Jashin J. Wu, MD

In November 2019, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released their first set of recommendations for the management of pediatric psoriasis.¹ The pediatric guidelines discuss methods of quantifying disease severity in children, triggers and comorbidities, and the efficacy and safety of various therapeutic agents. This review aims to discuss, in a condensed form, special considerations unique to the management of children with psoriasis as presented in the guidelines as well as grade A– and grade B–level treatment recommendations (Table).

Quantifying Psoriasis Severity in Children

Percentage body surface area (BSA) involvement is the most common mode of grading psoriasis severity, with less than 3% BSA involvement being considered mild, 3% to 10% BSA moderate, and more than 10% severe disease. In children, the standard method of measuring BSA is the rule of 9’s: the head and each arm make up 9% of the total BSA, each leg and the front and back of the torso respectively each make up 18%, and the genitalia make up 1%. It also is important to consider impact on quality of life, which may be remarkable in spite of limited BSA involvement. The children’s dermatology life quality index score may be utilized in combination with affected BSA to determine the burden of psoriasis in context of impact on daily life. This metric is available in both written and cartoon form, and it consists of 10 questions that include variables such as severity of itch, impact on social life, and effects on sleep. Most notably, this tool incorporates pruritus,² which generally is addressed inadequately in pediatric psoriasis.

Triggers and Comorbidities in Pediatric Patients

In children, it is important to identify and eliminate modifiable factors that may prompt psoriasis flares. Infections, particularly group A beta-hemolytic streptococcal infections, are a major trigger in neonates and infants. Other exacerbating factors in children include emotional stress, secondhand cigarette smoke, Kawasaki disease, and withdrawal from systemic corticosteroids.

Psoriatic arthritis (PsA) is a burdensome comorbidity affecting children with psoriasis. The prevalence of joint disease is 15-times greater in children with psoriasis vs those without,³ and 80% of children with PsA develop rheumatologic symptoms, which typically include oligoarticular disease and dactylitis in infants and girls and enthesitis and axial joint involvement in boys and older children, years prior to the onset of cutaneous disease.⁴ Uveitis often occurs in children with psoriasis and PsA but not in those with isolated cutaneous disease.

Compared to unaffected children, pediatric patients with psoriasis have greater prevalence of metabolic and cardiovascular risk factors during childhood, including central obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, atherosclerosis, arrythmia, and valvular heart disease. Family history of obesity increases the risk for early-onset development of cutaneous lesions,^5,6 and weight reduction may alleviate severity of psoriasis lesions.⁷ In the United States, many of the metabolic associations observed are particularly robust in Black and Hispanic children vs those of other races. Furthermore, the prevalence of inflammatory bowel disease is 3- to 4-times higher in children with psoriasis compared to those without.

As with other cutaneous diseases, it is important to be aware of social and mental health concerns in children with psoriasis. The majority of pediatric patients with psoriasis experience name-calling, shaming, or bullying, and many have concerns from skin shedding and malodor. Independent risk for depression after the onset of psoriasis is high. Affected older children and adolescents are at increased risk for alcohol and drug abuse as well as eating disorders.

Despite these identified comorbidities, there are no unique screening recommendations for arthritis, ophthalmologic disease, metabolic disease, cardiovascular disease, gastrointestinal tract disease, or mental health issues in children with psoriasis. Rather, these patients should be monitored according to the American Academy of Pediatrics or American Diabetes Association guidelines for all pediatric patients.^8,9 Nonetheless, educating patients and guardians about these potential issues may be warranted.

Topical Therapies

For children with mild to moderate psoriasis, topical therapies are first line. Despite being off label, topical corticosteroids are the mainstay of therapy for localized psoriatic plaques in children. Topical vitamin D analogues—calcitriol and calcipotriol/calcipotriene—are highly effective and well tolerated, and they frequently are used in combination with topical corticosteroids. Topical calcineurin inhibitors, namely tacrolimus, also are used off label but are considered first line for sensitive regions of the skin in children, including the face, genitalia, and body folds. There currently is limited evidence for supporting the use of the topical vitamin A analogue tazarotene in children with psoriasis, though some consider its off-label use effective for pediatric nail psoriasis. It also may be used as an adjunct to topical corticosteroids to minimize irritation.

Although there is no gold standard topical regimen, combination therapy with a high-potency topical steroid and topical vitamin D analogue commonly is used to minimize steroid-induced side effects. For the first 2 weeks of treatment, they each may be applied once daily or mixed together and applied twice daily. For subsequent maintenance, topical calcipotriene may be applied on weekdays and topical steroids only on weekends. Combination calcipotriol–betamethasone dipropionate also is available as cream, ointment, foam, and suspension vehicles for use on the body and scalp in children aged 12 years and older. Tacrolimus ointment 0.1% may be applied in a thin layer up to twice daily. Concurrent emollient use also is recommended with these therapies.

Health care providers should educate patients and guardians about the potential side effects of topical therapies. They also should provide explicit instructions for amount, site, frequency, and duration of application. Topical corticosteroids commonly result in burning on application and may potentially cause skin thinning and striae with overuse. Topical vitamin D analogues may result in local irritation that may be improved by concurrent emollient use, and they generally should be avoided on sensitive sites. Topical calcineurin inhibitors are associated with burning, stinging, and pruritus, and the US Food and Drug Administration has issued a black-box warning related to risk for lymphoma with their chronic intermittent use. However, it was based on rare reports of lymphoma in transplant patients taking oral calcineurin inhibitors; no clinical trials to date in humans have demonstrated an increased risk for malignancy with topical calcineurin inhibitors.¹⁰ Tazarotene should be used cautiously in females of childbearing age given its teratogenic potential.

Children younger than 7 years are especially prone to suppression of the hypothalamic-pituitary-adrenal axis from topical corticosteroid therapy and theoretically hypercalcemia and hypervitaminosis D from topical vitamin D analogues, as their high BSA-to-volume ratio increases potential for systemic absorption. Children should avoid occlusive application of topical vitamin D analogues to large areas of the skin. Monitoring of vitamin D metabolites in the serum may be considered if calcipotriene or calcipotriol application to a large BSA is warranted.

Light-Based Therapy

In children with widespread psoriasis or those refractory to topical therapy, phototherapy may be considered. Narrowband UVB (311- to 313-nm wavelength) therapy is considered a first-line form of phototherapy in pediatric psoriasis. Mineral oil or emollient pretreatment to affected areas may augment the efficacy of UV-based treatments.¹¹ Excimer laser and UVA also may be efficacious, though evidence is limited in children. Treatment is recommended to start at 3 days a week, and once improvement is seen, the frequency can be decreased to 2 days a week. Once desired clearance is achieved, maintenance therapy can be continued at even longer intervals. Adjunctive use of tar preparations may potentiate the efficacy of phototherapy, though there is a theoretical increased risk for carcinogenicity with prolonged use of coal tar. Side effects of phototherapy include erythema, blistering hyperpigmentation, and pruritus. Psoralen is contraindicated in children younger than 12 years. All forms of phototherapy are contraindicated in children with generalized erythroderma and cutaneous cancer syndromes. Other important pediatric-specific considerations include anxiety that may be provoked by UV light machines and inconvenience of frequent appointments.

Nonbiologic Systemic Therapies

Systemic therapies may be considered in children with recalcitrant, widespread, or rapidly progressing psoriasis, particularly if the disease is accompanied by severe emotional and psychological burden. These drugs, which include methotrexate, cyclosporine, and acitretin (see eTable for recommended dosing), are advantageous in that they may be combined with other therapies; however, they have potential for dangerous toxicities.

Methotrexate is the most frequently utilized systemic therapy for psoriasis worldwide in children because of its low cost, once-weekly dosing, and the substantial amount of long-term efficacy and safety data available in the pediatric population. It is slow acting initially but has excellent long-term efficacy for nearly every subtype of psoriasis. The most common side effect of methotrexate is gastrointestinal tract intolerance. Nonetheless, adverse events are rare in children without prior history, with 1 large study (N=289) reporting no adverse events in more than 90% of patients aged 9 to 14 years treated with methotrexate.¹² Current guidelines recommend monitoring for bone marrow suppression and elevated transaminase levels 4 to 6 days after initiating treatment.¹ The absolute contraindications for methotrexate are pregnancy and liver disease, and caution should be taken in children with metabolic risk factors. Adolescents must be counseled regarding the elevated risk for hepatotoxicity associated with alcohol ingestion. Methotrexate therapy also requires 1 mg folic acid supplementation 6 to 7 days a week, which decreases the risk for developing folic acid deficiency and may decrease gastrointestinal tract intolerance and hepatic side effects that may result from therapy.

Cyclosporine is an effective and well-tolerated option for rapid control of severe psoriasis in children. It is useful for various types of psoriasis but generally is reserved for more severe subtypes, such as generalized pustular psoriasis, erythrodermic psoriasis, and uncontrolled plaque psoriasis. Long-term use of cyclosporine may result in renal toxicity and hypertension, and this therapy is absolutely contraindicated in children with kidney disease or hypertension at baseline. It is strongly recommended to evaluate blood pressure every week for the first month of therapy and at every subsequent follow-up visit, which may occur at variable intervals based on the judgement of the provider. Evaluation before and during treatment with cyclosporine also should include a complete blood cell count, complete metabolic panel, and lipid panel.

Systemic retinoids have a unique advantage over methotrexate and cyclosporine in that they are not immunosuppressive and therefore are not contraindicated in children who are very young or immunosuppressed. Children receiving systemic retinoids also can receive routine live vaccines—measles-mumps-rubella, varicella zoster, and rotavirus—that are contraindicated with other systemic therapies. Acitretin is particularly effective in pediatric patients with diffuse guttate psoriasis, pustular psoriasis, and palmoplantar psoriasis. Narrowband UVB therapy has been shown to augment the effectiveness of acitretin in children, which may allow for reduced acitretin dosing. Pustular psoriasis may respond as quickly as 3 weeks after initiation, whereas it may take 2 to 3 months before improvement is noticed in plaque psoriasis. Side effects of retinoids include skin dryness, hyperlipidemia, and gastrointestinal tract upset. The most severe long-term concern is skeletal toxicity, including premature epiphyseal closure, hyperostosis, periosteal bone formation, and decreased bone mineral density.¹ Vitamin A derivatives also are known teratogens and should be avoided in females of childbearing potential. Lipids and transaminases should be monitored routinely, and screening for depression and psychiatric symptoms should be performed frequently.¹

When utilizing systemic therapies, the objective should be to control the disease, maintain stability, and ultimately taper to the lowest effective dose or transition to a topical therapy, if feasible. Although no particular systemic therapy is recommended as first line for children with psoriasis, it is important to consider comorbidities, contraindications, monitoring frequency, mode of administration (injectable therapies elicit more psychological trauma in children than oral therapies), and expense when determining the best choice.

Biologics

Biologic agents are associated with very high to total psoriatic plaque clearance rates and require infrequent dosing and monitoring. However, their use may be limited by cost and injection phobias in children as well as limited evidence for their efficacy and safety in pediatric psoriasis. Several studies have established the safety and effectiveness of biologics in children with plaque psoriasis (see eTable for recommended dosing), whereas the evidence supporting their use in treating pustular and erythrodermic variants are limited to case reports and case series. The tumor necrosis factor α (TNF-α) inhibitor etanercept has been approved for use in children aged 4 years and older, and the IL-12/IL-23 inhibitor ustekinumab is approved in children aged 6 years and older. Other TNF-α inhibitors, namely infliximab and adalimumab, commonly are utilized off label for pediatric psoriasis. The most common side effect of biologic therapies in pediatric patients is injection-site reactions.¹ Prior to initiating therapy, children must undergo tuberculosis screening either by purified protein derivative testing or IFN-γ release assay. Testing should be repeated annually in individuals taking TNF-α inhibitors, though the utility of repeat testing when taking biologics in other classes is not clear. High-risk patients also should be screened for human immunodeficiency virus and hepatitis. Follow-up frequency may range from every 3 months to annually, based on judgement of the provider. In children who develop loss of response to biologics, methotrexate can be added to the regimen to attenuate formation of efficacy-reducing antidrug antibodies.

Final Thoughts

When managing children with psoriasis, it is important for dermatologists to appropriately educate guardians and children on the disease course, as well as consider the psychological, emotional, social, and financial factors that may direct decision-making regarding optimal therapeutics. Dermatologists should consider collaboration with the child’s primary care physician and other specialists to ensure that all needs are met.

These guidelines provide a framework agreed upon by numerous experts in pediatric psoriasis, but they are limited by gaps in the research. There still is much to be learned regarding the pathophysiology of psoriasis; the risk for developing comorbidities during adulthood; and the efficacy and safety of certain therapeutics, particularly biologics, in pediatric patients with psoriasis.

In November 2019, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released their first set of recommendations for the management of pediatric psoriasis.¹ The pediatric guidelines discuss methods of quantifying disease severity in children, triggers and comorbidities, and the efficacy and safety of various therapeutic agents. This review aims to discuss, in a condensed form, special considerations unique to the management of children with psoriasis as presented in the guidelines as well as grade A– and grade B–level treatment recommendations (Table).

Quantifying Psoriasis Severity in Children

Percentage body surface area (BSA) involvement is the most common mode of grading psoriasis severity, with less than 3% BSA involvement being considered mild, 3% to 10% BSA moderate, and more than 10% severe disease. In children, the standard method of measuring BSA is the rule of 9’s: the head and each arm make up 9% of the total BSA, each leg and the front and back of the torso respectively each make up 18%, and the genitalia make up 1%. It also is important to consider impact on quality of life, which may be remarkable in spite of limited BSA involvement. The children’s dermatology life quality index score may be utilized in combination with affected BSA to determine the burden of psoriasis in context of impact on daily life. This metric is available in both written and cartoon form, and it consists of 10 questions that include variables such as severity of itch, impact on social life, and effects on sleep. Most notably, this tool incorporates pruritus,² which generally is addressed inadequately in pediatric psoriasis.

Triggers and Comorbidities in Pediatric Patients

In children, it is important to identify and eliminate modifiable factors that may prompt psoriasis flares. Infections, particularly group A beta-hemolytic streptococcal infections, are a major trigger in neonates and infants. Other exacerbating factors in children include emotional stress, secondhand cigarette smoke, Kawasaki disease, and withdrawal from systemic corticosteroids.

Psoriatic arthritis (PsA) is a burdensome comorbidity affecting children with psoriasis. The prevalence of joint disease is 15-times greater in children with psoriasis vs those without,³ and 80% of children with PsA develop rheumatologic symptoms, which typically include oligoarticular disease and dactylitis in infants and girls and enthesitis and axial joint involvement in boys and older children, years prior to the onset of cutaneous disease.⁴ Uveitis often occurs in children with psoriasis and PsA but not in those with isolated cutaneous disease.

Compared to unaffected children, pediatric patients with psoriasis have greater prevalence of metabolic and cardiovascular risk factors during childhood, including central obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, atherosclerosis, arrythmia, and valvular heart disease. Family history of obesity increases the risk for early-onset development of cutaneous lesions,^5,6 and weight reduction may alleviate severity of psoriasis lesions.⁷ In the United States, many of the metabolic associations observed are particularly robust in Black and Hispanic children vs those of other races. Furthermore, the prevalence of inflammatory bowel disease is 3- to 4-times higher in children with psoriasis compared to those without.

As with other cutaneous diseases, it is important to be aware of social and mental health concerns in children with psoriasis. The majority of pediatric patients with psoriasis experience name-calling, shaming, or bullying, and many have concerns from skin shedding and malodor. Independent risk for depression after the onset of psoriasis is high. Affected older children and adolescents are at increased risk for alcohol and drug abuse as well as eating disorders.

Despite these identified comorbidities, there are no unique screening recommendations for arthritis, ophthalmologic disease, metabolic disease, cardiovascular disease, gastrointestinal tract disease, or mental health issues in children with psoriasis. Rather, these patients should be monitored according to the American Academy of Pediatrics or American Diabetes Association guidelines for all pediatric patients.^8,9 Nonetheless, educating patients and guardians about these potential issues may be warranted.

Topical Therapies

For children with mild to moderate psoriasis, topical therapies are first line. Despite being off label, topical corticosteroids are the mainstay of therapy for localized psoriatic plaques in children. Topical vitamin D analogues—calcitriol and calcipotriol/calcipotriene—are highly effective and well tolerated, and they frequently are used in combination with topical corticosteroids. Topical calcineurin inhibitors, namely tacrolimus, also are used off label but are considered first line for sensitive regions of the skin in children, including the face, genitalia, and body folds. There currently is limited evidence for supporting the use of the topical vitamin A analogue tazarotene in children with psoriasis, though some consider its off-label use effective for pediatric nail psoriasis. It also may be used as an adjunct to topical corticosteroids to minimize irritation.

