Dermatology

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

Black and Hispanic patients had higher inpatient care utilization for mycosis fungoides (MF) – and were admitted at a younger age – compared with White patients, according to an analysis of the 2012-2017 National Inpatient Sample (NIS).

The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.

Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.

Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.

Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).

Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).

In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.

The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.

Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.

A punch biopsy revealed that the patient had granuloma annulare (GA).

GA is usually a self-limiting disorder that manifests as a single or, less commonly, multiple nonscaly, red, annular lesions that are typically found on the extremities. It frequently starts as a papule or cluster of papules before coalescing into its classic annular pattern. Biopsy is not usually needed to make the diagnosis when annular lesions are present. In this case, the lesions displayed the Koebner phenomenon, occurring along her areolar scar, making diagnosis more difficult and necessitating the biopsy. While the cause of GA is unknown, it has been found more often in women than men, but has no predilection for race, ethnicity, or geographic areas.¹

GA is typically asymptomatic and can resolve spontaneously. Treatment is often performed for cosmetic reasons. First-line therapies include topical corticosteroids, topical tacrolimus, imiquimod cream, intralesional injections into the elevated border with 2.5 to 5 mg/mL triamcinolone acetonide, or destructive methods such as cryosurgery or pulsed dye laser therapy.¹

After a discussion of treatment options, this patient chose watchful waiting.

‌

Image courtesy of Kamini Geer, MD, and text courtesy of Kamini Geer, MD, AdventHealth East Orlando Osteopathic Family Medicine Residency and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

A punch biopsy revealed that the patient had granuloma annulare (GA).

GA is usually a self-limiting disorder that manifests as a single or, less commonly, multiple nonscaly, red, annular lesions that are typically found on the extremities. It frequently starts as a papule or cluster of papules before coalescing into its classic annular pattern. Biopsy is not usually needed to make the diagnosis when annular lesions are present. In this case, the lesions displayed the Koebner phenomenon, occurring along her areolar scar, making diagnosis more difficult and necessitating the biopsy. While the cause of GA is unknown, it has been found more often in women than men, but has no predilection for race, ethnicity, or geographic areas.¹

GA is typically asymptomatic and can resolve spontaneously. Treatment is often performed for cosmetic reasons. First-line therapies include topical corticosteroids, topical tacrolimus, imiquimod cream, intralesional injections into the elevated border with 2.5 to 5 mg/mL triamcinolone acetonide, or destructive methods such as cryosurgery or pulsed dye laser therapy.¹

After a discussion of treatment options, this patient chose watchful waiting.

‌

Image courtesy of Kamini Geer, MD, and text courtesy of Kamini Geer, MD, AdventHealth East Orlando Osteopathic Family Medicine Residency and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

A punch biopsy revealed that the patient had granuloma annulare (GA).

GA is usually a self-limiting disorder that manifests as a single or, less commonly, multiple nonscaly, red, annular lesions that are typically found on the extremities. It frequently starts as a papule or cluster of papules before coalescing into its classic annular pattern. Biopsy is not usually needed to make the diagnosis when annular lesions are present. In this case, the lesions displayed the Koebner phenomenon, occurring along her areolar scar, making diagnosis more difficult and necessitating the biopsy. While the cause of GA is unknown, it has been found more often in women than men, but has no predilection for race, ethnicity, or geographic areas.¹

GA is typically asymptomatic and can resolve spontaneously. Treatment is often performed for cosmetic reasons. First-line therapies include topical corticosteroids, topical tacrolimus, imiquimod cream, intralesional injections into the elevated border with 2.5 to 5 mg/mL triamcinolone acetonide, or destructive methods such as cryosurgery or pulsed dye laser therapy.¹

After a discussion of treatment options, this patient chose watchful waiting.

‌

Image courtesy of Kamini Geer, MD, and text courtesy of Kamini Geer, MD, AdventHealth East Orlando Osteopathic Family Medicine Residency and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Two recent articles in the medical literature provide new information on mucocutaneous manifestations of COVID-19 in children, which may help guide dermatologists in making accurate diagnoses and stratifying children at risk for serious, systemic illness due to the virus.

In a single-center descriptive study carried out over a 9-month period, researchers in Madrid found that of 50 hospitalized children infected with COVID-19, 21 (42%) had mucocutaneous symptoms, most commonly exanthem, followed by conjunctival hyperemia without secretion and red cracked lips or strawberry tongue. In addition, 18 (36%) fulfilled criteria for Multisystem Inflammatory Syndrome in Children (MIS-C).

“Based on findings in adult patients, the skin manifestations of COVID-19 have been classified under five categories: acral pseudo-chilblain, vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis,” David Andina-Martinez, MD, of Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues wrote in the study, which was published online on April 2 in the Journal of the American Academy of Dermatology.

“Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks,” they added. “Besides, other cutaneous manifestations of COVID-19 in children have been the matter of case reports or small case series. Nevertheless, the mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and their implications on the clinical course have not yet been extensively described.”

In an effort to describe the mucocutaneous manifestations in children hospitalized for COVID-19, the researchers evaluated 50 children up to 18 years of age who were admitted between March 1 and Nov. 30, 2020, to Hospital Infantil Universitario Niño Jesús, which was designated as a pediatric reference center during the peak of the pandemic. The main reasons for admission were respiratory illness (40%) and MIS-C (40%).

Of the 50 patients, 44 (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met clinical suspicion criteria and had a negative RT-PCR with a positive IgG serology. In 34 patients (68%), a close contact with a suspected or confirmed case of COVID-19 was referred, while the source of the infection remained unknown in the remaining 16 patients (32%).

The researchers reported that 21 patients (42%) had mucocutaneous symptoms, most commonly maculopapular exanthem (86%), conjunctival hyperemia (81%), and red cracked lips or strawberry tongue (43%). In addition, 18 of the 21 patients (86%) fulfilled criteria for MIS-C.

“A tricky thing about MIS-C is that it often manifests 4-5 weeks after a child had COVID-19,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study. “MIS-C is associated with characteristic bright red lips and a red tongue that might resemble a strawberry. Such oral findings should prompt rapid evaluation for other signs and symptoms. There can be redness of the eyes or other more nonspecific skin findings (large or small areas of redness on the trunk or limbs, sometimes with surface change), but more importantly, fever, a rapid heartbeat, diarrhea, or breathing issues. The risk with MIS-C is a rapid decline in a child’s health, with admission to an intensive care unit.”

Dr. Andina-Martinez and his colleagues also contrast the skin findings of MIS-C, which are not generally on the hands or feet, with the so-called “COVID toe” or finger phenomenon, which has also been associated with SARS-CoV-2, particularly in children. “Only one of the patients in this series had skin involvement of a finger, and it only appeared after recovery from MIS-C,” Dr. Ko noted. “Distinguishing COVID toes from MIS-C is important, as COVID toes has a very good outcome, while MIS-C can have severe consequences, including protracted heart disease.”

In other findings, patients who presented with mucocutaneous signs tended to be older than those without skin signs and they presented at the emergency department with poor general status and extreme tachycardia. They also had higher C-reactive protein and D-dimer levels and lower lymphocyte counts and faced a more than a 10-fold increased risk of being admitted to the PICU, compared with patients who did not have skin signs (OR, 10.24; P = .003).

In a separate study published online on April 7 in JAMA Dermatology, Zachary E. Holcomb, MD, of the combined dermatology residency program at Massachusetts General Hospital, Boston, and colleagues presented what is believed to be the first case report of reactive infectious mucocutaneous eruption (RIME) triggered by SARS-CoV-2. RIME is the preferred term for pediatric patients who present with mucositis and rash (often a scant or even absent skin eruption) triggered by various infectious agents.

The patient, a 17-year-old male, presented to the emergency department with 3 days of mouth pain and nonpainful penile erosions. “One week prior, he experienced transient anosmia and ageusia that had since spontaneously resolved,” the researchers wrote. “At that time, he was tested for SARS-CoV-2 infection via nasopharyngeal polymerase chain reaction (PCR), the results of which were positive.”

At presentation, the patient had no fever, his vital signs were normal, and the physical exam revealed shallow erosions of the vermilion lips and hard palate, circumferential erythematous erosions of the periurethral glans penis, and five small vesicles on the trunk and upper extremities. Serum analysis revealed a normal white blood cell count with mild absolute lymphopenia, slightly elevated creatinine level, normal liver function, slightly elevated C-reactive protein level, and normal ferritin level.

Dr. Holcomb and colleagues made a diagnosis of SARS-CoV-2–associated RIME based on microbiological results, which revealed positive repeated SARS-CoV-2 nasopharyngeal PCR and negative nasopharyngeal PCR testing for Mycoplasma pneumoniae, adenovirus, Chlamydophila pneumoniae, human metapneumovirus, influenza A/B, parainfluenza 1 to 4, rhinovirus, and respiratory syncytial virus. In addition, titers of Mycoplasma pneumoniae IgM levels were negative, but Mycoplasma pneumoniae IgG levels were elevated.

The lesions resolved with 60 mg of oral prednisone taken daily for 4 days. A recurrence of oral mucositis 3 months later responded to 80 mg oral prednisone taken daily for 6 days.

“It’s not surprising that SARS-CoV-2 is yet another trigger for RIME,” said Anna Yasmine Kirkorian, MD, chief of the division of dermatology at Children’s National Hospital, Washington, who was asked to comment about the case report.

“The take-home message is for clinicians to be aware of this association and distinguish these patients from those with MIS-C, because patients with MIS-C require monitoring and urgent systemic treatment. RIME and MIS-C may potentially be distinguished clinically based on the nature of the mucositis (hemorrhagic and erosive in RIME, dry, cracked lips with ‘strawberry tongue’ in MIS-C) but more importantly patients with RIME lack laboratory evidence of severe systemic inflammation,” such as ESR, CRP, or ferritin, she said.

