MDedge Dermatology

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Generalized pustular psoriasis (GPP) is a rare but severe subtype of psoriasis that can present with systemic symptoms and organ failure, sometimes leading to hospitalization and even death.^1,2 Due to the rarity of this subtype and GPP being excluded from clinical trials for plaque psoriasis, there is limited information on the optimal treatment of this disease.

More than 20 systemic medications have been described in the literature for treating GPP, including systemic steroids, traditional immunosuppressants, retinoids, and biologics, which often are used in combination; none have been consistently effective.³ Among biologic therapies, the use of tumor necrosis factor α as well as IL-12/23 and IL-17 inhibitors has been reported, with the least amount of experience with IL-17 inhibitors.⁴

A 53-year-old Korean woman presented to the dermatology clinic for evaluation of a widespread painful rash involving the face, neck, torso, arms, and legs that had been treated intermittently with systemic steroids by her primary care physician for several months before presentation. She had no relevant medical or dermatologic history. She denied taking prescription or over-the-counter medications.

Physical examination revealed the patient was afebrile, but she reported general malaise and chills. She had widespread erythematous, annular, scaly plaques that coalesced into polycyclic plaques studded with nonfollicular-based pustules on the forehead, frontal hairline, neck, chest, abdomen, back, arms, and legs (Figure 1).

Two 4-mm punch biopsies were performed for hematoxylin and eosin staining and direct immunofluorescence. Histopathologic analysis showed prominent subcorneal neutrophilic pustules and spongiform collections of neutrophils in the spinous layer without notable eosinophils (Figure 2). Direct immunofluorescence was negative.

Based on the clinical history, physical examination, histopathology, and unremarkable drug history, a diagnosis of GPP was made. Initially, acitretin 25 mg/d was prescribed, but the patient was unable to start treatment because the cost of the drug was prohibitive. Her condition worsened, and she returned to the clinic 2 days later. Based on knowledge of an ongoing phase 3, open-label study for risankizumab in GPP, a sample of risankizumab 150 mg was administered subcutaneously in this patient. Three days later, most of the pustules on the upper half of the patient’s body had dried up and she began to desquamate from head to toe (Figure 3).The patient developed notable edema of the lower extremities, which required furosemide 20 mg/d andibuprofen 600 mg every 6 hours for symptom relief.

Ten days after the initial dose of risankizumab, the patient continued to steadily improve. All the pustules had dried up and she was already showing signs of re-epithelialization. Edema and pain also had notably improved. She received 2 additional samples of risankizumab 150 mg at weeks 4 and 16, at which point she was able to receive compassionate care through the drug manufacturer’s program. At follow-up 151 days after the initial dose of risankizumab, the patient’s skin was completely clear.

Generalized pustular psoriasis remains a difficult disease to study, given its rarity and unpredictable course. Spesolimab, a humanized anti–IL-36 receptor monoclonal antibody, was recently approved by the US Food and Drug Administration (FDA) for the treatment of GPP.⁵ In the pivotal trial (ClinicalTrials.gov Identifier NCT03782792),⁵ an astonishingly high 54% of patients (19/35) given a single dose of intravenous spesolimab reached the primary end point of no pustules at day 7. However, safety concerns, such as serious infections and severe cutaneous adverse reactions, as well as logistical challenges that come with intravenous administration for an acute disease, may prevent widespread adoption by community dermatologists.

Tumor necrosis factor α, IL-17, and IL-23 inhibitors currently are approved for the treatment of GPP in Japan, Thailand, and Taiwan based on small, nonrandomized, open-label studies.^6-10 More recently, results from a phase 3, randomized, open-label study to assess the efficacy and safety of 2 different dosing regimens of risankizumab with 8 Japanese patients with GPP were published.¹¹ However, there currently is only a single approved medication for GPP in Europe and the United States. Therefore, additional therapies, particularly those that have already been established in dermatology, would be welcome in treating this disease.

A number of questions still need to be answered regarding treating GPP with risankizumab:

• What is the optimal dose and schedule of this drug? Our patient received the standard 150-mg dose that is FDA approved for moderate to severe plaque psoriasis; would a higher dose, such as the FDA-approved 600-mg dosing used to treat Crohn disease, have led to a more rapid and durable response?¹²

• For how long should these patients be treated? Will their disease follow the same course as psoriasis vulgaris, requiring long-term, continuous treatment?

• An ongoing 5-year, open-label extension study of spesolimab might eventually answer that question and currently is recruiting participants (NCT03886246).

• Is there a way to predict a priori which patients will be responders? Biomarkers—especially through the use of tape stripping—are promising, but validation studies are still needed.¹³

• Because 69% (24/35) of enrolled patients in the treatment group of the spesolimab trial did not harbor a mutation of the IL36RN gene, how reliable is mutation status in predicting treatment response?⁵

Of note, some of these questions also apply to guttate psoriasis, a far more common subtype of psoriasis that also is worth exploring.

Nevertheless, these are exciting times for patients with GPP. What was once considered an obscure orphan disease is the focus of major recent publications³ and phase 3, randomized, placebo-controlled studies.⁵ We can be cautiously optimistic that in the next few years we will be in a better position to care for patients with GPP.

To the Editor:

Because the SARS-CoV-2 virus is constantly changing, routine vaccination to prevent COVID-19 infection is recommended. The messenger RNA (mRNA) vaccines from Pfizer-BioNTech and Moderna as well as the Ad26.COV2.S (Johnson & Johnson) and NVX-CoV2373 (Novavax) vaccines are the most commonly used COVID-19 vaccines in the United States. Adverse effects following vaccination against SARS-CoV-2 are well documented; recent studies report a small incidence of adverse effects in the general population, with most being minor (eg, headache, fever, muscle pain).^1,2 Interestingly, reports of exacerbation of psoriasis and new-onset psoriasis following COVID-19 vaccination suggest a potential association.^3,4 However, the literature investigating the vaccine adverse effect profile in this demographic is scarce. We examined the incidence of adverse effects from SARS-CoV-2 vaccines in patients with psoriasis.

This retrospective cohort study used the COVID-19 Research Database (https://covid19researchdatabase.org/) to examine the adverse effects following the first and second doses of the mRNA vaccines in patients with and without psoriasis. The sample size for the Ad26.COV2.S vaccine was too small to analyze.

Claims were evaluated from August to October 2021 for 2 diagnoses of psoriasis prior to January 1, 2020, using the International Classification of Diseases, Tenth Revision (ICD-10) code L40.9 to increase the positive predictive value and ensure that the diagnosis preceded the COVID-19 pandemic. Patients younger than 18 years and those who did not receive 2 doses of a SARS-CoV-2 vaccine were excluded. Controls who did not have a diagnosis of psoriasis were matched for age, sex, and hypertension at a 4:1 ratio. Hypertension represented the most common comorbidity that could feasibly be controlled for in this study population. Other comorbidities recorded included obesity, type 2 diabetes mellitus, congestive heart failure, asthma, chronic obstructive pulmonary disease, chronic ischemic heart disease, rhinitis, and chronic kidney disease.

Common adverse effects as long as 30 days after vaccination were identified using ICD-10 codes. Adverse effects of interest were anaphylactic reaction, initial encounter of adverse effect of viral vaccines, fever, allergic urticaria, weakness, altered mental status, malaise, allergic reaction, chest pain, symptoms involving circulatory or respiratory systems, localized rash, axillary lymphadenopathy, infection, and myocarditis.⁵ Poisson regression was performed using Stata 17 analytical software.

We identified 4273 patients with psoriasis and 17,092 controls who received mRNA COVID-19 vaccines (Table). Adjusted odds ratios (aORs) for doses 1 and 2 were calculated for each vaccine (eTable). Adverse effects with sufficient data to generate an aOR included weakness, altered mental status, malaise, chest pain, and symptoms involving the circulatory or respiratory system. The aORs for allergic urticaria and initial encounter of adverse effect of viral vaccines were only calculated for the Moderna mRNA vaccine due to low sample size.

This study demonstrated that patients with psoriasis do not appear to have a significantly increased risk of adverse effects from mRNA SARS-CoV-2 vaccines. Although the ORs in this study were not significant, most recorded adverse effects demonstrated an aOR less than 1, suggesting that there might be a lower risk of certain adverse effects in psoriasis patients. This could be explained by the immunomodulatory effects of certain systemic psoriasis treatments that might influence the adverse effect presentation.

The study is limited by the lack of treatment data, small sample size, and the fact that it did not assess flares or worsening of psoriasis with the vaccines. Underreporting of adverse effects by patients and underdiagnosis of adverse effects secondary to SARS-CoV-2 vaccines due to its novel nature, incompletely understood consequences, and limited ICD-10 codes associated with adverse effects all contributed to the small sample size.

Our findings suggest that the risk for immediate adverse effects from the mRNA SARS-CoV-2 vaccines is not increased among psoriasis patients. However, the impact of immunomodulatory agents on vaccine efficacy and expected adverse effects should be investigated. As more individuals receive the COVID-19 vaccine, the adverse effect profile in patients with psoriasis is an important area of investigation.

To the Editor:

Because the SARS-CoV-2 virus is constantly changing, routine vaccination to prevent COVID-19 infection is recommended. The messenger RNA (mRNA) vaccines from Pfizer-BioNTech and Moderna as well as the Ad26.COV2.S (Johnson & Johnson) and NVX-CoV2373 (Novavax) vaccines are the most commonly used COVID-19 vaccines in the United States. Adverse effects following vaccination against SARS-CoV-2 are well documented; recent studies report a small incidence of adverse effects in the general population, with most being minor (eg, headache, fever, muscle pain).^1,2 Interestingly, reports of exacerbation of psoriasis and new-onset psoriasis following COVID-19 vaccination suggest a potential association.^3,4 However, the literature investigating the vaccine adverse effect profile in this demographic is scarce. We examined the incidence of adverse effects from SARS-CoV-2 vaccines in patients with psoriasis.

This retrospective cohort study used the COVID-19 Research Database (https://covid19researchdatabase.org/) to examine the adverse effects following the first and second doses of the mRNA vaccines in patients with and without psoriasis. The sample size for the Ad26.COV2.S vaccine was too small to analyze.