Although there is no gold standard topical regimen, combination therapy with a high-potency topical steroid and topical vitamin D analogue commonly is used to minimize steroid-induced side effects. For the first 2 weeks of treatment, they each may be applied once daily or mixed together and applied twice daily. For subsequent maintenance, topical calcipotriene may be applied on weekdays and topical steroids only on weekends. Combination calcipotriol–betamethasone dipropionate also is available as cream, ointment, foam, and suspension vehicles for use on the body and scalp in children aged 12 years and older. Tacrolimus ointment 0.1% may be applied in a thin layer up to twice daily. Concurrent emollient use also is recommended with these therapies.

Health care providers should educate patients and guardians about the potential side effects of topical therapies. They also should provide explicit instructions for amount, site, frequency, and duration of application. Topical corticosteroids commonly result in burning on application and may potentially cause skin thinning and striae with overuse. Topical vitamin D analogues may result in local irritation that may be improved by concurrent emollient use, and they generally should be avoided on sensitive sites. Topical calcineurin inhibitors are associated with burning, stinging, and pruritus, and the US Food and Drug Administration has issued a black-box warning related to risk for lymphoma with their chronic intermittent use. However, it was based on rare reports of lymphoma in transplant patients taking oral calcineurin inhibitors; no clinical trials to date in humans have demonstrated an increased risk for malignancy with topical calcineurin inhibitors.¹⁰ Tazarotene should be used cautiously in females of childbearing age given its teratogenic potential.

Children younger than 7 years are especially prone to suppression of the hypothalamic-pituitary-adrenal axis from topical corticosteroid therapy and theoretically hypercalcemia and hypervitaminosis D from topical vitamin D analogues, as their high BSA-to-volume ratio increases potential for systemic absorption. Children should avoid occlusive application of topical vitamin D analogues to large areas of the skin. Monitoring of vitamin D metabolites in the serum may be considered if calcipotriene or calcipotriol application to a large BSA is warranted.

Light-Based Therapy

In children with widespread psoriasis or those refractory to topical therapy, phototherapy may be considered. Narrowband UVB (311- to 313-nm wavelength) therapy is considered a first-line form of phototherapy in pediatric psoriasis. Mineral oil or emollient pretreatment to affected areas may augment the efficacy of UV-based treatments.¹¹ Excimer laser and UVA also may be efficacious, though evidence is limited in children. Treatment is recommended to start at 3 days a week, and once improvement is seen, the frequency can be decreased to 2 days a week. Once desired clearance is achieved, maintenance therapy can be continued at even longer intervals. Adjunctive use of tar preparations may potentiate the efficacy of phototherapy, though there is a theoretical increased risk for carcinogenicity with prolonged use of coal tar. Side effects of phototherapy include erythema, blistering hyperpigmentation, and pruritus. Psoralen is contraindicated in children younger than 12 years. All forms of phototherapy are contraindicated in children with generalized erythroderma and cutaneous cancer syndromes. Other important pediatric-specific considerations include anxiety that may be provoked by UV light machines and inconvenience of frequent appointments.

Nonbiologic Systemic Therapies

Systemic therapies may be considered in children with recalcitrant, widespread, or rapidly progressing psoriasis, particularly if the disease is accompanied by severe emotional and psychological burden. These drugs, which include methotrexate, cyclosporine, and acitretin (see eTable for recommended dosing), are advantageous in that they may be combined with other therapies; however, they have potential for dangerous toxicities.

Methotrexate is the most frequently utilized systemic therapy for psoriasis worldwide in children because of its low cost, once-weekly dosing, and the substantial amount of long-term efficacy and safety data available in the pediatric population. It is slow acting initially but has excellent long-term efficacy for nearly every subtype of psoriasis. The most common side effect of methotrexate is gastrointestinal tract intolerance. Nonetheless, adverse events are rare in children without prior history, with 1 large study (N=289) reporting no adverse events in more than 90% of patients aged 9 to 14 years treated with methotrexate.¹² Current guidelines recommend monitoring for bone marrow suppression and elevated transaminase levels 4 to 6 days after initiating treatment.¹ The absolute contraindications for methotrexate are pregnancy and liver disease, and caution should be taken in children with metabolic risk factors. Adolescents must be counseled regarding the elevated risk for hepatotoxicity associated with alcohol ingestion. Methotrexate therapy also requires 1 mg folic acid supplementation 6 to 7 days a week, which decreases the risk for developing folic acid deficiency and may decrease gastrointestinal tract intolerance and hepatic side effects that may result from therapy.

Cyclosporine is an effective and well-tolerated option for rapid control of severe psoriasis in children. It is useful for various types of psoriasis but generally is reserved for more severe subtypes, such as generalized pustular psoriasis, erythrodermic psoriasis, and uncontrolled plaque psoriasis. Long-term use of cyclosporine may result in renal toxicity and hypertension, and this therapy is absolutely contraindicated in children with kidney disease or hypertension at baseline. It is strongly recommended to evaluate blood pressure every week for the first month of therapy and at every subsequent follow-up visit, which may occur at variable intervals based on the judgement of the provider. Evaluation before and during treatment with cyclosporine also should include a complete blood cell count, complete metabolic panel, and lipid panel.

Systemic retinoids have a unique advantage over methotrexate and cyclosporine in that they are not immunosuppressive and therefore are not contraindicated in children who are very young or immunosuppressed. Children receiving systemic retinoids also can receive routine live vaccines—measles-mumps-rubella, varicella zoster, and rotavirus—that are contraindicated with other systemic therapies. Acitretin is particularly effective in pediatric patients with diffuse guttate psoriasis, pustular psoriasis, and palmoplantar psoriasis. Narrowband UVB therapy has been shown to augment the effectiveness of acitretin in children, which may allow for reduced acitretin dosing. Pustular psoriasis may respond as quickly as 3 weeks after initiation, whereas it may take 2 to 3 months before improvement is noticed in plaque psoriasis. Side effects of retinoids include skin dryness, hyperlipidemia, and gastrointestinal tract upset. The most severe long-term concern is skeletal toxicity, including premature epiphyseal closure, hyperostosis, periosteal bone formation, and decreased bone mineral density.¹ Vitamin A derivatives also are known teratogens and should be avoided in females of childbearing potential. Lipids and transaminases should be monitored routinely, and screening for depression and psychiatric symptoms should be performed frequently.¹

When utilizing systemic therapies, the objective should be to control the disease, maintain stability, and ultimately taper to the lowest effective dose or transition to a topical therapy, if feasible. Although no particular systemic therapy is recommended as first line for children with psoriasis, it is important to consider comorbidities, contraindications, monitoring frequency, mode of administration (injectable therapies elicit more psychological trauma in children than oral therapies), and expense when determining the best choice.

Biologics

Biologic agents are associated with very high to total psoriatic plaque clearance rates and require infrequent dosing and monitoring. However, their use may be limited by cost and injection phobias in children as well as limited evidence for their efficacy and safety in pediatric psoriasis. Several studies have established the safety and effectiveness of biologics in children with plaque psoriasis (see eTable for recommended dosing), whereas the evidence supporting their use in treating pustular and erythrodermic variants are limited to case reports and case series. The tumor necrosis factor α (TNF-α) inhibitor etanercept has been approved for use in children aged 4 years and older, and the IL-12/IL-23 inhibitor ustekinumab is approved in children aged 6 years and older. Other TNF-α inhibitors, namely infliximab and adalimumab, commonly are utilized off label for pediatric psoriasis. The most common side effect of biologic therapies in pediatric patients is injection-site reactions.¹ Prior to initiating therapy, children must undergo tuberculosis screening either by purified protein derivative testing or IFN-γ release assay. Testing should be repeated annually in individuals taking TNF-α inhibitors, though the utility of repeat testing when taking biologics in other classes is not clear. High-risk patients also should be screened for human immunodeficiency virus and hepatitis. Follow-up frequency may range from every 3 months to annually, based on judgement of the provider. In children who develop loss of response to biologics, methotrexate can be added to the regimen to attenuate formation of efficacy-reducing antidrug antibodies.

Final Thoughts

When managing children with psoriasis, it is important for dermatologists to appropriately educate guardians and children on the disease course, as well as consider the psychological, emotional, social, and financial factors that may direct decision-making regarding optimal therapeutics. Dermatologists should consider collaboration with the child’s primary care physician and other specialists to ensure that all needs are met.

These guidelines provide a framework agreed upon by numerous experts in pediatric psoriasis, but they are limited by gaps in the research. There still is much to be learned regarding the pathophysiology of psoriasis; the risk for developing comorbidities during adulthood; and the efficacy and safety of certain therapeutics, particularly biologics, in pediatric patients with psoriasis.

In November 2019, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released their first set of recommendations for the management of pediatric psoriasis.¹ The pediatric guidelines discuss methods of quantifying disease severity in children, triggers and comorbidities, and the efficacy and safety of various therapeutic agents. This review aims to discuss, in a condensed form, special considerations unique to the management of children with psoriasis as presented in the guidelines as well as grade A– and grade B–level treatment recommendations (Table).

Quantifying Psoriasis Severity in Children

Percentage body surface area (BSA) involvement is the most common mode of grading psoriasis severity, with less than 3% BSA involvement being considered mild, 3% to 10% BSA moderate, and more than 10% severe disease. In children, the standard method of measuring BSA is the rule of 9’s: the head and each arm make up 9% of the total BSA, each leg and the front and back of the torso respectively each make up 18%, and the genitalia make up 1%. It also is important to consider impact on quality of life, which may be remarkable in spite of limited BSA involvement. The children’s dermatology life quality index score may be utilized in combination with affected BSA to determine the burden of psoriasis in context of impact on daily life. This metric is available in both written and cartoon form, and it consists of 10 questions that include variables such as severity of itch, impact on social life, and effects on sleep. Most notably, this tool incorporates pruritus,² which generally is addressed inadequately in pediatric psoriasis.

Triggers and Comorbidities in Pediatric Patients

In children, it is important to identify and eliminate modifiable factors that may prompt psoriasis flares. Infections, particularly group A beta-hemolytic streptococcal infections, are a major trigger in neonates and infants. Other exacerbating factors in children include emotional stress, secondhand cigarette smoke, Kawasaki disease, and withdrawal from systemic corticosteroids.

Psoriatic arthritis (PsA) is a burdensome comorbidity affecting children with psoriasis. The prevalence of joint disease is 15-times greater in children with psoriasis vs those without,³ and 80% of children with PsA develop rheumatologic symptoms, which typically include oligoarticular disease and dactylitis in infants and girls and enthesitis and axial joint involvement in boys and older children, years prior to the onset of cutaneous disease.⁴ Uveitis often occurs in children with psoriasis and PsA but not in those with isolated cutaneous disease.

Compared to unaffected children, pediatric patients with psoriasis have greater prevalence of metabolic and cardiovascular risk factors during childhood, including central obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, atherosclerosis, arrythmia, and valvular heart disease. Family history of obesity increases the risk for early-onset development of cutaneous lesions,^5,6 and weight reduction may alleviate severity of psoriasis lesions.⁷ In the United States, many of the metabolic associations observed are particularly robust in Black and Hispanic children vs those of other races. Furthermore, the prevalence of inflammatory bowel disease is 3- to 4-times higher in children with psoriasis compared to those without.

As with other cutaneous diseases, it is important to be aware of social and mental health concerns in children with psoriasis. The majority of pediatric patients with psoriasis experience name-calling, shaming, or bullying, and many have concerns from skin shedding and malodor. Independent risk for depression after the onset of psoriasis is high. Affected older children and adolescents are at increased risk for alcohol and drug abuse as well as eating disorders.

Despite these identified comorbidities, there are no unique screening recommendations for arthritis, ophthalmologic disease, metabolic disease, cardiovascular disease, gastrointestinal tract disease, or mental health issues in children with psoriasis. Rather, these patients should be monitored according to the American Academy of Pediatrics or American Diabetes Association guidelines for all pediatric patients.^8,9 Nonetheless, educating patients and guardians about these potential issues may be warranted.

Topical Therapies

For children with mild to moderate psoriasis, topical therapies are first line. Despite being off label, topical corticosteroids are the mainstay of therapy for localized psoriatic plaques in children. Topical vitamin D analogues—calcitriol and calcipotriol/calcipotriene—are highly effective and well tolerated, and they frequently are used in combination with topical corticosteroids. Topical calcineurin inhibitors, namely tacrolimus, also are used off label but are considered first line for sensitive regions of the skin in children, including the face, genitalia, and body folds. There currently is limited evidence for supporting the use of the topical vitamin A analogue tazarotene in children with psoriasis, though some consider its off-label use effective for pediatric nail psoriasis. It also may be used as an adjunct to topical corticosteroids to minimize irritation.

Although there is no gold standard topical regimen, combination therapy with a high-potency topical steroid and topical vitamin D analogue commonly is used to minimize steroid-induced side effects. For the first 2 weeks of treatment, they each may be applied once daily or mixed together and applied twice daily. For subsequent maintenance, topical calcipotriene may be applied on weekdays and topical steroids only on weekends. Combination calcipotriol–betamethasone dipropionate also is available as cream, ointment, foam, and suspension vehicles for use on the body and scalp in children aged 12 years and older. Tacrolimus ointment 0.1% may be applied in a thin layer up to twice daily. Concurrent emollient use also is recommended with these therapies.

Health care providers should educate patients and guardians about the potential side effects of topical therapies. They also should provide explicit instructions for amount, site, frequency, and duration of application. Topical corticosteroids commonly result in burning on application and may potentially cause skin thinning and striae with overuse. Topical vitamin D analogues may result in local irritation that may be improved by concurrent emollient use, and they generally should be avoided on sensitive sites. Topical calcineurin inhibitors are associated with burning, stinging, and pruritus, and the US Food and Drug Administration has issued a black-box warning related to risk for lymphoma with their chronic intermittent use. However, it was based on rare reports of lymphoma in transplant patients taking oral calcineurin inhibitors; no clinical trials to date in humans have demonstrated an increased risk for malignancy with topical calcineurin inhibitors.¹⁰ Tazarotene should be used cautiously in females of childbearing age given its teratogenic potential.

Children younger than 7 years are especially prone to suppression of the hypothalamic-pituitary-adrenal axis from topical corticosteroid therapy and theoretically hypercalcemia and hypervitaminosis D from topical vitamin D analogues, as their high BSA-to-volume ratio increases potential for systemic absorption. Children should avoid occlusive application of topical vitamin D analogues to large areas of the skin. Monitoring of vitamin D metabolites in the serum may be considered if calcipotriene or calcipotriol application to a large BSA is warranted.

Light-Based Therapy

In children with widespread psoriasis or those refractory to topical therapy, phototherapy may be considered. Narrowband UVB (311- to 313-nm wavelength) therapy is considered a first-line form of phototherapy in pediatric psoriasis. Mineral oil or emollient pretreatment to affected areas may augment the efficacy of UV-based treatments.¹¹ Excimer laser and UVA also may be efficacious, though evidence is limited in children. Treatment is recommended to start at 3 days a week, and once improvement is seen, the frequency can be decreased to 2 days a week. Once desired clearance is achieved, maintenance therapy can be continued at even longer intervals. Adjunctive use of tar preparations may potentiate the efficacy of phototherapy, though there is a theoretical increased risk for carcinogenicity with prolonged use of coal tar. Side effects of phototherapy include erythema, blistering hyperpigmentation, and pruritus. Psoralen is contraindicated in children younger than 12 years. All forms of phototherapy are contraindicated in children with generalized erythroderma and cutaneous cancer syndromes. Other important pediatric-specific considerations include anxiety that may be provoked by UV light machines and inconvenience of frequent appointments.

Nonbiologic Systemic Therapies

Systemic therapies may be considered in children with recalcitrant, widespread, or rapidly progressing psoriasis, particularly if the disease is accompanied by severe emotional and psychological burden. These drugs, which include methotrexate, cyclosporine, and acitretin (see eTable for recommended dosing), are advantageous in that they may be combined with other therapies; however, they have potential for dangerous toxicities.

Methotrexate is the most frequently utilized systemic therapy for psoriasis worldwide in children because of its low cost, once-weekly dosing, and the substantial amount of long-term efficacy and safety data available in the pediatric population. It is slow acting initially but has excellent long-term efficacy for nearly every subtype of psoriasis. The most common side effect of methotrexate is gastrointestinal tract intolerance. Nonetheless, adverse events are rare in children without prior history, with 1 large study (N=289) reporting no adverse events in more than 90% of patients aged 9 to 14 years treated with methotrexate.¹² Current guidelines recommend monitoring for bone marrow suppression and elevated transaminase levels 4 to 6 days after initiating treatment.¹ The absolute contraindications for methotrexate are pregnancy and liver disease, and caution should be taken in children with metabolic risk factors. Adolescents must be counseled regarding the elevated risk for hepatotoxicity associated with alcohol ingestion. Methotrexate therapy also requires 1 mg folic acid supplementation 6 to 7 days a week, which decreases the risk for developing folic acid deficiency and may decrease gastrointestinal tract intolerance and hepatic side effects that may result from therapy.