“A final interesting point in this article was the recurrence of mucositis in this patient, which could mean that recurrent mucositis/recurrent RIME might be yet another manifestation of ‘long-COVID’ (now called post-Acute Sequelae of SARS-CoV-2 infection) in some patients,” Dr. Kirkorian added. She noted that the American Academy of Dermatology–International League of Dermatologic Societies COVID-19 Dermatology Registry and articles like these “provide invaluable ‘hot off the presses’ information for clinicians who are facing the protean manifestations of a novel viral epidemic.”

The researchers reported having no financial disclosures.
 

dbrunk@mdedge.com

Two recent articles in the medical literature provide new information on mucocutaneous manifestations of COVID-19 in children, which may help guide dermatologists in making accurate diagnoses and stratifying children at risk for serious, systemic illness due to the virus.

In a single-center descriptive study carried out over a 9-month period, researchers in Madrid found that of 50 hospitalized children infected with COVID-19, 21 (42%) had mucocutaneous symptoms, most commonly exanthem, followed by conjunctival hyperemia without secretion and red cracked lips or strawberry tongue. In addition, 18 (36%) fulfilled criteria for Multisystem Inflammatory Syndrome in Children (MIS-C).

“Based on findings in adult patients, the skin manifestations of COVID-19 have been classified under five categories: acral pseudo-chilblain, vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis,” David Andina-Martinez, MD, of Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues wrote in the study, which was published online on April 2 in the Journal of the American Academy of Dermatology.

“Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks,” they added. “Besides, other cutaneous manifestations of COVID-19 in children have been the matter of case reports or small case series. Nevertheless, the mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and their implications on the clinical course have not yet been extensively described.”

In an effort to describe the mucocutaneous manifestations in children hospitalized for COVID-19, the researchers evaluated 50 children up to 18 years of age who were admitted between March 1 and Nov. 30, 2020, to Hospital Infantil Universitario Niño Jesús, which was designated as a pediatric reference center during the peak of the pandemic. The main reasons for admission were respiratory illness (40%) and MIS-C (40%).

Of the 50 patients, 44 (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met clinical suspicion criteria and had a negative RT-PCR with a positive IgG serology. In 34 patients (68%), a close contact with a suspected or confirmed case of COVID-19 was referred, while the source of the infection remained unknown in the remaining 16 patients (32%).

The researchers reported that 21 patients (42%) had mucocutaneous symptoms, most commonly maculopapular exanthem (86%), conjunctival hyperemia (81%), and red cracked lips or strawberry tongue (43%). In addition, 18 of the 21 patients (86%) fulfilled criteria for MIS-C.

“A tricky thing about MIS-C is that it often manifests 4-5 weeks after a child had COVID-19,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study. “MIS-C is associated with characteristic bright red lips and a red tongue that might resemble a strawberry. Such oral findings should prompt rapid evaluation for other signs and symptoms. There can be redness of the eyes or other more nonspecific skin findings (large or small areas of redness on the trunk or limbs, sometimes with surface change), but more importantly, fever, a rapid heartbeat, diarrhea, or breathing issues. The risk with MIS-C is a rapid decline in a child’s health, with admission to an intensive care unit.”

Dr. Andina-Martinez and his colleagues also contrast the skin findings of MIS-C, which are not generally on the hands or feet, with the so-called “COVID toe” or finger phenomenon, which has also been associated with SARS-CoV-2, particularly in children. “Only one of the patients in this series had skin involvement of a finger, and it only appeared after recovery from MIS-C,” Dr. Ko noted. “Distinguishing COVID toes from MIS-C is important, as COVID toes has a very good outcome, while MIS-C can have severe consequences, including protracted heart disease.”

In other findings, patients who presented with mucocutaneous signs tended to be older than those without skin signs and they presented at the emergency department with poor general status and extreme tachycardia. They also had higher C-reactive protein and D-dimer levels and lower lymphocyte counts and faced a more than a 10-fold increased risk of being admitted to the PICU, compared with patients who did not have skin signs (OR, 10.24; P = .003).

In a separate study published online on April 7 in JAMA Dermatology, Zachary E. Holcomb, MD, of the combined dermatology residency program at Massachusetts General Hospital, Boston, and colleagues presented what is believed to be the first case report of reactive infectious mucocutaneous eruption (RIME) triggered by SARS-CoV-2. RIME is the preferred term for pediatric patients who present with mucositis and rash (often a scant or even absent skin eruption) triggered by various infectious agents.

The patient, a 17-year-old male, presented to the emergency department with 3 days of mouth pain and nonpainful penile erosions. “One week prior, he experienced transient anosmia and ageusia that had since spontaneously resolved,” the researchers wrote. “At that time, he was tested for SARS-CoV-2 infection via nasopharyngeal polymerase chain reaction (PCR), the results of which were positive.”

At presentation, the patient had no fever, his vital signs were normal, and the physical exam revealed shallow erosions of the vermilion lips and hard palate, circumferential erythematous erosions of the periurethral glans penis, and five small vesicles on the trunk and upper extremities. Serum analysis revealed a normal white blood cell count with mild absolute lymphopenia, slightly elevated creatinine level, normal liver function, slightly elevated C-reactive protein level, and normal ferritin level.

Dr. Holcomb and colleagues made a diagnosis of SARS-CoV-2–associated RIME based on microbiological results, which revealed positive repeated SARS-CoV-2 nasopharyngeal PCR and negative nasopharyngeal PCR testing for Mycoplasma pneumoniae, adenovirus, Chlamydophila pneumoniae, human metapneumovirus, influenza A/B, parainfluenza 1 to 4, rhinovirus, and respiratory syncytial virus. In addition, titers of Mycoplasma pneumoniae IgM levels were negative, but Mycoplasma pneumoniae IgG levels were elevated.

The lesions resolved with 60 mg of oral prednisone taken daily for 4 days. A recurrence of oral mucositis 3 months later responded to 80 mg oral prednisone taken daily for 6 days.

“It’s not surprising that SARS-CoV-2 is yet another trigger for RIME,” said Anna Yasmine Kirkorian, MD, chief of the division of dermatology at Children’s National Hospital, Washington, who was asked to comment about the case report.

“The take-home message is for clinicians to be aware of this association and distinguish these patients from those with MIS-C, because patients with MIS-C require monitoring and urgent systemic treatment. RIME and MIS-C may potentially be distinguished clinically based on the nature of the mucositis (hemorrhagic and erosive in RIME, dry, cracked lips with ‘strawberry tongue’ in MIS-C) but more importantly patients with RIME lack laboratory evidence of severe systemic inflammation,” such as ESR, CRP, or ferritin, she said.

“A final interesting point in this article was the recurrence of mucositis in this patient, which could mean that recurrent mucositis/recurrent RIME might be yet another manifestation of ‘long-COVID’ (now called post-Acute Sequelae of SARS-CoV-2 infection) in some patients,” Dr. Kirkorian added. She noted that the American Academy of Dermatology–International League of Dermatologic Societies COVID-19 Dermatology Registry and articles like these “provide invaluable ‘hot off the presses’ information for clinicians who are facing the protean manifestations of a novel viral epidemic.”

The researchers reported having no financial disclosures.
 

dbrunk@mdedge.com

Two recent articles in the medical literature provide new information on mucocutaneous manifestations of COVID-19 in children, which may help guide dermatologists in making accurate diagnoses and stratifying children at risk for serious, systemic illness due to the virus.

In a single-center descriptive study carried out over a 9-month period, researchers in Madrid found that of 50 hospitalized children infected with COVID-19, 21 (42%) had mucocutaneous symptoms, most commonly exanthem, followed by conjunctival hyperemia without secretion and red cracked lips or strawberry tongue. In addition, 18 (36%) fulfilled criteria for Multisystem Inflammatory Syndrome in Children (MIS-C).

“Based on findings in adult patients, the skin manifestations of COVID-19 have been classified under five categories: acral pseudo-chilblain, vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis,” David Andina-Martinez, MD, of Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues wrote in the study, which was published online on April 2 in the Journal of the American Academy of Dermatology.

“Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks,” they added. “Besides, other cutaneous manifestations of COVID-19 in children have been the matter of case reports or small case series. Nevertheless, the mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and their implications on the clinical course have not yet been extensively described.”

In an effort to describe the mucocutaneous manifestations in children hospitalized for COVID-19, the researchers evaluated 50 children up to 18 years of age who were admitted between March 1 and Nov. 30, 2020, to Hospital Infantil Universitario Niño Jesús, which was designated as a pediatric reference center during the peak of the pandemic. The main reasons for admission were respiratory illness (40%) and MIS-C (40%).

Of the 50 patients, 44 (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met clinical suspicion criteria and had a negative RT-PCR with a positive IgG serology. In 34 patients (68%), a close contact with a suspected or confirmed case of COVID-19 was referred, while the source of the infection remained unknown in the remaining 16 patients (32%).

The researchers reported that 21 patients (42%) had mucocutaneous symptoms, most commonly maculopapular exanthem (86%), conjunctival hyperemia (81%), and red cracked lips or strawberry tongue (43%). In addition, 18 of the 21 patients (86%) fulfilled criteria for MIS-C.

“A tricky thing about MIS-C is that it often manifests 4-5 weeks after a child had COVID-19,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study. “MIS-C is associated with characteristic bright red lips and a red tongue that might resemble a strawberry. Such oral findings should prompt rapid evaluation for other signs and symptoms. There can be redness of the eyes or other more nonspecific skin findings (large or small areas of redness on the trunk or limbs, sometimes with surface change), but more importantly, fever, a rapid heartbeat, diarrhea, or breathing issues. The risk with MIS-C is a rapid decline in a child’s health, with admission to an intensive care unit.”

Dr. Andina-Martinez and his colleagues also contrast the skin findings of MIS-C, which are not generally on the hands or feet, with the so-called “COVID toe” or finger phenomenon, which has also been associated with SARS-CoV-2, particularly in children. “Only one of the patients in this series had skin involvement of a finger, and it only appeared after recovery from MIS-C,” Dr. Ko noted. “Distinguishing COVID toes from MIS-C is important, as COVID toes has a very good outcome, while MIS-C can have severe consequences, including protracted heart disease.”