Claims were evaluated from August to October 2021 for 2 diagnoses of psoriasis prior to January 1, 2020, using the International Classification of Diseases, Tenth Revision (ICD-10) code L40.9 to increase the positive predictive value and ensure that the diagnosis preceded the COVID-19 pandemic. Patients younger than 18 years and those who did not receive 2 doses of a SARS-CoV-2 vaccine were excluded. Controls who did not have a diagnosis of psoriasis were matched for age, sex, and hypertension at a 4:1 ratio. Hypertension represented the most common comorbidity that could feasibly be controlled for in this study population. Other comorbidities recorded included obesity, type 2 diabetes mellitus, congestive heart failure, asthma, chronic obstructive pulmonary disease, chronic ischemic heart disease, rhinitis, and chronic kidney disease.

Common adverse effects as long as 30 days after vaccination were identified using ICD-10 codes. Adverse effects of interest were anaphylactic reaction, initial encounter of adverse effect of viral vaccines, fever, allergic urticaria, weakness, altered mental status, malaise, allergic reaction, chest pain, symptoms involving circulatory or respiratory systems, localized rash, axillary lymphadenopathy, infection, and myocarditis.⁵ Poisson regression was performed using Stata 17 analytical software.

We identified 4273 patients with psoriasis and 17,092 controls who received mRNA COVID-19 vaccines (Table). Adjusted odds ratios (aORs) for doses 1 and 2 were calculated for each vaccine (eTable). Adverse effects with sufficient data to generate an aOR included weakness, altered mental status, malaise, chest pain, and symptoms involving the circulatory or respiratory system. The aORs for allergic urticaria and initial encounter of adverse effect of viral vaccines were only calculated for the Moderna mRNA vaccine due to low sample size.

This study demonstrated that patients with psoriasis do not appear to have a significantly increased risk of adverse effects from mRNA SARS-CoV-2 vaccines. Although the ORs in this study were not significant, most recorded adverse effects demonstrated an aOR less than 1, suggesting that there might be a lower risk of certain adverse effects in psoriasis patients. This could be explained by the immunomodulatory effects of certain systemic psoriasis treatments that might influence the adverse effect presentation.

The study is limited by the lack of treatment data, small sample size, and the fact that it did not assess flares or worsening of psoriasis with the vaccines. Underreporting of adverse effects by patients and underdiagnosis of adverse effects secondary to SARS-CoV-2 vaccines due to its novel nature, incompletely understood consequences, and limited ICD-10 codes associated with adverse effects all contributed to the small sample size.

Our findings suggest that the risk for immediate adverse effects from the mRNA SARS-CoV-2 vaccines is not increased among psoriasis patients. However, the impact of immunomodulatory agents on vaccine efficacy and expected adverse effects should be investigated. As more individuals receive the COVID-19 vaccine, the adverse effect profile in patients with psoriasis is an important area of investigation.

To the Editor:

Because the SARS-CoV-2 virus is constantly changing, routine vaccination to prevent COVID-19 infection is recommended. The messenger RNA (mRNA) vaccines from Pfizer-BioNTech and Moderna as well as the Ad26.COV2.S (Johnson & Johnson) and NVX-CoV2373 (Novavax) vaccines are the most commonly used COVID-19 vaccines in the United States. Adverse effects following vaccination against SARS-CoV-2 are well documented; recent studies report a small incidence of adverse effects in the general population, with most being minor (eg, headache, fever, muscle pain).^1,2 Interestingly, reports of exacerbation of psoriasis and new-onset psoriasis following COVID-19 vaccination suggest a potential association.^3,4 However, the literature investigating the vaccine adverse effect profile in this demographic is scarce. We examined the incidence of adverse effects from SARS-CoV-2 vaccines in patients with psoriasis.

This retrospective cohort study used the COVID-19 Research Database (https://covid19researchdatabase.org/) to examine the adverse effects following the first and second doses of the mRNA vaccines in patients with and without psoriasis. The sample size for the Ad26.COV2.S vaccine was too small to analyze.

Claims were evaluated from August to October 2021 for 2 diagnoses of psoriasis prior to January 1, 2020, using the International Classification of Diseases, Tenth Revision (ICD-10) code L40.9 to increase the positive predictive value and ensure that the diagnosis preceded the COVID-19 pandemic. Patients younger than 18 years and those who did not receive 2 doses of a SARS-CoV-2 vaccine were excluded. Controls who did not have a diagnosis of psoriasis were matched for age, sex, and hypertension at a 4:1 ratio. Hypertension represented the most common comorbidity that could feasibly be controlled for in this study population. Other comorbidities recorded included obesity, type 2 diabetes mellitus, congestive heart failure, asthma, chronic obstructive pulmonary disease, chronic ischemic heart disease, rhinitis, and chronic kidney disease.

Common adverse effects as long as 30 days after vaccination were identified using ICD-10 codes. Adverse effects of interest were anaphylactic reaction, initial encounter of adverse effect of viral vaccines, fever, allergic urticaria, weakness, altered mental status, malaise, allergic reaction, chest pain, symptoms involving circulatory or respiratory systems, localized rash, axillary lymphadenopathy, infection, and myocarditis.⁵ Poisson regression was performed using Stata 17 analytical software.

We identified 4273 patients with psoriasis and 17,092 controls who received mRNA COVID-19 vaccines (Table). Adjusted odds ratios (aORs) for doses 1 and 2 were calculated for each vaccine (eTable). Adverse effects with sufficient data to generate an aOR included weakness, altered mental status, malaise, chest pain, and symptoms involving the circulatory or respiratory system. The aORs for allergic urticaria and initial encounter of adverse effect of viral vaccines were only calculated for the Moderna mRNA vaccine due to low sample size.

This study demonstrated that patients with psoriasis do not appear to have a significantly increased risk of adverse effects from mRNA SARS-CoV-2 vaccines. Although the ORs in this study were not significant, most recorded adverse effects demonstrated an aOR less than 1, suggesting that there might be a lower risk of certain adverse effects in psoriasis patients. This could be explained by the immunomodulatory effects of certain systemic psoriasis treatments that might influence the adverse effect presentation.

The study is limited by the lack of treatment data, small sample size, and the fact that it did not assess flares or worsening of psoriasis with the vaccines. Underreporting of adverse effects by patients and underdiagnosis of adverse effects secondary to SARS-CoV-2 vaccines due to its novel nature, incompletely understood consequences, and limited ICD-10 codes associated with adverse effects all contributed to the small sample size.

Our findings suggest that the risk for immediate adverse effects from the mRNA SARS-CoV-2 vaccines is not increased among psoriasis patients. However, the impact of immunomodulatory agents on vaccine efficacy and expected adverse effects should be investigated. As more individuals receive the COVID-19 vaccine, the adverse effect profile in patients with psoriasis is an important area of investigation.

Consultations and referrals are an important component of many dermatology practices. There are several families of consultation codes that can be utilized based on the setting and format of the patient encounter. In this article, I describe appropriate use of 3 families of consultation codes and recent updates in these areas.

Consultation Definitions

For all of these code sets, the same definition of consultationapplies—namely that the encounter is provided at the request of another physician, other qualified health care professional, or other appropriate source (eg, nonclinical social worker, educator, lawyer, insurance company) for a specific condition or problem. Importantly, a consultation initiated by a patient or family, or both, and not requested by one of the professionals listed above is not reported using a consultation code.¹

The consultant’s opinion and any services that were ordered or performed also must be communicated to the requesting provider. The type of communication required varies based on the consultation code set in question.

Outpatient Consultation Codes

Outpatient consultation CPT (Current Procedural Terminology) codes (99241-99245) are a family of codes that can be utilized for evaluation of a new patient or an existing patient with a new problem in the outpatient setting. These codes are not reimbursed by the Centers for Medicare & Medicaid Services, but some private payers do recognize and reimburse for them.²

The consultant’s opinion and any services that were ordered or performed must be communicated by written report to the requesting physician, other qualified health care professional, or other appropriate source. If a consultation is mandated (eg, by a third-party payer), then modifier -32 also should be reported.¹ Modifier -32 should not be used for a second request by a patient or a patient’s family.¹

This family of codes has been revised in tandem with other evaluation and management (E/M) code sets; changes went into effect January 1, 2023. These updates are part of the ongoing effort to update code wording and structures to reflect guiding principles of the American Medical Association when redesigning E/M codes. These principles include decreasing administrative burden and the need for audits, decreasing unnecessary documentation that is not needed for patient care, and ensuring that payment for E/M is resource based.³ Updated code language and payment structure is found in Table 1.^1,2 The main updates to these codes include:

• Code 99241 was deleted. This was in line with removal of 99201 from the outpatient E/M family set.

• Level of service is now based solely on either time on the date of encounter or medical decision-making.

• Definitions regarding medical decision-making are in line with those utilized for outpatient E/M codes.

• If coding by time and the maximum amount of time has been exceeded by 15 or more minutes, prolonged services code 99417 can be utilized.

Inpatient Consultation Codes

Similar to the outpatient consultation codes, the inpatient consultation codes also have been revised as part of E/M updates; revisions went into effect January 1, 2023. Also, as with the outpatient consultation codes, the consultant’s opinion and any services that were ordered or performed must be communicated by written report to the requesting physician, other qualified health care professional, or other appropriate source. If a consultation is mandated (eg, by a third-party payer), then modifier -32 also should be reported.¹

When inpatient consultations are performed, 2 code families generally are utilized. For initial consultation, initial inpatient consultation codes (99251-99255) are used; for any follow-up encounters performed while the patient is an inpatient, subsequent inpatient consultation codes (99231-99233) are used. The subsequent code family is the same that is utilized for all subsequent care within the inpatient or observation care setting, regardless of how the care was initiated.¹

“Initial service” is when the patient has not received any professional services from either the physician or other qualified health care professional or from another physician or other qualified health care professional ofthe exact same specialty and subspecialty who belongs to the same group practice during the inpatient, observation, or nursing facility admission and stay. “Subsequent service” is when the patient has received professional service(s) from either the physician or other qualified health care professional or from another physician or other qualified health care professional.¹ Updated code language and payment structure is found in Table 2.^1,2 Major changes include:

• Code 99251 was deleted. This is in line with deletion of a new low-level patient encounter in the outpatient E/M family set and consultation code family set, as noted above.

• Level of service is now based solely on either time on the date of encounter or medical decision-making.

• Definitions regarding medical decision-making are in line with those utilized for outpatient E/M codes.

• If coding by time and the maximum amount of time has been exceeded by 15 or more minutes, prolonged services code 993X0 can be utilized.

Interprofessional Consultation Codes

An additional code family that can be utilized for consultations is the interprofessional consultation codes. These codes can be utilized when assisting in the diagnosis or management, or both, of a patient without face-to-face contact. These codes are listed in Table 3.^2,4 For all of these codes, the consultation is performed by telephone, internet or electronic health record, or a combination of these means. The consultation can be for a new problem or a worsening existing problem. The patient can be a new or established patient to the consultant. Documentation should be performed in the patient’s medical record, including the reason for the request.