Cyclosporine is an effective and well-tolerated option for rapid control of severe psoriasis in children. It is useful for various types of psoriasis but generally is reserved for more severe subtypes, such as generalized pustular psoriasis, erythrodermic psoriasis, and uncontrolled plaque psoriasis. Long-term use of cyclosporine may result in renal toxicity and hypertension, and this therapy is absolutely contraindicated in children with kidney disease or hypertension at baseline. It is strongly recommended to evaluate blood pressure every week for the first month of therapy and at every subsequent follow-up visit, which may occur at variable intervals based on the judgement of the provider. Evaluation before and during treatment with cyclosporine also should include a complete blood cell count, complete metabolic panel, and lipid panel.

Systemic retinoids have a unique advantage over methotrexate and cyclosporine in that they are not immunosuppressive and therefore are not contraindicated in children who are very young or immunosuppressed. Children receiving systemic retinoids also can receive routine live vaccines—measles-mumps-rubella, varicella zoster, and rotavirus—that are contraindicated with other systemic therapies. Acitretin is particularly effective in pediatric patients with diffuse guttate psoriasis, pustular psoriasis, and palmoplantar psoriasis. Narrowband UVB therapy has been shown to augment the effectiveness of acitretin in children, which may allow for reduced acitretin dosing. Pustular psoriasis may respond as quickly as 3 weeks after initiation, whereas it may take 2 to 3 months before improvement is noticed in plaque psoriasis. Side effects of retinoids include skin dryness, hyperlipidemia, and gastrointestinal tract upset. The most severe long-term concern is skeletal toxicity, including premature epiphyseal closure, hyperostosis, periosteal bone formation, and decreased bone mineral density.¹ Vitamin A derivatives also are known teratogens and should be avoided in females of childbearing potential. Lipids and transaminases should be monitored routinely, and screening for depression and psychiatric symptoms should be performed frequently.¹

When utilizing systemic therapies, the objective should be to control the disease, maintain stability, and ultimately taper to the lowest effective dose or transition to a topical therapy, if feasible. Although no particular systemic therapy is recommended as first line for children with psoriasis, it is important to consider comorbidities, contraindications, monitoring frequency, mode of administration (injectable therapies elicit more psychological trauma in children than oral therapies), and expense when determining the best choice.

Biologics

Biologic agents are associated with very high to total psoriatic plaque clearance rates and require infrequent dosing and monitoring. However, their use may be limited by cost and injection phobias in children as well as limited evidence for their efficacy and safety in pediatric psoriasis. Several studies have established the safety and effectiveness of biologics in children with plaque psoriasis (see eTable for recommended dosing), whereas the evidence supporting their use in treating pustular and erythrodermic variants are limited to case reports and case series. The tumor necrosis factor α (TNF-α) inhibitor etanercept has been approved for use in children aged 4 years and older, and the IL-12/IL-23 inhibitor ustekinumab is approved in children aged 6 years and older. Other TNF-α inhibitors, namely infliximab and adalimumab, commonly are utilized off label for pediatric psoriasis. The most common side effect of biologic therapies in pediatric patients is injection-site reactions.¹ Prior to initiating therapy, children must undergo tuberculosis screening either by purified protein derivative testing or IFN-γ release assay. Testing should be repeated annually in individuals taking TNF-α inhibitors, though the utility of repeat testing when taking biologics in other classes is not clear. High-risk patients also should be screened for human immunodeficiency virus and hepatitis. Follow-up frequency may range from every 3 months to annually, based on judgement of the provider. In children who develop loss of response to biologics, methotrexate can be added to the regimen to attenuate formation of efficacy-reducing antidrug antibodies.

Final Thoughts

When managing children with psoriasis, it is important for dermatologists to appropriately educate guardians and children on the disease course, as well as consider the psychological, emotional, social, and financial factors that may direct decision-making regarding optimal therapeutics. Dermatologists should consider collaboration with the child’s primary care physician and other specialists to ensure that all needs are met.

These guidelines provide a framework agreed upon by numerous experts in pediatric psoriasis, but they are limited by gaps in the research. There still is much to be learned regarding the pathophysiology of psoriasis; the risk for developing comorbidities during adulthood; and the efficacy and safety of certain therapeutics, particularly biologics, in pediatric patients with psoriasis.

On December 31, 2019, cases of a severe pneumonia in patients in Wuhan, Hubei Province, China, were reported to the World Health Organization.^1,2 The novel coronavirus—severe acute respiratory syndrome coronavirus 2—was identified, and the coronavirus disease 2019 (COVID-19) became a public health emergency of international concern.¹ In March 2020, the World Health Organization officially characterized COVID-19 as a pandemic.³ As of October 2020, more than 42.3 million cases and 1.1 million deaths from COVID-19 have been confirmed worldwide.⁴

As more understanding of severe acute respiratory syndrome coronavirus 2 develops, various cutaneous manifestations of COVID-19 are being uncovered.⁵ The most common cutaneous manifestations of COVID-19 reported in the literature are maculopapular or morbilliform exanthem (36.1% of cutaneous manifestations), papulovesicular rash (34.7%), painful acral red purple papules (15.3%), urticaria (9.7%), livedo reticularis lesions (2.8%), and petechiae (1.4%).⁵

Interestingly, a series of unique cases was identified in April 2020 by a group of dermatologists in Spain. Most patients were children (median age, 13 years) or young adults (median age, 31 years; average age, 36 years; adult age range, 18–91 years).¹ Reporting on a representative sample of 6 patients in that series, the group noted that lesions, initially reddish, papular, and resembling chilblains (pernio), progressively became purpuric and flattened in the course of 1 week. Although the lesions presented with some referred discomfort or pain with palpation, they were not highly symptomatic, and no signs of ischemia or Raynaud syndrome were identified. Over time, lesions self-resolved without intervention. Most patients also did not present with what are considered classic COVID-19 signs or symptoms. Only the oldest patient (aged 91 years) presented with a notable respiratory condition; the remaining patients generally were in good health.¹ Dermatologists in Italy, France, and the United States also have witnessed these COVID-19–associated cutaneous manifestations.

Scientific understanding of COVID-19 and its associated dermatologic symptoms is evolving. Attention has turned to social media to inform and provide possible health solutions during this unprecedented medical crisis.⁶ Strict physical distancing measures have made patients and providers alike reliant on global digital social networks, such as Instagram, Twitter, and Facebook, to facilitate information sharing about COVID-19.⁷ The abundance of nonexpert advice and misinformation on social media makes communication of unbiased expert information difficult.^8,9 Furthermore, there is a need for dermatologists to provide medical information to patients regarding COVID-19, such as dermatologic manifestations, and clear guidance on immunobiologic or systemic medications during this unprecedented time.⁹

In recent years, dermatologists have established a growing presence on social media, with many recognized as social media influencers with the ability to affect patients’ health-related behavior.¹⁰ Social media frequently has been used by patients to solicit advice regarding skin concerns.^9,10 Many individuals, in fact, never see a physician after consulting social media for medical concerns or professional advice.⁹

In addition, as of March 2020, more than 61% of health care workers were found to use social media as a source of COVID-19–related information.¹¹ Therefore, dermatologists should utilize social media as a platform to share evidence-based information with the public and other health care workers.

Through social media, dermatologists can post high-quality images with clear descriptions to fully characterize skin manifestations in patients with COVID-19. The process of capturing and posting images to the virtual world using a smartphone allows practitioners to gain advice from peers and consultants, share findings with colleagues, and inform the public.¹² Social media posts of many deidentified clinical images of rashes in COVID-19–infected patients already have enabled rapid recognition of skin signs by dermatologists.¹³

Social media sites also are resources where organizations can post updated, evidence-based findings from academic journals. For example, the American Academy of Dermatology and its official journal, the Journal of the American Academy of Dermatology, had more than 22,000 and 27,000 Instagram followers, respectively, as of a March 2020 analysis.¹⁴ Recent online forums and social media posts contain accessible, graphical, patient-friendly images and information on evidence-based treatments for skin disease during the COVID-19 pandemic.¹³

We should consider initiatives that empower dermatologists to use social media to post unbiased, evidence-based information regarding manifestations of COVID-19 and guidelines for treatment of skin disease during this medical crisis. We hope that dermatologists will help lead the global response to the COVID-19 pandemic and contribute to the evolving knowledge base by characterizing COVID-19–related rashes, understanding their implications, and determining the best evidence for treatment.

On December 31, 2019, cases of a severe pneumonia in patients in Wuhan, Hubei Province, China, were reported to the World Health Organization.^1,2 The novel coronavirus—severe acute respiratory syndrome coronavirus 2—was identified, and the coronavirus disease 2019 (COVID-19) became a public health emergency of international concern.¹ In March 2020, the World Health Organization officially characterized COVID-19 as a pandemic.³ As of October 2020, more than 42.3 million cases and 1.1 million deaths from COVID-19 have been confirmed worldwide.⁴

As more understanding of severe acute respiratory syndrome coronavirus 2 develops, various cutaneous manifestations of COVID-19 are being uncovered.⁵ The most common cutaneous manifestations of COVID-19 reported in the literature are maculopapular or morbilliform exanthem (36.1% of cutaneous manifestations), papulovesicular rash (34.7%), painful acral red purple papules (15.3%), urticaria (9.7%), livedo reticularis lesions (2.8%), and petechiae (1.4%).⁵

Interestingly, a series of unique cases was identified in April 2020 by a group of dermatologists in Spain. Most patients were children (median age, 13 years) or young adults (median age, 31 years; average age, 36 years; adult age range, 18–91 years).¹ Reporting on a representative sample of 6 patients in that series, the group noted that lesions, initially reddish, papular, and resembling chilblains (pernio), progressively became purpuric and flattened in the course of 1 week. Although the lesions presented with some referred discomfort or pain with palpation, they were not highly symptomatic, and no signs of ischemia or Raynaud syndrome were identified. Over time, lesions self-resolved without intervention. Most patients also did not present with what are considered classic COVID-19 signs or symptoms. Only the oldest patient (aged 91 years) presented with a notable respiratory condition; the remaining patients generally were in good health.¹ Dermatologists in Italy, France, and the United States also have witnessed these COVID-19–associated cutaneous manifestations.

Scientific understanding of COVID-19 and its associated dermatologic symptoms is evolving. Attention has turned to social media to inform and provide possible health solutions during this unprecedented medical crisis.⁶ Strict physical distancing measures have made patients and providers alike reliant on global digital social networks, such as Instagram, Twitter, and Facebook, to facilitate information sharing about COVID-19.⁷ The abundance of nonexpert advice and misinformation on social media makes communication of unbiased expert information difficult.^8,9 Furthermore, there is a need for dermatologists to provide medical information to patients regarding COVID-19, such as dermatologic manifestations, and clear guidance on immunobiologic or systemic medications during this unprecedented time.⁹

In recent years, dermatologists have established a growing presence on social media, with many recognized as social media influencers with the ability to affect patients’ health-related behavior.¹⁰ Social media frequently has been used by patients to solicit advice regarding skin concerns.^9,10 Many individuals, in fact, never see a physician after consulting social media for medical concerns or professional advice.⁹

In addition, as of March 2020, more than 61% of health care workers were found to use social media as a source of COVID-19–related information.¹¹ Therefore, dermatologists should utilize social media as a platform to share evidence-based information with the public and other health care workers.

Through social media, dermatologists can post high-quality images with clear descriptions to fully characterize skin manifestations in patients with COVID-19. The process of capturing and posting images to the virtual world using a smartphone allows practitioners to gain advice from peers and consultants, share findings with colleagues, and inform the public.¹² Social media posts of many deidentified clinical images of rashes in COVID-19–infected patients already have enabled rapid recognition of skin signs by dermatologists.¹³

Social media sites also are resources where organizations can post updated, evidence-based findings from academic journals. For example, the American Academy of Dermatology and its official journal, the Journal of the American Academy of Dermatology, had more than 22,000 and 27,000 Instagram followers, respectively, as of a March 2020 analysis.¹⁴ Recent online forums and social media posts contain accessible, graphical, patient-friendly images and information on evidence-based treatments for skin disease during the COVID-19 pandemic.¹³

We should consider initiatives that empower dermatologists to use social media to post unbiased, evidence-based information regarding manifestations of COVID-19 and guidelines for treatment of skin disease during this medical crisis. We hope that dermatologists will help lead the global response to the COVID-19 pandemic and contribute to the evolving knowledge base by characterizing COVID-19–related rashes, understanding their implications, and determining the best evidence for treatment.

On December 31, 2019, cases of a severe pneumonia in patients in Wuhan, Hubei Province, China, were reported to the World Health Organization.^1,2 The novel coronavirus—severe acute respiratory syndrome coronavirus 2—was identified, and the coronavirus disease 2019 (COVID-19) became a public health emergency of international concern.¹ In March 2020, the World Health Organization officially characterized COVID-19 as a pandemic.³ As of October 2020, more than 42.3 million cases and 1.1 million deaths from COVID-19 have been confirmed worldwide.⁴

As more understanding of severe acute respiratory syndrome coronavirus 2 develops, various cutaneous manifestations of COVID-19 are being uncovered.⁵ The most common cutaneous manifestations of COVID-19 reported in the literature are maculopapular or morbilliform exanthem (36.1% of cutaneous manifestations), papulovesicular rash (34.7%), painful acral red purple papules (15.3%), urticaria (9.7%), livedo reticularis lesions (2.8%), and petechiae (1.4%).⁵

Interestingly, a series of unique cases was identified in April 2020 by a group of dermatologists in Spain. Most patients were children (median age, 13 years) or young adults (median age, 31 years; average age, 36 years; adult age range, 18–91 years).¹ Reporting on a representative sample of 6 patients in that series, the group noted that lesions, initially reddish, papular, and resembling chilblains (pernio), progressively became purpuric and flattened in the course of 1 week. Although the lesions presented with some referred discomfort or pain with palpation, they were not highly symptomatic, and no signs of ischemia or Raynaud syndrome were identified. Over time, lesions self-resolved without intervention. Most patients also did not present with what are considered classic COVID-19 signs or symptoms. Only the oldest patient (aged 91 years) presented with a notable respiratory condition; the remaining patients generally were in good health.¹ Dermatologists in Italy, France, and the United States also have witnessed these COVID-19–associated cutaneous manifestations.

Scientific understanding of COVID-19 and its associated dermatologic symptoms is evolving. Attention has turned to social media to inform and provide possible health solutions during this unprecedented medical crisis.⁶ Strict physical distancing measures have made patients and providers alike reliant on global digital social networks, such as Instagram, Twitter, and Facebook, to facilitate information sharing about COVID-19.⁷ The abundance of nonexpert advice and misinformation on social media makes communication of unbiased expert information difficult.^8,9 Furthermore, there is a need for dermatologists to provide medical information to patients regarding COVID-19, such as dermatologic manifestations, and clear guidance on immunobiologic or systemic medications during this unprecedented time.⁹

In recent years, dermatologists have established a growing presence on social media, with many recognized as social media influencers with the ability to affect patients’ health-related behavior.¹⁰ Social media frequently has been used by patients to solicit advice regarding skin concerns.^9,10 Many individuals, in fact, never see a physician after consulting social media for medical concerns or professional advice.⁹

In addition, as of March 2020, more than 61% of health care workers were found to use social media as a source of COVID-19–related information.¹¹ Therefore, dermatologists should utilize social media as a platform to share evidence-based information with the public and other health care workers.

Through social media, dermatologists can post high-quality images with clear descriptions to fully characterize skin manifestations in patients with COVID-19. The process of capturing and posting images to the virtual world using a smartphone allows practitioners to gain advice from peers and consultants, share findings with colleagues, and inform the public.¹² Social media posts of many deidentified clinical images of rashes in COVID-19–infected patients already have enabled rapid recognition of skin signs by dermatologists.¹³

Social media sites also are resources where organizations can post updated, evidence-based findings from academic journals. For example, the American Academy of Dermatology and its official journal, the Journal of the American Academy of Dermatology, had more than 22,000 and 27,000 Instagram followers, respectively, as of a March 2020 analysis.¹⁴ Recent online forums and social media posts contain accessible, graphical, patient-friendly images and information on evidence-based treatments for skin disease during the COVID-19 pandemic.¹³

We should consider initiatives that empower dermatologists to use social media to post unbiased, evidence-based information regarding manifestations of COVID-19 and guidelines for treatment of skin disease during this medical crisis. We hope that dermatologists will help lead the global response to the COVID-19 pandemic and contribute to the evolving knowledge base by characterizing COVID-19–related rashes, understanding their implications, and determining the best evidence for treatment.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

The advent of biologic therapy over the last 2 decades has transformed the treatment of psoriasis; patients who either are not good candidates for or have an inadequate response to traditional treatments (topicals and/or phototherapy) now have numerous options for treatment.¹ Patients burdened by extensive disease, recurrent flares, and stubborn treatment areas are ideal candidates for biologics. There are 11 biologics approved by the US Food and Drug Administration (FDA)(Table) for treating moderate to severe plaque psoriasis as supported by grade A evidence. The FDA has authorized 1 new biologic—risankizumab—since the joint guidelines from the American Academy of Dermatology and National Psoriasis Foundation were released for the treatment of psoriasis with biologics.² This article aims to address updates on recent clinical trial findings (April 2019 to April 2020) regarding biologic therapy initiation and maintenance for adult patients. Prescribers should use this update as guidance for determining the appropriate biologic class based on patient characteristics and for approaching biologic-experienced patients with refractory psoriasis. This update also may serve as a reference for the recommended dosing regimens of the 11 approved biologics.