In other findings, patients who presented with mucocutaneous signs tended to be older than those without skin signs and they presented at the emergency department with poor general status and extreme tachycardia. They also had higher C-reactive protein and D-dimer levels and lower lymphocyte counts and faced a more than a 10-fold increased risk of being admitted to the PICU, compared with patients who did not have skin signs (OR, 10.24; P = .003).

In a separate study published online on April 7 in JAMA Dermatology, Zachary E. Holcomb, MD, of the combined dermatology residency program at Massachusetts General Hospital, Boston, and colleagues presented what is believed to be the first case report of reactive infectious mucocutaneous eruption (RIME) triggered by SARS-CoV-2. RIME is the preferred term for pediatric patients who present with mucositis and rash (often a scant or even absent skin eruption) triggered by various infectious agents.

The patient, a 17-year-old male, presented to the emergency department with 3 days of mouth pain and nonpainful penile erosions. “One week prior, he experienced transient anosmia and ageusia that had since spontaneously resolved,” the researchers wrote. “At that time, he was tested for SARS-CoV-2 infection via nasopharyngeal polymerase chain reaction (PCR), the results of which were positive.”

At presentation, the patient had no fever, his vital signs were normal, and the physical exam revealed shallow erosions of the vermilion lips and hard palate, circumferential erythematous erosions of the periurethral glans penis, and five small vesicles on the trunk and upper extremities. Serum analysis revealed a normal white blood cell count with mild absolute lymphopenia, slightly elevated creatinine level, normal liver function, slightly elevated C-reactive protein level, and normal ferritin level.

Dr. Holcomb and colleagues made a diagnosis of SARS-CoV-2–associated RIME based on microbiological results, which revealed positive repeated SARS-CoV-2 nasopharyngeal PCR and negative nasopharyngeal PCR testing for Mycoplasma pneumoniae, adenovirus, Chlamydophila pneumoniae, human metapneumovirus, influenza A/B, parainfluenza 1 to 4, rhinovirus, and respiratory syncytial virus. In addition, titers of Mycoplasma pneumoniae IgM levels were negative, but Mycoplasma pneumoniae IgG levels were elevated.

The lesions resolved with 60 mg of oral prednisone taken daily for 4 days. A recurrence of oral mucositis 3 months later responded to 80 mg oral prednisone taken daily for 6 days.

“It’s not surprising that SARS-CoV-2 is yet another trigger for RIME,” said Anna Yasmine Kirkorian, MD, chief of the division of dermatology at Children’s National Hospital, Washington, who was asked to comment about the case report.

“The take-home message is for clinicians to be aware of this association and distinguish these patients from those with MIS-C, because patients with MIS-C require monitoring and urgent systemic treatment. RIME and MIS-C may potentially be distinguished clinically based on the nature of the mucositis (hemorrhagic and erosive in RIME, dry, cracked lips with ‘strawberry tongue’ in MIS-C) but more importantly patients with RIME lack laboratory evidence of severe systemic inflammation,” such as ESR, CRP, or ferritin, she said.

“A final interesting point in this article was the recurrence of mucositis in this patient, which could mean that recurrent mucositis/recurrent RIME might be yet another manifestation of ‘long-COVID’ (now called post-Acute Sequelae of SARS-CoV-2 infection) in some patients,” Dr. Kirkorian added. She noted that the American Academy of Dermatology–International League of Dermatologic Societies COVID-19 Dermatology Registry and articles like these “provide invaluable ‘hot off the presses’ information for clinicians who are facing the protean manifestations of a novel viral epidemic.”

The researchers reported having no financial disclosures.
 

dbrunk@mdedge.com

Asian Americans with melanoma presented at a younger age but with higher rates of invasive disease and at later stages of disease, compared with non-Hispanic Whites, according to a secondary analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The findings are consistent with previous studies indicating delayed detection of melanoma in Asians, compared with non-Hispanic Whites, and provide a window into Asian American communities specifically, Erica M. Lin, a medical student at Brown University, Providence, R.I., said at the annual Skin of Color Society Symposium. The majority of studies on melanoma in Asians have originated in Asia, noted Ms. Lin, whose coauthor was Eunyoung Cho, ScD, an associate professor in the department of dermatology and director of the clinical and translational research program at Brown University. Their analysis covered registries from 10 geographic areas representing 54% of the U.S. Asian American population over a 25-year period, from 1990 to 2014.

Asian Americans with melanoma were more likely to present at an invasive stage than non-Hispanic Whites (82.9% vs. 72.2%, P < .001), and they were significantly more likely to present when the disease had progressed to a distant stage (9.39% vs. 2.51%, P < .001), even though they were of younger ages at the time of those diagnoses, Ms. Lin reported at the meeting. (The numbers do not account for unknown or unstaged melanoma cases.)

Significantly fewer Asian Americans presented at the “in situ” stage, compared with non-Hispanic Whites (17.11% vs. 27.78%). The lower extremities were the most common site in Asian Americans, compared with the trunk in Non-Hispanic Whites.

The SEER registries covered the eight largest Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans (Cambodians), Koreans, Laotians, and Vietnamese. Melanoma was more common in females across the groups (53% of females vs. 47% of males), with the exception of Asian Indians/Pakistanis.

While melanoma increased significantly over time among non-Hispanic Whites – a mean 24% increase per 5-year period – there was “no significant change in melanoma rates in Asians,” Ms. Lin said.

The lack of increase in Asian American communities combined with the other findings is “potentially concerning” and suggests “that there may be cases that are not being identified,” she said in an interview after the meeting. In their abstract, she and Dr. Cho noted that their findings underscore the need for further prevention, screening, and surveillance measures.

The NCI’s SEER program is a coordinated system of cancer registries across the United States that collects data on every case of cancer reported in 19 geographic areas.

Asian Americans with melanoma presented at a younger age but with higher rates of invasive disease and at later stages of disease, compared with non-Hispanic Whites, according to a secondary analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The findings are consistent with previous studies indicating delayed detection of melanoma in Asians, compared with non-Hispanic Whites, and provide a window into Asian American communities specifically, Erica M. Lin, a medical student at Brown University, Providence, R.I., said at the annual Skin of Color Society Symposium. The majority of studies on melanoma in Asians have originated in Asia, noted Ms. Lin, whose coauthor was Eunyoung Cho, ScD, an associate professor in the department of dermatology and director of the clinical and translational research program at Brown University. Their analysis covered registries from 10 geographic areas representing 54% of the U.S. Asian American population over a 25-year period, from 1990 to 2014.

Asian Americans with melanoma were more likely to present at an invasive stage than non-Hispanic Whites (82.9% vs. 72.2%, P < .001), and they were significantly more likely to present when the disease had progressed to a distant stage (9.39% vs. 2.51%, P < .001), even though they were of younger ages at the time of those diagnoses, Ms. Lin reported at the meeting. (The numbers do not account for unknown or unstaged melanoma cases.)

Significantly fewer Asian Americans presented at the “in situ” stage, compared with non-Hispanic Whites (17.11% vs. 27.78%). The lower extremities were the most common site in Asian Americans, compared with the trunk in Non-Hispanic Whites.

The SEER registries covered the eight largest Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans (Cambodians), Koreans, Laotians, and Vietnamese. Melanoma was more common in females across the groups (53% of females vs. 47% of males), with the exception of Asian Indians/Pakistanis.

While melanoma increased significantly over time among non-Hispanic Whites – a mean 24% increase per 5-year period – there was “no significant change in melanoma rates in Asians,” Ms. Lin said.

The lack of increase in Asian American communities combined with the other findings is “potentially concerning” and suggests “that there may be cases that are not being identified,” she said in an interview after the meeting. In their abstract, she and Dr. Cho noted that their findings underscore the need for further prevention, screening, and surveillance measures.

The NCI’s SEER program is a coordinated system of cancer registries across the United States that collects data on every case of cancer reported in 19 geographic areas.

Asian Americans with melanoma presented at a younger age but with higher rates of invasive disease and at later stages of disease, compared with non-Hispanic Whites, according to a secondary analysis of data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.

The findings are consistent with previous studies indicating delayed detection of melanoma in Asians, compared with non-Hispanic Whites, and provide a window into Asian American communities specifically, Erica M. Lin, a medical student at Brown University, Providence, R.I., said at the annual Skin of Color Society Symposium. The majority of studies on melanoma in Asians have originated in Asia, noted Ms. Lin, whose coauthor was Eunyoung Cho, ScD, an associate professor in the department of dermatology and director of the clinical and translational research program at Brown University. Their analysis covered registries from 10 geographic areas representing 54% of the U.S. Asian American population over a 25-year period, from 1990 to 2014.

Asian Americans with melanoma were more likely to present at an invasive stage than non-Hispanic Whites (82.9% vs. 72.2%, P < .001), and they were significantly more likely to present when the disease had progressed to a distant stage (9.39% vs. 2.51%, P < .001), even though they were of younger ages at the time of those diagnoses, Ms. Lin reported at the meeting. (The numbers do not account for unknown or unstaged melanoma cases.)

Significantly fewer Asian Americans presented at the “in situ” stage, compared with non-Hispanic Whites (17.11% vs. 27.78%). The lower extremities were the most common site in Asian Americans, compared with the trunk in Non-Hispanic Whites.

The SEER registries covered the eight largest Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans (Cambodians), Koreans, Laotians, and Vietnamese. Melanoma was more common in females across the groups (53% of females vs. 47% of males), with the exception of Asian Indians/Pakistanis.

While melanoma increased significantly over time among non-Hispanic Whites – a mean 24% increase per 5-year period – there was “no significant change in melanoma rates in Asians,” Ms. Lin said.

The lack of increase in Asian American communities combined with the other findings is “potentially concerning” and suggests “that there may be cases that are not being identified,” she said in an interview after the meeting. In their abstract, she and Dr. Cho noted that their findings underscore the need for further prevention, screening, and surveillance measures.