To bill for interprofessional consultation, the consultant should not have seen the patient in a face-to-face encounter within the prior 14 days or see them in the following 14 days. The codes should not be reported more than once in a 7-day period or more than once in a 14-day period in the case of code 99452.⁴ For codes 99446 to 99449, more than 50% of the time spent by the consulting physician must be devoted to verbal or internet discussion, or both, with the referring physician. For code 99451, service time is based on total review and interprofessional communication time.⁴ The correct code is chosen based on the following parameters:

• 99446-99449: Describes interprofessional consultation services, which include both a written and a verbal report to the patient’s treating or requesting physician or qualified health care professional. These codes can be utilized by a consulting physician. The correct code is chosen based on time spent by the consulting physician.

• 99451: Describes an interprofessional consultation service, which includes a written report to the patient’s treating or requesting physician or qualified health care professional. This code can be utilized by a consulting physician once 5 minutes of consultative discussion and review has been performed.

• 99452: Describes an interprofessional consultation service provided by the requesting physician. This code can be utilized when a requesting physician spends 16 to 30 minutes in medical consultative discussion and review.

Final Thoughts

Consultation codes can be an important part of a dermatologist’s practice. Differences exist between consultation code sets based on the encounter setting and whether the encounter was performed with or without face-to-face contact. In addition, updates to the E/M inpatient and outpatient consultation codes went into effect January 1, 2023. It is important to understand those changes to correctly bill for these encounters.

Consultations and referrals are an important component of many dermatology practices. There are several families of consultation codes that can be utilized based on the setting and format of the patient encounter. In this article, I describe appropriate use of 3 families of consultation codes and recent updates in these areas.

Consultation Definitions

For all of these code sets, the same definition of consultationapplies—namely that the encounter is provided at the request of another physician, other qualified health care professional, or other appropriate source (eg, nonclinical social worker, educator, lawyer, insurance company) for a specific condition or problem. Importantly, a consultation initiated by a patient or family, or both, and not requested by one of the professionals listed above is not reported using a consultation code.¹

The consultant’s opinion and any services that were ordered or performed also must be communicated to the requesting provider. The type of communication required varies based on the consultation code set in question.

Outpatient Consultation Codes

Outpatient consultation CPT (Current Procedural Terminology) codes (99241-99245) are a family of codes that can be utilized for evaluation of a new patient or an existing patient with a new problem in the outpatient setting. These codes are not reimbursed by the Centers for Medicare & Medicaid Services, but some private payers do recognize and reimburse for them.²

The consultant’s opinion and any services that were ordered or performed must be communicated by written report to the requesting physician, other qualified health care professional, or other appropriate source. If a consultation is mandated (eg, by a third-party payer), then modifier -32 also should be reported.¹ Modifier -32 should not be used for a second request by a patient or a patient’s family.¹

This family of codes has been revised in tandem with other evaluation and management (E/M) code sets; changes went into effect January 1, 2023. These updates are part of the ongoing effort to update code wording and structures to reflect guiding principles of the American Medical Association when redesigning E/M codes. These principles include decreasing administrative burden and the need for audits, decreasing unnecessary documentation that is not needed for patient care, and ensuring that payment for E/M is resource based.³ Updated code language and payment structure is found in Table 1.^1,2 The main updates to these codes include:

• Code 99241 was deleted. This was in line with removal of 99201 from the outpatient E/M family set.

• Level of service is now based solely on either time on the date of encounter or medical decision-making.

• Definitions regarding medical decision-making are in line with those utilized for outpatient E/M codes.

• If coding by time and the maximum amount of time has been exceeded by 15 or more minutes, prolonged services code 99417 can be utilized.

Inpatient Consultation Codes

Similar to the outpatient consultation codes, the inpatient consultation codes also have been revised as part of E/M updates; revisions went into effect January 1, 2023. Also, as with the outpatient consultation codes, the consultant’s opinion and any services that were ordered or performed must be communicated by written report to the requesting physician, other qualified health care professional, or other appropriate source. If a consultation is mandated (eg, by a third-party payer), then modifier -32 also should be reported.¹

When inpatient consultations are performed, 2 code families generally are utilized. For initial consultation, initial inpatient consultation codes (99251-99255) are used; for any follow-up encounters performed while the patient is an inpatient, subsequent inpatient consultation codes (99231-99233) are used. The subsequent code family is the same that is utilized for all subsequent care within the inpatient or observation care setting, regardless of how the care was initiated.¹

“Initial service” is when the patient has not received any professional services from either the physician or other qualified health care professional or from another physician or other qualified health care professional ofthe exact same specialty and subspecialty who belongs to the same group practice during the inpatient, observation, or nursing facility admission and stay. “Subsequent service” is when the patient has received professional service(s) from either the physician or other qualified health care professional or from another physician or other qualified health care professional.¹ Updated code language and payment structure is found in Table 2.^1,2 Major changes include:

• Code 99251 was deleted. This is in line with deletion of a new low-level patient encounter in the outpatient E/M family set and consultation code family set, as noted above.

• Level of service is now based solely on either time on the date of encounter or medical decision-making.

• Definitions regarding medical decision-making are in line with those utilized for outpatient E/M codes.

• If coding by time and the maximum amount of time has been exceeded by 15 or more minutes, prolonged services code 993X0 can be utilized.

Interprofessional Consultation Codes

An additional code family that can be utilized for consultations is the interprofessional consultation codes. These codes can be utilized when assisting in the diagnosis or management, or both, of a patient without face-to-face contact. These codes are listed in Table 3.^2,4 For all of these codes, the consultation is performed by telephone, internet or electronic health record, or a combination of these means. The consultation can be for a new problem or a worsening existing problem. The patient can be a new or established patient to the consultant. Documentation should be performed in the patient’s medical record, including the reason for the request.

To bill for interprofessional consultation, the consultant should not have seen the patient in a face-to-face encounter within the prior 14 days or see them in the following 14 days. The codes should not be reported more than once in a 7-day period or more than once in a 14-day period in the case of code 99452.⁴ For codes 99446 to 99449, more than 50% of the time spent by the consulting physician must be devoted to verbal or internet discussion, or both, with the referring physician. For code 99451, service time is based on total review and interprofessional communication time.⁴ The correct code is chosen based on the following parameters:

• 99446-99449: Describes interprofessional consultation services, which include both a written and a verbal report to the patient’s treating or requesting physician or qualified health care professional. These codes can be utilized by a consulting physician. The correct code is chosen based on time spent by the consulting physician.

• 99451: Describes an interprofessional consultation service, which includes a written report to the patient’s treating or requesting physician or qualified health care professional. This code can be utilized by a consulting physician once 5 minutes of consultative discussion and review has been performed.

• 99452: Describes an interprofessional consultation service provided by the requesting physician. This code can be utilized when a requesting physician spends 16 to 30 minutes in medical consultative discussion and review.

Final Thoughts

Consultation codes can be an important part of a dermatologist’s practice. Differences exist between consultation code sets based on the encounter setting and whether the encounter was performed with or without face-to-face contact. In addition, updates to the E/M inpatient and outpatient consultation codes went into effect January 1, 2023. It is important to understand those changes to correctly bill for these encounters.

Consultations and referrals are an important component of many dermatology practices. There are several families of consultation codes that can be utilized based on the setting and format of the patient encounter. In this article, I describe appropriate use of 3 families of consultation codes and recent updates in these areas.

Consultation Definitions

For all of these code sets, the same definition of consultationapplies—namely that the encounter is provided at the request of another physician, other qualified health care professional, or other appropriate source (eg, nonclinical social worker, educator, lawyer, insurance company) for a specific condition or problem. Importantly, a consultation initiated by a patient or family, or both, and not requested by one of the professionals listed above is not reported using a consultation code.¹

The consultant’s opinion and any services that were ordered or performed also must be communicated to the requesting provider. The type of communication required varies based on the consultation code set in question.

Outpatient Consultation Codes

Outpatient consultation CPT (Current Procedural Terminology) codes (99241-99245) are a family of codes that can be utilized for evaluation of a new patient or an existing patient with a new problem in the outpatient setting. These codes are not reimbursed by the Centers for Medicare & Medicaid Services, but some private payers do recognize and reimburse for them.²

The consultant’s opinion and any services that were ordered or performed must be communicated by written report to the requesting physician, other qualified health care professional, or other appropriate source. If a consultation is mandated (eg, by a third-party payer), then modifier -32 also should be reported.¹ Modifier -32 should not be used for a second request by a patient or a patient’s family.¹

This family of codes has been revised in tandem with other evaluation and management (E/M) code sets; changes went into effect January 1, 2023. These updates are part of the ongoing effort to update code wording and structures to reflect guiding principles of the American Medical Association when redesigning E/M codes. These principles include decreasing administrative burden and the need for audits, decreasing unnecessary documentation that is not needed for patient care, and ensuring that payment for E/M is resource based.³ Updated code language and payment structure is found in Table 1.^1,2 The main updates to these codes include:

• Code 99241 was deleted. This was in line with removal of 99201 from the outpatient E/M family set.

• Level of service is now based solely on either time on the date of encounter or medical decision-making.

• Definitions regarding medical decision-making are in line with those utilized for outpatient E/M codes.

• If coding by time and the maximum amount of time has been exceeded by 15 or more minutes, prolonged services code 99417 can be utilized.

Inpatient Consultation Codes

Similar to the outpatient consultation codes, the inpatient consultation codes also have been revised as part of E/M updates; revisions went into effect January 1, 2023. Also, as with the outpatient consultation codes, the consultant’s opinion and any services that were ordered or performed must be communicated by written report to the requesting physician, other qualified health care professional, or other appropriate source. If a consultation is mandated (eg, by a third-party payer), then modifier -32 also should be reported.¹

When inpatient consultations are performed, 2 code families generally are utilized. For initial consultation, initial inpatient consultation codes (99251-99255) are used; for any follow-up encounters performed while the patient is an inpatient, subsequent inpatient consultation codes (99231-99233) are used. The subsequent code family is the same that is utilized for all subsequent care within the inpatient or observation care setting, regardless of how the care was initiated.¹

“Initial service” is when the patient has not received any professional services from either the physician or other qualified health care professional or from another physician or other qualified health care professional ofthe exact same specialty and subspecialty who belongs to the same group practice during the inpatient, observation, or nursing facility admission and stay. “Subsequent service” is when the patient has received professional service(s) from either the physician or other qualified health care professional or from another physician or other qualified health care professional.¹ Updated code language and payment structure is found in Table 2.^1,2 Major changes include:

• Code 99251 was deleted. This is in line with deletion of a new low-level patient encounter in the outpatient E/M family set and consultation code family set, as noted above.