Using Risankizumab

Risankizumab is a new biologic that selectively targets the IL-23 pathway by binding the p19 subunit of IL-23. It was approved by the FDA in April 2019. Two recent studies have demonstrated the efficacy of risankizumab in disease management.^3,4

IMMvent was a double-blind, 2-part, phase 3, randomized controlled trial (RCT) of participants 18 years and older (N=605) with moderate to severe psoriasis (with or without psoriatic arthritis) across 11 countries.³ Inclusion criteria consisted of psoriasis involving at least 10% of the body surface area (BSA), absolute psoriasis area and severity index (PASI) score of 12 or higher, and static physician global assessment (sPGA) score of 3 or higher. Prior biologic treatment did not preclude study entry (excluding risankizumab or adalimumab), and nearly 40% of participants previously had been on a different biologic. Notably, this trial allowed for inclusion of patients with prior malignancy (>5 years prior) and patients who tested positive for exposure to tuberculosis (TB) but were not shown to have active TB (provided appropriate treatment for latent TB was started). Study participants identified as white (81%), Asian (14%), black/African American (4%), or other ethnicity (1%). Part A involved administration of 150 mg risankizumab (n=301) at weeks 0 and 4 or 80 mg adalimumab (n=304) loading dose at week 0 followed by 40 mg at week 1 and 40 mg every other week thereafter until the end of week 15. At week 16 there was a significant difference in proportion of participants achieving 90% or more improvement (PASI-90) with risankizumab (72%) vs adalimumab (47%)(P<.0001) and achieving an sPGA score of 0 or 1 (clear or almost clear) with risankizumab (84%) vs adalimumab (60%)(P<.0001). In part B (weeks 16–44), adalimumab immediate responder (PASI ≥50 to PASI <90) participants were re-randomized to continue adalimumab 40 mg every other week (starting from week 17 and stopping at week 44) or switch to 150 mg risankizumab administered at weeks 16, 20, and 32. Patients taking risankizumab in part A continued the drug, administered at weeks 16 and 28. At week 44, there was a significant difference in percentage of participants achieving PASI-90 with risankizumab (66%) vs adalimumab (21%)(P<.0001).³

IMMhance was another double-blind phase 3 RCT with 2 parts that assessed the clinical efficacy of risankizumab compared to placebo in patients 18 years or older (N=507) across 9 countries with the same inclusion criteria for patients as IMMvent.⁴ Part A involved administration of 150 mg risankizumab (n=407) or placebo (n=100) at weeks 0 and 4 using a 4:1 random allocation ratio. At week 16, regardless of initial treatment, all participants received 150 mg risankizumab. Treatment results at week 16 showed a significant difference in percentage of participants achieving PASI-90 with risankizumab (73.2%) vs placebo (2.0%)(P<.001) and sPGA score of 0 or 1 with risankizumab (83.5%) vs placebo (7.0%)(P<.001). Furthermore, in part B (weeks 16–104), at week 28 participants on risankizumab with an sPGA score of 0 or 1 were randomized with a 1:2 allocation ratio to continue 150 mg risankizumab or switch to placebo to produce a treatment withdrawal effect. Part B results showed a significant difference in the proportion of participants achieving an sPGA score of 0 or 1 with risankizumab (87.4%) vs placebo (61.3%)(P<.001) at week 52 and at week 104 with risankizumab (81.1%) vs placebo (7.1%)(P<.001). Risankizumab was well tolerated, with the most common adverse events (AEs) being nasopharyngitis (23.4%), upper respiratory tract infection (15.4%), and headache (6.8%). Serious AEs included cancer (2.6%; 2.2 events per 100 patient-years), hepatic events (4.6%) including hepatic cirrhosis (0.2%), and serious infections (1.8%; 1.4 events per 100 patient-years).⁴

Overall, the strengths of risankizumab with regard to its clinical efficacy and utility in biologic-experienced patients were confirmed in these studies. The inclusion of patients with prior treated malignancy and positive TB tests also was more in line with what one might encounter with real-world practice and, as such, provided valuable data to help aid treatment decisions. These 2 studies provided valuable evidence for the therapeutic benefit and relatively mild safety profile of risankizumab in treatment of moderate to severe psoriasis for patients with and without prior biologic therapy.

Choosing a Biologic

Refractory psoriasis involves nonresponse (primary failure) or return of disease symptoms after initial improvement (secondary failure) with a biologic. Selecting a biologic for patients who have experienced prior biologic failure is difficult. It is still unknown whether it is more efficacious for patients to try a same-class drug or a biologic targeting a different inflammatory pathway or cytokine. Studies have shown mixed results regarding how to manage patients with biologic failure, with both approaches demonstrating positive outcomes.

One analysis of the Corrona Psoriasis Registry included 144 patients, the majority of whom (89.8%) were biologic experienced, who began secukinumab treatment and returned for a 6-month follow-up (5–9 months).⁵ Patients enrolled in the registry were 18 years or older, had been diagnosed with psoriasis by a dermatologist, and initiated or switched an FDA-approved systemic agent or biologic within the last 12 months. Of biologic-experienced participants, 37.7% had used 3 or more biologics. More than half of included participants were either male (55%) or obese (53.4%). Comorbidities included hypertension (43.2%), hyperlipidemia (33.9%), anxiety (20.3%), diabetes mellitus (15.3%), cardiovascular disease (14.4%), and depression (13.6%). After 6 months of treatment, there was significant improvement in the involvement of BSA (mean difference, −12.1), investigator global assessment score (−1.5), dermatology life quality index (DLQI)(−4.8), pain (−23.2), itch (−30.8), fatigue (−8.8), and work productivity (−9.2)(P<.01). Secukinumab therapy displayed notable reduction in symptom severity in this population with difficult-to-treat psoriasis. Its relative success in this cohort provides support for its use in treating patients who have failed other classes of biologics.⁵

Evidence supporting reduction of pruritus and pain with secukinumab also was notable. The CLEAR phase 3 RCT involved participants treated with 300 mg secukinumab every week for the first 4 weeks and then every 4 weeks thereafter for 48 weeks (n=312), up to 100 weeks (n=277).⁶ Participants had complete relief of pain (score 0), itching, and scaling at week 16 (69.4%, 49.7%, and 61.2%, respectively), week 52 (67.1%, 48.9%, and 53.3%, respectively), and week 104 (70.9%, 47.4%, and 54.8%, respectively). Reported AEs included candida infections (7.2%), malignant or unspecified tumors (1.5%), and neutropenia (<1%).⁶

Researchers investigated intraclass switching to brodalumab with prior failure of IL-17 inhibitors. An open-label study involved participants (n=39) with prior failure with secukinumab or ixekizumab therapy.⁷ Participants were administered 210 mg brodalumab with standard dosing at weeks 0, 1, and 2, and then every 2 weeks thereafter. At week 16, 69% of participants achieved PASI-75, 44% achieved PASI-90, 28% achieved PASI-100, and 62% achieved an sPGA score of 0 or 1. The authors attributed the relative success of brodalumab compared to prior anti–IL-17 agents to inhibition of the IL-17 receptor with brodalumab rather than the IL-17A ligand.⁷ Brodalumab may be a useful alternative biologic for patients with nonresponse to and secondary failure with biologics, including the IL-17A inhibitors.

Recent findings support effective skin clearance and improved symptom management with ixekizumab and ustekinumab. Of note, ixekizumab was reported to provide rapid improvement in skin lesions and quality of life to a greater extent than guselkumab.

The IXORA-R double-blinded RCT compared the clinical benefit of participants 18 years and older taking standard approved dosages of ixekizumab (n=520) or guselkumab (n=507).⁸ Patients were included if they had plaque psoriasis for at least 6 months before baseline, an sPGA score of at least 3, PASI score of 12 or higher, 10% or greater BSA, no prior IL-17 inhibitor failure, no use of IL-23 p19 inhibitors, and no use of any biologic within the specified period prior to baseline. At week 12, ixekizumab showed superior clinical improvement measured by the proportion of participants achieving complete skin clearance (ie, PASI-100)(41%) compared to guselkumab (25%)(P<.001). There were more participants taking ixekizumab who reported DLQI of 0 or 1 (no impact of disease on quality of life)(34%) compared to guselkumab (21%)(P<.001) as early on as week 4. The most common AE was upper respiratory tract infection (7%) in both groups. The risk of treatment-emergent AEs (56%), discontinuation because of AEs (2%), and serious AEs (3%) were comparable in both groups. The number of injection-site reactions was higher with ixekizumab (13%) vs guselkumab (3%). The authors concluded that ixekizumab offers the ability to provide rapid relief of symptoms, which is associated with improved DLQI.⁸

Response to ustekinumab therapy was assessed in a patient cohort enrolled in the Corrona Psoriasis Registry. This study involved 178 participants 18 years and older with psoriasis involvement of 3% or greater BSA who were treated with ustekinumab.⁹ By their 6-month follow-up visit, 55.6% of participants achieved adequate treatment response (BSA improving to <3% or 75% from enrollment). Increasing patient age was significantly associated with decreased likelihood of achieving a response (odds ratio, 0.981 [95% confidence interval, 0.962-0.999]; P=.049). Ustekinumab is a practical option for psoriasis treatment that seems to yield better results in younger patients.⁹ This evidence reveals that increased patient age is a characteristic that may contribute to poor treatment response and should be considered when choosing the best fit for biologic therapy.

Final Thoughts

Using evidence-based interventions to treat patients is the cornerstone of ethical and high-quality medical care. This guide sought to provide relevant updates in a variety of both comparator and pivotal trials, with the goal of summarizing clinically relevant information that may be extracted from these trials to guide patient care. It is not an exhaustive review but may be utilized as a reference tool to fine-tune selection criteria in choosing 1 of 11 biologics for the treatment of psoriasis.

The advent of biologic therapy over the last 2 decades has transformed the treatment of psoriasis; patients who either are not good candidates for or have an inadequate response to traditional treatments (topicals and/or phototherapy) now have numerous options for treatment.¹ Patients burdened by extensive disease, recurrent flares, and stubborn treatment areas are ideal candidates for biologics. There are 11 biologics approved by the US Food and Drug Administration (FDA)(Table) for treating moderate to severe plaque psoriasis as supported by grade A evidence. The FDA has authorized 1 new biologic—risankizumab—since the joint guidelines from the American Academy of Dermatology and National Psoriasis Foundation were released for the treatment of psoriasis with biologics.² This article aims to address updates on recent clinical trial findings (April 2019 to April 2020) regarding biologic therapy initiation and maintenance for adult patients. Prescribers should use this update as guidance for determining the appropriate biologic class based on patient characteristics and for approaching biologic-experienced patients with refractory psoriasis. This update also may serve as a reference for the recommended dosing regimens of the 11 approved biologics.

Using Risankizumab

Risankizumab is a new biologic that selectively targets the IL-23 pathway by binding the p19 subunit of IL-23. It was approved by the FDA in April 2019. Two recent studies have demonstrated the efficacy of risankizumab in disease management.^3,4

IMMvent was a double-blind, 2-part, phase 3, randomized controlled trial (RCT) of participants 18 years and older (N=605) with moderate to severe psoriasis (with or without psoriatic arthritis) across 11 countries.³ Inclusion criteria consisted of psoriasis involving at least 10% of the body surface area (BSA), absolute psoriasis area and severity index (PASI) score of 12 or higher, and static physician global assessment (sPGA) score of 3 or higher. Prior biologic treatment did not preclude study entry (excluding risankizumab or adalimumab), and nearly 40% of participants previously had been on a different biologic. Notably, this trial allowed for inclusion of patients with prior malignancy (>5 years prior) and patients who tested positive for exposure to tuberculosis (TB) but were not shown to have active TB (provided appropriate treatment for latent TB was started). Study participants identified as white (81%), Asian (14%), black/African American (4%), or other ethnicity (1%). Part A involved administration of 150 mg risankizumab (n=301) at weeks 0 and 4 or 80 mg adalimumab (n=304) loading dose at week 0 followed by 40 mg at week 1 and 40 mg every other week thereafter until the end of week 15. At week 16 there was a significant difference in proportion of participants achieving 90% or more improvement (PASI-90) with risankizumab (72%) vs adalimumab (47%)(P<.0001) and achieving an sPGA score of 0 or 1 (clear or almost clear) with risankizumab (84%) vs adalimumab (60%)(P<.0001). In part B (weeks 16–44), adalimumab immediate responder (PASI ≥50 to PASI <90) participants were re-randomized to continue adalimumab 40 mg every other week (starting from week 17 and stopping at week 44) or switch to 150 mg risankizumab administered at weeks 16, 20, and 32. Patients taking risankizumab in part A continued the drug, administered at weeks 16 and 28. At week 44, there was a significant difference in percentage of participants achieving PASI-90 with risankizumab (66%) vs adalimumab (21%)(P<.0001).³

IMMhance was another double-blind phase 3 RCT with 2 parts that assessed the clinical efficacy of risankizumab compared to placebo in patients 18 years or older (N=507) across 9 countries with the same inclusion criteria for patients as IMMvent.⁴ Part A involved administration of 150 mg risankizumab (n=407) or placebo (n=100) at weeks 0 and 4 using a 4:1 random allocation ratio. At week 16, regardless of initial treatment, all participants received 150 mg risankizumab. Treatment results at week 16 showed a significant difference in percentage of participants achieving PASI-90 with risankizumab (73.2%) vs placebo (2.0%)(P<.001) and sPGA score of 0 or 1 with risankizumab (83.5%) vs placebo (7.0%)(P<.001). Furthermore, in part B (weeks 16–104), at week 28 participants on risankizumab with an sPGA score of 0 or 1 were randomized with a 1:2 allocation ratio to continue 150 mg risankizumab or switch to placebo to produce a treatment withdrawal effect. Part B results showed a significant difference in the proportion of participants achieving an sPGA score of 0 or 1 with risankizumab (87.4%) vs placebo (61.3%)(P<.001) at week 52 and at week 104 with risankizumab (81.1%) vs placebo (7.1%)(P<.001). Risankizumab was well tolerated, with the most common adverse events (AEs) being nasopharyngitis (23.4%), upper respiratory tract infection (15.4%), and headache (6.8%). Serious AEs included cancer (2.6%; 2.2 events per 100 patient-years), hepatic events (4.6%) including hepatic cirrhosis (0.2%), and serious infections (1.8%; 1.4 events per 100 patient-years).⁴

Overall, the strengths of risankizumab with regard to its clinical efficacy and utility in biologic-experienced patients were confirmed in these studies. The inclusion of patients with prior treated malignancy and positive TB tests also was more in line with what one might encounter with real-world practice and, as such, provided valuable data to help aid treatment decisions. These 2 studies provided valuable evidence for the therapeutic benefit and relatively mild safety profile of risankizumab in treatment of moderate to severe psoriasis for patients with and without prior biologic therapy.

Choosing a Biologic

Refractory psoriasis involves nonresponse (primary failure) or return of disease symptoms after initial improvement (secondary failure) with a biologic. Selecting a biologic for patients who have experienced prior biologic failure is difficult. It is still unknown whether it is more efficacious for patients to try a same-class drug or a biologic targeting a different inflammatory pathway or cytokine. Studies have shown mixed results regarding how to manage patients with biologic failure, with both approaches demonstrating positive outcomes.