The NCI’s SEER program is a coordinated system of cancer registries across the United States that collects data on every case of cancer reported in 19 geographic areas.

Secukinumab proved highly effective at improving skin symptoms and quality of life in 6- to 17-year-old patients with moderate to severe plaque psoriasis at 24 weeks of follow-up in an ongoing 4-year phase 2 clinical trial, Adam Reich, MD, PhD, reported at Innovations in Dermatology: Virtual Spring Conference 2021.

Secukinumab (Cosentyx), a fully human monoclonal antibody that inhibits interleukin-17A, is widely approved for treatment of psoriasis in adults. In August 2020, the biologic received an expanded indication in Europe for treatment of 6- to 17-year-olds. Two phase 3 clinical trials are underway in an effort to gain a similar broadened indication in the United States to help address the high unmet need for new treatments for psoriasis in the pediatric population, said Dr. Reich, professor and head of the department of dermatology at the University of Rzeszow (Poland).

He reported on 84 pediatric patients participating in the open-label, phase 2, international study. They were randomized to one of two weight-based dosing regimens. Those in the low-dose arm received secukinumab dosed at 75 mg if they weighed less than 50 kg and 150 mg if they weighed more. In the high-dose arm, patients got secukinumab 75 mg if they weighed less than 25 kg, 150 mg if they weighed 25-50 kg, and 300 mg if they tipped the scales in excess of 50 kg.

The primary endpoint in the study was the week-12 rate of at least a 75% improvement from baseline in the Psoriasis Area and Severity Index score, or PASI 75. The rates were similar: 92.9% of patients in the high-dose arm achieved this endpoint, as did 90.5% in the low-dose arm. The PASI 90 rates were 83.3% and 78%, the PASI 100 rates were 61.9% and 54.8%, and clear or almost clear skin, as measured by the Investigator Global Assessment, was achieved in 88.7% of the high- and 85.7% of the low-dose groups. In addition,61.9% of those in the high-dose secukinumab group and 50% in the low-dose group had a score of 0 or 1 on the Children’s Dermatology Life Quality Index – indicating psoriasis has no impact on daily quality of life, he said at the conference sponsored by MedscapeLIVE! and the producers of the Hawaii Dermatology Seminar and Caribbean Dermatology Symposium.

At week 24, roughly 95% of patients in both the low- and high-dose secukinumab groups had achieved PASI 75s, 88% reached a PASI 90 response, and 67% were at PASI 100. Nearly 60% of the low-dose and 70% of the high-dose groups had a score of 0 or 1 on the Children’s Dermatology Life Quality Index.

Treatment-emergent adverse event rates were similar in the two study arms. Of note, there was one case of new-onset inflammatory bowel disease in the high-dose group, and one case of vulvovaginal candidiasis as well.

Discussant Bruce E. Strober, MD, PhD, said that, if secukinumab gets a pediatric indication from the Food and Drug Administration, as seems likely, it won’t alter his biologic treatment hierarchy.

“I treat a lot of kids with psoriasis. We have three approved drugs now in etanercept [Enbrel], ustekinumab [Stelara], and ixekizumab [Taltz]. My bias is still towards ustekinumab because it’s infrequently dosed and that’s a huge issue for children. You want to expose them to as few injections as possible, for obvious reasons: It’s easier for parents and other caregivers,” explained Dr. Strober, a dermatologist at Yale University, New Haven, Conn., and Central Connecticut Dermatology, Cromwell, Conn.

“The other issue is in IL-17 inhibition there has been a slight signal of inflammatory bowel disease popping up in children getting these drugs, and therefore you need to screen patients in this age group very carefully – not only the patients themselves, but their family – for IBD risk. If there is any sign of that I would move the IL-17 inhibitors to the back of the line, compared to ustekinumab and etanercept. Ustekinumab is still clearly the one that I think has to be used first line,” he said.

Dr. Strober offered a final word of advice for his colleagues: “You can’t be afraid to treat children with biologic therapies. In fact, preferentially I would use a biologic therapy over methotrexate or light therapy, which is really difficult for children.”

Dr. Reich and Dr. Strober reported receiving research grants from and serving as a consultant to numerous pharmaceutical companies, including Novartis, which markets secukinumab and funded the study.

MedscapeLIVE! and this news organization are owned by the same parent company.

Secukinumab proved highly effective at improving skin symptoms and quality of life in 6- to 17-year-old patients with moderate to severe plaque psoriasis at 24 weeks of follow-up in an ongoing 4-year phase 2 clinical trial, Adam Reich, MD, PhD, reported at Innovations in Dermatology: Virtual Spring Conference 2021.

Secukinumab (Cosentyx), a fully human monoclonal antibody that inhibits interleukin-17A, is widely approved for treatment of psoriasis in adults. In August 2020, the biologic received an expanded indication in Europe for treatment of 6- to 17-year-olds. Two phase 3 clinical trials are underway in an effort to gain a similar broadened indication in the United States to help address the high unmet need for new treatments for psoriasis in the pediatric population, said Dr. Reich, professor and head of the department of dermatology at the University of Rzeszow (Poland).

He reported on 84 pediatric patients participating in the open-label, phase 2, international study. They were randomized to one of two weight-based dosing regimens. Those in the low-dose arm received secukinumab dosed at 75 mg if they weighed less than 50 kg and 150 mg if they weighed more. In the high-dose arm, patients got secukinumab 75 mg if they weighed less than 25 kg, 150 mg if they weighed 25-50 kg, and 300 mg if they tipped the scales in excess of 50 kg.

The primary endpoint in the study was the week-12 rate of at least a 75% improvement from baseline in the Psoriasis Area and Severity Index score, or PASI 75. The rates were similar: 92.9% of patients in the high-dose arm achieved this endpoint, as did 90.5% in the low-dose arm. The PASI 90 rates were 83.3% and 78%, the PASI 100 rates were 61.9% and 54.8%, and clear or almost clear skin, as measured by the Investigator Global Assessment, was achieved in 88.7% of the high- and 85.7% of the low-dose groups. In addition,61.9% of those in the high-dose secukinumab group and 50% in the low-dose group had a score of 0 or 1 on the Children’s Dermatology Life Quality Index – indicating psoriasis has no impact on daily quality of life, he said at the conference sponsored by MedscapeLIVE! and the producers of the Hawaii Dermatology Seminar and Caribbean Dermatology Symposium.

At week 24, roughly 95% of patients in both the low- and high-dose secukinumab groups had achieved PASI 75s, 88% reached a PASI 90 response, and 67% were at PASI 100. Nearly 60% of the low-dose and 70% of the high-dose groups had a score of 0 or 1 on the Children’s Dermatology Life Quality Index.

Treatment-emergent adverse event rates were similar in the two study arms. Of note, there was one case of new-onset inflammatory bowel disease in the high-dose group, and one case of vulvovaginal candidiasis as well.

Discussant Bruce E. Strober, MD, PhD, said that, if secukinumab gets a pediatric indication from the Food and Drug Administration, as seems likely, it won’t alter his biologic treatment hierarchy.

“I treat a lot of kids with psoriasis. We have three approved drugs now in etanercept [Enbrel], ustekinumab [Stelara], and ixekizumab [Taltz]. My bias is still towards ustekinumab because it’s infrequently dosed and that’s a huge issue for children. You want to expose them to as few injections as possible, for obvious reasons: It’s easier for parents and other caregivers,” explained Dr. Strober, a dermatologist at Yale University, New Haven, Conn., and Central Connecticut Dermatology, Cromwell, Conn.

“The other issue is in IL-17 inhibition there has been a slight signal of inflammatory bowel disease popping up in children getting these drugs, and therefore you need to screen patients in this age group very carefully – not only the patients themselves, but their family – for IBD risk. If there is any sign of that I would move the IL-17 inhibitors to the back of the line, compared to ustekinumab and etanercept. Ustekinumab is still clearly the one that I think has to be used first line,” he said.

Dr. Strober offered a final word of advice for his colleagues: “You can’t be afraid to treat children with biologic therapies. In fact, preferentially I would use a biologic therapy over methotrexate or light therapy, which is really difficult for children.”

Dr. Reich and Dr. Strober reported receiving research grants from and serving as a consultant to numerous pharmaceutical companies, including Novartis, which markets secukinumab and funded the study.

MedscapeLIVE! and this news organization are owned by the same parent company.

Secukinumab proved highly effective at improving skin symptoms and quality of life in 6- to 17-year-old patients with moderate to severe plaque psoriasis at 24 weeks of follow-up in an ongoing 4-year phase 2 clinical trial, Adam Reich, MD, PhD, reported at Innovations in Dermatology: Virtual Spring Conference 2021.

Secukinumab (Cosentyx), a fully human monoclonal antibody that inhibits interleukin-17A, is widely approved for treatment of psoriasis in adults. In August 2020, the biologic received an expanded indication in Europe for treatment of 6- to 17-year-olds. Two phase 3 clinical trials are underway in an effort to gain a similar broadened indication in the United States to help address the high unmet need for new treatments for psoriasis in the pediatric population, said Dr. Reich, professor and head of the department of dermatology at the University of Rzeszow (Poland).

He reported on 84 pediatric patients participating in the open-label, phase 2, international study. They were randomized to one of two weight-based dosing regimens. Those in the low-dose arm received secukinumab dosed at 75 mg if they weighed less than 50 kg and 150 mg if they weighed more. In the high-dose arm, patients got secukinumab 75 mg if they weighed less than 25 kg, 150 mg if they weighed 25-50 kg, and 300 mg if they tipped the scales in excess of 50 kg.

