’s actually looking at a better measure of on-the-ground implementation than just change in policy,” Dr. Fichtner explained. “You’re looking at what was actually accomplished in terms of making cannabis legally available.”

The choice to evaluate storefront dispensaries only and not include delivery services in their data, “probably makes it a relatively conservative estimate. I think that would be a strength, that their findings may be even stronger than what it is they’re reporting,” Dr. Fichtner said.

“I do think, if anything, the paper is relatively tentative about advancing its conclusions, which I think is a weakness in a lot of these studies,” he added. In 2017, the National Academy of Sciences released a report that found evidence cannabis or cannabinoids can significantly reduce pain symptoms. In that report, “one of their strongest conclusions is that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective management of chronic pain,” Dr. Fichtner said.

He said that digging deeper into what kinds of pain cannabis can treat is one area for future research. “Certainly, it seems that it’s unlikely that cannabis is going to be good for every kind of pain,” he said. “What kinds of pain is it better for than others? Is it some benefit for many kinds of pain, or only a few types of pain?”

The authors reported no relevant financial disclosures. Dr. Fichtner is the author of a book on cannabis policy in the United States, but reported no other financial disclosures.
 

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Shaukat has relationships with Freenome and Iterative Scopes.

Help your patients understand colorectal cancer prevention, and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Shaukat has relationships with Freenome and Iterative Scopes.

Help your patients understand colorectal cancer prevention, and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

A novel blood test has shown promise for colorectal cancer screening.

The “multiomics” test, under development by Freenome, has previously been shown to detect early-stage (I/II) colorectal cancer with a sensitivity of 94% and a specificity of 94%.

A new study shows that it can also detect precancerous lesions, colorectal advanced adenomas (AAs).

“The ability to detect advanced adenomas is incredibly important because we can remove them before they become cancerous,” senior author Aasma Shaukat, MD, MPH, chief of gastroenterology at Minneapolis VA Health Care System and professor of medicine at the University of Minnesota, Minneapolis, said in a statement.

At the Gastrointestinal Cancers Symposium 2021, she presented data showing that the novel test was able to detect AAs with a sensitivity of 41% and a specificity of 90%.

This sensitivity of the new test is better than or similar to that of currently available stool tests, noted study author C. Jimmy Lin, MD, PhD, MHS, chief scientific officer at Freenome.

The new test had almost double the sensitivity for detecting AAs (41% vs. 24%) as the fecal immunochemical test (FIT), and its sensitivity was comparable to that of FIT-DNA testing (41% vs. 42%).

In addition, it showed much higher sensitivity (41% vs 22%) for detecting AAs than the Epi proColon, a screening blood test that has been approved by the U.S. Food and Drug Administration for detecting methylated septin 9 DNA (mSEPT9).

“What’s special about our company is ... that we use a multinomic technology, meaning we look at DNA, RNA, protein, and other biomarkers – all of these things together,” Dr. Lin told this news organization.

Their platform integrates assays for circulating free DNA, methylation, and proteins using advanced computational biology and machine-learning techniques, which provide a multidimensional view of both tumor- and immune-derived signatures that enable the early detection of cancer.

In contrast to other blood tests that are under development for cancer screening, some of which claim to detect several common cancer types, Freenome is focusing on only colorectal cancer. “There are other companies in the early-detection space, but some of them are doing multicancer screening and have a generalized product,” said Dr. Lin. “Our approach is to focus on a specific cancer type, and we are beginning with colorectal cancer screening, and then will expand to other types.”
 

Better sensitivity

The study that was presented at the meeting evaluated the novel multiomics blood test for AA detection.

Blood samples were obtained from participants in the AI-EMERGE study, a prospective, multicenter study that included primarily average-risk screening patients from 30 clinical sites in the United States and Canada. The study included a total of 542 samples, including 122 histopathologically confirmed AAs and 420 colonoscopy-confirmed negative control samples.