One analysis of the Corrona Psoriasis Registry included 144 patients, the majority of whom (89.8%) were biologic experienced, who began secukinumab treatment and returned for a 6-month follow-up (5–9 months).⁵ Patients enrolled in the registry were 18 years or older, had been diagnosed with psoriasis by a dermatologist, and initiated or switched an FDA-approved systemic agent or biologic within the last 12 months. Of biologic-experienced participants, 37.7% had used 3 or more biologics. More than half of included participants were either male (55%) or obese (53.4%). Comorbidities included hypertension (43.2%), hyperlipidemia (33.9%), anxiety (20.3%), diabetes mellitus (15.3%), cardiovascular disease (14.4%), and depression (13.6%). After 6 months of treatment, there was significant improvement in the involvement of BSA (mean difference, −12.1), investigator global assessment score (−1.5), dermatology life quality index (DLQI)(−4.8), pain (−23.2), itch (−30.8), fatigue (−8.8), and work productivity (−9.2)(P<.01). Secukinumab therapy displayed notable reduction in symptom severity in this population with difficult-to-treat psoriasis. Its relative success in this cohort provides support for its use in treating patients who have failed other classes of biologics.⁵

Evidence supporting reduction of pruritus and pain with secukinumab also was notable. The CLEAR phase 3 RCT involved participants treated with 300 mg secukinumab every week for the first 4 weeks and then every 4 weeks thereafter for 48 weeks (n=312), up to 100 weeks (n=277).⁶ Participants had complete relief of pain (score 0), itching, and scaling at week 16 (69.4%, 49.7%, and 61.2%, respectively), week 52 (67.1%, 48.9%, and 53.3%, respectively), and week 104 (70.9%, 47.4%, and 54.8%, respectively). Reported AEs included candida infections (7.2%), malignant or unspecified tumors (1.5%), and neutropenia (<1%).⁶

Researchers investigated intraclass switching to brodalumab with prior failure of IL-17 inhibitors. An open-label study involved participants (n=39) with prior failure with secukinumab or ixekizumab therapy.⁷ Participants were administered 210 mg brodalumab with standard dosing at weeks 0, 1, and 2, and then every 2 weeks thereafter. At week 16, 69% of participants achieved PASI-75, 44% achieved PASI-90, 28% achieved PASI-100, and 62% achieved an sPGA score of 0 or 1. The authors attributed the relative success of brodalumab compared to prior anti–IL-17 agents to inhibition of the IL-17 receptor with brodalumab rather than the IL-17A ligand.⁷ Brodalumab may be a useful alternative biologic for patients with nonresponse to and secondary failure with biologics, including the IL-17A inhibitors.

Recent findings support effective skin clearance and improved symptom management with ixekizumab and ustekinumab. Of note, ixekizumab was reported to provide rapid improvement in skin lesions and quality of life to a greater extent than guselkumab.

The IXORA-R double-blinded RCT compared the clinical benefit of participants 18 years and older taking standard approved dosages of ixekizumab (n=520) or guselkumab (n=507).⁸ Patients were included if they had plaque psoriasis for at least 6 months before baseline, an sPGA score of at least 3, PASI score of 12 or higher, 10% or greater BSA, no prior IL-17 inhibitor failure, no use of IL-23 p19 inhibitors, and no use of any biologic within the specified period prior to baseline. At week 12, ixekizumab showed superior clinical improvement measured by the proportion of participants achieving complete skin clearance (ie, PASI-100)(41%) compared to guselkumab (25%)(P<.001). There were more participants taking ixekizumab who reported DLQI of 0 or 1 (no impact of disease on quality of life)(34%) compared to guselkumab (21%)(P<.001) as early on as week 4. The most common AE was upper respiratory tract infection (7%) in both groups. The risk of treatment-emergent AEs (56%), discontinuation because of AEs (2%), and serious AEs (3%) were comparable in both groups. The number of injection-site reactions was higher with ixekizumab (13%) vs guselkumab (3%). The authors concluded that ixekizumab offers the ability to provide rapid relief of symptoms, which is associated with improved DLQI.⁸

Response to ustekinumab therapy was assessed in a patient cohort enrolled in the Corrona Psoriasis Registry. This study involved 178 participants 18 years and older with psoriasis involvement of 3% or greater BSA who were treated with ustekinumab.⁹ By their 6-month follow-up visit, 55.6% of participants achieved adequate treatment response (BSA improving to <3% or 75% from enrollment). Increasing patient age was significantly associated with decreased likelihood of achieving a response (odds ratio, 0.981 [95% confidence interval, 0.962-0.999]; P=.049). Ustekinumab is a practical option for psoriasis treatment that seems to yield better results in younger patients.⁹ This evidence reveals that increased patient age is a characteristic that may contribute to poor treatment response and should be considered when choosing the best fit for biologic therapy.

Final Thoughts

Using evidence-based interventions to treat patients is the cornerstone of ethical and high-quality medical care. This guide sought to provide relevant updates in a variety of both comparator and pivotal trials, with the goal of summarizing clinically relevant information that may be extracted from these trials to guide patient care. It is not an exhaustive review but may be utilized as a reference tool to fine-tune selection criteria in choosing 1 of 11 biologics for the treatment of psoriasis.

The advent of biologic therapy over the last 2 decades has transformed the treatment of psoriasis; patients who either are not good candidates for or have an inadequate response to traditional treatments (topicals and/or phototherapy) now have numerous options for treatment.¹ Patients burdened by extensive disease, recurrent flares, and stubborn treatment areas are ideal candidates for biologics. There are 11 biologics approved by the US Food and Drug Administration (FDA)(Table) for treating moderate to severe plaque psoriasis as supported by grade A evidence. The FDA has authorized 1 new biologic—risankizumab—since the joint guidelines from the American Academy of Dermatology and National Psoriasis Foundation were released for the treatment of psoriasis with biologics.² This article aims to address updates on recent clinical trial findings (April 2019 to April 2020) regarding biologic therapy initiation and maintenance for adult patients. Prescribers should use this update as guidance for determining the appropriate biologic class based on patient characteristics and for approaching biologic-experienced patients with refractory psoriasis. This update also may serve as a reference for the recommended dosing regimens of the 11 approved biologics.

Using Risankizumab

Risankizumab is a new biologic that selectively targets the IL-23 pathway by binding the p19 subunit of IL-23. It was approved by the FDA in April 2019. Two recent studies have demonstrated the efficacy of risankizumab in disease management.^3,4

IMMvent was a double-blind, 2-part, phase 3, randomized controlled trial (RCT) of participants 18 years and older (N=605) with moderate to severe psoriasis (with or without psoriatic arthritis) across 11 countries.³ Inclusion criteria consisted of psoriasis involving at least 10% of the body surface area (BSA), absolute psoriasis area and severity index (PASI) score of 12 or higher, and static physician global assessment (sPGA) score of 3 or higher. Prior biologic treatment did not preclude study entry (excluding risankizumab or adalimumab), and nearly 40% of participants previously had been on a different biologic. Notably, this trial allowed for inclusion of patients with prior malignancy (>5 years prior) and patients who tested positive for exposure to tuberculosis (TB) but were not shown to have active TB (provided appropriate treatment for latent TB was started). Study participants identified as white (81%), Asian (14%), black/African American (4%), or other ethnicity (1%). Part A involved administration of 150 mg risankizumab (n=301) at weeks 0 and 4 or 80 mg adalimumab (n=304) loading dose at week 0 followed by 40 mg at week 1 and 40 mg every other week thereafter until the end of week 15. At week 16 there was a significant difference in proportion of participants achieving 90% or more improvement (PASI-90) with risankizumab (72%) vs adalimumab (47%)(P<.0001) and achieving an sPGA score of 0 or 1 (clear or almost clear) with risankizumab (84%) vs adalimumab (60%)(P<.0001). In part B (weeks 16–44), adalimumab immediate responder (PASI ≥50 to PASI <90) participants were re-randomized to continue adalimumab 40 mg every other week (starting from week 17 and stopping at week 44) or switch to 150 mg risankizumab administered at weeks 16, 20, and 32. Patients taking risankizumab in part A continued the drug, administered at weeks 16 and 28. At week 44, there was a significant difference in percentage of participants achieving PASI-90 with risankizumab (66%) vs adalimumab (21%)(P<.0001).³

IMMhance was another double-blind phase 3 RCT with 2 parts that assessed the clinical efficacy of risankizumab compared to placebo in patients 18 years or older (N=507) across 9 countries with the same inclusion criteria for patients as IMMvent.⁴ Part A involved administration of 150 mg risankizumab (n=407) or placebo (n=100) at weeks 0 and 4 using a 4:1 random allocation ratio. At week 16, regardless of initial treatment, all participants received 150 mg risankizumab. Treatment results at week 16 showed a significant difference in percentage of participants achieving PASI-90 with risankizumab (73.2%) vs placebo (2.0%)(P<.001) and sPGA score of 0 or 1 with risankizumab (83.5%) vs placebo (7.0%)(P<.001). Furthermore, in part B (weeks 16–104), at week 28 participants on risankizumab with an sPGA score of 0 or 1 were randomized with a 1:2 allocation ratio to continue 150 mg risankizumab or switch to placebo to produce a treatment withdrawal effect. Part B results showed a significant difference in the proportion of participants achieving an sPGA score of 0 or 1 with risankizumab (87.4%) vs placebo (61.3%)(P<.001) at week 52 and at week 104 with risankizumab (81.1%) vs placebo (7.1%)(P<.001). Risankizumab was well tolerated, with the most common adverse events (AEs) being nasopharyngitis (23.4%), upper respiratory tract infection (15.4%), and headache (6.8%). Serious AEs included cancer (2.6%; 2.2 events per 100 patient-years), hepatic events (4.6%) including hepatic cirrhosis (0.2%), and serious infections (1.8%; 1.4 events per 100 patient-years).⁴

Overall, the strengths of risankizumab with regard to its clinical efficacy and utility in biologic-experienced patients were confirmed in these studies. The inclusion of patients with prior treated malignancy and positive TB tests also was more in line with what one might encounter with real-world practice and, as such, provided valuable data to help aid treatment decisions. These 2 studies provided valuable evidence for the therapeutic benefit and relatively mild safety profile of risankizumab in treatment of moderate to severe psoriasis for patients with and without prior biologic therapy.

Choosing a Biologic

Refractory psoriasis involves nonresponse (primary failure) or return of disease symptoms after initial improvement (secondary failure) with a biologic. Selecting a biologic for patients who have experienced prior biologic failure is difficult. It is still unknown whether it is more efficacious for patients to try a same-class drug or a biologic targeting a different inflammatory pathway or cytokine. Studies have shown mixed results regarding how to manage patients with biologic failure, with both approaches demonstrating positive outcomes.

One analysis of the Corrona Psoriasis Registry included 144 patients, the majority of whom (89.8%) were biologic experienced, who began secukinumab treatment and returned for a 6-month follow-up (5–9 months).⁵ Patients enrolled in the registry were 18 years or older, had been diagnosed with psoriasis by a dermatologist, and initiated or switched an FDA-approved systemic agent or biologic within the last 12 months. Of biologic-experienced participants, 37.7% had used 3 or more biologics. More than half of included participants were either male (55%) or obese (53.4%). Comorbidities included hypertension (43.2%), hyperlipidemia (33.9%), anxiety (20.3%), diabetes mellitus (15.3%), cardiovascular disease (14.4%), and depression (13.6%). After 6 months of treatment, there was significant improvement in the involvement of BSA (mean difference, −12.1), investigator global assessment score (−1.5), dermatology life quality index (DLQI)(−4.8), pain (−23.2), itch (−30.8), fatigue (−8.8), and work productivity (−9.2)(P<.01). Secukinumab therapy displayed notable reduction in symptom severity in this population with difficult-to-treat psoriasis. Its relative success in this cohort provides support for its use in treating patients who have failed other classes of biologics.⁵

Evidence supporting reduction of pruritus and pain with secukinumab also was notable. The CLEAR phase 3 RCT involved participants treated with 300 mg secukinumab every week for the first 4 weeks and then every 4 weeks thereafter for 48 weeks (n=312), up to 100 weeks (n=277).⁶ Participants had complete relief of pain (score 0), itching, and scaling at week 16 (69.4%, 49.7%, and 61.2%, respectively), week 52 (67.1%, 48.9%, and 53.3%, respectively), and week 104 (70.9%, 47.4%, and 54.8%, respectively). Reported AEs included candida infections (7.2%), malignant or unspecified tumors (1.5%), and neutropenia (<1%).⁶

Researchers investigated intraclass switching to brodalumab with prior failure of IL-17 inhibitors. An open-label study involved participants (n=39) with prior failure with secukinumab or ixekizumab therapy.⁷ Participants were administered 210 mg brodalumab with standard dosing at weeks 0, 1, and 2, and then every 2 weeks thereafter. At week 16, 69% of participants achieved PASI-75, 44% achieved PASI-90, 28% achieved PASI-100, and 62% achieved an sPGA score of 0 or 1. The authors attributed the relative success of brodalumab compared to prior anti–IL-17 agents to inhibition of the IL-17 receptor with brodalumab rather than the IL-17A ligand.⁷ Brodalumab may be a useful alternative biologic for patients with nonresponse to and secondary failure with biologics, including the IL-17A inhibitors.

Recent findings support effective skin clearance and improved symptom management with ixekizumab and ustekinumab. Of note, ixekizumab was reported to provide rapid improvement in skin lesions and quality of life to a greater extent than guselkumab.

The IXORA-R double-blinded RCT compared the clinical benefit of participants 18 years and older taking standard approved dosages of ixekizumab (n=520) or guselkumab (n=507).⁸ Patients were included if they had plaque psoriasis for at least 6 months before baseline, an sPGA score of at least 3, PASI score of 12 or higher, 10% or greater BSA, no prior IL-17 inhibitor failure, no use of IL-23 p19 inhibitors, and no use of any biologic within the specified period prior to baseline. At week 12, ixekizumab showed superior clinical improvement measured by the proportion of participants achieving complete skin clearance (ie, PASI-100)(41%) compared to guselkumab (25%)(P<.001). There were more participants taking ixekizumab who reported DLQI of 0 or 1 (no impact of disease on quality of life)(34%) compared to guselkumab (21%)(P<.001) as early on as week 4. The most common AE was upper respiratory tract infection (7%) in both groups. The risk of treatment-emergent AEs (56%), discontinuation because of AEs (2%), and serious AEs (3%) were comparable in both groups. The number of injection-site reactions was higher with ixekizumab (13%) vs guselkumab (3%). The authors concluded that ixekizumab offers the ability to provide rapid relief of symptoms, which is associated with improved DLQI.⁸

Response to ustekinumab therapy was assessed in a patient cohort enrolled in the Corrona Psoriasis Registry. This study involved 178 participants 18 years and older with psoriasis involvement of 3% or greater BSA who were treated with ustekinumab.⁹ By their 6-month follow-up visit, 55.6% of participants achieved adequate treatment response (BSA improving to <3% or 75% from enrollment). Increasing patient age was significantly associated with decreased likelihood of achieving a response (odds ratio, 0.981 [95% confidence interval, 0.962-0.999]; P=.049). Ustekinumab is a practical option for psoriasis treatment that seems to yield better results in younger patients.⁹ This evidence reveals that increased patient age is a characteristic that may contribute to poor treatment response and should be considered when choosing the best fit for biologic therapy.

Final Thoughts

Using evidence-based interventions to treat patients is the cornerstone of ethical and high-quality medical care. This guide sought to provide relevant updates in a variety of both comparator and pivotal trials, with the goal of summarizing clinically relevant information that may be extracted from these trials to guide patient care. It is not an exhaustive review but may be utilized as a reference tool to fine-tune selection criteria in choosing 1 of 11 biologics for the treatment of psoriasis.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ Although topical therapies often are the first-line treatment of mild to moderate psoriasis, approximately 1 in 6 individuals has moderate to severe disease that requires systemic treatment such as biologics or phototherapy.² In patients with localized disease that is refractory to treatment or who have moderate to severe psoriasis requiring systemic treatment, phototherapy should be considered as a potential low-risk treatment option.

In July 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of phototherapy in treating adult patients with psoriasis.³ Since the prior guidelines were released in 2010, there have been numerous studies affirming the efficacy of phototherapy, with several large meta-analyses helping to refine clinical recommendations.^4,5 Each treatment was ranked using Strength of Recommendation Taxonomy, with a score of A, B, or C based on the strength of the evidence supporting the given modality. With the ever-increasing number of treatment options for patients with psoriasis, these guidelines inform dermatologists of the recommendations for the initiation, maintenance, and optimization of phototherapy in the treatment of psoriasis.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and frequency of adverse events of 10 commonly used phototherapy/photochemotherapy modalities. They also address dosing regimens, the potential to combine phototherapy with other therapies, and the efficacy of treatment modalities for different types of psoriasis.³ The purpose of this discussion is to present these guidelines in a condensed form for prescribers of phototherapy and to review the most clinically significant considerations during each step of treatment. Of note, we only highlight the treatment of adult patients and do not discuss information relevant to pediatric patients with psoriasis.