• Level of service is now based solely on either time on the date of encounter or medical decision-making.

• Definitions regarding medical decision-making are in line with those utilized for outpatient E/M codes.

• If coding by time and the maximum amount of time has been exceeded by 15 or more minutes, prolonged services code 993X0 can be utilized.

Interprofessional Consultation Codes

An additional code family that can be utilized for consultations is the interprofessional consultation codes. These codes can be utilized when assisting in the diagnosis or management, or both, of a patient without face-to-face contact. These codes are listed in Table 3.^2,4 For all of these codes, the consultation is performed by telephone, internet or electronic health record, or a combination of these means. The consultation can be for a new problem or a worsening existing problem. The patient can be a new or established patient to the consultant. Documentation should be performed in the patient’s medical record, including the reason for the request.

To bill for interprofessional consultation, the consultant should not have seen the patient in a face-to-face encounter within the prior 14 days or see them in the following 14 days. The codes should not be reported more than once in a 7-day period or more than once in a 14-day period in the case of code 99452.⁴ For codes 99446 to 99449, more than 50% of the time spent by the consulting physician must be devoted to verbal or internet discussion, or both, with the referring physician. For code 99451, service time is based on total review and interprofessional communication time.⁴ The correct code is chosen based on the following parameters:

• 99446-99449: Describes interprofessional consultation services, which include both a written and a verbal report to the patient’s treating or requesting physician or qualified health care professional. These codes can be utilized by a consulting physician. The correct code is chosen based on time spent by the consulting physician.

• 99451: Describes an interprofessional consultation service, which includes a written report to the patient’s treating or requesting physician or qualified health care professional. This code can be utilized by a consulting physician once 5 minutes of consultative discussion and review has been performed.

• 99452: Describes an interprofessional consultation service provided by the requesting physician. This code can be utilized when a requesting physician spends 16 to 30 minutes in medical consultative discussion and review.

Final Thoughts

Consultation codes can be an important part of a dermatologist’s practice. Differences exist between consultation code sets based on the encounter setting and whether the encounter was performed with or without face-to-face contact. In addition, updates to the E/M inpatient and outpatient consultation codes went into effect January 1, 2023. It is important to understand those changes to correctly bill for these encounters.

New treatments for psoriasis constitute an embarrassment of riches compared to any other area of dermatology. Despite the many advances over the last 25 years, additional topical and systemic treatments have recently become available. Gosh, it’s great!

In May 2022, once-daily tapinarof cream 1% was approved for the topical treatment of plaque psoriasis in adults.¹ Tapinarof was identified as a metabolite made by bacteria symbiotic to a nematode, allowing the nematode to infect insects.² Tapinarof’s anti-inflammatory effect extends to mammals. The drug works by activating the aryl hydrocarbon receptor, downregulating proinflammatory cytokines such as IL-17, and normalizing the expression of skin barrier proteins such as filaggrin.² In two 12-week, phase 3, randomized trials with 510 and 515 patients, respectively, 35% to 40% of tapinarof-treated psoriasis patients were clear or almost clear compared with only 6% of patients in the placebo group. The drug appears safe; common adverse events (AEs) included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.³

A second new topical treatment for plaque psoriasis was approved in July 2022—once-daily roflumilast 0.3% cream—for patients 12 years and older.⁴ Similar to apremilast, roflumilast is a phosphodiesterase 4 inhibitor that blocks the degradation of cAMP and reduces the downstream production of inflammatory molecules implicated in psoriasis.⁵ In two 8-week, phase 3 clinical trials (ClinicalTrials.gov Identifiers NCT04211363 and NCT04211389)(N=881), approximately 40% of roflumilast-treated patients were clear or almost clear vs approximately 6% in the placebo group. Topical roflumilast was well-tolerated; the most common AEs included diarrhea, headache, insomnia, nausea, application-site pain, upper respiratory tract infection, and urinary tract infection.⁶

We have so many patients—and many more people with psoriasis who are not yet patients—with limited psoriasis who would be amenable to topical treatment but who are not responding to current treatments. There is considerable enthusiasm for the new topicals, but it is still questionable how much they will help our patients. The main reason the current topicals fail is poor adherence to the treatment. If we give these new treatments to patients who used existing topicals and failed, thereby inadvertently selecting patients with poor adherence to topicals, it will be surprising if the new treatments live up to expectations. Perhaps tapinarof and roflumilast will revolutionize the management of localized psoriasis; perhaps their impact will be similar to topical crisaborole— exciting in trials and less practical in real life. It may be that apremilast, which is now approved for psoriasis of any severity, will make a bigger difference for patients who can access it for limited psoriasis.

Deucravacitinib is a once-daily oral selective tyrosine kinase 2 inhibitor that blocks IL-23 and type I interferon signaling. It was approved for adults with moderate to severe plaque psoriasis in September 2021.⁷ We know patients want oral treatment; they ask for apremilast even though injections may be much more potent. In a 16-week, phase 3 clinical trial comparing daily deucravacitinib (n=332), apremilast (n=168), and placebo (n=166), rates of clear or almost clear were approximately 55% in the deucravacitinib group, 32% in the apremilast group, and 7% with placebo. The most common AEs included nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.⁸ Although deucravacitinib is much more effective than apremilast, deucravacitinib will require monitoring and may have some risk for viral reactivation of herpes simplex and zoster (and hopefully not much else). Whether physicians view it as a replacement for apremilast, which requires no laboratory monitoring, remains to be seen.

Bimekizumab, a humanized monoclonal IgG1 antibody expected to receive US Food and Drug Administration approval in the coming months, inhibits both IL-17A and IL-17F and may become our most effective treatment of psoriasis. Although we are probably not hungering for a more effective psoriasis treatment (given our current embarrassment of riches), bimekizumab’s remarkably high efficacy for psoriatic arthritis may be a quantum leap forward, especially if no new safety signals are identified; bimekizumab treatment is associated with a higher risk of oral candidiasis than other currently available IL-17 antagonists.⁹ Biosimilars may reduce the cost of psoriasis management to the health system, but it seems unlikely that biosimilars will allow us to help patients who we cannot already help with the existing extensive psoriasis treatment armamentarium.

New treatments for psoriasis constitute an embarrassment of riches compared to any other area of dermatology. Despite the many advances over the last 25 years, additional topical and systemic treatments have recently become available. Gosh, it’s great!

In May 2022, once-daily tapinarof cream 1% was approved for the topical treatment of plaque psoriasis in adults.¹ Tapinarof was identified as a metabolite made by bacteria symbiotic to a nematode, allowing the nematode to infect insects.² Tapinarof’s anti-inflammatory effect extends to mammals. The drug works by activating the aryl hydrocarbon receptor, downregulating proinflammatory cytokines such as IL-17, and normalizing the expression of skin barrier proteins such as filaggrin.² In two 12-week, phase 3, randomized trials with 510 and 515 patients, respectively, 35% to 40% of tapinarof-treated psoriasis patients were clear or almost clear compared with only 6% of patients in the placebo group. The drug appears safe; common adverse events (AEs) included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.³

A second new topical treatment for plaque psoriasis was approved in July 2022—once-daily roflumilast 0.3% cream—for patients 12 years and older.⁴ Similar to apremilast, roflumilast is a phosphodiesterase 4 inhibitor that blocks the degradation of cAMP and reduces the downstream production of inflammatory molecules implicated in psoriasis.⁵ In two 8-week, phase 3 clinical trials (ClinicalTrials.gov Identifiers NCT04211363 and NCT04211389)(N=881), approximately 40% of roflumilast-treated patients were clear or almost clear vs approximately 6% in the placebo group. Topical roflumilast was well-tolerated; the most common AEs included diarrhea, headache, insomnia, nausea, application-site pain, upper respiratory tract infection, and urinary tract infection.⁶

We have so many patients—and many more people with psoriasis who are not yet patients—with limited psoriasis who would be amenable to topical treatment but who are not responding to current treatments. There is considerable enthusiasm for the new topicals, but it is still questionable how much they will help our patients. The main reason the current topicals fail is poor adherence to the treatment. If we give these new treatments to patients who used existing topicals and failed, thereby inadvertently selecting patients with poor adherence to topicals, it will be surprising if the new treatments live up to expectations. Perhaps tapinarof and roflumilast will revolutionize the management of localized psoriasis; perhaps their impact will be similar to topical crisaborole— exciting in trials and less practical in real life. It may be that apremilast, which is now approved for psoriasis of any severity, will make a bigger difference for patients who can access it for limited psoriasis.

Deucravacitinib is a once-daily oral selective tyrosine kinase 2 inhibitor that blocks IL-23 and type I interferon signaling. It was approved for adults with moderate to severe plaque psoriasis in September 2021.⁷ We know patients want oral treatment; they ask for apremilast even though injections may be much more potent. In a 16-week, phase 3 clinical trial comparing daily deucravacitinib (n=332), apremilast (n=168), and placebo (n=166), rates of clear or almost clear were approximately 55% in the deucravacitinib group, 32% in the apremilast group, and 7% with placebo. The most common AEs included nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.⁸ Although deucravacitinib is much more effective than apremilast, deucravacitinib will require monitoring and may have some risk for viral reactivation of herpes simplex and zoster (and hopefully not much else). Whether physicians view it as a replacement for apremilast, which requires no laboratory monitoring, remains to be seen.

Bimekizumab, a humanized monoclonal IgG1 antibody expected to receive US Food and Drug Administration approval in the coming months, inhibits both IL-17A and IL-17F and may become our most effective treatment of psoriasis. Although we are probably not hungering for a more effective psoriasis treatment (given our current embarrassment of riches), bimekizumab’s remarkably high efficacy for psoriatic arthritis may be a quantum leap forward, especially if no new safety signals are identified; bimekizumab treatment is associated with a higher risk of oral candidiasis than other currently available IL-17 antagonists.⁹ Biosimilars may reduce the cost of psoriasis management to the health system, but it seems unlikely that biosimilars will allow us to help patients who we cannot already help with the existing extensive psoriasis treatment armamentarium.

New treatments for psoriasis constitute an embarrassment of riches compared to any other area of dermatology. Despite the many advances over the last 25 years, additional topical and systemic treatments have recently become available. Gosh, it’s great!