AA sensitivity of the novel test was greater than that with the mSEPT9 test, which is the only blood test currently available for colorectal cancer screening. The new test’s sensitivity was much higher than that of FIT and was comparable to that of FIT-DNA. Sensitivity increased with increasing lesion size and was consistent across location and histology except for serrated lesions, the authors noted in the abstract.

“By combining signatures from both tumor and non–tumor-derived sources, our multiomics signatures detect twice as many AAs as methylation only or single-protein approaches,” Dr. Lin said. “And we have now shown that sensitive AA detection at a level similar to or better than currently available stool tests is achievable in blood, which is necessary for effective early detection and prevention of colorectal cancers.”

The company has begun the regulatory process for having the test approved by the FDA. The company’s goal is to enroll 14,000 participants and have prospectively collected data.

The research was funded by Freenome. Dr. Lin is the chief scientific officer at Freenome and has relationships with Labroots, Natera, and Neon Therapeutics. Shaukat has relationships with Freenome and Iterative Scopes.

Help your patients understand colorectal cancer prevention, and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

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

When a patient presents with a palpable nodule greater than 1 cm in diameter more than 2 weeks after injection of cosmetic filler, sorting out whether the culprit is an infection or an immune reaction is no easy task.

“It’s sometime very difficult to distinguish between the two,” Terrence Keaney, MD, said during the Orlando Dermatology Aesthetic and Clinical Conference. “Classically, an early-onset infection presents as a suppurative mass that’s fluctuant and tender. The challenge with delayed-onset infection is that it often does not tend to be fluctuant. It doesn’t resemble the classic infection you see in regular dermatology practice.”

Dr. Keaney, a dermatologist who is founder and director of SkinDC in Arlington, Va., said that the source of delayed infection could stem from inoculation at the time of injection – primarily via the skin microflora. “There are also rare case reports of mycobacterial infections from watered gauze,” which he said is why he does not use watered gauze in his practice. “This risk reinforces the importance of filler hygiene when you’re using dermal fillers. Isopropyl alcohol is often not enough. A lot of practices use chlorhexidine, avoiding its use around the eyes, to reduce the skin flora. Hypochlorous acid is another safe antiseptic for the face. You also want to be very careful with the needle or cannula tip not to touch your glove and to minimize going in and out of the skin so you’re not seeding the filler with bacteria.”

Other potential sources of a delayed infection described in the literature include a dental abscess, pimple popping, and subsequent injections from acupuncture or hyaluronidase.

When patients present with a nonfluctuant delayed nodule that shows no obvious signs of infection, however, the root cause can stump clinicians. “Is this infectious or not?” asked Dr. Keaney, who is also clinical associate faculty in the department of dermatology at George Washington University, Washington. “Is this a focus on chronic inflammation in response to the product, or is this a collection of chronic bacteria, a biofilm too large to be engulfed by a single cell?” A review of the topic found that three risk factors for the development of biofilms include the surface area of product (large boluses of filler), longevity of the product, and inadequate sterilization technique.

Dr. Keaney said that biofilms create an impaired immune system penetration, which boosts their resistance to antibiotics by 1,000-fold. “These bacteria also have a reduced growth rate, an altered microenvironment, and altered gene expression, so it makes it difficult to clear these biofilms.”

To determine if a delayed nodule is infectious or not, performing a biopsy with polymerase chain reaction (PCR) analysis of tissue samples is ideal. “This would amplify the DNA by electrophoresis,” Dr. Keaney continued. “The problem is, it is often difficult to find labs to perform PCR. Also, you’re likely going to have to biopsy someone’s face. The patient is likely already upset that they have a delayed nodule. Ideally, you would want to avoid having to do a punch biopsy of a patient’s lip, tear trough, temple, or chin. The flip side of the coin is, how do you accurately determine if this is a noninfectious delayed nodule? If it is noninfectious, what is the mechanism of action?”