The primary endpoint in the study was the week-12 rate of at least a 75% improvement from baseline in the Psoriasis Area and Severity Index score, or PASI 75. The rates were similar: 92.9% of patients in the high-dose arm achieved this endpoint, as did 90.5% in the low-dose arm. The PASI 90 rates were 83.3% and 78%, the PASI 100 rates were 61.9% and 54.8%, and clear or almost clear skin, as measured by the Investigator Global Assessment, was achieved in 88.7% of the high- and 85.7% of the low-dose groups. In addition,61.9% of those in the high-dose secukinumab group and 50% in the low-dose group had a score of 0 or 1 on the Children’s Dermatology Life Quality Index – indicating psoriasis has no impact on daily quality of life, he said at the conference sponsored by MedscapeLIVE! and the producers of the Hawaii Dermatology Seminar and Caribbean Dermatology Symposium.

At week 24, roughly 95% of patients in both the low- and high-dose secukinumab groups had achieved PASI 75s, 88% reached a PASI 90 response, and 67% were at PASI 100. Nearly 60% of the low-dose and 70% of the high-dose groups had a score of 0 or 1 on the Children’s Dermatology Life Quality Index.

Treatment-emergent adverse event rates were similar in the two study arms. Of note, there was one case of new-onset inflammatory bowel disease in the high-dose group, and one case of vulvovaginal candidiasis as well.

Discussant Bruce E. Strober, MD, PhD, said that, if secukinumab gets a pediatric indication from the Food and Drug Administration, as seems likely, it won’t alter his biologic treatment hierarchy.

“I treat a lot of kids with psoriasis. We have three approved drugs now in etanercept [Enbrel], ustekinumab [Stelara], and ixekizumab [Taltz]. My bias is still towards ustekinumab because it’s infrequently dosed and that’s a huge issue for children. You want to expose them to as few injections as possible, for obvious reasons: It’s easier for parents and other caregivers,” explained Dr. Strober, a dermatologist at Yale University, New Haven, Conn., and Central Connecticut Dermatology, Cromwell, Conn.

“The other issue is in IL-17 inhibition there has been a slight signal of inflammatory bowel disease popping up in children getting these drugs, and therefore you need to screen patients in this age group very carefully – not only the patients themselves, but their family – for IBD risk. If there is any sign of that I would move the IL-17 inhibitors to the back of the line, compared to ustekinumab and etanercept. Ustekinumab is still clearly the one that I think has to be used first line,” he said.

Dr. Strober offered a final word of advice for his colleagues: “You can’t be afraid to treat children with biologic therapies. In fact, preferentially I would use a biologic therapy over methotrexate or light therapy, which is really difficult for children.”

Dr. Reich and Dr. Strober reported receiving research grants from and serving as a consultant to numerous pharmaceutical companies, including Novartis, which markets secukinumab and funded the study.

MedscapeLIVE! and this news organization are owned by the same parent company.

For as many disorders of cornification and types of ichthyosis that have been shown to benefit from retinoids, a seemingly equal number have no data or show no improvement.

According to a consensus statement published in the February issue of Pediatric Dermatology, adequate data exist in the medical literature to demonstrate an improvement in use of systemic retinoids for select genotypes of congenital ichthyosiform erythroderma, epidermolytic ichthyosis, erythrokeratodermia variabilis, harlequin ichthyosis, IFAP syndrome (ichthyosis with confetti, ichthyosis follicularis, atrichia, and photophobia), KID syndrome (keratitis-ichthyosis-deafness), KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma), lamellar ichthyosis, loricrin keratoderma, neutral lipid storage disease with ichthyosis, recessive X-linked ichthyosis, and Sjögren-Larsson syndrome.

At the same time, limited or no data exist to support the use of systemic retinoids for CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects), CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and either ear defects or epilepsy), Conradi-Hunermann-Happle syndrome, ichthyosis-hypotrichosis, ichthyosis-hypotrichosis-sclerosis cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma), peeling skin disease, Refsum syndrome, and trichothiodystrophy, according to the statement.

“In particular, we did note that, with any disorder that was associated with atopy, the retinoids were often counterproductive,” one of the consensus statement cochairs, Andrea L. Zaenglein, MD, said during the Society for Pediatric Dermatology pre-AAD meeting. “In Netherton syndrome, for example, retinoids seemed to make the skin fragility a lot worse, so typically, they would be avoided in those patients.”

The statement, which she assembled with cochair pediatric dermatologist Moise L. Levy, MD, professor of pediatrics, University of Texas at Austin, and 21 other multidisciplinary experts, recommends considering use of topical retinoids to help decrease scaling of the skin,“but [they] are particularly helpful for more localized complications of ichthyosis, such as digital contractures and ectropion,” said Dr. Zaenglein, professor of dermatology and pediatrics at Penn State University, Hershey. “A lot of it has to do with the size and the volume of the tubes and getting enough [product] to be able to apply it over larger areas. We do tend to use them more focally.”

While systemic absorption can occur with widespread use, no specific lab monitoring is required. Dr. Zaenglein and her colleagues also recommend avoiding the use of tazarotene during pregnancy, since it is contraindicated in pregnancy (category X), but monthly pregnancy tests are not recommended.

During an overview of the document at the meeting, she noted that the recommended dosing for both isotretinoin and acitretin is 0.5-1.0 mg/kg per day and the side effects tend to be dose dependent, “except teratogenicity, which can occur with even low doses of systemic retinoid exposure and early on in pregnancy.” The authors also advise patients to consider drug holidays or lower doses “especially during warmer, more humid months, where you might not need the higher doses to achieve cutaneous effects,” she said.

They emphasized the importance of avoiding pregnancy for 3 years after completion of treatment with acitretin. “While the half-life of acitretin is 49 hours, it’s easily converted with any alcohol exposure to etretinate,” Dr. Zaenglein noted. “Then, the half-life is 120 days.”

The statement, which was sponsored by the Pediatric Dermatology Research Alliance (PEDRA), also addresses the clinical considerations and consequences of long-term systemic retinoid use on bone health, such as premature epiphyseal closure in preadolescent children. “In general, this risk is greater with higher doses of therapies – above 1 mg/kg per day – and over prolonged periods of time, typically 4-6 years,” she said. Other potential effects on bone health include calcifications of tendons and ligaments, osteophytes or “bone spurs,” DISH (diffuse idiopathic skeletal hyperostosis), and potential alterations in bone density and growth.

“We also have to worry about concomitant effects of contraception, particularly if you’re using progestin-only formulations that carry a black box warning for osteoporosis,” Dr. Zaenglein said. “It is recommended that you limit their use to 3 years.” Other factors to consider include genetic risk and modifiable factors that affect bone health, such as diet and physical activity, which may impact susceptibility to systemic retinoid bone toxicity and should be discussed with the patient.

Recommended bone monitoring in children starts with a comprehensive family and personal medical history for skeletal toxicity risk factors, followed by an annual growth assessment (height, weight, body mass index, and growth curve), asking regularly about musculoskeletal symptoms, and following up with appropriate imaging. “Inquiring about their diet is recommended as well, so making sure they’re getting sufficient amounts of calcium and vitamin D, and no additional vitamin A sources that may compound the side effects from systemic retinoids,” Dr. Zaenglein said.

The document also advises that a baseline skeletal radiographic survey be performed in patients aged 16-18 years. This may include imaging of the lateral cervical and thoracic spine, lateral view of the calcanei to include Achilles tendon, hips and symptomatic areas, and bone density evaluation.

The statement addressed the psychiatric considerations and consequences of long-term systemic retinoid use. One cross-sectional study of children with ichthyosis found that 30% screened positive for depression and 38% screened positive for anxiety, “but the role of retinoids is unclear,” Dr. Zaenglein said. “It’s a complicated matter, but patients with a personal history of depression, anxiety, and other affective disorders prior to initiation of systemic retinoid treatment should be monitored carefully for exacerbation of symptoms. Comanagement with a mental health provider should be considered.”

As for contraception considerations with long-term systemic retinoid therapy use, the authors recommend that two forms of contraception be used. “Consider long-acting reversible contraception, especially in sexually active adolescents who have a history of noncompliance, or to remove the risk of teratogenicity for them,” she said. “We’re not sure what additive effects progestin/lower estrogen have on long-term cardiovascular health, including lipids and bone density.”

The authors noted that iPLEDGE is not designed for long-term use. “It’s really designed for the on-label use of systemic retinoids in severe acne, where you’re using it for 5-6 months, not for 5-6 years,” Dr. Zaenglein said. “iPLEDGE does impose significant and financial barriers for our patients. More advocacy is needed to adapt that program for our patients.”

She and her coauthors acknowledged practice gaps and unmet needs in patients with disorders of cornification/types of ichthyosis, including the optimal formulation of retinoids based on ichthyosis subtype, whether there is a benefit to intermittent therapy with respect to risk of toxicity and maintenance of efficacy, and how to minimize the bone-related changes that can occur with treatment. “These are some of the things that we can look further into,” she said. “For now, though, retinoids can improve function and quality of life in patients with ichthyosis and disorders of cornification. Many questions still exist, and more data and research are needed.”

Sun Pharmaceuticals and the Foundation for Ichthyosis and Related Skin Types (FIRST) provided an unrestricted grant for development of the recommendations.

Dr. Zaenglein disclosed that she is a consultant for Pfizer. She is also an advisory board member for Dermata, Sol-Gel, Regeneron, Verrica, and Cassiopea, and has conducted contracted research for AbbVie, Incyte, Arcutis, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or had other relationships with various pharmaceutical companies.

dbrunk@mdedge.com

For as many disorders of cornification and types of ichthyosis that have been shown to benefit from retinoids, a seemingly equal number have no data or show no improvement.

According to a consensus statement published in the February issue of Pediatric Dermatology, adequate data exist in the medical literature to demonstrate an improvement in use of systemic retinoids for select genotypes of congenital ichthyosiform erythroderma, epidermolytic ichthyosis, erythrokeratodermia variabilis, harlequin ichthyosis, IFAP syndrome (ichthyosis with confetti, ichthyosis follicularis, atrichia, and photophobia), KID syndrome (keratitis-ichthyosis-deafness), KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma), lamellar ichthyosis, loricrin keratoderma, neutral lipid storage disease with ichthyosis, recessive X-linked ichthyosis, and Sjögren-Larsson syndrome.