In May 2022, once-daily tapinarof cream 1% was approved for the topical treatment of plaque psoriasis in adults.¹ Tapinarof was identified as a metabolite made by bacteria symbiotic to a nematode, allowing the nematode to infect insects.² Tapinarof’s anti-inflammatory effect extends to mammals. The drug works by activating the aryl hydrocarbon receptor, downregulating proinflammatory cytokines such as IL-17, and normalizing the expression of skin barrier proteins such as filaggrin.² In two 12-week, phase 3, randomized trials with 510 and 515 patients, respectively, 35% to 40% of tapinarof-treated psoriasis patients were clear or almost clear compared with only 6% of patients in the placebo group. The drug appears safe; common adverse events (AEs) included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus.³

A second new topical treatment for plaque psoriasis was approved in July 2022—once-daily roflumilast 0.3% cream—for patients 12 years and older.⁴ Similar to apremilast, roflumilast is a phosphodiesterase 4 inhibitor that blocks the degradation of cAMP and reduces the downstream production of inflammatory molecules implicated in psoriasis.⁵ In two 8-week, phase 3 clinical trials (ClinicalTrials.gov Identifiers NCT04211363 and NCT04211389)(N=881), approximately 40% of roflumilast-treated patients were clear or almost clear vs approximately 6% in the placebo group. Topical roflumilast was well-tolerated; the most common AEs included diarrhea, headache, insomnia, nausea, application-site pain, upper respiratory tract infection, and urinary tract infection.⁶

We have so many patients—and many more people with psoriasis who are not yet patients—with limited psoriasis who would be amenable to topical treatment but who are not responding to current treatments. There is considerable enthusiasm for the new topicals, but it is still questionable how much they will help our patients. The main reason the current topicals fail is poor adherence to the treatment. If we give these new treatments to patients who used existing topicals and failed, thereby inadvertently selecting patients with poor adherence to topicals, it will be surprising if the new treatments live up to expectations. Perhaps tapinarof and roflumilast will revolutionize the management of localized psoriasis; perhaps their impact will be similar to topical crisaborole— exciting in trials and less practical in real life. It may be that apremilast, which is now approved for psoriasis of any severity, will make a bigger difference for patients who can access it for limited psoriasis.

Deucravacitinib is a once-daily oral selective tyrosine kinase 2 inhibitor that blocks IL-23 and type I interferon signaling. It was approved for adults with moderate to severe plaque psoriasis in September 2021.⁷ We know patients want oral treatment; they ask for apremilast even though injections may be much more potent. In a 16-week, phase 3 clinical trial comparing daily deucravacitinib (n=332), apremilast (n=168), and placebo (n=166), rates of clear or almost clear were approximately 55% in the deucravacitinib group, 32% in the apremilast group, and 7% with placebo. The most common AEs included nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea.⁸ Although deucravacitinib is much more effective than apremilast, deucravacitinib will require monitoring and may have some risk for viral reactivation of herpes simplex and zoster (and hopefully not much else). Whether physicians view it as a replacement for apremilast, which requires no laboratory monitoring, remains to be seen.

Bimekizumab, a humanized monoclonal IgG1 antibody expected to receive US Food and Drug Administration approval in the coming months, inhibits both IL-17A and IL-17F and may become our most effective treatment of psoriasis. Although we are probably not hungering for a more effective psoriasis treatment (given our current embarrassment of riches), bimekizumab’s remarkably high efficacy for psoriatic arthritis may be a quantum leap forward, especially if no new safety signals are identified; bimekizumab treatment is associated with a higher risk of oral candidiasis than other currently available IL-17 antagonists.⁹ Biosimilars may reduce the cost of psoriasis management to the health system, but it seems unlikely that biosimilars will allow us to help patients who we cannot already help with the existing extensive psoriasis treatment armamentarium.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The Diagnosis: Annular Elastolytic Giant Cell Granuloma

Histologic examination of the shave biopsies showed a granulomatous infiltrate of small lymphocytes, histiocytes, and multinucleated giant cells. The giant cells have abundant eosinophilic cytoplasm, with several also containing fragments of basophilic elastic fibers (elastophagocytosis)(Figure). Additionally, the granulomas revealed no signs of necrosis, making an infectious source unlikely, and examination under polarized light was negative for foreign material. These clinical and histologic findings were diagnostic for annular elastolytic giant cell granuloma (AEGCG).

Annular elastolytic giant cell granuloma is a rare chronic inflammatory disorder that classically presents on sun-exposed skin as annular plaques with elevated borders and atrophic centers.^1-4 Histologically, AEGCG is characterized by diffuse granulomatous infiltrates composed of multinucleated giant cells, histiocytes, and lymphocytes in the dermis, along with phagocytosis of elastic fibers by multinucleated giant cells.⁵ The underlying etiology and pathogenesis of AEGCG remains unknown.⁶

Annular elastolytic giant cell granuloma commonly affects females aged 35 to 75 years; however, cases have been reported in the male and pediatric patient populations.^1,2 Documented cases are known to last from 1 month to 10 years.^7,8 Although the mechanisms underlying the development of AEGCG remain to be elucidated, studies have determined that the skin disorder is associated with sarcoidosis, molluscum contagiosum, amyloidosis, diabetes mellitus, and cutaneous T-cell lymphoma.⁹ Diabetes mellitus is the most common comorbidity associated with AEGCG, and it is theorized that diabetes contributes to the increased incidence of AEGCG in this population by inducing damage to elastic fibers in the skin.¹⁰ One study that examined 50 cases of AEGCG found that 38 patients had serum glucose levels evaluated, with 8 cases being subsequently diagnosed with diabetes mellitus and 6 cases with apparent impaired glucose tolerance, indicating that 37% of the sample population with AEGCG who were evaluated for metabolic disease were found to have definitive or latent type 2 diabetes mellitus.¹¹ Although AEGCG is a rare disorder, a substantial number of patients diagnosed with AEGCG also have diabetes mellitus, making it important to consider screening all patients with AEGCG for diabetes given the ease and widely available resources to check glucose levels.

Actinic granuloma, granuloma annulare, atypical facial necrobiosis lipoidica, granuloma multiforme, secondary syphilis, tinea corporis, and erythema annulare centrifugum most commonly are included in the differential diagnosis with AEGCG; histopathology is the key determinant in discerning between these conditions.¹² Our patient presented with typical annular plaques overlying hyperpigmented telangiectatic patches. With known type 2 diabetes mellitus and the clinical findings, granuloma annulare, erythema annulare centrifugum, and AEGCG remained high on the differential.

No standard of care exists for AEGCG due to its rare nature and tendency to spontaneously resolve. The most common first-line treatment includes topical and intralesional steroids, topical pimecrolimus, and the use of sunscreen and other sun-protective measures. UV radiation, specifically UVA, has been determined to be a causal factor for AEGCG by changing the antigenicity of elastic fibers and producing an immune response in individuals with fair skin.¹³ Further, resistant cases of AEGCG successfully have been treated with cyclosporine, systemic steroids, antimalarials, dapsone, and oral retinoids.^14,15 Some studies reported partial regression or full resolution with topical tretinoin; adalimumab; clobetasol ointment; or a combination of corticosteroids, antihistamines, and hydroxychloroquine.² Only 1 case series using sulfasalazine reported worsening symptoms after treatment initiation.¹⁶ Our patient deferred systemic medications and was treated with 4 weeks of topical triamcinolone followed by 4 weeks of topical tacrolimus with minimal improvement. At the time of diagnosis, our patient also was encouraged to use sun-protective measures. At 6-month follow-up, the lesions remained stable, and the decision was made to continue with photoprotection.

The Diagnosis: Annular Elastolytic Giant Cell Granuloma

Histologic examination of the shave biopsies showed a granulomatous infiltrate of small lymphocytes, histiocytes, and multinucleated giant cells. The giant cells have abundant eosinophilic cytoplasm, with several also containing fragments of basophilic elastic fibers (elastophagocytosis)(Figure). Additionally, the granulomas revealed no signs of necrosis, making an infectious source unlikely, and examination under polarized light was negative for foreign material. These clinical and histologic findings were diagnostic for annular elastolytic giant cell granuloma (AEGCG).

Annular elastolytic giant cell granuloma is a rare chronic inflammatory disorder that classically presents on sun-exposed skin as annular plaques with elevated borders and atrophic centers.^1-4 Histologically, AEGCG is characterized by diffuse granulomatous infiltrates composed of multinucleated giant cells, histiocytes, and lymphocytes in the dermis, along with phagocytosis of elastic fibers by multinucleated giant cells.⁵ The underlying etiology and pathogenesis of AEGCG remains unknown.⁶

Annular elastolytic giant cell granuloma commonly affects females aged 35 to 75 years; however, cases have been reported in the male and pediatric patient populations.^1,2 Documented cases are known to last from 1 month to 10 years.^7,8 Although the mechanisms underlying the development of AEGCG remain to be elucidated, studies have determined that the skin disorder is associated with sarcoidosis, molluscum contagiosum, amyloidosis, diabetes mellitus, and cutaneous T-cell lymphoma.⁹ Diabetes mellitus is the most common comorbidity associated with AEGCG, and it is theorized that diabetes contributes to the increased incidence of AEGCG in this population by inducing damage to elastic fibers in the skin.¹⁰ One study that examined 50 cases of AEGCG found that 38 patients had serum glucose levels evaluated, with 8 cases being subsequently diagnosed with diabetes mellitus and 6 cases with apparent impaired glucose tolerance, indicating that 37% of the sample population with AEGCG who were evaluated for metabolic disease were found to have definitive or latent type 2 diabetes mellitus.¹¹ Although AEGCG is a rare disorder, a substantial number of patients diagnosed with AEGCG also have diabetes mellitus, making it important to consider screening all patients with AEGCG for diabetes given the ease and widely available resources to check glucose levels.

Actinic granuloma, granuloma annulare, atypical facial necrobiosis lipoidica, granuloma multiforme, secondary syphilis, tinea corporis, and erythema annulare centrifugum most commonly are included in the differential diagnosis with AEGCG; histopathology is the key determinant in discerning between these conditions.¹² Our patient presented with typical annular plaques overlying hyperpigmented telangiectatic patches. With known type 2 diabetes mellitus and the clinical findings, granuloma annulare, erythema annulare centrifugum, and AEGCG remained high on the differential.

No standard of care exists for AEGCG due to its rare nature and tendency to spontaneously resolve. The most common first-line treatment includes topical and intralesional steroids, topical pimecrolimus, and the use of sunscreen and other sun-protective measures. UV radiation, specifically UVA, has been determined to be a causal factor for AEGCG by changing the antigenicity of elastic fibers and producing an immune response in individuals with fair skin.¹³ Further, resistant cases of AEGCG successfully have been treated with cyclosporine, systemic steroids, antimalarials, dapsone, and oral retinoids.^14,15 Some studies reported partial regression or full resolution with topical tretinoin; adalimumab; clobetasol ointment; or a combination of corticosteroids, antihistamines, and hydroxychloroquine.² Only 1 case series using sulfasalazine reported worsening symptoms after treatment initiation.¹⁶ Our patient deferred systemic medications and was treated with 4 weeks of topical triamcinolone followed by 4 weeks of topical tacrolimus with minimal improvement. At the time of diagnosis, our patient also was encouraged to use sun-protective measures. At 6-month follow-up, the lesions remained stable, and the decision was made to continue with photoprotection.

The Diagnosis: Annular Elastolytic Giant Cell Granuloma

Histologic examination of the shave biopsies showed a granulomatous infiltrate of small lymphocytes, histiocytes, and multinucleated giant cells. The giant cells have abundant eosinophilic cytoplasm, with several also containing fragments of basophilic elastic fibers (elastophagocytosis)(Figure). Additionally, the granulomas revealed no signs of necrosis, making an infectious source unlikely, and examination under polarized light was negative for foreign material. These clinical and histologic findings were diagnostic for annular elastolytic giant cell granuloma (AEGCG).

Annular elastolytic giant cell granuloma is a rare chronic inflammatory disorder that classically presents on sun-exposed skin as annular plaques with elevated borders and atrophic centers.^1-4 Histologically, AEGCG is characterized by diffuse granulomatous infiltrates composed of multinucleated giant cells, histiocytes, and lymphocytes in the dermis, along with phagocytosis of elastic fibers by multinucleated giant cells.⁵ The underlying etiology and pathogenesis of AEGCG remains unknown.⁶

Annular elastolytic giant cell granuloma commonly affects females aged 35 to 75 years; however, cases have been reported in the male and pediatric patient populations.^1,2 Documented cases are known to last from 1 month to 10 years.^7,8 Although the mechanisms underlying the development of AEGCG remain to be elucidated, studies have determined that the skin disorder is associated with sarcoidosis, molluscum contagiosum, amyloidosis, diabetes mellitus, and cutaneous T-cell lymphoma.⁹ Diabetes mellitus is the most common comorbidity associated with AEGCG, and it is theorized that diabetes contributes to the increased incidence of AEGCG in this population by inducing damage to elastic fibers in the skin.¹⁰ One study that examined 50 cases of AEGCG found that 38 patients had serum glucose levels evaluated, with 8 cases being subsequently diagnosed with diabetes mellitus and 6 cases with apparent impaired glucose tolerance, indicating that 37% of the sample population with AEGCG who were evaluated for metabolic disease were found to have definitive or latent type 2 diabetes mellitus.¹¹ Although AEGCG is a rare disorder, a substantial number of patients diagnosed with AEGCG also have diabetes mellitus, making it important to consider screening all patients with AEGCG for diabetes given the ease and widely available resources to check glucose levels.

Actinic granuloma, granuloma annulare, atypical facial necrobiosis lipoidica, granuloma multiforme, secondary syphilis, tinea corporis, and erythema annulare centrifugum most commonly are included in the differential diagnosis with AEGCG; histopathology is the key determinant in discerning between these conditions.¹² Our patient presented with typical annular plaques overlying hyperpigmented telangiectatic patches. With known type 2 diabetes mellitus and the clinical findings, granuloma annulare, erythema annulare centrifugum, and AEGCG remained high on the differential.

No standard of care exists for AEGCG due to its rare nature and tendency to spontaneously resolve. The most common first-line treatment includes topical and intralesional steroids, topical pimecrolimus, and the use of sunscreen and other sun-protective measures. UV radiation, specifically UVA, has been determined to be a causal factor for AEGCG by changing the antigenicity of elastic fibers and producing an immune response in individuals with fair skin.¹³ Further, resistant cases of AEGCG successfully have been treated with cyclosporine, systemic steroids, antimalarials, dapsone, and oral retinoids.^14,15 Some studies reported partial regression or full resolution with topical tretinoin; adalimumab; clobetasol ointment; or a combination of corticosteroids, antihistamines, and hydroxychloroquine.² Only 1 case series using sulfasalazine reported worsening symptoms after treatment initiation.¹⁶ Our patient deferred systemic medications and was treated with 4 weeks of topical triamcinolone followed by 4 weeks of topical tacrolimus with minimal improvement. At the time of diagnosis, our patient also was encouraged to use sun-protective measures. At 6-month follow-up, the lesions remained stable, and the decision was made to continue with photoprotection.

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

petekarici/Getty Images

This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.

Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.

An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.

“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.

While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.

While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.

“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”

While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.

This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“

From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.

Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

petekarici/Getty Images

This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.

Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.

An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.

“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.

While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.

While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.

“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”

While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.

This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“

From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.

Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.

A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.

Independent of low-density lipoprotein cholesterol (LDL-C), which is reduced when PCSK9 is inhibited, a reduction in PCSK9 levels appears to have a direct impact on lowering psoriasis risk. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.

petekarici/Getty Images

This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.

In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.

“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.

Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.

Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.

Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.

In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.

Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.

An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.

“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.

While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.

While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.

“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”

While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.

This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“

From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.

Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.

ORLANDO – When he was applying for residency, Omar N. Qutub, MD, eagerly arrived at his first interview of the day. But he was quickly thrown off his game.

The interviewer, he said, spent a surprising amount of time asking about his ethnicity and his last name. “I think I spent about 3-5 minutes in the first interview talking about my last name,” said Dr. Qutub, who practices in Portland, Ore., during a session titled “unconscious bias and microaggressions in dermatology” at the ODAC Dermatology, Aesthetic and Surgical Conference. “I really would have rather talked about my research interests.” The interaction threw him off for the rest of the interview process, he said.

The experience is an example of how the field has a ways to go in acquiring cultural competence and in overcoming unconscious biases, said Dr. Qutub. In 2020, a review in Clinics in Dermatology referred to a report that dermatology was the second-least diverse medical specialty, only behind orthopedic surgery, because of its low numbers of residents and faculty from groups underrepresented in medicine.

“We really need to put cultural competency at the forefront in order to do better for our patients,” he said.

Adam Friedman, MD, professor and chair of dermatology and director of the residency program at George Washington University, Washington, who also spoke during the session, said that the process of diversifying the field has to go deeper than the resident interviewing process. “If we just focus on trying to increase the diversity of our applicant pool for residents, it’s too late.”

Nada Elbuluk, MD, associate professor of dermatology at the University of Southern California, Los Angeles, pointed to USC’s Derm RISES initiative, a service program that aims to reach inner-city students through education in the sciences, starting from kindergarten to 12th grade. The program also includes premed undergraduate and medical students, “with the goal of increasing exposure to the sciences, medicine, and dermatology,” according to the USC website. “It’s crucial to begin the process early to get a high yield of students who reach medical school and eventually dermatology, she said, because of the inevitable attrition at each level of the education process.

“It’s incredibly rewarding,” added Dr. Elbuluk, who is also director of the dermatology diversity and inclusion program at USC. “And we get these thank-you letters back from students who [say], ‘I didn’t know I could be a doctor.’ ”

In another presentation, Kavita Mariwalla, MD, who practices in West Islip, N.Y., provided tips on boosting cultural competence during aesthetic consults.

One was to “know your fillers,” she said, noting that fillers have different effects on different skin tones, because of differences in fibroblast content, and fat cells will interact with fillers in different ways across skin tones.

Another is to “understand the shortfall of facial canons,” the idea that you can divide a face into sections that can be viewed and enhanced discretely. This concept was based on a White European model and has to be expanded when considering other ethnicities, Dr. Mariwalla said.

Overgeneralizing categories is another pitfall, she said. “Asian” is a term that covers countries from India to Japan, but within that category are a multitude of notions and nuances about aesthetics, and dermatologists have to be sensitive to all of them.

When meeting with a patient, Dr. Mariwalla said, asking the typical “Where are you from?” is not a helpful question. Instead, she suggested asking: “What is your cultural background? Can you tell me more about what your expectations are?”

“I ask for pictures,” she said. “I want to know what they looked like as a kid. I want to know what their family looks like. And I always hand patients a mirror. Patients will say to me: ‘I want to do what you think.’ It’s not about what I think, because what I see, and what you see in your magnifying mirror, are totally different things.”

After the session ended, a member of the audience, Sharon Stokes, MD, a dermatologist in the Orlando area, provided her view of the presentations, noting that it was an important discussion.

“I think it’s past time in medicine for cultural diversity training and awareness for physicians to understand their patients better and getting to know them – and how to even approach the patient and not to offensively and microaggressively approach the patient,” she said.

Dr. Elbuluk reported relevant relationships with Avita, Incyte, Beiersdorf, and other companies. Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis and other companies. Dr. Mariwalla reported relevant financial relationships with Abbvie, Sanofi, Regeneron and other companies. Dr. Qutub reported no relevant financial relationships. Dr. Qutub is the ODAC director of equity, diversity, and inclusion.

ORLANDO – When he was applying for residency, Omar N. Qutub, MD, eagerly arrived at his first interview of the day. But he was quickly thrown off his game.

The interviewer, he said, spent a surprising amount of time asking about his ethnicity and his last name. “I think I spent about 3-5 minutes in the first interview talking about my last name,” said Dr. Qutub, who practices in Portland, Ore., during a session titled “unconscious bias and microaggressions in dermatology” at the ODAC Dermatology, Aesthetic and Surgical Conference. “I really would have rather talked about my research interests.” The interaction threw him off for the rest of the interview process, he said.

The experience is an example of how the field has a ways to go in acquiring cultural competence and in overcoming unconscious biases, said Dr. Qutub. In 2020, a review in Clinics in Dermatology referred to a report that dermatology was the second-least diverse medical specialty, only behind orthopedic surgery, because of its low numbers of residents and faculty from groups underrepresented in medicine.

“We really need to put cultural competency at the forefront in order to do better for our patients,” he said.

Adam Friedman, MD, professor and chair of dermatology and director of the residency program at George Washington University, Washington, who also spoke during the session, said that the process of diversifying the field has to go deeper than the resident interviewing process. “If we just focus on trying to increase the diversity of our applicant pool for residents, it’s too late.”