Choosing a Phototherapy Modality

Phototherapy may be considered for patients with psoriasis that affects more than 3% body surface area or for localized disease refractory to conventional treatments. UV light is believed to provide relief from psoriasis via multiple mechanisms, such as through favorable alterations in cytokine profiles, initiation of apoptosis, and local immunosupression.⁶ There is no single first-line phototherapeutic modality recommended for all patients with psoriasis. Rather, the decision to implement a particular modality should be individualized to the patient, considering factors such as percentage of body surface area affected by disease, quality-of-life assessment, comorbidities, lifestyle, and cost of treatment.

Of the 10 phototherapy modalities reviewed in these guidelines, 4 were ranked by the AAD and NPF as having grade A evidence for efficacy in the treatment of moderate to severe plaque psoriasis. Treatments with a grade A level of recommendation included narrowband UVB (NB-UVB), broadband UVB (BB-UVB), targeted phototherapy (excimer laser and excimer lamp), and oral psoralen plus UVA (PUVA) therapy. Photodynamic therapy for psoriasis was given an A-level recommendation against its use, as it was found to be ineffective with an unfavorable side-effect profile. Treatments with a grade B level of recommendation—nonoral routes of PUVA therapy, pulsed dye laser/intense pulsed light for nail psoriasis only, Goeckerman therapy, and climatotherapy—have sufficient evidence available to support their treatment of moderate to severe psoriasis in some cases. Treatments with a grade C level of recommendation—Grenz ray therapy (also called borderline or ultrasoft therapy) and visible light therapy—have insufficient evidence to support their use in patients with moderate to severe psoriasis (Table 1).

Psoralen plus UVA, which may be used topically (ie, bathwater PUVA) or taken orally, refers to treatment with photosensitizing psoralens. Psoralens are agents that intercalate with DNA and enhance the efficacy of phototherapy.¹⁰ Topical PUVA, with a grade B level of recommendation, is an effective treatment option for patients with localized disease and has been shown to be particularly efficacious in the treatment of palmoplantar pustular psoriasis. Oral PUVA is an effective option for psoriasis with a grade A recommendation, while bathwater PUVA has a grade B level of recommendation for moderate to severe plaque psoriasis. Oral PUVA is associated with greater systemic side effects (both acute and subacute) compared with NB-UVB and also is associated with photocarcinogenesis, particularly squamous cell carcinoma in white patients.¹¹ Other side effects from PUVA include pigmented macules in sun-protected areas (known as PUVA lentigines), which may make evaluation of skin lesions challenging. Because of the increased risk for cancer with oral PUVA, NB-UVB is preferable as a first-line treatment vs PUVA, especially in patients with a history of skin cancer.^12,13

Goeckerman therapy, which involves the synergistic combination of UVB and crude coal tar, is an older treatment that has shown efficacy in the treatment of severe or recalcitrant psoriasis (grade B level of recommendation). One prior case-control study comparing the efficacy of Goeckerman therapy with newer treatments, such as biologic therapies, steroids, and oral immunosuppressants, found a similar reduction in symptoms among both treatment groups, with longer disease-free periods in patients who received Goeckerman therapy than those who received newer therapies (22.3 years vs 4.6 months).¹⁴ However, Goeckerman therapy is utilized less frequently than more modern therapies because of the time required for treatment and declining insurance reimbursements for it. Climatotherapy, another older established therapy, involves the temporary or permanent relocation of patients to an environment that is favorable for disease control (grade B level of recommendation). Locations such as the Dead Sea and Canary Islands have been studied and shown to provide both subjective and objective improvement in patients’ psoriasis disease course. Patients had notable improvement in both their psoriasis area and severity index score and quality of life after a 3- to 4-week relocation to these areas.^15,16 Access to climatotherapy and the transient nature of disease relief are apparent limitations of this treatment modality.

Grenz ray is a type of phototherapy that uses longer-wavelength ionizing radiation, which has low penetrance into surrounding tissues and a 95% absorption rate within the first 3 mm of the skin depth. This treatment has been used less frequently since the development of newer alternatives but should still be considered as a second line to UV therapy, especially in cases of recalcitrant disease and palmoplantar psoriasis, and when access to other treatment options is limited. Grenz ray has a grade C level of recommendation due to the paucity of evidence that supports its efficacy. Thus, it is not recommended as first-line therapy for the treatment of moderate to severe psoriasis. Visible light therapy is another treatment option that uses light in the visible wavelength spectrum but predominantly utilizes blue and red light. Psoriatic lesions are sensitive to light therapy because of the elevated levels of naturally occurring photosensitizing agents, called protoporphyrins, in these lesions.¹⁷ Several small studies have shown improvement in psoriatic lesions treated with visible light therapy, with blue light showing greater efficacy in lesional clearance than red light.^18,19

Pulsed dye laser is a phototherapy modality that has shown efficacy in the treatment of nail psoriasis (grade B level of recommendation). One study comparing the effects of tazarotene cream 0.1% with pulsed dye laser and tazarotene cream 0.1% alone showed that patients receiving combination therapy had a greater decrease in nail psoriasis severity index scores, higher scores on the patient’s global assessment of improvement, and higher rates of improvement on the physician global assessment score. A physician global assessment score of 75% improvement or more was seen in patients treated with combination therapy vs monotherapy (5.3% vs 31.6%).²⁰ Intense pulsed light, a type of visible light therapy, also has been used to treat nail psoriasis, with one study showing notable improvement in nail bed and matrix disease and a global improvement in nail psoriasis severity index score after 6 months of biweekly treatment.²¹ However, this treatment has a grade B level of recommendation given the limited number of studies supporting the efficacy of this modality.

Initiation of Phototherapy

Prior to initiating phototherapy, it is important to assess the patient for any personal or family history of skin cancer, as phototherapy carries an increased risk for cutaneous malignancy, especially in patients with a history of skin cancer.^22,23 All patients also should be evaluated for their Fitzpatrick skin type, and the minimal erythema dose should be defined for those initiating UVB treatment. These classifications can be useful for the initial determination of treatment dose and the prevention of treatment-related adverse events (TRAEs). A careful drug history also should be taken before the initiation of phototherapy to avoid photosensitizing reactions. Thiazide diuretics and tetracyclines are 2 such examples of medications commonly associated with photosensitizing reactions.²⁴

Fitzpatrick skin type and/or minimal erythema dose testing also are essential in determining the appropriate initial NB-UVB dose required for treatment initiation (Table 2). Patient response to the initial NB-UVB trial will determine the optimal dosage for subsequent maintenance treatments.

Assessment and Optimization of Phototherapy

After an appropriate starting dosage has been established, patients should be evaluated at each subsequent visit for the degree of treatment response. Excessive erythema (lasting more than 48 hours) or adverse effects, such as itching, stinging, or burning, are indications that the patient should have their dose adjusted back to the last dose without such adverse responses. Because tolerance to treatment develops over time, patients who miss a scheduled dose of NB-UVB phototherapy require their dose to be temporarily lowered. Targeted dosage of UVB phototherapy at a frequency of 2 to 3 times weekly is preferred over treatment 1 to 2 times weekly; however, consideration should be given toward patient preference.²⁶ Dosing may be increased at a rate of 5% to 10% after each treatment, as tolerated, if there is no clearance of skin lesions with the original treatment dose. Patient skin type also is helpful in dictating the maximum phototherapy dose for each patient (Table 3).

Once a patient’s psoriatic lesions have cleared, the patient has the option to taper or indefinitely continue maintenance therapy. The established protocol for patients who choose to taper therapy is treatment twice weekly for 4 weeks, followed by once-weekly treatment for the second month. The maintenance dosage is held constant during the taper. For patients who prefer indefinite maintenance therapy, treatment is administered every 1 to 2 weeks, with a maintenance dosage that is approximately 25% lower than the original maintenance dosage.

Treatment Considerations

Efforts should be made to ensure that the long-term sequalae of phototherapy are minimized (Table 1). Development of cataracts is a recognized consequence of prolonged UVB exposure; therefore, eye protection is recommended during all UVB treatment sessions to reduce the risk for ocular toxicity. Although pregnancy is not a contraindication to phototherapy, except for PUVA, there is a dose-dependent degradation of folate with NB-UVB treatment, so folate supplementation (0.8 mg) is recommended during NB-UVB treatment to prevent development of neural tube defects in fetuses of patients who are pregnant or who may become pregnant.²⁷

Although phototherapy carries the theoretical risk for photocarcinogenesis, multiple studies have shown no increased risk for malignancy with either NB-UVB or BB-UVB phototherapy.^22,23 Regardless, patients who develop new-onset skin cancer while receiving any phototherapeutic treatment should discuss the potential risks and benefits of continued treatment with their physician. Providers should take extra caution prior to initiating treatment, especially in patients with a history of cutaneous malignancy. Because oral PUVA is a systemic therapy, it is associated with a greater risk for photocarcinogenesis than any other modality, particularly in fair-skinned individuals. Patients younger than 10 years; pregnant or nursing patients; and those with a history of lupus, xeroderma pigmentosum, or melanoma should not receive PUVA therapy because of their increased risk for photocarcinogenesis and TRAEs.

The decision to switch patients between different phototherapy modalities during treatment should be individualized to each patient based on factors such as disease severity, quality of life, and treatment burden. Other factors to consider include dosing frequency, treatment cost, and logistical factors, such as proximity to a treatment facility. Physicians should have a detailed discussion about the risks and benefits of continuing therapy for patients who develop new-onset skin cancer during phototherapy.

Final Thoughts

Phototherapy is an effective and safe treatment for patients with psoriasis who have localized and systemic disease. There are several treatment modalities that can be tailored to patient needs and preferences, such as home NB-UVB for patients who are unable or unwilling to undergo office-based treatments. Phototherapy has few absolute contraindications; however, relative contraindications to phototherapy exist. Patients with a history of skin cancer, photosensitivity disorders, and autoimmune diseases (eg, lupus) carry greater risks for adverse events, such as sun-related damage, cancer, and dysplasia. Because these conditions may preclude patients from pursuing phototherapy as a safe and effective approach to treating moderate to severe psoriasis, these patients should be considered for other therapies, such as biologic medications, which may carry a more favorable risk-benefit ratio given that individual’s background.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ Although topical therapies often are the first-line treatment of mild to moderate psoriasis, approximately 1 in 6 individuals has moderate to severe disease that requires systemic treatment such as biologics or phototherapy.² In patients with localized disease that is refractory to treatment or who have moderate to severe psoriasis requiring systemic treatment, phototherapy should be considered as a potential low-risk treatment option.

In July 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of phototherapy in treating adult patients with psoriasis.³ Since the prior guidelines were released in 2010, there have been numerous studies affirming the efficacy of phototherapy, with several large meta-analyses helping to refine clinical recommendations.^4,5 Each treatment was ranked using Strength of Recommendation Taxonomy, with a score of A, B, or C based on the strength of the evidence supporting the given modality. With the ever-increasing number of treatment options for patients with psoriasis, these guidelines inform dermatologists of the recommendations for the initiation, maintenance, and optimization of phototherapy in the treatment of psoriasis.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and frequency of adverse events of 10 commonly used phototherapy/photochemotherapy modalities. They also address dosing regimens, the potential to combine phototherapy with other therapies, and the efficacy of treatment modalities for different types of psoriasis.³ The purpose of this discussion is to present these guidelines in a condensed form for prescribers of phototherapy and to review the most clinically significant considerations during each step of treatment. Of note, we only highlight the treatment of adult patients and do not discuss information relevant to pediatric patients with psoriasis.

Choosing a Phototherapy Modality

Phototherapy may be considered for patients with psoriasis that affects more than 3% body surface area or for localized disease refractory to conventional treatments. UV light is believed to provide relief from psoriasis via multiple mechanisms, such as through favorable alterations in cytokine profiles, initiation of apoptosis, and local immunosupression.⁶ There is no single first-line phototherapeutic modality recommended for all patients with psoriasis. Rather, the decision to implement a particular modality should be individualized to the patient, considering factors such as percentage of body surface area affected by disease, quality-of-life assessment, comorbidities, lifestyle, and cost of treatment.

Of the 10 phototherapy modalities reviewed in these guidelines, 4 were ranked by the AAD and NPF as having grade A evidence for efficacy in the treatment of moderate to severe plaque psoriasis. Treatments with a grade A level of recommendation included narrowband UVB (NB-UVB), broadband UVB (BB-UVB), targeted phototherapy (excimer laser and excimer lamp), and oral psoralen plus UVA (PUVA) therapy. Photodynamic therapy for psoriasis was given an A-level recommendation against its use, as it was found to be ineffective with an unfavorable side-effect profile. Treatments with a grade B level of recommendation—nonoral routes of PUVA therapy, pulsed dye laser/intense pulsed light for nail psoriasis only, Goeckerman therapy, and climatotherapy—have sufficient evidence available to support their treatment of moderate to severe psoriasis in some cases. Treatments with a grade C level of recommendation—Grenz ray therapy (also called borderline or ultrasoft therapy) and visible light therapy—have insufficient evidence to support their use in patients with moderate to severe psoriasis (Table 1).

Psoralen plus UVA, which may be used topically (ie, bathwater PUVA) or taken orally, refers to treatment with photosensitizing psoralens. Psoralens are agents that intercalate with DNA and enhance the efficacy of phototherapy.¹⁰ Topical PUVA, with a grade B level of recommendation, is an effective treatment option for patients with localized disease and has been shown to be particularly efficacious in the treatment of palmoplantar pustular psoriasis. Oral PUVA is an effective option for psoriasis with a grade A recommendation, while bathwater PUVA has a grade B level of recommendation for moderate to severe plaque psoriasis. Oral PUVA is associated with greater systemic side effects (both acute and subacute) compared with NB-UVB and also is associated with photocarcinogenesis, particularly squamous cell carcinoma in white patients.¹¹ Other side effects from PUVA include pigmented macules in sun-protected areas (known as PUVA lentigines), which may make evaluation of skin lesions challenging. Because of the increased risk for cancer with oral PUVA, NB-UVB is preferable as a first-line treatment vs PUVA, especially in patients with a history of skin cancer.^12,13

Goeckerman therapy, which involves the synergistic combination of UVB and crude coal tar, is an older treatment that has shown efficacy in the treatment of severe or recalcitrant psoriasis (grade B level of recommendation). One prior case-control study comparing the efficacy of Goeckerman therapy with newer treatments, such as biologic therapies, steroids, and oral immunosuppressants, found a similar reduction in symptoms among both treatment groups, with longer disease-free periods in patients who received Goeckerman therapy than those who received newer therapies (22.3 years vs 4.6 months).¹⁴ However, Goeckerman therapy is utilized less frequently than more modern therapies because of the time required for treatment and declining insurance reimbursements for it. Climatotherapy, another older established therapy, involves the temporary or permanent relocation of patients to an environment that is favorable for disease control (grade B level of recommendation). Locations such as the Dead Sea and Canary Islands have been studied and shown to provide both subjective and objective improvement in patients’ psoriasis disease course. Patients had notable improvement in both their psoriasis area and severity index score and quality of life after a 3- to 4-week relocation to these areas.^15,16 Access to climatotherapy and the transient nature of disease relief are apparent limitations of this treatment modality.

Grenz ray is a type of phototherapy that uses longer-wavelength ionizing radiation, which has low penetrance into surrounding tissues and a 95% absorption rate within the first 3 mm of the skin depth. This treatment has been used less frequently since the development of newer alternatives but should still be considered as a second line to UV therapy, especially in cases of recalcitrant disease and palmoplantar psoriasis, and when access to other treatment options is limited. Grenz ray has a grade C level of recommendation due to the paucity of evidence that supports its efficacy. Thus, it is not recommended as first-line therapy for the treatment of moderate to severe psoriasis. Visible light therapy is another treatment option that uses light in the visible wavelength spectrum but predominantly utilizes blue and red light. Psoriatic lesions are sensitive to light therapy because of the elevated levels of naturally occurring photosensitizing agents, called protoporphyrins, in these lesions.¹⁷ Several small studies have shown improvement in psoriatic lesions treated with visible light therapy, with blue light showing greater efficacy in lesional clearance than red light.^18,19

Pulsed dye laser is a phototherapy modality that has shown efficacy in the treatment of nail psoriasis (grade B level of recommendation). One study comparing the effects of tazarotene cream 0.1% with pulsed dye laser and tazarotene cream 0.1% alone showed that patients receiving combination therapy had a greater decrease in nail psoriasis severity index scores, higher scores on the patient’s global assessment of improvement, and higher rates of improvement on the physician global assessment score. A physician global assessment score of 75% improvement or more was seen in patients treated with combination therapy vs monotherapy (5.3% vs 31.6%).²⁰ Intense pulsed light, a type of visible light therapy, also has been used to treat nail psoriasis, with one study showing notable improvement in nail bed and matrix disease and a global improvement in nail psoriasis severity index score after 6 months of biweekly treatment.²¹ However, this treatment has a grade B level of recommendation given the limited number of studies supporting the efficacy of this modality.