At the same time, limited or no data exist to support the use of systemic retinoids for CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects), CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and either ear defects or epilepsy), Conradi-Hunermann-Happle syndrome, ichthyosis-hypotrichosis, ichthyosis-hypotrichosis-sclerosis cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma), peeling skin disease, Refsum syndrome, and trichothiodystrophy, according to the statement.

“In particular, we did note that, with any disorder that was associated with atopy, the retinoids were often counterproductive,” one of the consensus statement cochairs, Andrea L. Zaenglein, MD, said during the Society for Pediatric Dermatology pre-AAD meeting. “In Netherton syndrome, for example, retinoids seemed to make the skin fragility a lot worse, so typically, they would be avoided in those patients.”

The statement, which she assembled with cochair pediatric dermatologist Moise L. Levy, MD, professor of pediatrics, University of Texas at Austin, and 21 other multidisciplinary experts, recommends considering use of topical retinoids to help decrease scaling of the skin,“but [they] are particularly helpful for more localized complications of ichthyosis, such as digital contractures and ectropion,” said Dr. Zaenglein, professor of dermatology and pediatrics at Penn State University, Hershey. “A lot of it has to do with the size and the volume of the tubes and getting enough [product] to be able to apply it over larger areas. We do tend to use them more focally.”

While systemic absorption can occur with widespread use, no specific lab monitoring is required. Dr. Zaenglein and her colleagues also recommend avoiding the use of tazarotene during pregnancy, since it is contraindicated in pregnancy (category X), but monthly pregnancy tests are not recommended.

During an overview of the document at the meeting, she noted that the recommended dosing for both isotretinoin and acitretin is 0.5-1.0 mg/kg per day and the side effects tend to be dose dependent, “except teratogenicity, which can occur with even low doses of systemic retinoid exposure and early on in pregnancy.” The authors also advise patients to consider drug holidays or lower doses “especially during warmer, more humid months, where you might not need the higher doses to achieve cutaneous effects,” she said.

They emphasized the importance of avoiding pregnancy for 3 years after completion of treatment with acitretin. “While the half-life of acitretin is 49 hours, it’s easily converted with any alcohol exposure to etretinate,” Dr. Zaenglein noted. “Then, the half-life is 120 days.”

The statement, which was sponsored by the Pediatric Dermatology Research Alliance (PEDRA), also addresses the clinical considerations and consequences of long-term systemic retinoid use on bone health, such as premature epiphyseal closure in preadolescent children. “In general, this risk is greater with higher doses of therapies – above 1 mg/kg per day – and over prolonged periods of time, typically 4-6 years,” she said. Other potential effects on bone health include calcifications of tendons and ligaments, osteophytes or “bone spurs,” DISH (diffuse idiopathic skeletal hyperostosis), and potential alterations in bone density and growth.

“We also have to worry about concomitant effects of contraception, particularly if you’re using progestin-only formulations that carry a black box warning for osteoporosis,” Dr. Zaenglein said. “It is recommended that you limit their use to 3 years.” Other factors to consider include genetic risk and modifiable factors that affect bone health, such as diet and physical activity, which may impact susceptibility to systemic retinoid bone toxicity and should be discussed with the patient.

Recommended bone monitoring in children starts with a comprehensive family and personal medical history for skeletal toxicity risk factors, followed by an annual growth assessment (height, weight, body mass index, and growth curve), asking regularly about musculoskeletal symptoms, and following up with appropriate imaging. “Inquiring about their diet is recommended as well, so making sure they’re getting sufficient amounts of calcium and vitamin D, and no additional vitamin A sources that may compound the side effects from systemic retinoids,” Dr. Zaenglein said.

The document also advises that a baseline skeletal radiographic survey be performed in patients aged 16-18 years. This may include imaging of the lateral cervical and thoracic spine, lateral view of the calcanei to include Achilles tendon, hips and symptomatic areas, and bone density evaluation.

The statement addressed the psychiatric considerations and consequences of long-term systemic retinoid use. One cross-sectional study of children with ichthyosis found that 30% screened positive for depression and 38% screened positive for anxiety, “but the role of retinoids is unclear,” Dr. Zaenglein said. “It’s a complicated matter, but patients with a personal history of depression, anxiety, and other affective disorders prior to initiation of systemic retinoid treatment should be monitored carefully for exacerbation of symptoms. Comanagement with a mental health provider should be considered.”

As for contraception considerations with long-term systemic retinoid therapy use, the authors recommend that two forms of contraception be used. “Consider long-acting reversible contraception, especially in sexually active adolescents who have a history of noncompliance, or to remove the risk of teratogenicity for them,” she said. “We’re not sure what additive effects progestin/lower estrogen have on long-term cardiovascular health, including lipids and bone density.”

The authors noted that iPLEDGE is not designed for long-term use. “It’s really designed for the on-label use of systemic retinoids in severe acne, where you’re using it for 5-6 months, not for 5-6 years,” Dr. Zaenglein said. “iPLEDGE does impose significant and financial barriers for our patients. More advocacy is needed to adapt that program for our patients.”

She and her coauthors acknowledged practice gaps and unmet needs in patients with disorders of cornification/types of ichthyosis, including the optimal formulation of retinoids based on ichthyosis subtype, whether there is a benefit to intermittent therapy with respect to risk of toxicity and maintenance of efficacy, and how to minimize the bone-related changes that can occur with treatment. “These are some of the things that we can look further into,” she said. “For now, though, retinoids can improve function and quality of life in patients with ichthyosis and disorders of cornification. Many questions still exist, and more data and research are needed.”

Sun Pharmaceuticals and the Foundation for Ichthyosis and Related Skin Types (FIRST) provided an unrestricted grant for development of the recommendations.

Dr. Zaenglein disclosed that she is a consultant for Pfizer. She is also an advisory board member for Dermata, Sol-Gel, Regeneron, Verrica, and Cassiopea, and has conducted contracted research for AbbVie, Incyte, Arcutis, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or had other relationships with various pharmaceutical companies.

dbrunk@mdedge.com

For as many disorders of cornification and types of ichthyosis that have been shown to benefit from retinoids, a seemingly equal number have no data or show no improvement.

According to a consensus statement published in the February issue of Pediatric Dermatology, adequate data exist in the medical literature to demonstrate an improvement in use of systemic retinoids for select genotypes of congenital ichthyosiform erythroderma, epidermolytic ichthyosis, erythrokeratodermia variabilis, harlequin ichthyosis, IFAP syndrome (ichthyosis with confetti, ichthyosis follicularis, atrichia, and photophobia), KID syndrome (keratitis-ichthyosis-deafness), KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma), lamellar ichthyosis, loricrin keratoderma, neutral lipid storage disease with ichthyosis, recessive X-linked ichthyosis, and Sjögren-Larsson syndrome.

At the same time, limited or no data exist to support the use of systemic retinoids for CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects), CHIME syndrome (colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, and either ear defects or epilepsy), Conradi-Hunermann-Happle syndrome, ichthyosis-hypotrichosis, ichthyosis-hypotrichosis-sclerosis cholangitis, ichthyosis prematurity syndrome, MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma), peeling skin disease, Refsum syndrome, and trichothiodystrophy, according to the statement.

“In particular, we did note that, with any disorder that was associated with atopy, the retinoids were often counterproductive,” one of the consensus statement cochairs, Andrea L. Zaenglein, MD, said during the Society for Pediatric Dermatology pre-AAD meeting. “In Netherton syndrome, for example, retinoids seemed to make the skin fragility a lot worse, so typically, they would be avoided in those patients.”

The statement, which she assembled with cochair pediatric dermatologist Moise L. Levy, MD, professor of pediatrics, University of Texas at Austin, and 21 other multidisciplinary experts, recommends considering use of topical retinoids to help decrease scaling of the skin,“but [they] are particularly helpful for more localized complications of ichthyosis, such as digital contractures and ectropion,” said Dr. Zaenglein, professor of dermatology and pediatrics at Penn State University, Hershey. “A lot of it has to do with the size and the volume of the tubes and getting enough [product] to be able to apply it over larger areas. We do tend to use them more focally.”

While systemic absorption can occur with widespread use, no specific lab monitoring is required. Dr. Zaenglein and her colleagues also recommend avoiding the use of tazarotene during pregnancy, since it is contraindicated in pregnancy (category X), but monthly pregnancy tests are not recommended.

During an overview of the document at the meeting, she noted that the recommended dosing for both isotretinoin and acitretin is 0.5-1.0 mg/kg per day and the side effects tend to be dose dependent, “except teratogenicity, which can occur with even low doses of systemic retinoid exposure and early on in pregnancy.” The authors also advise patients to consider drug holidays or lower doses “especially during warmer, more humid months, where you might not need the higher doses to achieve cutaneous effects,” she said.

They emphasized the importance of avoiding pregnancy for 3 years after completion of treatment with acitretin. “While the half-life of acitretin is 49 hours, it’s easily converted with any alcohol exposure to etretinate,” Dr. Zaenglein noted. “Then, the half-life is 120 days.”

The statement, which was sponsored by the Pediatric Dermatology Research Alliance (PEDRA), also addresses the clinical considerations and consequences of long-term systemic retinoid use on bone health, such as premature epiphyseal closure in preadolescent children. “In general, this risk is greater with higher doses of therapies – above 1 mg/kg per day – and over prolonged periods of time, typically 4-6 years,” she said. Other potential effects on bone health include calcifications of tendons and ligaments, osteophytes or “bone spurs,” DISH (diffuse idiopathic skeletal hyperostosis), and potential alterations in bone density and growth.

“We also have to worry about concomitant effects of contraception, particularly if you’re using progestin-only formulations that carry a black box warning for osteoporosis,” Dr. Zaenglein said. “It is recommended that you limit their use to 3 years.” Other factors to consider include genetic risk and modifiable factors that affect bone health, such as diet and physical activity, which may impact susceptibility to systemic retinoid bone toxicity and should be discussed with the patient.