Nada Elbuluk, MD, associate professor of dermatology at the University of Southern California, Los Angeles, pointed to USC’s Derm RISES initiative, a service program that aims to reach inner-city students through education in the sciences, starting from kindergarten to 12th grade. The program also includes premed undergraduate and medical students, “with the goal of increasing exposure to the sciences, medicine, and dermatology,” according to the USC website. “It’s crucial to begin the process early to get a high yield of students who reach medical school and eventually dermatology, she said, because of the inevitable attrition at each level of the education process.

“It’s incredibly rewarding,” added Dr. Elbuluk, who is also director of the dermatology diversity and inclusion program at USC. “And we get these thank-you letters back from students who [say], ‘I didn’t know I could be a doctor.’ ”

In another presentation, Kavita Mariwalla, MD, who practices in West Islip, N.Y., provided tips on boosting cultural competence during aesthetic consults.

One was to “know your fillers,” she said, noting that fillers have different effects on different skin tones, because of differences in fibroblast content, and fat cells will interact with fillers in different ways across skin tones.

Another is to “understand the shortfall of facial canons,” the idea that you can divide a face into sections that can be viewed and enhanced discretely. This concept was based on a White European model and has to be expanded when considering other ethnicities, Dr. Mariwalla said.

Overgeneralizing categories is another pitfall, she said. “Asian” is a term that covers countries from India to Japan, but within that category are a multitude of notions and nuances about aesthetics, and dermatologists have to be sensitive to all of them.

When meeting with a patient, Dr. Mariwalla said, asking the typical “Where are you from?” is not a helpful question. Instead, she suggested asking: “What is your cultural background? Can you tell me more about what your expectations are?”

“I ask for pictures,” she said. “I want to know what they looked like as a kid. I want to know what their family looks like. And I always hand patients a mirror. Patients will say to me: ‘I want to do what you think.’ It’s not about what I think, because what I see, and what you see in your magnifying mirror, are totally different things.”

After the session ended, a member of the audience, Sharon Stokes, MD, a dermatologist in the Orlando area, provided her view of the presentations, noting that it was an important discussion.

“I think it’s past time in medicine for cultural diversity training and awareness for physicians to understand their patients better and getting to know them – and how to even approach the patient and not to offensively and microaggressively approach the patient,” she said.

Dr. Elbuluk reported relevant relationships with Avita, Incyte, Beiersdorf, and other companies. Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis and other companies. Dr. Mariwalla reported relevant financial relationships with Abbvie, Sanofi, Regeneron and other companies. Dr. Qutub reported no relevant financial relationships. Dr. Qutub is the ODAC director of equity, diversity, and inclusion.

ORLANDO – When he was applying for residency, Omar N. Qutub, MD, eagerly arrived at his first interview of the day. But he was quickly thrown off his game.

The interviewer, he said, spent a surprising amount of time asking about his ethnicity and his last name. “I think I spent about 3-5 minutes in the first interview talking about my last name,” said Dr. Qutub, who practices in Portland, Ore., during a session titled “unconscious bias and microaggressions in dermatology” at the ODAC Dermatology, Aesthetic and Surgical Conference. “I really would have rather talked about my research interests.” The interaction threw him off for the rest of the interview process, he said.

The experience is an example of how the field has a ways to go in acquiring cultural competence and in overcoming unconscious biases, said Dr. Qutub. In 2020, a review in Clinics in Dermatology referred to a report that dermatology was the second-least diverse medical specialty, only behind orthopedic surgery, because of its low numbers of residents and faculty from groups underrepresented in medicine.

“We really need to put cultural competency at the forefront in order to do better for our patients,” he said.

Adam Friedman, MD, professor and chair of dermatology and director of the residency program at George Washington University, Washington, who also spoke during the session, said that the process of diversifying the field has to go deeper than the resident interviewing process. “If we just focus on trying to increase the diversity of our applicant pool for residents, it’s too late.”

Nada Elbuluk, MD, associate professor of dermatology at the University of Southern California, Los Angeles, pointed to USC’s Derm RISES initiative, a service program that aims to reach inner-city students through education in the sciences, starting from kindergarten to 12th grade. The program also includes premed undergraduate and medical students, “with the goal of increasing exposure to the sciences, medicine, and dermatology,” according to the USC website. “It’s crucial to begin the process early to get a high yield of students who reach medical school and eventually dermatology, she said, because of the inevitable attrition at each level of the education process.

“It’s incredibly rewarding,” added Dr. Elbuluk, who is also director of the dermatology diversity and inclusion program at USC. “And we get these thank-you letters back from students who [say], ‘I didn’t know I could be a doctor.’ ”

In another presentation, Kavita Mariwalla, MD, who practices in West Islip, N.Y., provided tips on boosting cultural competence during aesthetic consults.

One was to “know your fillers,” she said, noting that fillers have different effects on different skin tones, because of differences in fibroblast content, and fat cells will interact with fillers in different ways across skin tones.

Another is to “understand the shortfall of facial canons,” the idea that you can divide a face into sections that can be viewed and enhanced discretely. This concept was based on a White European model and has to be expanded when considering other ethnicities, Dr. Mariwalla said.

Overgeneralizing categories is another pitfall, she said. “Asian” is a term that covers countries from India to Japan, but within that category are a multitude of notions and nuances about aesthetics, and dermatologists have to be sensitive to all of them.

When meeting with a patient, Dr. Mariwalla said, asking the typical “Where are you from?” is not a helpful question. Instead, she suggested asking: “What is your cultural background? Can you tell me more about what your expectations are?”

“I ask for pictures,” she said. “I want to know what they looked like as a kid. I want to know what their family looks like. And I always hand patients a mirror. Patients will say to me: ‘I want to do what you think.’ It’s not about what I think, because what I see, and what you see in your magnifying mirror, are totally different things.”

After the session ended, a member of the audience, Sharon Stokes, MD, a dermatologist in the Orlando area, provided her view of the presentations, noting that it was an important discussion.

“I think it’s past time in medicine for cultural diversity training and awareness for physicians to understand their patients better and getting to know them – and how to even approach the patient and not to offensively and microaggressively approach the patient,” she said.

Dr. Elbuluk reported relevant relationships with Avita, Incyte, Beiersdorf, and other companies. Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis and other companies. Dr. Mariwalla reported relevant financial relationships with Abbvie, Sanofi, Regeneron and other companies. Dr. Qutub reported no relevant financial relationships. Dr. Qutub is the ODAC director of equity, diversity, and inclusion.

SAN DIEGO – Evidence of melanoma in the ancient past is rare, but according to James W. Patterson, MD, signs of melanoma with cutaneous lesions and diffuse bony metastases have been discovered in Peruvian Inca mummies.

“Radiocarbon dating indicated that these mummies were 2,400 years old,” Dr. Patterson, professor emeritus of pathology and dermatology at the University of Virginia, Charlottesville, said at the annual Cutaneous Malignancy Update.

In 1820, William Norris, a general practitioner from Stourbridge, England, published the first English language report of melanoma in the Edinburgh Medical and Surgical Journal. “The report was titled ‘A case of fungoid disease,’ so it appears that melanoma was often regarded as a fungal infection back then,” Dr. Patterson said. In the report, Dr. Norris described the tumor in a 59-year-old man as “nearly half the size of a hen’s egg, of a deep brown color, of a firm and fleshy feel, [and] ulcerated on its surface.” Dr. Norris authored a later work titled “Eight cases of melanosis, with pathological and therapeutical remarks on that disease.”

In 1840, a full 2 decades following the first published report from Dr. Norris, the British surgeon Samuel Cooper published a book titled “First Lines of Theory and Practice of Surgery,” in which he described patients with advanced stage melanoma as untreatable and postulated that the only chance for survival was early removal of the tumor.

Dr. Patterson reported having no relevant disclosures.

SAN DIEGO – Evidence of melanoma in the ancient past is rare, but according to James W. Patterson, MD, signs of melanoma with cutaneous lesions and diffuse bony metastases have been discovered in Peruvian Inca mummies.

“Radiocarbon dating indicated that these mummies were 2,400 years old,” Dr. Patterson, professor emeritus of pathology and dermatology at the University of Virginia, Charlottesville, said at the annual Cutaneous Malignancy Update.

In 1820, William Norris, a general practitioner from Stourbridge, England, published the first English language report of melanoma in the Edinburgh Medical and Surgical Journal. “The report was titled ‘A case of fungoid disease,’ so it appears that melanoma was often regarded as a fungal infection back then,” Dr. Patterson said. In the report, Dr. Norris described the tumor in a 59-year-old man as “nearly half the size of a hen’s egg, of a deep brown color, of a firm and fleshy feel, [and] ulcerated on its surface.” Dr. Norris authored a later work titled “Eight cases of melanosis, with pathological and therapeutical remarks on that disease.”

In 1840, a full 2 decades following the first published report from Dr. Norris, the British surgeon Samuel Cooper published a book titled “First Lines of Theory and Practice of Surgery,” in which he described patients with advanced stage melanoma as untreatable and postulated that the only chance for survival was early removal of the tumor.

Dr. Patterson reported having no relevant disclosures.

SAN DIEGO – Evidence of melanoma in the ancient past is rare, but according to James W. Patterson, MD, signs of melanoma with cutaneous lesions and diffuse bony metastases have been discovered in Peruvian Inca mummies.

“Radiocarbon dating indicated that these mummies were 2,400 years old,” Dr. Patterson, professor emeritus of pathology and dermatology at the University of Virginia, Charlottesville, said at the annual Cutaneous Malignancy Update.

In 1820, William Norris, a general practitioner from Stourbridge, England, published the first English language report of melanoma in the Edinburgh Medical and Surgical Journal. “The report was titled ‘A case of fungoid disease,’ so it appears that melanoma was often regarded as a fungal infection back then,” Dr. Patterson said. In the report, Dr. Norris described the tumor in a 59-year-old man as “nearly half the size of a hen’s egg, of a deep brown color, of a firm and fleshy feel, [and] ulcerated on its surface.” Dr. Norris authored a later work titled “Eight cases of melanosis, with pathological and therapeutical remarks on that disease.”

In 1840, a full 2 decades following the first published report from Dr. Norris, the British surgeon Samuel Cooper published a book titled “First Lines of Theory and Practice of Surgery,” in which he described patients with advanced stage melanoma as untreatable and postulated that the only chance for survival was early removal of the tumor.

Dr. Patterson reported having no relevant disclosures.

I love registries! With large numbers of participants, registries can be very helpful to identify rare side effects and to assess the efficacy and safety of medications in populations that may not be fully represented in clinical trials. I also love dupilumab; it was revolutionary in the management of patients with AD.

Vittrup and colleagues have created a registry of 347 participants treated with dupilumab. This does not yet have the large number of participants needed to identify new issues that wouldn't have been detected in clinical trials, but the study is informative about real-life use. The dramatic improvement in the Eczema Area and Severity Index (EASI) score is consistent with the high efficacy of dupilumab. The high rate of treatment persistence is also consistent with dupilumab being a very effective and safe treatment (because if the drug wasn't working well or was causing a severe problem, patients would probably stop the treatment). Though the study reported persistent head and neck involvement, the residual involvement may be quite minimal.

The EASI-75 and Investigator Global Assessment response rates reported in dupilumab trials underestimate the value of this drug. With a 2-year persistence rate of nearly 90%, it's clear that dupilumab is making a huge difference in the lives of patients with AD.

Fatigue is a fascinating issue in AD. We might wonder if all the inflammation in patients with AD would directly cause fatigue. Almost certainly all the itching in AD adversely affects sleep and would cause tremendous fatigue. It surprised me that most of the children in the study by Rangel and colleagues were reported as having no or mild fatigue; severe fatigue was very uncommon. It leaves me wondering whether the assessments of fatigue fully capture what's happening. Also, since the fatigue score was reported by the parents, I (as the parent of a child with AD) am wondering whether the parents were projecting, with the score more reflective of the parents' fatigue than with that of the child; alternatively, perhaps the child's hyperactivity leaves parents thinking there is no fatigue when there actually is (and possibly even causing the perceived hyperactivity).

The lack of a control group without AD is another major limitation in our ability to interpret the study findings. Is fatigue more common or less common in children with AD than in children without AD? I cannot tell from these findings. Does fatigue warrant, as the authors suggest, more attention in clinical practice? I don't know. If we are already treating our patients based on patients' global impressions of how they are doing — combined, of course, with our observations of their objective disease severity — I'm not sure how asking about fatigue would change anything, even if future studies were to definitively show that AD is associated with fatigue.

I hate new drugs (well, maybe not hate, but I worry about unknown long-term risks). Clinical trials that help a drug get approved can tell us a lot about a drug's efficacy, but these studies are generally limited in what they tell us about a drug's safety. Clinical trials are generally not powered enough (not enough participants and not followed for long enough) to be informative about rare risks. I love long-term studies of new drugs in large numbers of people because those studies can be very reassuring about the risks of medications. Studying nearly 10,000 patients for 5 years is quite reassuring, confirming my impression that dupilumab has a remarkable, excellent safety profile (Owji et al). Blocking interleukin 4 and interleukin 13 seems to be very specific to AD. Finding no association to cancer is what I would have expected; being able to share this information with patients is likely to be reassuring to them.

Oh, lord help me, another study that claims we should change our disease management because they've identified an increased risk for something. When you compare 70,000 patients with 270,000 controls, you have huge power to detect statistically significant associations of no clinical consequence. Let's assume for the moment that the detected association the authors found between AD and juvenile idiopathic arthritis (JIA) is real. The odds ratio is 2; the odds ratio for smoking causing cancer is on the order of 100.

In this study, over 99% of individuals in both AD and control groups did not have JIA. The difference between rates of JIA in patients with AD compared with controls was 0.3%! The authors conclude "it is important to inquire actively about symptoms not directly linked to the patients' skin disease"; based on the findings of this study, I would conclude that we don't need to worry about JIA in patients with AD even if there is a (marginally) higher prevalence of JIA in this group.

I love registries! With large numbers of participants, registries can be very helpful to identify rare side effects and to assess the efficacy and safety of medications in populations that may not be fully represented in clinical trials. I also love dupilumab; it was revolutionary in the management of patients with AD.

Vittrup and colleagues have created a registry of 347 participants treated with dupilumab. This does not yet have the large number of participants needed to identify new issues that wouldn't have been detected in clinical trials, but the study is informative about real-life use. The dramatic improvement in the Eczema Area and Severity Index (EASI) score is consistent with the high efficacy of dupilumab. The high rate of treatment persistence is also consistent with dupilumab being a very effective and safe treatment (because if the drug wasn't working well or was causing a severe problem, patients would probably stop the treatment). Though the study reported persistent head and neck involvement, the residual involvement may be quite minimal.

The EASI-75 and Investigator Global Assessment response rates reported in dupilumab trials underestimate the value of this drug. With a 2-year persistence rate of nearly 90%, it's clear that dupilumab is making a huge difference in the lives of patients with AD.

Fatigue is a fascinating issue in AD. We might wonder if all the inflammation in patients with AD would directly cause fatigue. Almost certainly all the itching in AD adversely affects sleep and would cause tremendous fatigue. It surprised me that most of the children in the study by Rangel and colleagues were reported as having no or mild fatigue; severe fatigue was very uncommon. It leaves me wondering whether the assessments of fatigue fully capture what's happening. Also, since the fatigue score was reported by the parents, I (as the parent of a child with AD) am wondering whether the parents were projecting, with the score more reflective of the parents' fatigue than with that of the child; alternatively, perhaps the child's hyperactivity leaves parents thinking there is no fatigue when there actually is (and possibly even causing the perceived hyperactivity).

The lack of a control group without AD is another major limitation in our ability to interpret the study findings. Is fatigue more common or less common in children with AD than in children without AD? I cannot tell from these findings. Does fatigue warrant, as the authors suggest, more attention in clinical practice? I don't know. If we are already treating our patients based on patients' global impressions of how they are doing — combined, of course, with our observations of their objective disease severity — I'm not sure how asking about fatigue would change anything, even if future studies were to definitively show that AD is associated with fatigue.

I hate new drugs (well, maybe not hate, but I worry about unknown long-term risks). Clinical trials that help a drug get approved can tell us a lot about a drug's efficacy, but these studies are generally limited in what they tell us about a drug's safety. Clinical trials are generally not powered enough (not enough participants and not followed for long enough) to be informative about rare risks. I love long-term studies of new drugs in large numbers of people because those studies can be very reassuring about the risks of medications. Studying nearly 10,000 patients for 5 years is quite reassuring, confirming my impression that dupilumab has a remarkable, excellent safety profile (Owji et al). Blocking interleukin 4 and interleukin 13 seems to be very specific to AD. Finding no association to cancer is what I would have expected; being able to share this information with patients is likely to be reassuring to them.

Oh, lord help me, another study that claims we should change our disease management because they've identified an increased risk for something. When you compare 70,000 patients with 270,000 controls, you have huge power to detect statistically significant associations of no clinical consequence. Let's assume for the moment that the detected association the authors found between AD and juvenile idiopathic arthritis (JIA) is real. The odds ratio is 2; the odds ratio for smoking causing cancer is on the order of 100.

In this study, over 99% of individuals in both AD and control groups did not have JIA. The difference between rates of JIA in patients with AD compared with controls was 0.3%! The authors conclude "it is important to inquire actively about symptoms not directly linked to the patients' skin disease"; based on the findings of this study, I would conclude that we don't need to worry about JIA in patients with AD even if there is a (marginally) higher prevalence of JIA in this group.

I love registries! With large numbers of participants, registries can be very helpful to identify rare side effects and to assess the efficacy and safety of medications in populations that may not be fully represented in clinical trials. I also love dupilumab; it was revolutionary in the management of patients with AD.

Vittrup and colleagues have created a registry of 347 participants treated with dupilumab. This does not yet have the large number of participants needed to identify new issues that wouldn't have been detected in clinical trials, but the study is informative about real-life use. The dramatic improvement in the Eczema Area and Severity Index (EASI) score is consistent with the high efficacy of dupilumab. The high rate of treatment persistence is also consistent with dupilumab being a very effective and safe treatment (because if the drug wasn't working well or was causing a severe problem, patients would probably stop the treatment). Though the study reported persistent head and neck involvement, the residual involvement may be quite minimal.

The EASI-75 and Investigator Global Assessment response rates reported in dupilumab trials underestimate the value of this drug. With a 2-year persistence rate of nearly 90%, it's clear that dupilumab is making a huge difference in the lives of patients with AD.

Fatigue is a fascinating issue in AD. We might wonder if all the inflammation in patients with AD would directly cause fatigue. Almost certainly all the itching in AD adversely affects sleep and would cause tremendous fatigue. It surprised me that most of the children in the study by Rangel and colleagues were reported as having no or mild fatigue; severe fatigue was very uncommon. It leaves me wondering whether the assessments of fatigue fully capture what's happening. Also, since the fatigue score was reported by the parents, I (as the parent of a child with AD) am wondering whether the parents were projecting, with the score more reflective of the parents' fatigue than with that of the child; alternatively, perhaps the child's hyperactivity leaves parents thinking there is no fatigue when there actually is (and possibly even causing the perceived hyperactivity).

The lack of a control group without AD is another major limitation in our ability to interpret the study findings. Is fatigue more common or less common in children with AD than in children without AD? I cannot tell from these findings. Does fatigue warrant, as the authors suggest, more attention in clinical practice? I don't know. If we are already treating our patients based on patients' global impressions of how they are doing — combined, of course, with our observations of their objective disease severity — I'm not sure how asking about fatigue would change anything, even if future studies were to definitively show that AD is associated with fatigue.

I hate new drugs (well, maybe not hate, but I worry about unknown long-term risks). Clinical trials that help a drug get approved can tell us a lot about a drug's efficacy, but these studies are generally limited in what they tell us about a drug's safety. Clinical trials are generally not powered enough (not enough participants and not followed for long enough) to be informative about rare risks. I love long-term studies of new drugs in large numbers of people because those studies can be very reassuring about the risks of medications. Studying nearly 10,000 patients for 5 years is quite reassuring, confirming my impression that dupilumab has a remarkable, excellent safety profile (Owji et al). Blocking interleukin 4 and interleukin 13 seems to be very specific to AD. Finding no association to cancer is what I would have expected; being able to share this information with patients is likely to be reassuring to them.

Oh, lord help me, another study that claims we should change our disease management because they've identified an increased risk for something. When you compare 70,000 patients with 270,000 controls, you have huge power to detect statistically significant associations of no clinical consequence. Let's assume for the moment that the detected association the authors found between AD and juvenile idiopathic arthritis (JIA) is real. The odds ratio is 2; the odds ratio for smoking causing cancer is on the order of 100.

In this study, over 99% of individuals in both AD and control groups did not have JIA. The difference between rates of JIA in patients with AD compared with controls was 0.3%! The authors conclude "it is important to inquire actively about symptoms not directly linked to the patients' skin disease"; based on the findings of this study, I would conclude that we don't need to worry about JIA in patients with AD even if there is a (marginally) higher prevalence of JIA in this group.