According to Dr. Keaney, short hyaluronic acid (HA) fragments can act as substrates for cell trafficking and can activate macrophages, dendritic cells, and T cells. In an analysis of immune cell response that used in vitro cell-based assays and was presented during a poster session at the 2018 Anti-Aging Medicine World Congress, researchers found no evidence of inflammatory or immune response to HA used for dermal fillers, regardless of size or formulation. However, physiologic degradation of HA to intermediate/small fragments tends to occur 4-5 months after injection.

“The hypothesis is that proinflammatory HA fragments may prime the immune system for an inflammatory response in the setting of a triggering event,” Dr. Keaney said. “The presence of an inflammatory reaction triggers an immune response to the HA fragments. Possible triggers include infections, dental procedures, and immunizations.”

The American Society for Dermatologic Surgery (ASDS) recently published a guidance regarding SARS-CoV-2 mRNA vaccine side effects in dermal filler patients after three patients developed a reaction to the Moderna vaccine, in clinical trials. “One patient, a 29-year-old, had previous angioedema from a flu vaccine, so the question is: Is it truly a delayed nodule or an immunologic reaction to the ingredients in the vaccine?” Dr. Keaney said. Two other patients, a 51-year-old female and a 46-year-old female, developed facial swelling that were believed to be related to a previous filler injection. Both cases resolved.

“Is the COVID vaccine more of an immunologic trigger than other vaccines?” Dr. Keaney asked. “Are we going to see this more frequently? We may. We just don’t know the denominator. We do not know how many patients in the Moderna or Pfizer vaccine studies had been previously treated with dermal fillers. In patients who have had previous filler treatments, I’m still advising them to get the COVID vaccine if they can.”

Dr. Keaney’s algorithm for treating a delayed nodule that is fluctuant starts with culturing any exudate and beginning a course of empiric antibiotic therapy. “If it’s a nonfluctuant delayed nodule where you’re not sure if it’s related to a biofilm or to an immunologic reaction, there are multiple global consensus papers about this challenging condition in the medical literature,” he said. “Among the papers, there is no consensus treatment, even among consensus panels. They often recommend multiple antibiotic regimens when biofilm is the suspected culprit. For a noninfectious delayed nodule, they recommend prednisone or anti-inflammatory medications. If the nodule is recalcitrant to anti-inflammatory treatments, consider adding empiric antibiotic therapy or dissolve the product.”

In other specialties, the No. 1 priority of a biofilm infection is to get rid of the implant. In orthopedics, for example, the surgeon may remove the artificial joint, Dr. Keaney said. “If that delayed nodule is not responding to comprehensive antibiotic therapy or prednisone anti-inflammatories, you may consider dissolving the filler. The challenge is, there is wide variation in the ability of different hyaluronidase [products] and fillers to dissolve. Another concern is that you may make smaller, more immunogenic HA fragments by dissolving the filler.”

One approach for vascular occlusions introduced by Claudio DeLorenzi, MD, a plastic surgeon in private practice in Kitchener, Ontario, is to dissolve dermal fillers with high-dose pulsed hyaluronidase using up to 1,500 IU every hour. “In the U.S., hyaluronidase comes in 150-200-unit sizes,” Dr. Keaney said. “In my practice, it’s not enough to have one bottle of hyaluronidase. You need around 15-20 bottles to be able to treat for a vascular incident, but if you have a delayed nodule you may also have to use high doses of hyaluronidase.”

Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.

[email protected]

When a patient presents with a palpable nodule greater than 1 cm in diameter more than 2 weeks after injection of cosmetic filler, sorting out whether the culprit is an infection or an immune reaction is no easy task.

“It’s sometime very difficult to distinguish between the two,” Terrence Keaney, MD, said during the Orlando Dermatology Aesthetic and Clinical Conference. “Classically, an early-onset infection presents as a suppurative mass that’s fluctuant and tender. The challenge with delayed-onset infection is that it often does not tend to be fluctuant. It doesn’t resemble the classic infection you see in regular dermatology practice.”

Dr. Keaney, a dermatologist who is founder and director of SkinDC in Arlington, Va., said that the source of delayed infection could stem from inoculation at the time of injection – primarily via the skin microflora. “There are also rare case reports of mycobacterial infections from watered gauze,” which he said is why he does not use watered gauze in his practice. “This risk reinforces the importance of filler hygiene when you’re using dermal fillers. Isopropyl alcohol is often not enough. A lot of practices use chlorhexidine, avoiding its use around the eyes, to reduce the skin flora. Hypochlorous acid is another safe antiseptic for the face. You also want to be very careful with the needle or cannula tip not to touch your glove and to minimize going in and out of the skin so you’re not seeding the filler with bacteria.”

Other potential sources of a delayed infection described in the literature include a dental abscess, pimple popping, and subsequent injections from acupuncture or hyaluronidase.

When patients present with a nonfluctuant delayed nodule that shows no obvious signs of infection, however, the root cause can stump clinicians. “Is this infectious or not?” asked Dr. Keaney, who is also clinical associate faculty in the department of dermatology at George Washington University, Washington. “Is this a focus on chronic inflammation in response to the product, or is this a collection of chronic bacteria, a biofilm too large to be engulfed by a single cell?” A review of the topic found that three risk factors for the development of biofilms include the surface area of product (large boluses of filler), longevity of the product, and inadequate sterilization technique.

Dr. Keaney said that biofilms create an impaired immune system penetration, which boosts their resistance to antibiotics by 1,000-fold. “These bacteria also have a reduced growth rate, an altered microenvironment, and altered gene expression, so it makes it difficult to clear these biofilms.”

To determine if a delayed nodule is infectious or not, performing a biopsy with polymerase chain reaction (PCR) analysis of tissue samples is ideal. “This would amplify the DNA by electrophoresis,” Dr. Keaney continued. “The problem is, it is often difficult to find labs to perform PCR. Also, you’re likely going to have to biopsy someone’s face. The patient is likely already upset that they have a delayed nodule. Ideally, you would want to avoid having to do a punch biopsy of a patient’s lip, tear trough, temple, or chin. The flip side of the coin is, how do you accurately determine if this is a noninfectious delayed nodule? If it is noninfectious, what is the mechanism of action?”

According to Dr. Keaney, short hyaluronic acid (HA) fragments can act as substrates for cell trafficking and can activate macrophages, dendritic cells, and T cells. In an analysis of immune cell response that used in vitro cell-based assays and was presented during a poster session at the 2018 Anti-Aging Medicine World Congress, researchers found no evidence of inflammatory or immune response to HA used for dermal fillers, regardless of size or formulation. However, physiologic degradation of HA to intermediate/small fragments tends to occur 4-5 months after injection.

“The hypothesis is that proinflammatory HA fragments may prime the immune system for an inflammatory response in the setting of a triggering event,” Dr. Keaney said. “The presence of an inflammatory reaction triggers an immune response to the HA fragments. Possible triggers include infections, dental procedures, and immunizations.”

The American Society for Dermatologic Surgery (ASDS) recently published a guidance regarding SARS-CoV-2 mRNA vaccine side effects in dermal filler patients after three patients developed a reaction to the Moderna vaccine, in clinical trials. “One patient, a 29-year-old, had previous angioedema from a flu vaccine, so the question is: Is it truly a delayed nodule or an immunologic reaction to the ingredients in the vaccine?” Dr. Keaney said. Two other patients, a 51-year-old female and a 46-year-old female, developed facial swelling that were believed to be related to a previous filler injection. Both cases resolved.

“Is the COVID vaccine more of an immunologic trigger than other vaccines?” Dr. Keaney asked. “Are we going to see this more frequently? We may. We just don’t know the denominator. We do not know how many patients in the Moderna or Pfizer vaccine studies had been previously treated with dermal fillers. In patients who have had previous filler treatments, I’m still advising them to get the COVID vaccine if they can.”

Dr. Keaney’s algorithm for treating a delayed nodule that is fluctuant starts with culturing any exudate and beginning a course of empiric antibiotic therapy. “If it’s a nonfluctuant delayed nodule where you’re not sure if it’s related to a biofilm or to an immunologic reaction, there are multiple global consensus papers about this challenging condition in the medical literature,” he said. “Among the papers, there is no consensus treatment, even among consensus panels. They often recommend multiple antibiotic regimens when biofilm is the suspected culprit. For a noninfectious delayed nodule, they recommend prednisone or anti-inflammatory medications. If the nodule is recalcitrant to anti-inflammatory treatments, consider adding empiric antibiotic therapy or dissolve the product.”

In other specialties, the No. 1 priority of a biofilm infection is to get rid of the implant. In orthopedics, for example, the surgeon may remove the artificial joint, Dr. Keaney said. “If that delayed nodule is not responding to comprehensive antibiotic therapy or prednisone anti-inflammatories, you may consider dissolving the filler. The challenge is, there is wide variation in the ability of different hyaluronidase [products] and fillers to dissolve. Another concern is that you may make smaller, more immunogenic HA fragments by dissolving the filler.”

One approach for vascular occlusions introduced by Claudio DeLorenzi, MD, a plastic surgeon in private practice in Kitchener, Ontario, is to dissolve dermal fillers with high-dose pulsed hyaluronidase using up to 1,500 IU every hour. “In the U.S., hyaluronidase comes in 150-200-unit sizes,” Dr. Keaney said. “In my practice, it’s not enough to have one bottle of hyaluronidase. You need around 15-20 bottles to be able to treat for a vascular incident, but if you have a delayed nodule you may also have to use high doses of hyaluronidase.”

Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.

[email protected]

When a patient presents with a palpable nodule greater than 1 cm in diameter more than 2 weeks after injection of cosmetic filler, sorting out whether the culprit is an infection or an immune reaction is no easy task.

“It’s sometime very difficult to distinguish between the two,” Terrence Keaney, MD, said during the Orlando Dermatology Aesthetic and Clinical Conference. “Classically, an early-onset infection presents as a suppurative mass that’s fluctuant and tender. The challenge with delayed-onset infection is that it often does not tend to be fluctuant. It doesn’t resemble the classic infection you see in regular dermatology practice.”

Dr. Keaney, a dermatologist who is founder and director of SkinDC in Arlington, Va., said that the source of delayed infection could stem from inoculation at the time of injection – primarily via the skin microflora. “There are also rare case reports of mycobacterial infections from watered gauze,” which he said is why he does not use watered gauze in his practice. “This risk reinforces the importance of filler hygiene when you’re using dermal fillers. Isopropyl alcohol is often not enough. A lot of practices use chlorhexidine, avoiding its use around the eyes, to reduce the skin flora. Hypochlorous acid is another safe antiseptic for the face. You also want to be very careful with the needle or cannula tip not to touch your glove and to minimize going in and out of the skin so you’re not seeding the filler with bacteria.”

Other potential sources of a delayed infection described in the literature include a dental abscess, pimple popping, and subsequent injections from acupuncture or hyaluronidase.

When patients present with a nonfluctuant delayed nodule that shows no obvious signs of infection, however, the root cause can stump clinicians. “Is this infectious or not?” asked Dr. Keaney, who is also clinical associate faculty in the department of dermatology at George Washington University, Washington. “Is this a focus on chronic inflammation in response to the product, or is this a collection of chronic bacteria, a biofilm too large to be engulfed by a single cell?” A review of the topic found that three risk factors for the development of biofilms include the surface area of product (large boluses of filler), longevity of the product, and inadequate sterilization technique.

Dr. Keaney said that biofilms create an impaired immune system penetration, which boosts their resistance to antibiotics by 1,000-fold. “These bacteria also have a reduced growth rate, an altered microenvironment, and altered gene expression, so it makes it difficult to clear these biofilms.”

To determine if a delayed nodule is infectious or not, performing a biopsy with polymerase chain reaction (PCR) analysis of tissue samples is ideal. “This would amplify the DNA by electrophoresis,” Dr. Keaney continued. “The problem is, it is often difficult to find labs to perform PCR. Also, you’re likely going to have to biopsy someone’s face. The patient is likely already upset that they have a delayed nodule. Ideally, you would want to avoid having to do a punch biopsy of a patient’s lip, tear trough, temple, or chin. The flip side of the coin is, how do you accurately determine if this is a noninfectious delayed nodule? If it is noninfectious, what is the mechanism of action?”

According to Dr. Keaney, short hyaluronic acid (HA) fragments can act as substrates for cell trafficking and can activate macrophages, dendritic cells, and T cells. In an analysis of immune cell response that used in vitro cell-based assays and was presented during a poster session at the 2018 Anti-Aging Medicine World Congress, researchers found no evidence of inflammatory or immune response to HA used for dermal fillers, regardless of size or formulation. However, physiologic degradation of HA to intermediate/small fragments tends to occur 4-5 months after injection.

“The hypothesis is that proinflammatory HA fragments may prime the immune system for an inflammatory response in the setting of a triggering event,” Dr. Keaney said. “The presence of an inflammatory reaction triggers an immune response to the HA fragments. Possible triggers include infections, dental procedures, and immunizations.”

The American Society for Dermatologic Surgery (ASDS) recently published a guidance regarding SARS-CoV-2 mRNA vaccine side effects in dermal filler patients after three patients developed a reaction to the Moderna vaccine, in clinical trials. “One patient, a 29-year-old, had previous angioedema from a flu vaccine, so the question is: Is it truly a delayed nodule or an immunologic reaction to the ingredients in the vaccine?” Dr. Keaney said. Two other patients, a 51-year-old female and a 46-year-old female, developed facial swelling that were believed to be related to a previous filler injection. Both cases resolved.

“Is the COVID vaccine more of an immunologic trigger than other vaccines?” Dr. Keaney asked. “Are we going to see this more frequently? We may. We just don’t know the denominator. We do not know how many patients in the Moderna or Pfizer vaccine studies had been previously treated with dermal fillers. In patients who have had previous filler treatments, I’m still advising them to get the COVID vaccine if they can.”

Dr. Keaney’s algorithm for treating a delayed nodule that is fluctuant starts with culturing any exudate and beginning a course of empiric antibiotic therapy. “If it’s a nonfluctuant delayed nodule where you’re not sure if it’s related to a biofilm or to an immunologic reaction, there are multiple global consensus papers about this challenging condition in the medical literature,” he said. “Among the papers, there is no consensus treatment, even among consensus panels. They often recommend multiple antibiotic regimens when biofilm is the suspected culprit. For a noninfectious delayed nodule, they recommend prednisone or anti-inflammatory medications. If the nodule is recalcitrant to anti-inflammatory treatments, consider adding empiric antibiotic therapy or dissolve the product.”

In other specialties, the No. 1 priority of a biofilm infection is to get rid of the implant. In orthopedics, for example, the surgeon may remove the artificial joint, Dr. Keaney said. “If that delayed nodule is not responding to comprehensive antibiotic therapy or prednisone anti-inflammatories, you may consider dissolving the filler. The challenge is, there is wide variation in the ability of different hyaluronidase [products] and fillers to dissolve. Another concern is that you may make smaller, more immunogenic HA fragments by dissolving the filler.”

One approach for vascular occlusions introduced by Claudio DeLorenzi, MD, a plastic surgeon in private practice in Kitchener, Ontario, is to dissolve dermal fillers with high-dose pulsed hyaluronidase using up to 1,500 IU every hour. “In the U.S., hyaluronidase comes in 150-200-unit sizes,” Dr. Keaney said. “In my practice, it’s not enough to have one bottle of hyaluronidase. You need around 15-20 bottles to be able to treat for a vascular incident, but if you have a delayed nodule you may also have to use high doses of hyaluronidase.”

Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.

[email protected]