Recommended bone monitoring in children starts with a comprehensive family and personal medical history for skeletal toxicity risk factors, followed by an annual growth assessment (height, weight, body mass index, and growth curve), asking regularly about musculoskeletal symptoms, and following up with appropriate imaging. “Inquiring about their diet is recommended as well, so making sure they’re getting sufficient amounts of calcium and vitamin D, and no additional vitamin A sources that may compound the side effects from systemic retinoids,” Dr. Zaenglein said.

The document also advises that a baseline skeletal radiographic survey be performed in patients aged 16-18 years. This may include imaging of the lateral cervical and thoracic spine, lateral view of the calcanei to include Achilles tendon, hips and symptomatic areas, and bone density evaluation.

The statement addressed the psychiatric considerations and consequences of long-term systemic retinoid use. One cross-sectional study of children with ichthyosis found that 30% screened positive for depression and 38% screened positive for anxiety, “but the role of retinoids is unclear,” Dr. Zaenglein said. “It’s a complicated matter, but patients with a personal history of depression, anxiety, and other affective disorders prior to initiation of systemic retinoid treatment should be monitored carefully for exacerbation of symptoms. Comanagement with a mental health provider should be considered.”

As for contraception considerations with long-term systemic retinoid therapy use, the authors recommend that two forms of contraception be used. “Consider long-acting reversible contraception, especially in sexually active adolescents who have a history of noncompliance, or to remove the risk of teratogenicity for them,” she said. “We’re not sure what additive effects progestin/lower estrogen have on long-term cardiovascular health, including lipids and bone density.”

The authors noted that iPLEDGE is not designed for long-term use. “It’s really designed for the on-label use of systemic retinoids in severe acne, where you’re using it for 5-6 months, not for 5-6 years,” Dr. Zaenglein said. “iPLEDGE does impose significant and financial barriers for our patients. More advocacy is needed to adapt that program for our patients.”

She and her coauthors acknowledged practice gaps and unmet needs in patients with disorders of cornification/types of ichthyosis, including the optimal formulation of retinoids based on ichthyosis subtype, whether there is a benefit to intermittent therapy with respect to risk of toxicity and maintenance of efficacy, and how to minimize the bone-related changes that can occur with treatment. “These are some of the things that we can look further into,” she said. “For now, though, retinoids can improve function and quality of life in patients with ichthyosis and disorders of cornification. Many questions still exist, and more data and research are needed.”

Sun Pharmaceuticals and the Foundation for Ichthyosis and Related Skin Types (FIRST) provided an unrestricted grant for development of the recommendations.

Dr. Zaenglein disclosed that she is a consultant for Pfizer. She is also an advisory board member for Dermata, Sol-Gel, Regeneron, Verrica, and Cassiopea, and has conducted contracted research for AbbVie, Incyte, Arcutis, and Pfizer. The other authors disclosed serving as investigators, advisers, consultants, and/or had other relationships with various pharmaceutical companies.

dbrunk@mdedge.com

The use of telehealth may have skyrocketed during the COVID-19 pandemic, but it also exposed a digital divide, speaker after speaker said during a panel discussion at the Society for Pediatric Dermatology (SPD) pre-AAD meeting.

“We have seen large numbers of children struggle with access to school and access to health care because of lack of access to devices, challenges of broadband Internet access, culture, language, and educational barriers – just having trouble being comfortable with this technology,” said Natalie Pageler, MD, a pediatric intensivist and chief medical information officer at Stanford Children’s Health, Palo Alto, Calif.

“There are also privacy concerns, especially in situations where there are multiple families within a household. Finally, it’s important to remember that policy and reimbursement issues may have a significant effect on some of the socioeconomic barriers,” she added. “For example, many of our families who don’t have access to audio and video may be able to do a telephone call, but it’s important that telephone calls be considered a form of telehealth and be reimbursed to help increase the access to health care by these families. It also makes it easier to facilitate coordination of care. All of this leads to decreased time and costs for patients, families, and providers.”

Within the first few weeks of the pandemic, Dr. Pageler and colleagues at Stanford Children’s Health observed an increase from about 20 telehealth visits per day to more than 700 per day, which has held stable. While the benefits of telehealth are clear, many perceived barriers exist. In a study conducted prior to the COVID-19 pandemic, researchers identified a wide variety of barriers to implementation of telehealth, led by reimbursement, followed by poor business model sustainability, lack of provider time, and provider interest.

“Some of the barriers, like patient preferences for inpatient care, lack of provider interest in telehealth, and lack of provider time were easily overcome during the COVID pandemic,” Dr. Pageler said. “We dedicated the time to train immediately, because the need was so great.”

In 2018, Patrick McMahon, MD, and colleagues at Children’s Hospital of Philadelphia, launched a teledermatology program that provided direct-to-patient “E-visits” and recently pivoted to using this service only for acne patients through a program called “Acne Express.” The out-of-pocket cost to patients is $50 per consult and nearly 1,500 cases have been completed since 2018, which has saved patients and their parents an estimated 65,000 miles driving to the clinic.

To optimize the teledermatology experience, he suggested four pillars: educate, optimize, reach out, and tailor. “I think we need to draw upon some of the digital education we already have, including a handout for patients [on the SPD website] that offers tips on taking a clear photograph on their smartphones,” he said. “We’re also trying to use some of the cases and learnings from our teledermatology experiences to teach the providers. We are setting up CME modules that are sort of a flashcard-based teaching mechanism.”

To optimize teledermatology experiences, he continued, tracking demographics, diagnoses, number of cases, and turnaround time is helpful. “We can then track who’s coming in to see us at follow-up after a new visit through telehealth,” Dr. McMahon said. “This helps us repurpose things, pivot as needed, and find any glitches. Surveying the families is also critical. Finally, we need clinical support to tee-up visits and to ensure photos are submitted and efficient, and to match diagnoses and family preference with the right modality.”

Another panelist, Justin M. Ko, MD, MBA, who chairs the American Academy of Dermatology’s Task Force on Augmented Intelligence, said that digitally enabled and artificial intelligence (AI)-augmented care delivery offers a “unique opportunity” for increasing access and increasing the value of care delivered to patients.

“The role that we play as clinicians is central, and I think we can make significant strides by doing two things,” said Dr. Ko, chief of medical dermatology for Stanford (Calif.) Health Care. “One: extending the reach of our expertise, and the second: scaling the impact of the care we deliver by clinician-driven, patient-centered, digitally-enabled, AI-augmented care delivery innovation. This opportunity for digital care transformation is more than just a transition from in-person visits to video visits. We have to look at this as an opportunity to leverage the unique aspects of digital capabilities and fundamentally reimagine how we deliver care.”

The AAD’s Position Statement on Augmented Intelligence was published in 2019.

Between March and June of 2021, Neil S. Prose, MD, conducted about 300 televisits with patients. “I had a few spectacular visits where, for example, a teenage patient who had been challenging showed me all of her artwork and we became instantly more connected,” said Dr. Prose, professor of dermatology, pediatrics, and global health at Duke University, Durham, N.C. “Then there’s the potential for a long-term improvement in health care for some patients.”

dbrunk@mdedge.com

The use of telehealth may have skyrocketed during the COVID-19 pandemic, but it also exposed a digital divide, speaker after speaker said during a panel discussion at the Society for Pediatric Dermatology (SPD) pre-AAD meeting.

“We have seen large numbers of children struggle with access to school and access to health care because of lack of access to devices, challenges of broadband Internet access, culture, language, and educational barriers – just having trouble being comfortable with this technology,” said Natalie Pageler, MD, a pediatric intensivist and chief medical information officer at Stanford Children’s Health, Palo Alto, Calif.

“There are also privacy concerns, especially in situations where there are multiple families within a household. Finally, it’s important to remember that policy and reimbursement issues may have a significant effect on some of the socioeconomic barriers,” she added. “For example, many of our families who don’t have access to audio and video may be able to do a telephone call, but it’s important that telephone calls be considered a form of telehealth and be reimbursed to help increase the access to health care by these families. It also makes it easier to facilitate coordination of care. All of this leads to decreased time and costs for patients, families, and providers.”

Within the first few weeks of the pandemic, Dr. Pageler and colleagues at Stanford Children’s Health observed an increase from about 20 telehealth visits per day to more than 700 per day, which has held stable. While the benefits of telehealth are clear, many perceived barriers exist. In a study conducted prior to the COVID-19 pandemic, researchers identified a wide variety of barriers to implementation of telehealth, led by reimbursement, followed by poor business model sustainability, lack of provider time, and provider interest.

“Some of the barriers, like patient preferences for inpatient care, lack of provider interest in telehealth, and lack of provider time were easily overcome during the COVID pandemic,” Dr. Pageler said. “We dedicated the time to train immediately, because the need was so great.”

In 2018, Patrick McMahon, MD, and colleagues at Children’s Hospital of Philadelphia, launched a teledermatology program that provided direct-to-patient “E-visits” and recently pivoted to using this service only for acne patients through a program called “Acne Express.” The out-of-pocket cost to patients is $50 per consult and nearly 1,500 cases have been completed since 2018, which has saved patients and their parents an estimated 65,000 miles driving to the clinic.

To optimize the teledermatology experience, he suggested four pillars: educate, optimize, reach out, and tailor. “I think we need to draw upon some of the digital education we already have, including a handout for patients [on the SPD website] that offers tips on taking a clear photograph on their smartphones,” he said. “We’re also trying to use some of the cases and learnings from our teledermatology experiences to teach the providers. We are setting up CME modules that are sort of a flashcard-based teaching mechanism.”

To optimize teledermatology experiences, he continued, tracking demographics, diagnoses, number of cases, and turnaround time is helpful. “We can then track who’s coming in to see us at follow-up after a new visit through telehealth,” Dr. McMahon said. “This helps us repurpose things, pivot as needed, and find any glitches. Surveying the families is also critical. Finally, we need clinical support to tee-up visits and to ensure photos are submitted and efficient, and to match diagnoses and family preference with the right modality.”