Initiation of Phototherapy

Prior to initiating phototherapy, it is important to assess the patient for any personal or family history of skin cancer, as phototherapy carries an increased risk for cutaneous malignancy, especially in patients with a history of skin cancer.^22,23 All patients also should be evaluated for their Fitzpatrick skin type, and the minimal erythema dose should be defined for those initiating UVB treatment. These classifications can be useful for the initial determination of treatment dose and the prevention of treatment-related adverse events (TRAEs). A careful drug history also should be taken before the initiation of phototherapy to avoid photosensitizing reactions. Thiazide diuretics and tetracyclines are 2 such examples of medications commonly associated with photosensitizing reactions.²⁴

Fitzpatrick skin type and/or minimal erythema dose testing also are essential in determining the appropriate initial NB-UVB dose required for treatment initiation (Table 2). Patient response to the initial NB-UVB trial will determine the optimal dosage for subsequent maintenance treatments.

Assessment and Optimization of Phototherapy

After an appropriate starting dosage has been established, patients should be evaluated at each subsequent visit for the degree of treatment response. Excessive erythema (lasting more than 48 hours) or adverse effects, such as itching, stinging, or burning, are indications that the patient should have their dose adjusted back to the last dose without such adverse responses. Because tolerance to treatment develops over time, patients who miss a scheduled dose of NB-UVB phototherapy require their dose to be temporarily lowered. Targeted dosage of UVB phototherapy at a frequency of 2 to 3 times weekly is preferred over treatment 1 to 2 times weekly; however, consideration should be given toward patient preference.²⁶ Dosing may be increased at a rate of 5% to 10% after each treatment, as tolerated, if there is no clearance of skin lesions with the original treatment dose. Patient skin type also is helpful in dictating the maximum phototherapy dose for each patient (Table 3).

Once a patient’s psoriatic lesions have cleared, the patient has the option to taper or indefinitely continue maintenance therapy. The established protocol for patients who choose to taper therapy is treatment twice weekly for 4 weeks, followed by once-weekly treatment for the second month. The maintenance dosage is held constant during the taper. For patients who prefer indefinite maintenance therapy, treatment is administered every 1 to 2 weeks, with a maintenance dosage that is approximately 25% lower than the original maintenance dosage.

Treatment Considerations

Efforts should be made to ensure that the long-term sequalae of phototherapy are minimized (Table 1). Development of cataracts is a recognized consequence of prolonged UVB exposure; therefore, eye protection is recommended during all UVB treatment sessions to reduce the risk for ocular toxicity. Although pregnancy is not a contraindication to phototherapy, except for PUVA, there is a dose-dependent degradation of folate with NB-UVB treatment, so folate supplementation (0.8 mg) is recommended during NB-UVB treatment to prevent development of neural tube defects in fetuses of patients who are pregnant or who may become pregnant.²⁷

Although phototherapy carries the theoretical risk for photocarcinogenesis, multiple studies have shown no increased risk for malignancy with either NB-UVB or BB-UVB phototherapy.^22,23 Regardless, patients who develop new-onset skin cancer while receiving any phototherapeutic treatment should discuss the potential risks and benefits of continued treatment with their physician. Providers should take extra caution prior to initiating treatment, especially in patients with a history of cutaneous malignancy. Because oral PUVA is a systemic therapy, it is associated with a greater risk for photocarcinogenesis than any other modality, particularly in fair-skinned individuals. Patients younger than 10 years; pregnant or nursing patients; and those with a history of lupus, xeroderma pigmentosum, or melanoma should not receive PUVA therapy because of their increased risk for photocarcinogenesis and TRAEs.

The decision to switch patients between different phototherapy modalities during treatment should be individualized to each patient based on factors such as disease severity, quality of life, and treatment burden. Other factors to consider include dosing frequency, treatment cost, and logistical factors, such as proximity to a treatment facility. Physicians should have a detailed discussion about the risks and benefits of continuing therapy for patients who develop new-onset skin cancer during phototherapy.

Final Thoughts

Phototherapy is an effective and safe treatment for patients with psoriasis who have localized and systemic disease. There are several treatment modalities that can be tailored to patient needs and preferences, such as home NB-UVB for patients who are unable or unwilling to undergo office-based treatments. Phototherapy has few absolute contraindications; however, relative contraindications to phototherapy exist. Patients with a history of skin cancer, photosensitivity disorders, and autoimmune diseases (eg, lupus) carry greater risks for adverse events, such as sun-related damage, cancer, and dysplasia. Because these conditions may preclude patients from pursuing phototherapy as a safe and effective approach to treating moderate to severe psoriasis, these patients should be considered for other therapies, such as biologic medications, which may carry a more favorable risk-benefit ratio given that individual’s background.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ Although topical therapies often are the first-line treatment of mild to moderate psoriasis, approximately 1 in 6 individuals has moderate to severe disease that requires systemic treatment such as biologics or phototherapy.² In patients with localized disease that is refractory to treatment or who have moderate to severe psoriasis requiring systemic treatment, phototherapy should be considered as a potential low-risk treatment option.

In July 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of phototherapy in treating adult patients with psoriasis.³ Since the prior guidelines were released in 2010, there have been numerous studies affirming the efficacy of phototherapy, with several large meta-analyses helping to refine clinical recommendations.^4,5 Each treatment was ranked using Strength of Recommendation Taxonomy, with a score of A, B, or C based on the strength of the evidence supporting the given modality. With the ever-increasing number of treatment options for patients with psoriasis, these guidelines inform dermatologists of the recommendations for the initiation, maintenance, and optimization of phototherapy in the treatment of psoriasis.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and frequency of adverse events of 10 commonly used phototherapy/photochemotherapy modalities. They also address dosing regimens, the potential to combine phototherapy with other therapies, and the efficacy of treatment modalities for different types of psoriasis.³ The purpose of this discussion is to present these guidelines in a condensed form for prescribers of phototherapy and to review the most clinically significant considerations during each step of treatment. Of note, we only highlight the treatment of adult patients and do not discuss information relevant to pediatric patients with psoriasis.

Choosing a Phototherapy Modality

Phototherapy may be considered for patients with psoriasis that affects more than 3% body surface area or for localized disease refractory to conventional treatments. UV light is believed to provide relief from psoriasis via multiple mechanisms, such as through favorable alterations in cytokine profiles, initiation of apoptosis, and local immunosupression.⁶ There is no single first-line phototherapeutic modality recommended for all patients with psoriasis. Rather, the decision to implement a particular modality should be individualized to the patient, considering factors such as percentage of body surface area affected by disease, quality-of-life assessment, comorbidities, lifestyle, and cost of treatment.

Of the 10 phototherapy modalities reviewed in these guidelines, 4 were ranked by the AAD and NPF as having grade A evidence for efficacy in the treatment of moderate to severe plaque psoriasis. Treatments with a grade A level of recommendation included narrowband UVB (NB-UVB), broadband UVB (BB-UVB), targeted phototherapy (excimer laser and excimer lamp), and oral psoralen plus UVA (PUVA) therapy. Photodynamic therapy for psoriasis was given an A-level recommendation against its use, as it was found to be ineffective with an unfavorable side-effect profile. Treatments with a grade B level of recommendation—nonoral routes of PUVA therapy, pulsed dye laser/intense pulsed light for nail psoriasis only, Goeckerman therapy, and climatotherapy—have sufficient evidence available to support their treatment of moderate to severe psoriasis in some cases. Treatments with a grade C level of recommendation—Grenz ray therapy (also called borderline or ultrasoft therapy) and visible light therapy—have insufficient evidence to support their use in patients with moderate to severe psoriasis (Table 1).

Psoralen plus UVA, which may be used topically (ie, bathwater PUVA) or taken orally, refers to treatment with photosensitizing psoralens. Psoralens are agents that intercalate with DNA and enhance the efficacy of phototherapy.¹⁰ Topical PUVA, with a grade B level of recommendation, is an effective treatment option for patients with localized disease and has been shown to be particularly efficacious in the treatment of palmoplantar pustular psoriasis. Oral PUVA is an effective option for psoriasis with a grade A recommendation, while bathwater PUVA has a grade B level of recommendation for moderate to severe plaque psoriasis. Oral PUVA is associated with greater systemic side effects (both acute and subacute) compared with NB-UVB and also is associated with photocarcinogenesis, particularly squamous cell carcinoma in white patients.¹¹ Other side effects from PUVA include pigmented macules in sun-protected areas (known as PUVA lentigines), which may make evaluation of skin lesions challenging. Because of the increased risk for cancer with oral PUVA, NB-UVB is preferable as a first-line treatment vs PUVA, especially in patients with a history of skin cancer.^12,13

Goeckerman therapy, which involves the synergistic combination of UVB and crude coal tar, is an older treatment that has shown efficacy in the treatment of severe or recalcitrant psoriasis (grade B level of recommendation). One prior case-control study comparing the efficacy of Goeckerman therapy with newer treatments, such as biologic therapies, steroids, and oral immunosuppressants, found a similar reduction in symptoms among both treatment groups, with longer disease-free periods in patients who received Goeckerman therapy than those who received newer therapies (22.3 years vs 4.6 months).¹⁴ However, Goeckerman therapy is utilized less frequently than more modern therapies because of the time required for treatment and declining insurance reimbursements for it. Climatotherapy, another older established therapy, involves the temporary or permanent relocation of patients to an environment that is favorable for disease control (grade B level of recommendation). Locations such as the Dead Sea and Canary Islands have been studied and shown to provide both subjective and objective improvement in patients’ psoriasis disease course. Patients had notable improvement in both their psoriasis area and severity index score and quality of life after a 3- to 4-week relocation to these areas.^15,16 Access to climatotherapy and the transient nature of disease relief are apparent limitations of this treatment modality.

Grenz ray is a type of phototherapy that uses longer-wavelength ionizing radiation, which has low penetrance into surrounding tissues and a 95% absorption rate within the first 3 mm of the skin depth. This treatment has been used less frequently since the development of newer alternatives but should still be considered as a second line to UV therapy, especially in cases of recalcitrant disease and palmoplantar psoriasis, and when access to other treatment options is limited. Grenz ray has a grade C level of recommendation due to the paucity of evidence that supports its efficacy. Thus, it is not recommended as first-line therapy for the treatment of moderate to severe psoriasis. Visible light therapy is another treatment option that uses light in the visible wavelength spectrum but predominantly utilizes blue and red light. Psoriatic lesions are sensitive to light therapy because of the elevated levels of naturally occurring photosensitizing agents, called protoporphyrins, in these lesions.¹⁷ Several small studies have shown improvement in psoriatic lesions treated with visible light therapy, with blue light showing greater efficacy in lesional clearance than red light.^18,19

Pulsed dye laser is a phototherapy modality that has shown efficacy in the treatment of nail psoriasis (grade B level of recommendation). One study comparing the effects of tazarotene cream 0.1% with pulsed dye laser and tazarotene cream 0.1% alone showed that patients receiving combination therapy had a greater decrease in nail psoriasis severity index scores, higher scores on the patient’s global assessment of improvement, and higher rates of improvement on the physician global assessment score. A physician global assessment score of 75% improvement or more was seen in patients treated with combination therapy vs monotherapy (5.3% vs 31.6%).²⁰ Intense pulsed light, a type of visible light therapy, also has been used to treat nail psoriasis, with one study showing notable improvement in nail bed and matrix disease and a global improvement in nail psoriasis severity index score after 6 months of biweekly treatment.²¹ However, this treatment has a grade B level of recommendation given the limited number of studies supporting the efficacy of this modality.

Initiation of Phototherapy

Prior to initiating phototherapy, it is important to assess the patient for any personal or family history of skin cancer, as phototherapy carries an increased risk for cutaneous malignancy, especially in patients with a history of skin cancer.^22,23 All patients also should be evaluated for their Fitzpatrick skin type, and the minimal erythema dose should be defined for those initiating UVB treatment. These classifications can be useful for the initial determination of treatment dose and the prevention of treatment-related adverse events (TRAEs). A careful drug history also should be taken before the initiation of phototherapy to avoid photosensitizing reactions. Thiazide diuretics and tetracyclines are 2 such examples of medications commonly associated with photosensitizing reactions.²⁴

Fitzpatrick skin type and/or minimal erythema dose testing also are essential in determining the appropriate initial NB-UVB dose required for treatment initiation (Table 2). Patient response to the initial NB-UVB trial will determine the optimal dosage for subsequent maintenance treatments.

Assessment and Optimization of Phototherapy

After an appropriate starting dosage has been established, patients should be evaluated at each subsequent visit for the degree of treatment response. Excessive erythema (lasting more than 48 hours) or adverse effects, such as itching, stinging, or burning, are indications that the patient should have their dose adjusted back to the last dose without such adverse responses. Because tolerance to treatment develops over time, patients who miss a scheduled dose of NB-UVB phototherapy require their dose to be temporarily lowered. Targeted dosage of UVB phototherapy at a frequency of 2 to 3 times weekly is preferred over treatment 1 to 2 times weekly; however, consideration should be given toward patient preference.²⁶ Dosing may be increased at a rate of 5% to 10% after each treatment, as tolerated, if there is no clearance of skin lesions with the original treatment dose. Patient skin type also is helpful in dictating the maximum phototherapy dose for each patient (Table 3).

Once a patient’s psoriatic lesions have cleared, the patient has the option to taper or indefinitely continue maintenance therapy. The established protocol for patients who choose to taper therapy is treatment twice weekly for 4 weeks, followed by once-weekly treatment for the second month. The maintenance dosage is held constant during the taper. For patients who prefer indefinite maintenance therapy, treatment is administered every 1 to 2 weeks, with a maintenance dosage that is approximately 25% lower than the original maintenance dosage.

Treatment Considerations

Efforts should be made to ensure that the long-term sequalae of phototherapy are minimized (Table 1). Development of cataracts is a recognized consequence of prolonged UVB exposure; therefore, eye protection is recommended during all UVB treatment sessions to reduce the risk for ocular toxicity. Although pregnancy is not a contraindication to phototherapy, except for PUVA, there is a dose-dependent degradation of folate with NB-UVB treatment, so folate supplementation (0.8 mg) is recommended during NB-UVB treatment to prevent development of neural tube defects in fetuses of patients who are pregnant or who may become pregnant.²⁷

Although phototherapy carries the theoretical risk for photocarcinogenesis, multiple studies have shown no increased risk for malignancy with either NB-UVB or BB-UVB phototherapy.^22,23 Regardless, patients who develop new-onset skin cancer while receiving any phototherapeutic treatment should discuss the potential risks and benefits of continued treatment with their physician. Providers should take extra caution prior to initiating treatment, especially in patients with a history of cutaneous malignancy. Because oral PUVA is a systemic therapy, it is associated with a greater risk for photocarcinogenesis than any other modality, particularly in fair-skinned individuals. Patients younger than 10 years; pregnant or nursing patients; and those with a history of lupus, xeroderma pigmentosum, or melanoma should not receive PUVA therapy because of their increased risk for photocarcinogenesis and TRAEs.

The decision to switch patients between different phototherapy modalities during treatment should be individualized to each patient based on factors such as disease severity, quality of life, and treatment burden. Other factors to consider include dosing frequency, treatment cost, and logistical factors, such as proximity to a treatment facility. Physicians should have a detailed discussion about the risks and benefits of continuing therapy for patients who develop new-onset skin cancer during phototherapy.

Final Thoughts

Phototherapy is an effective and safe treatment for patients with psoriasis who have localized and systemic disease. There are several treatment modalities that can be tailored to patient needs and preferences, such as home NB-UVB for patients who are unable or unwilling to undergo office-based treatments. Phototherapy has few absolute contraindications; however, relative contraindications to phototherapy exist. Patients with a history of skin cancer, photosensitivity disorders, and autoimmune diseases (eg, lupus) carry greater risks for adverse events, such as sun-related damage, cancer, and dysplasia. Because these conditions may preclude patients from pursuing phototherapy as a safe and effective approach to treating moderate to severe psoriasis, these patients should be considered for other therapies, such as biologic medications, which may carry a more favorable risk-benefit ratio given that individual’s background.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

Prevalence of Scalp Psoriasis

Scalp psoriasis is a common and difficult-to-treat manifestation of psoriasis.^1,2 The prevalence of scalp psoriasis in patients with psoriasis is estimated to be 45% to 56%.³ Other studies have shown 80% to 90% of patients with psoriasis have scalp involvement at some point during the course of their disease.^2,4-6 

Clinical Presentation

Scalp psoriasis typically presents as red thickened patches with silvery white scales that flake and may be mistaken for dandruff.^7,8 

The lesions may be limited to the hairline or may extend to the forehead, ears, and back of the neck.^1,9 Patients often report intense itching, feelings of soreness, and burning.^10,11 Patients with scalp psoriasis also are vulnerable to Koebner phenomenon because normal hair care along with scratching or picking at lesions can result in skin trauma and a cycle of exacerbating disease.¹¹ 

Quality of Life Implications

Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.^2,12,13 In one study, more than 70% of patients with scalp psoriasis reported difficulty with daily life.¹² Patients frequently report feelings of shame, embarrassment, or self-consciousness about scalp psoriasis; many grow their hair long or wear hats to hide scalp lesions. Others report that flaking sometimes, often, or always affects their choice of clothing color.^7,12 

Psoriatic Alopecia

Alopecia is another common sequala in the setting of scalp psoriasis, though it is not well understood.^14,15 First described by Shuster¹⁶ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.^14,17 Clinically, it presents as pink scaly plaques consistent with psoriasis with overlying alopecia. In most patients, hair loss is usually reversible following effective treatment of psoriasis; however, instances of psoriatic alopecia have been reported as cicatricial (permanent) hair loss and generalized telogen effluvium. Cicatricial alopecia is increasingly being linked with chronic relapsing episodes of psoriasis.^14,15 Patients with psoriatic alopecia are known to have a higher proportion of telogen and catagen hairs.^14,18 Moreover, patients with psoriasis have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients.¹⁴ 

The patient described here had scalp psoriasis with increased and preserved hair density. The case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.^14,15  

Therapeutic Options

Although numerous treatment options for psoriasis are available, the scalp remains a difficult area to treat.^1,14 Increased hair density can complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.¹⁴ The presence of hair also has been shown to strongly influence treatment adherence.^1,8 Patients often discuss the greasy effect of medications in this area and difficulty removing products from the hair.¹ 

Topical corticosteroids, with or without the addition of the vitamin D analogs calcipotriol or calcipotriene, remain the first-line treatment of mild scalp psoriasis. It is possible that the development of new formulations in recent years—foams, shampoos, and sprays—may improve adherence. Systemic treatment should be considered in severe or intractable cases. 

Bottom Line

Although hair loss is more common, scalp psoriasis also may present with increased hair density, which may make topical medications more difficult to apply and can affect treatment adherence. Topical corticosteroids, with or without the addition of the vitamin D analog calcipotriol, remain the first-line treatment of mild scalp psoriasis. Systemic therapy should be considered in severe or recalcitrant cases.

Prevalence of Scalp Psoriasis

Scalp psoriasis is a common and difficult-to-treat manifestation of psoriasis.^1,2 The prevalence of scalp psoriasis in patients with psoriasis is estimated to be 45% to 56%.³ Other studies have shown 80% to 90% of patients with psoriasis have scalp involvement at some point during the course of their disease.^2,4-6 

Clinical Presentation

Scalp psoriasis typically presents as red thickened patches with silvery white scales that flake and may be mistaken for dandruff.^7,8 

The lesions may be limited to the hairline or may extend to the forehead, ears, and back of the neck.^1,9 Patients often report intense itching, feelings of soreness, and burning.^10,11 Patients with scalp psoriasis also are vulnerable to Koebner phenomenon because normal hair care along with scratching or picking at lesions can result in skin trauma and a cycle of exacerbating disease.¹¹ 

Quality of Life Implications

Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.^2,12,13 In one study, more than 70% of patients with scalp psoriasis reported difficulty with daily life.¹² Patients frequently report feelings of shame, embarrassment, or self-consciousness about scalp psoriasis; many grow their hair long or wear hats to hide scalp lesions. Others report that flaking sometimes, often, or always affects their choice of clothing color.^7,12 

Psoriatic Alopecia

Alopecia is another common sequala in the setting of scalp psoriasis, though it is not well understood.^14,15 First described by Shuster¹⁶ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.^14,17 Clinically, it presents as pink scaly plaques consistent with psoriasis with overlying alopecia. In most patients, hair loss is usually reversible following effective treatment of psoriasis; however, instances of psoriatic alopecia have been reported as cicatricial (permanent) hair loss and generalized telogen effluvium. Cicatricial alopecia is increasingly being linked with chronic relapsing episodes of psoriasis.^14,15 Patients with psoriatic alopecia are known to have a higher proportion of telogen and catagen hairs.^14,18 Moreover, patients with psoriasis have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients.¹⁴ 

The patient described here had scalp psoriasis with increased and preserved hair density. The case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.^14,15  

Therapeutic Options

Although numerous treatment options for psoriasis are available, the scalp remains a difficult area to treat.^1,14 Increased hair density can complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.¹⁴ The presence of hair also has been shown to strongly influence treatment adherence.^1,8 Patients often discuss the greasy effect of medications in this area and difficulty removing products from the hair.¹ 

Topical corticosteroids, with or without the addition of the vitamin D analogs calcipotriol or calcipotriene, remain the first-line treatment of mild scalp psoriasis. It is possible that the development of new formulations in recent years—foams, shampoos, and sprays—may improve adherence. Systemic treatment should be considered in severe or intractable cases. 

Bottom Line

Although hair loss is more common, scalp psoriasis also may present with increased hair density, which may make topical medications more difficult to apply and can affect treatment adherence. Topical corticosteroids, with or without the addition of the vitamin D analog calcipotriol, remain the first-line treatment of mild scalp psoriasis. Systemic therapy should be considered in severe or recalcitrant cases.

Prevalence of Scalp Psoriasis

Scalp psoriasis is a common and difficult-to-treat manifestation of psoriasis.^1,2 The prevalence of scalp psoriasis in patients with psoriasis is estimated to be 45% to 56%.³ Other studies have shown 80% to 90% of patients with psoriasis have scalp involvement at some point during the course of their disease.^2,4-6 

Clinical Presentation

Scalp psoriasis typically presents as red thickened patches with silvery white scales that flake and may be mistaken for dandruff.^7,8 

The lesions may be limited to the hairline or may extend to the forehead, ears, and back of the neck.^1,9 Patients often report intense itching, feelings of soreness, and burning.^10,11 Patients with scalp psoriasis also are vulnerable to Koebner phenomenon because normal hair care along with scratching or picking at lesions can result in skin trauma and a cycle of exacerbating disease.¹¹ 

Quality of Life Implications

Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.^2,12,13 In one study, more than 70% of patients with scalp psoriasis reported difficulty with daily life.¹² Patients frequently report feelings of shame, embarrassment, or self-consciousness about scalp psoriasis; many grow their hair long or wear hats to hide scalp lesions. Others report that flaking sometimes, often, or always affects their choice of clothing color.^7,12 

Psoriatic Alopecia

Alopecia is another common sequala in the setting of scalp psoriasis, though it is not well understood.^14,15 First described by Shuster¹⁶ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.^14,17 Clinically, it presents as pink scaly plaques consistent with psoriasis with overlying alopecia. In most patients, hair loss is usually reversible following effective treatment of psoriasis; however, instances of psoriatic alopecia have been reported as cicatricial (permanent) hair loss and generalized telogen effluvium. Cicatricial alopecia is increasingly being linked with chronic relapsing episodes of psoriasis.^14,15 Patients with psoriatic alopecia are known to have a higher proportion of telogen and catagen hairs.^14,18 Moreover, patients with psoriasis have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients.¹⁴ 

The patient described here had scalp psoriasis with increased and preserved hair density. The case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.^14,15  

Therapeutic Options

Although numerous treatment options for psoriasis are available, the scalp remains a difficult area to treat.^1,14 Increased hair density can complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.¹⁴ The presence of hair also has been shown to strongly influence treatment adherence.^1,8 Patients often discuss the greasy effect of medications in this area and difficulty removing products from the hair.¹ 

Topical corticosteroids, with or without the addition of the vitamin D analogs calcipotriol or calcipotriene, remain the first-line treatment of mild scalp psoriasis. It is possible that the development of new formulations in recent years—foams, shampoos, and sprays—may improve adherence. Systemic treatment should be considered in severe or intractable cases. 

Bottom Line

Although hair loss is more common, scalp psoriasis also may present with increased hair density, which may make topical medications more difficult to apply and can affect treatment adherence. Topical corticosteroids, with or without the addition of the vitamin D analog calcipotriol, remain the first-line treatment of mild scalp psoriasis. Systemic therapy should be considered in severe or recalcitrant cases.

Background

Psoriasis is a complex, multifactorial, systemic disease that is associated with numerous neurologic comorbidities, including stroke, multiple sclerosis, epilepsy, migraine, restless leg syndrome, Parkinson disease, and less frequently Guillain-Barré syndrome and myasthenia gravis. Anxiety and depression also are frequently seen in patients with psoriasis.¹ In recent years, heightened understanding of the pathogenesis and disease mechanisms involved in psoriasis has led to the development of therapies designed to help to control the chronic inflammation associated with the disease, such as immunobiologics and small molecules.² 

Nerves and Neuropeptides 

Psychological stress is known to exacerbate psoriasis, which points to the involvement of the nervous system in psoriasis.^3,5,6 In addition to provoking the sympathetic response, psychological stressors have been shown to affect the peripheral nervous system in psoriasis by modulating the skin’s network of nerves and neuropeptides.^6-11 A small study divided patients with psoriasis into low-stress and high-stress groups based on their clinical examinations and answers to questionnaires. Immunohistochemical analysis showed patients in the high-stress group had elevated levels of calcitonin gene-related peptide and vasoactive intestinal polypeptide as well as reduced levels of the neuropeptide-degrading enzyme chymase compared to the low-stress group.¹² Two later studies showed calcitonin gene-related peptide stimulates keratinocyte proliferation^3,13 and is found at increased levels in psoriatic skin.^3,14 Similarly, higher quantities of vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in psoriatic plaques compared to nonlesional and normal skin.^3,15 

Nerve growth factor (NGF), a principal mediator of neurogenic inflammation, also is suspected of playing a role in the pathogenesis of psoriasis.^3,6 Studies have shown NGF prevents apoptosis of keratinocytes, activates T cells, and is found in higher levels in psoriatic skin compared to controls.^3,18,19 

Spontaneous Clearing of Psoriasis 

Spontaneous remission of psoriasis after cerebrovascular accident was first described in a case report published in 1998.²² Other cases have reported protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^23,24 Conversely, recurrence of skin lesions in areas corresponding to nervous system injury also have been reported in cases in which patients regained neurologic function; when permanent nerve damage was sustained, psoriasis did not recur,⁴ which confirms that peripheral nerves play a role in the pathogenesis of psoriasis.³ It is believed that peripheral nerve damage leads to reduced secretion of neuropeptides, and central nervous system injury can propagate similar downstream effects.^3,25 

Bottom Line

This case report describes spontaneous clearing of psoriasis following a cerebrovascular accident. Improvement in psoriasis in the absence of neural inputs suggest the nervous system plays a crucial role in the development of psoriatic disease.⁴ A better understanding of the neuropeptides involved in the neurologic-mediated clearance of psoriasis may contribute to the development of improved targeted therapies, specifically designed to target the neurologic aspects of psoriasis.³ Neuropeptides such as nerve growth factor, calcitonin gene-related peptide, and vasoactive intestinal peptide, and possibly SP may play an important role in the pathogenesis of psoriasis and may one day be ideal targets for novel therapies. 

Background

Psoriasis is a complex, multifactorial, systemic disease that is associated with numerous neurologic comorbidities, including stroke, multiple sclerosis, epilepsy, migraine, restless leg syndrome, Parkinson disease, and less frequently Guillain-Barré syndrome and myasthenia gravis. Anxiety and depression also are frequently seen in patients with psoriasis.¹ In recent years, heightened understanding of the pathogenesis and disease mechanisms involved in psoriasis has led to the development of therapies designed to help to control the chronic inflammation associated with the disease, such as immunobiologics and small molecules.² 

Nerves and Neuropeptides 

Psychological stress is known to exacerbate psoriasis, which points to the involvement of the nervous system in psoriasis.^3,5,6 In addition to provoking the sympathetic response, psychological stressors have been shown to affect the peripheral nervous system in psoriasis by modulating the skin’s network of nerves and neuropeptides.^6-11 A small study divided patients with psoriasis into low-stress and high-stress groups based on their clinical examinations and answers to questionnaires. Immunohistochemical analysis showed patients in the high-stress group had elevated levels of calcitonin gene-related peptide and vasoactive intestinal polypeptide as well as reduced levels of the neuropeptide-degrading enzyme chymase compared to the low-stress group.¹² Two later studies showed calcitonin gene-related peptide stimulates keratinocyte proliferation^3,13 and is found at increased levels in psoriatic skin.^3,14 Similarly, higher quantities of vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in psoriatic plaques compared to nonlesional and normal skin.^3,15 

Nerve growth factor (NGF), a principal mediator of neurogenic inflammation, also is suspected of playing a role in the pathogenesis of psoriasis.^3,6 Studies have shown NGF prevents apoptosis of keratinocytes, activates T cells, and is found in higher levels in psoriatic skin compared to controls.^3,18,19 

Spontaneous Clearing of Psoriasis 

Spontaneous remission of psoriasis after cerebrovascular accident was first described in a case report published in 1998.²² Other cases have reported protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^23,24 Conversely, recurrence of skin lesions in areas corresponding to nervous system injury also have been reported in cases in which patients regained neurologic function; when permanent nerve damage was sustained, psoriasis did not recur,⁴ which confirms that peripheral nerves play a role in the pathogenesis of psoriasis.³ It is believed that peripheral nerve damage leads to reduced secretion of neuropeptides, and central nervous system injury can propagate similar downstream effects.^3,25 

Bottom Line

This case report describes spontaneous clearing of psoriasis following a cerebrovascular accident. Improvement in psoriasis in the absence of neural inputs suggest the nervous system plays a crucial role in the development of psoriatic disease.⁴ A better understanding of the neuropeptides involved in the neurologic-mediated clearance of psoriasis may contribute to the development of improved targeted therapies, specifically designed to target the neurologic aspects of psoriasis.³ Neuropeptides such as nerve growth factor, calcitonin gene-related peptide, and vasoactive intestinal peptide, and possibly SP may play an important role in the pathogenesis of psoriasis and may one day be ideal targets for novel therapies. 

Background

Psoriasis is a complex, multifactorial, systemic disease that is associated with numerous neurologic comorbidities, including stroke, multiple sclerosis, epilepsy, migraine, restless leg syndrome, Parkinson disease, and less frequently Guillain-Barré syndrome and myasthenia gravis. Anxiety and depression also are frequently seen in patients with psoriasis.¹ In recent years, heightened understanding of the pathogenesis and disease mechanisms involved in psoriasis has led to the development of therapies designed to help to control the chronic inflammation associated with the disease, such as immunobiologics and small molecules.² 

Nerves and Neuropeptides 

Psychological stress is known to exacerbate psoriasis, which points to the involvement of the nervous system in psoriasis.^3,5,6 In addition to provoking the sympathetic response, psychological stressors have been shown to affect the peripheral nervous system in psoriasis by modulating the skin’s network of nerves and neuropeptides.^6-11 A small study divided patients with psoriasis into low-stress and high-stress groups based on their clinical examinations and answers to questionnaires. Immunohistochemical analysis showed patients in the high-stress group had elevated levels of calcitonin gene-related peptide and vasoactive intestinal polypeptide as well as reduced levels of the neuropeptide-degrading enzyme chymase compared to the low-stress group.¹² Two later studies showed calcitonin gene-related peptide stimulates keratinocyte proliferation^3,13 and is found at increased levels in psoriatic skin.^3,14 Similarly, higher quantities of vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in psoriatic plaques compared to nonlesional and normal skin.^3,15 

Nerve growth factor (NGF), a principal mediator of neurogenic inflammation, also is suspected of playing a role in the pathogenesis of psoriasis.^3,6 Studies have shown NGF prevents apoptosis of keratinocytes, activates T cells, and is found in higher levels in psoriatic skin compared to controls.^3,18,19 

Spontaneous Clearing of Psoriasis 

Spontaneous remission of psoriasis after cerebrovascular accident was first described in a case report published in 1998.²² Other cases have reported protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^23,24 Conversely, recurrence of skin lesions in areas corresponding to nervous system injury also have been reported in cases in which patients regained neurologic function; when permanent nerve damage was sustained, psoriasis did not recur,⁴ which confirms that peripheral nerves play a role in the pathogenesis of psoriasis.³ It is believed that peripheral nerve damage leads to reduced secretion of neuropeptides, and central nervous system injury can propagate similar downstream effects.^3,25 

Bottom Line

This case report describes spontaneous clearing of psoriasis following a cerebrovascular accident. Improvement in psoriasis in the absence of neural inputs suggest the nervous system plays a crucial role in the development of psoriatic disease.⁴ A better understanding of the neuropeptides involved in the neurologic-mediated clearance of psoriasis may contribute to the development of improved targeted therapies, specifically designed to target the neurologic aspects of psoriasis.³ Neuropeptides such as nerve growth factor, calcitonin gene-related peptide, and vasoactive intestinal peptide, and possibly SP may play an important role in the pathogenesis of psoriasis and may one day be ideal targets for novel therapies.