Another panelist, Justin M. Ko, MD, MBA, who chairs the American Academy of Dermatology’s Task Force on Augmented Intelligence, said that digitally enabled and artificial intelligence (AI)-augmented care delivery offers a “unique opportunity” for increasing access and increasing the value of care delivered to patients.

“The role that we play as clinicians is central, and I think we can make significant strides by doing two things,” said Dr. Ko, chief of medical dermatology for Stanford (Calif.) Health Care. “One: extending the reach of our expertise, and the second: scaling the impact of the care we deliver by clinician-driven, patient-centered, digitally-enabled, AI-augmented care delivery innovation. This opportunity for digital care transformation is more than just a transition from in-person visits to video visits. We have to look at this as an opportunity to leverage the unique aspects of digital capabilities and fundamentally reimagine how we deliver care.”

The AAD’s Position Statement on Augmented Intelligence was published in 2019.

Between March and June of 2021, Neil S. Prose, MD, conducted about 300 televisits with patients. “I had a few spectacular visits where, for example, a teenage patient who had been challenging showed me all of her artwork and we became instantly more connected,” said Dr. Prose, professor of dermatology, pediatrics, and global health at Duke University, Durham, N.C. “Then there’s the potential for a long-term improvement in health care for some patients.”

dbrunk@mdedge.com

The use of telehealth may have skyrocketed during the COVID-19 pandemic, but it also exposed a digital divide, speaker after speaker said during a panel discussion at the Society for Pediatric Dermatology (SPD) pre-AAD meeting.

“We have seen large numbers of children struggle with access to school and access to health care because of lack of access to devices, challenges of broadband Internet access, culture, language, and educational barriers – just having trouble being comfortable with this technology,” said Natalie Pageler, MD, a pediatric intensivist and chief medical information officer at Stanford Children’s Health, Palo Alto, Calif.

“There are also privacy concerns, especially in situations where there are multiple families within a household. Finally, it’s important to remember that policy and reimbursement issues may have a significant effect on some of the socioeconomic barriers,” she added. “For example, many of our families who don’t have access to audio and video may be able to do a telephone call, but it’s important that telephone calls be considered a form of telehealth and be reimbursed to help increase the access to health care by these families. It also makes it easier to facilitate coordination of care. All of this leads to decreased time and costs for patients, families, and providers.”

Within the first few weeks of the pandemic, Dr. Pageler and colleagues at Stanford Children’s Health observed an increase from about 20 telehealth visits per day to more than 700 per day, which has held stable. While the benefits of telehealth are clear, many perceived barriers exist. In a study conducted prior to the COVID-19 pandemic, researchers identified a wide variety of barriers to implementation of telehealth, led by reimbursement, followed by poor business model sustainability, lack of provider time, and provider interest.

“Some of the barriers, like patient preferences for inpatient care, lack of provider interest in telehealth, and lack of provider time were easily overcome during the COVID pandemic,” Dr. Pageler said. “We dedicated the time to train immediately, because the need was so great.”

In 2018, Patrick McMahon, MD, and colleagues at Children’s Hospital of Philadelphia, launched a teledermatology program that provided direct-to-patient “E-visits” and recently pivoted to using this service only for acne patients through a program called “Acne Express.” The out-of-pocket cost to patients is $50 per consult and nearly 1,500 cases have been completed since 2018, which has saved patients and their parents an estimated 65,000 miles driving to the clinic.

To optimize the teledermatology experience, he suggested four pillars: educate, optimize, reach out, and tailor. “I think we need to draw upon some of the digital education we already have, including a handout for patients [on the SPD website] that offers tips on taking a clear photograph on their smartphones,” he said. “We’re also trying to use some of the cases and learnings from our teledermatology experiences to teach the providers. We are setting up CME modules that are sort of a flashcard-based teaching mechanism.”

To optimize teledermatology experiences, he continued, tracking demographics, diagnoses, number of cases, and turnaround time is helpful. “We can then track who’s coming in to see us at follow-up after a new visit through telehealth,” Dr. McMahon said. “This helps us repurpose things, pivot as needed, and find any glitches. Surveying the families is also critical. Finally, we need clinical support to tee-up visits and to ensure photos are submitted and efficient, and to match diagnoses and family preference with the right modality.”

Another panelist, Justin M. Ko, MD, MBA, who chairs the American Academy of Dermatology’s Task Force on Augmented Intelligence, said that digitally enabled and artificial intelligence (AI)-augmented care delivery offers a “unique opportunity” for increasing access and increasing the value of care delivered to patients.

“The role that we play as clinicians is central, and I think we can make significant strides by doing two things,” said Dr. Ko, chief of medical dermatology for Stanford (Calif.) Health Care. “One: extending the reach of our expertise, and the second: scaling the impact of the care we deliver by clinician-driven, patient-centered, digitally-enabled, AI-augmented care delivery innovation. This opportunity for digital care transformation is more than just a transition from in-person visits to video visits. We have to look at this as an opportunity to leverage the unique aspects of digital capabilities and fundamentally reimagine how we deliver care.”

The AAD’s Position Statement on Augmented Intelligence was published in 2019.

Between March and June of 2021, Neil S. Prose, MD, conducted about 300 televisits with patients. “I had a few spectacular visits where, for example, a teenage patient who had been challenging showed me all of her artwork and we became instantly more connected,” said Dr. Prose, professor of dermatology, pediatrics, and global health at Duke University, Durham, N.C. “Then there’s the potential for a long-term improvement in health care for some patients.”

dbrunk@mdedge.com

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

 

 

Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; Lindsey-Collins@ouhsc.edu

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

 

 

Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; Lindsey-Collins@ouhsc.edu

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

 

 

Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; Lindsey-Collins@ouhsc.edu

A unilateral, neuropathic itch accompanied by postinflammatory pigmentation changes or lichenification at the medial inferior tip of the scapula are the hallmarks of notalgia paresthetica (NP).

NP is thought to result from nerve impingement or chronic nerve trauma to the posterior rami of the upper thoracic spinal nerves. The hyperpigmentation and lichenification arise from repeated scratching or rubbing of the skin.

NP is a clinical diagnosis and does not require biopsy or imaging. The differential diagnosis includes brachioradial pruritus, postherpetic neuralgia, multiple sclerosis, and other small fiber neuropathies.

The standard treatment is topical capsaicin 0.025% tid for 5 weeks, with repeat treatments (for a few days or weeks) if there are relapses. Higher doses (0.075%) may work more quickly but may also lead to more burning. A lidocaine 5% patch bid can also be considered. Second-line treatment options include cutaneous electrical field stimulation or transcutaneous electrical nerve stimulation, gabapentin, or oxcarbazepine. Topical steroids are considered ineffective for this condition.¹

The patient in this case was started on capsaicin 0.025%. She was encouraged to keep her skin moisturized and well hydrated because dyshidrosis can exacerbate itching. A prescription for gabapentin was offered in case topical treatments were unsuccessful, but she declined after she weighed the risks of adverse effects against her current symptoms.

‌

Photo courtesy of Daniel Stulberg, MD, and text courtesy of Nathan Birnbaum, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

A unilateral, neuropathic itch accompanied by postinflammatory pigmentation changes or lichenification at the medial inferior tip of the scapula are the hallmarks of notalgia paresthetica (NP).

NP is thought to result from nerve impingement or chronic nerve trauma to the posterior rami of the upper thoracic spinal nerves. The hyperpigmentation and lichenification arise from repeated scratching or rubbing of the skin.

NP is a clinical diagnosis and does not require biopsy or imaging. The differential diagnosis includes brachioradial pruritus, postherpetic neuralgia, multiple sclerosis, and other small fiber neuropathies.

The standard treatment is topical capsaicin 0.025% tid for 5 weeks, with repeat treatments (for a few days or weeks) if there are relapses. Higher doses (0.075%) may work more quickly but may also lead to more burning. A lidocaine 5% patch bid can also be considered. Second-line treatment options include cutaneous electrical field stimulation or transcutaneous electrical nerve stimulation, gabapentin, or oxcarbazepine. Topical steroids are considered ineffective for this condition.¹

The patient in this case was started on capsaicin 0.025%. She was encouraged to keep her skin moisturized and well hydrated because dyshidrosis can exacerbate itching. A prescription for gabapentin was offered in case topical treatments were unsuccessful, but she declined after she weighed the risks of adverse effects against her current symptoms.

‌

Photo courtesy of Daniel Stulberg, MD, and text courtesy of Nathan Birnbaum, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque

A unilateral, neuropathic itch accompanied by postinflammatory pigmentation changes or lichenification at the medial inferior tip of the scapula are the hallmarks of notalgia paresthetica (NP).

NP is thought to result from nerve impingement or chronic nerve trauma to the posterior rami of the upper thoracic spinal nerves. The hyperpigmentation and lichenification arise from repeated scratching or rubbing of the skin.

NP is a clinical diagnosis and does not require biopsy or imaging. The differential diagnosis includes brachioradial pruritus, postherpetic neuralgia, multiple sclerosis, and other small fiber neuropathies.

The standard treatment is topical capsaicin 0.025% tid for 5 weeks, with repeat treatments (for a few days or weeks) if there are relapses. Higher doses (0.075%) may work more quickly but may also lead to more burning. A lidocaine 5% patch bid can also be considered. Second-line treatment options include cutaneous electrical field stimulation or transcutaneous electrical nerve stimulation, gabapentin, or oxcarbazepine. Topical steroids are considered ineffective for this condition.¹

The patient in this case was started on capsaicin 0.025%. She was encouraged to keep her skin moisturized and well hydrated because dyshidrosis can exacerbate itching. A prescription for gabapentin was offered in case topical treatments were unsuccessful, but she declined after she weighed the risks of adverse effects against her current symptoms.

‌

Photo courtesy of Daniel Stulberg, MD, and text courtesy of Nathan Birnbaum, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque