Atopic Dermatitis

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of baricitinib tablets for adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Baricitinib (Olumiant) is already approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis.

If approved in Europe, it will be the first Janus kinase (JAK) inhibitor and first oral medication indicated to treat patients with AD.

The CHMP’s positive opinion on baricitinib for AD was based on three phase 3, randomized, double-blind, placebo-controlled studies where the JAK inhibitor was used alone or in combination with topical treatments in adults with moderate to severe AD for whom topical treatments were insufficient or not tolerated. In all three studies, baricitinib was shown to be more effective than placebo in achieving skin that is “clear” or “almost clear” at 16 weeks.

“Patients living with AD face difficulties on a daily basis, and this CHMP opinion marks an important milestone in providing adult AD patients with a new potential treatment option,” Thomas Bieber, MD, PhD, professor of dermatology and allergy, University of Bonn (Germany), said in a company news release.

The most common side effects with baricitinib in clinical trials include increased LDL cholesterol, upper respiratory tract infections, and headache.

Patients receiving baricitinib, particularly in combination with immunosuppressants, are at risk of developing serious infections that may lead to hospitalization or death. If a serious infection develops, baricitinib should be stopped until the infection is controlled.

The CHMP’s positive opinion will be sent to the European Commission, which will adopt a final decision regarding an European Union–wide marketing authorization. Once granted, each member state will make decisions about price and reimbursement, taking into account the potential role/use of baricitinib in the context of that country’s national health system.

A version of this story originally appeared on Medscape.com.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of baricitinib tablets for adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Baricitinib (Olumiant) is already approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis.

If approved in Europe, it will be the first Janus kinase (JAK) inhibitor and first oral medication indicated to treat patients with AD.

The CHMP’s positive opinion on baricitinib for AD was based on three phase 3, randomized, double-blind, placebo-controlled studies where the JAK inhibitor was used alone or in combination with topical treatments in adults with moderate to severe AD for whom topical treatments were insufficient or not tolerated. In all three studies, baricitinib was shown to be more effective than placebo in achieving skin that is “clear” or “almost clear” at 16 weeks.

“Patients living with AD face difficulties on a daily basis, and this CHMP opinion marks an important milestone in providing adult AD patients with a new potential treatment option,” Thomas Bieber, MD, PhD, professor of dermatology and allergy, University of Bonn (Germany), said in a company news release.

The most common side effects with baricitinib in clinical trials include increased LDL cholesterol, upper respiratory tract infections, and headache.

Patients receiving baricitinib, particularly in combination with immunosuppressants, are at risk of developing serious infections that may lead to hospitalization or death. If a serious infection develops, baricitinib should be stopped until the infection is controlled.

The CHMP’s positive opinion will be sent to the European Commission, which will adopt a final decision regarding an European Union–wide marketing authorization. Once granted, each member state will make decisions about price and reimbursement, taking into account the potential role/use of baricitinib in the context of that country’s national health system.

A version of this story originally appeared on Medscape.com.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of baricitinib tablets for adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Baricitinib (Olumiant) is already approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis.

If approved in Europe, it will be the first Janus kinase (JAK) inhibitor and first oral medication indicated to treat patients with AD.

The CHMP’s positive opinion on baricitinib for AD was based on three phase 3, randomized, double-blind, placebo-controlled studies where the JAK inhibitor was used alone or in combination with topical treatments in adults with moderate to severe AD for whom topical treatments were insufficient or not tolerated. In all three studies, baricitinib was shown to be more effective than placebo in achieving skin that is “clear” or “almost clear” at 16 weeks.

“Patients living with AD face difficulties on a daily basis, and this CHMP opinion marks an important milestone in providing adult AD patients with a new potential treatment option,” Thomas Bieber, MD, PhD, professor of dermatology and allergy, University of Bonn (Germany), said in a company news release.

The most common side effects with baricitinib in clinical trials include increased LDL cholesterol, upper respiratory tract infections, and headache.

Patients receiving baricitinib, particularly in combination with immunosuppressants, are at risk of developing serious infections that may lead to hospitalization or death. If a serious infection develops, baricitinib should be stopped until the infection is controlled.

The CHMP’s positive opinion will be sent to the European Commission, which will adopt a final decision regarding an European Union–wide marketing authorization. Once granted, each member state will make decisions about price and reimbursement, taking into account the potential role/use of baricitinib in the context of that country’s national health system.

A version of this story originally appeared on Medscape.com.

A three-step approach may help relieve itch in patients with lichen simplex chronicus, “one of the itchiest conditions that we ever see on the vulva,” an expert advised at the virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.

For some patients, such as those with excessive sweating or underlying psoriasis, seeing a dermatologist may be beneficial, physicians at the meeting suggested.

Treatment should aim to optimize epithelial barrier function, reduce inflammation, and stop scratching, Lynette Margesson, MD, said in a lecture at the biennial meeting, which is held by the International Society for the Study of Vulvovaginal Disease (ISSVD). “With this condition, please look always for more than one problem.”

Lichen simplex chronicus is a thick, hyperkeratotic, firm, itchy rash that can develop on top of any dermatitis. “It doesn’t show up out of nowhere,” said Dr. Margesson, an obstetrician and gynecologist at Geisel School of Medicine at Dartmouth in Hanover, N.H. “It is because of chronic rubbing and scratching on top of something else.”

It may develop on top of atopic dermatitis, psoriasis, or contact dermatitis, as well as infection, lichen sclerosus, lichen planus, or neoplasia.

Lichen simplex chronicus is characterized by years of relentless itching, and patients may wake up at night scratching. The skin looks and feels leathery, and the condition can be localized or around the entire vulva. Heat, humidity, stress, and irritants may exacerbate the condition.

Patients often try to wash the rash away with scrubbers and cleansers, which only makes it worse, Dr. Margesson said.

To get patients better, improve barrier function, such as by controlling infections, reducing sweating, avoiding irritants, and stopping excessive hygiene. Immediate therapy may include soaks, cool compresses, and ointments.

A superpotent steroid taper (e.g., clobetasol 0.05% ointment), a prednisone taper, or intramuscular triamcinolone may reduce inflammation. Dr. Margesson usually uses clobetasol, although this treatment or halobetasol can burn if patients have open skin. In such cases, she uses prednisone or intramuscular triamcinolone.

Sedating medications may help patients stop scratching, especially at night. Hydroxyzine, doxepin, or amitriptyline 2-3 hours before bedtime can help. Scratching can be a form of obsessive-compulsive disorder, and a small dose of citalopram may help during the day. Patients with significant psychological factors can be difficult to manage and tend to relapse easily, Dr. Margesson said.

If lichen simplex chronicus recurs, test for infections and allergies. “Maybe they need a mild corticosteroid all the time, like 2.5% hydrocortisone to alternate with your superpotent steroid so you can use it longer without thinning the skin,” she suggested.

Although Dr. Margesson does not often treat hyperhidrosis, addressing excessive sweating can make a big difference for patients, she said.

If a gynecologist identifies a patient who may benefit from treatment of hyperhidrosis but has limited experience with medications for this condition, it might make sense to work with a dermatologist, Aruna Venkatesan, MD, chief of dermatology and director of the genital dermatology clinic at Santa Clara Valley Medical Center in San Jose, Calif., suggested during a panel discussion. Most dermatologists treat hyperhidrosis regularly, she said.

Dermatologists also may help treat patients with psoriasis who need systemic medication, Dr. Margesson said.

“In terms of ... doing the lab monitoring and knowing what side effects to look out for, your colleagues who use these medicines more are going to be more comfortable with that,” Dr. Venkatesan said. They also may have more experience navigating insurance denials to obtain a therapy. “Don’t think you are passing the buck to someone else. Sometimes that is the right thing to do, to get that help from someone else.”

Dr. Margesson is an author for UpToDate. Dr. Venkatesan had no conflicts of interest.

jremaly@mdedge.com

A three-step approach may help relieve itch in patients with lichen simplex chronicus, “one of the itchiest conditions that we ever see on the vulva,” an expert advised at the virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.

For some patients, such as those with excessive sweating or underlying psoriasis, seeing a dermatologist may be beneficial, physicians at the meeting suggested.

Treatment should aim to optimize epithelial barrier function, reduce inflammation, and stop scratching, Lynette Margesson, MD, said in a lecture at the biennial meeting, which is held by the International Society for the Study of Vulvovaginal Disease (ISSVD). “With this condition, please look always for more than one problem.”

Lichen simplex chronicus is a thick, hyperkeratotic, firm, itchy rash that can develop on top of any dermatitis. “It doesn’t show up out of nowhere,” said Dr. Margesson, an obstetrician and gynecologist at Geisel School of Medicine at Dartmouth in Hanover, N.H. “It is because of chronic rubbing and scratching on top of something else.”

It may develop on top of atopic dermatitis, psoriasis, or contact dermatitis, as well as infection, lichen sclerosus, lichen planus, or neoplasia.

Lichen simplex chronicus is characterized by years of relentless itching, and patients may wake up at night scratching. The skin looks and feels leathery, and the condition can be localized or around the entire vulva. Heat, humidity, stress, and irritants may exacerbate the condition.

Patients often try to wash the rash away with scrubbers and cleansers, which only makes it worse, Dr. Margesson said.

To get patients better, improve barrier function, such as by controlling infections, reducing sweating, avoiding irritants, and stopping excessive hygiene. Immediate therapy may include soaks, cool compresses, and ointments.

A superpotent steroid taper (e.g., clobetasol 0.05% ointment), a prednisone taper, or intramuscular triamcinolone may reduce inflammation. Dr. Margesson usually uses clobetasol, although this treatment or halobetasol can burn if patients have open skin. In such cases, she uses prednisone or intramuscular triamcinolone.

Sedating medications may help patients stop scratching, especially at night. Hydroxyzine, doxepin, or amitriptyline 2-3 hours before bedtime can help. Scratching can be a form of obsessive-compulsive disorder, and a small dose of citalopram may help during the day. Patients with significant psychological factors can be difficult to manage and tend to relapse easily, Dr. Margesson said.

If lichen simplex chronicus recurs, test for infections and allergies. “Maybe they need a mild corticosteroid all the time, like 2.5% hydrocortisone to alternate with your superpotent steroid so you can use it longer without thinning the skin,” she suggested.

Although Dr. Margesson does not often treat hyperhidrosis, addressing excessive sweating can make a big difference for patients, she said.

If a gynecologist identifies a patient who may benefit from treatment of hyperhidrosis but has limited experience with medications for this condition, it might make sense to work with a dermatologist, Aruna Venkatesan, MD, chief of dermatology and director of the genital dermatology clinic at Santa Clara Valley Medical Center in San Jose, Calif., suggested during a panel discussion. Most dermatologists treat hyperhidrosis regularly, she said.

Dermatologists also may help treat patients with psoriasis who need systemic medication, Dr. Margesson said.

“In terms of ... doing the lab monitoring and knowing what side effects to look out for, your colleagues who use these medicines more are going to be more comfortable with that,” Dr. Venkatesan said. They also may have more experience navigating insurance denials to obtain a therapy. “Don’t think you are passing the buck to someone else. Sometimes that is the right thing to do, to get that help from someone else.”

Dr. Margesson is an author for UpToDate. Dr. Venkatesan had no conflicts of interest.

jremaly@mdedge.com

A three-step approach may help relieve itch in patients with lichen simplex chronicus, “one of the itchiest conditions that we ever see on the vulva,” an expert advised at the virtual conference on diseases of the vulva and vagina, hosted by the International Society for the Study of Vulvovaginal Disease.

For some patients, such as those with excessive sweating or underlying psoriasis, seeing a dermatologist may be beneficial, physicians at the meeting suggested.

Treatment should aim to optimize epithelial barrier function, reduce inflammation, and stop scratching, Lynette Margesson, MD, said in a lecture at the biennial meeting, which is held by the International Society for the Study of Vulvovaginal Disease (ISSVD). “With this condition, please look always for more than one problem.”

Lichen simplex chronicus is a thick, hyperkeratotic, firm, itchy rash that can develop on top of any dermatitis. “It doesn’t show up out of nowhere,” said Dr. Margesson, an obstetrician and gynecologist at Geisel School of Medicine at Dartmouth in Hanover, N.H. “It is because of chronic rubbing and scratching on top of something else.”

It may develop on top of atopic dermatitis, psoriasis, or contact dermatitis, as well as infection, lichen sclerosus, lichen planus, or neoplasia.

Lichen simplex chronicus is characterized by years of relentless itching, and patients may wake up at night scratching. The skin looks and feels leathery, and the condition can be localized or around the entire vulva. Heat, humidity, stress, and irritants may exacerbate the condition.

Patients often try to wash the rash away with scrubbers and cleansers, which only makes it worse, Dr. Margesson said.

To get patients better, improve barrier function, such as by controlling infections, reducing sweating, avoiding irritants, and stopping excessive hygiene. Immediate therapy may include soaks, cool compresses, and ointments.

A superpotent steroid taper (e.g., clobetasol 0.05% ointment), a prednisone taper, or intramuscular triamcinolone may reduce inflammation. Dr. Margesson usually uses clobetasol, although this treatment or halobetasol can burn if patients have open skin. In such cases, she uses prednisone or intramuscular triamcinolone.

Sedating medications may help patients stop scratching, especially at night. Hydroxyzine, doxepin, or amitriptyline 2-3 hours before bedtime can help. Scratching can be a form of obsessive-compulsive disorder, and a small dose of citalopram may help during the day. Patients with significant psychological factors can be difficult to manage and tend to relapse easily, Dr. Margesson said.

If lichen simplex chronicus recurs, test for infections and allergies. “Maybe they need a mild corticosteroid all the time, like 2.5% hydrocortisone to alternate with your superpotent steroid so you can use it longer without thinning the skin,” she suggested.

Although Dr. Margesson does not often treat hyperhidrosis, addressing excessive sweating can make a big difference for patients, she said.

If a gynecologist identifies a patient who may benefit from treatment of hyperhidrosis but has limited experience with medications for this condition, it might make sense to work with a dermatologist, Aruna Venkatesan, MD, chief of dermatology and director of the genital dermatology clinic at Santa Clara Valley Medical Center in San Jose, Calif., suggested during a panel discussion. Most dermatologists treat hyperhidrosis regularly, she said.

Dermatologists also may help treat patients with psoriasis who need systemic medication, Dr. Margesson said.

“In terms of ... doing the lab monitoring and knowing what side effects to look out for, your colleagues who use these medicines more are going to be more comfortable with that,” Dr. Venkatesan said. They also may have more experience navigating insurance denials to obtain a therapy. “Don’t think you are passing the buck to someone else. Sometimes that is the right thing to do, to get that help from someone else.”

Dr. Margesson is an author for UpToDate. Dr. Venkatesan had no conflicts of interest.

jremaly@mdedge.com

It is a brand-new day for the treatment of children with severe inflammatory skin diseases. Not coincidentally, it also is a new day for the treatment of atopic dermatitis (AD). Why?

Historically, children have largely been ignored by pharmaceutical companies and the US Food and Drug Administration (FDA). Drug trials of new medications have been the exclusive province of adults; therefore, information they have generated has had only derivative relevance to the pediatric population. Pediatricians and providers who care for children, aware that they are not simply “little adults,” have been forced to extrapolate best practices.

My institution is poised to enroll a 3-year-old child with severe AD into a biologic trial (ClinicalTrials.gov identifier NCT03346434). The age range for this study is 6 months to 6 years. This extraordinary democratization of clinical trials is no accident. The Best Pharmaceuticals for Children Act, which was passed in 2002, was a first step. This legislation incentivized pharmaceutical companies to include children, who are notoriously more costly to study for myriad reasons, by extending patent protection for approved medications. Subsequent efforts spearheaded by advocacy groups such as the National Eczema Association included the production of guidance documents for industry¹ and presentations directly to the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee meeting punctuated by powerful patient testimonials.²

Serendipitously, AD, a disease that presents by kindergarten in up to 90% of affected individuals, also has caught the eye of the pharmaceutical industry. Remarkable advances in the understanding of AD inflammation have led to an explosion of new therapeutic targets of interest. By way of context, between the introduction of topical calcineurin inhibitors in 2001 and the FDA approval of dupilumab and crisaborole in 2017, there were precisely zero new molecules approved for the treatment of AD. Viewed through another lens, prior to 2017, the only FDA-approved systemic medication for AD was prednisone, a drug most AD experts would list as the least appropriate choice for treatment of this condition.

Fast-forward to 2020 and we have a plethora of new possibilities. The National Eczema Association’s research web page (https://nationaleczema.org/research/eczema-treatment-research/) reveals no fewer than 24 systemic agents in phase 2 development or beyond, including selective IL-13 inhibitors such as tralokinumab and lebrikizumab; Janus kinase inhibitors such as baricitinib³; and novel targets such as histamine 4 (ZPL-3893787), IL-31 (nemolizumab), and thymic stromal lymphopoietin. This list does not even include other biologics being repurposed for AD (eg, omalizumab⁴) or a host of exciting new topical agents (eg, tapinarof).

This confluence of better science, powerful advocacy, and enlightened self-interest has been revolutionary. It is most evident when parents/guardians—many of whom had long ago given up on new therapies for themselves—are gobsmacked by the new therapeutic landscape outlined for their children. Parents/guardians realize their children need not struggle as they may have themselves. The impact on quality of life has long been known, but several recent publications have brought it into finer relief. Drucker et al⁵ highlighted the overall burden of disease, and several subsequent papers have focused specifically on affective impacts including increased risk for depression, suicidal ideation, and suicide.^6,7 In this issue of Cutis, Tracy et al⁸ provide an update on pediatric AD with an emphasis on comorbidities, quality of life, and evolving practices and therapies.

Better science, better drugs, better advocacy, better outcomes—it has not been a straight line, but it has indisputably been a forward-marching one. It is a new day, indeed.

It is a brand-new day for the treatment of children with severe inflammatory skin diseases. Not coincidentally, it also is a new day for the treatment of atopic dermatitis (AD). Why?

Historically, children have largely been ignored by pharmaceutical companies and the US Food and Drug Administration (FDA). Drug trials of new medications have been the exclusive province of adults; therefore, information they have generated has had only derivative relevance to the pediatric population. Pediatricians and providers who care for children, aware that they are not simply “little adults,” have been forced to extrapolate best practices.

My institution is poised to enroll a 3-year-old child with severe AD into a biologic trial (ClinicalTrials.gov identifier NCT03346434). The age range for this study is 6 months to 6 years. This extraordinary democratization of clinical trials is no accident. The Best Pharmaceuticals for Children Act, which was passed in 2002, was a first step. This legislation incentivized pharmaceutical companies to include children, who are notoriously more costly to study for myriad reasons, by extending patent protection for approved medications. Subsequent efforts spearheaded by advocacy groups such as the National Eczema Association included the production of guidance documents for industry¹ and presentations directly to the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee meeting punctuated by powerful patient testimonials.²

Serendipitously, AD, a disease that presents by kindergarten in up to 90% of affected individuals, also has caught the eye of the pharmaceutical industry. Remarkable advances in the understanding of AD inflammation have led to an explosion of new therapeutic targets of interest. By way of context, between the introduction of topical calcineurin inhibitors in 2001 and the FDA approval of dupilumab and crisaborole in 2017, there were precisely zero new molecules approved for the treatment of AD. Viewed through another lens, prior to 2017, the only FDA-approved systemic medication for AD was prednisone, a drug most AD experts would list as the least appropriate choice for treatment of this condition.

Fast-forward to 2020 and we have a plethora of new possibilities. The National Eczema Association’s research web page (https://nationaleczema.org/research/eczema-treatment-research/) reveals no fewer than 24 systemic agents in phase 2 development or beyond, including selective IL-13 inhibitors such as tralokinumab and lebrikizumab; Janus kinase inhibitors such as baricitinib³; and novel targets such as histamine 4 (ZPL-3893787), IL-31 (nemolizumab), and thymic stromal lymphopoietin. This list does not even include other biologics being repurposed for AD (eg, omalizumab⁴) or a host of exciting new topical agents (eg, tapinarof).

This confluence of better science, powerful advocacy, and enlightened self-interest has been revolutionary. It is most evident when parents/guardians—many of whom had long ago given up on new therapies for themselves—are gobsmacked by the new therapeutic landscape outlined for their children. Parents/guardians realize their children need not struggle as they may have themselves. The impact on quality of life has long been known, but several recent publications have brought it into finer relief. Drucker et al⁵ highlighted the overall burden of disease, and several subsequent papers have focused specifically on affective impacts including increased risk for depression, suicidal ideation, and suicide.^6,7 In this issue of Cutis, Tracy et al⁸ provide an update on pediatric AD with an emphasis on comorbidities, quality of life, and evolving practices and therapies.

Better science, better drugs, better advocacy, better outcomes—it has not been a straight line, but it has indisputably been a forward-marching one. It is a new day, indeed.

It is a brand-new day for the treatment of children with severe inflammatory skin diseases. Not coincidentally, it also is a new day for the treatment of atopic dermatitis (AD). Why?

Historically, children have largely been ignored by pharmaceutical companies and the US Food and Drug Administration (FDA). Drug trials of new medications have been the exclusive province of adults; therefore, information they have generated has had only derivative relevance to the pediatric population. Pediatricians and providers who care for children, aware that they are not simply “little adults,” have been forced to extrapolate best practices.

My institution is poised to enroll a 3-year-old child with severe AD into a biologic trial (ClinicalTrials.gov identifier NCT03346434). The age range for this study is 6 months to 6 years. This extraordinary democratization of clinical trials is no accident. The Best Pharmaceuticals for Children Act, which was passed in 2002, was a first step. This legislation incentivized pharmaceutical companies to include children, who are notoriously more costly to study for myriad reasons, by extending patent protection for approved medications. Subsequent efforts spearheaded by advocacy groups such as the National Eczema Association included the production of guidance documents for industry¹ and presentations directly to the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee meeting punctuated by powerful patient testimonials.²

Serendipitously, AD, a disease that presents by kindergarten in up to 90% of affected individuals, also has caught the eye of the pharmaceutical industry. Remarkable advances in the understanding of AD inflammation have led to an explosion of new therapeutic targets of interest. By way of context, between the introduction of topical calcineurin inhibitors in 2001 and the FDA approval of dupilumab and crisaborole in 2017, there were precisely zero new molecules approved for the treatment of AD. Viewed through another lens, prior to 2017, the only FDA-approved systemic medication for AD was prednisone, a drug most AD experts would list as the least appropriate choice for treatment of this condition.

Fast-forward to 2020 and we have a plethora of new possibilities. The National Eczema Association’s research web page (https://nationaleczema.org/research/eczema-treatment-research/) reveals no fewer than 24 systemic agents in phase 2 development or beyond, including selective IL-13 inhibitors such as tralokinumab and lebrikizumab; Janus kinase inhibitors such as baricitinib³; and novel targets such as histamine 4 (ZPL-3893787), IL-31 (nemolizumab), and thymic stromal lymphopoietin. This list does not even include other biologics being repurposed for AD (eg, omalizumab⁴) or a host of exciting new topical agents (eg, tapinarof).

This confluence of better science, powerful advocacy, and enlightened self-interest has been revolutionary. It is most evident when parents/guardians—many of whom had long ago given up on new therapies for themselves—are gobsmacked by the new therapeutic landscape outlined for their children. Parents/guardians realize their children need not struggle as they may have themselves. The impact on quality of life has long been known, but several recent publications have brought it into finer relief. Drucker et al⁵ highlighted the overall burden of disease, and several subsequent papers have focused specifically on affective impacts including increased risk for depression, suicidal ideation, and suicide.^6,7 In this issue of Cutis, Tracy et al⁸ provide an update on pediatric AD with an emphasis on comorbidities, quality of life, and evolving practices and therapies.

Better science, better drugs, better advocacy, better outcomes—it has not been a straight line, but it has indisputably been a forward-marching one. It is a new day, indeed.

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects many adolescents and adults. There has been a tremendous evolution of knowledge in AD, with insights into pathogenesis, epidemiology, impact of disease, and new therapies. A variety of studies examine the epidemiology of AD and associated comorbidities. The broad developments in disease state research are reflected in new publication numbers of AD citations on PubMed. A PubMed search of articles indexed for MEDLINE at the end of 2010 using the term atopic dermatitis would have shown 965 citations during the preceding 1-year period. In the 1-year period of June 2019 to June 2020, there were more than 2000 articles. The large body of research includes work of great significance in pediatric AD, and in this article we review recent findings that are important in understanding the progress being made in the field.

Epidemiology and Comorbidities

The epidemiology of AD has evolved over the last few decades, with emerging trends and novel insights into the burden of disease.¹ In a recent cross-sectional study on the epidemiology of AD in children aged 6 to 11 years, the 1-year diagnosed AD prevalence estimates worldwide included the following: United States, 10.0%; Canada, 13.3%; the EU5 Countries, 15.5%; Japan, 10.3%; and all countries studied, 12.2%.² Another recent paper that analyzed data from the Fragile Families and Child Wellbeing Study showed that the prevalence and persistence of AD in urban US children was 15.0%.³Although pediatric AD may spontaneously remit over time, disease continuing into adolescence and adulthood is common. Paternoster et al⁴ studied the longitudinal course of AD in children from 2 birth cohort prospective studies, showing distinct AD phenotypes having differing course trajectories over time. Disease subsets included patients with early-onset-persistent and early-onset-late-resolving disease.⁴ Whether phenotyping or subgroup analysis can be used to predict disease course or risk for development of comorbidities is unknown, but it is interesting to consider how such work could influence tailoring of specific therapies to early disease presentation.

Atopic dermatitis poses a serious public health burden owing to its high prevalence, considerable morbidity and disability, increased health care utilization, and cost of care.¹ Recent studies have found notably higher rates of multiple medical and mental health comorbidities in both children and adults with AD, including infections, atopic comorbidities (eg, allergic rhinitis, asthma, food allergies), eye diseases (eg, keratitis, conjunctivitis, keratoconus), and possible cardiovascular diseases and autoimmune disorders.^1,5-9 Allergic comorbidities are quite common in pediatric AD patients.¹⁰ In a recent study examining the efficacy and safety of dupilumab monotherapy in 251 adolescents with moderate to severe inadequately controlled AD, most had comorbid type 2 diseases including asthma (53.6%), food allergies (60.8%), and allergic rhinitis (65.6%).¹¹

Quality of Life/Life Impact of AD

Pediatric AD has a major impact on the quality of life of patients and their families.¹² The well-being and development of children are strongly influenced by the physical and psychosocial health of parents/guardians. Two studies by Ramirez and colleagues^13,14 published in 2019 examined sleep disturbances and exhaustion in mothers of children with AD. Data for the studies came from the Avon Longitudinal Study of Parents and Children. Children with active AD reported worse sleep quality than those without AD, with nearly 50% higher odds of sleep-quality disturbances. Analysis of the cohort data from 11,649 mother-child pairs who were followed up with a time-varying measure of child AD activity and severity as well as self-reported maternal sleep measures repeated at multiple time points for children aged 6 months to 11 years showed that mothers of children with AD reported difficulty falling asleep, subjectively insufficient sleep, and daytime exhaustion throughout the first 11 years of childhood.^13,14 These data suggest that sleep disturbance may be a family affair.

A cross-sectional, real-world study on the burden of AD in children aged 6 to 11 years assessed by self-report demonstrated a substantial and multidimensional impact of AD, including itch, sleep disturbance, skin pain, and health-related quality-of-life impact, as well as comorbidities and school productivity losses. The burden associated with AD was remarkable and increased with disease severity.¹⁵

Drucker et al¹⁶ completed a comprehensive literature review on the burden of AD, summarized as a report for the National Eczema Association. Quality-of-life impact on pediatric patients included high rates of emotional distress; social isolation; depression; limitations in activities due to lesions with fear of triggers; and behavioral problems such as irritability, crying, and sleep disturbance resulting in difficulty performing at school.¹⁶ The psychological impact on children as well as emotional and behavioral difficulties may impact the ability for parents/guardians to implement treatment plans.¹⁷

There is a striking association between mental health disorders and AD in the US pediatric population, with a clear dose-dependent relationship that has been observed between the prevalence of a mental health disorder and the reported severity of the skin disease. Data suggest children with AD may be at increased risk for developing mental health disorders. The National Survey of Children’s Health found statistically significant increases in the likelihood of attention deficit hyperactivity disorder (odds ratio [OR], 1.87), depression (OR, 1.81), anxiety (OR, 1.77), conduct disorder (OR, 1.87), and autism (OR, 3.04).⁶

Evolving Practices and Therapies

Bathing Practices
There has long been much controversy regarding best bathing habits for patients with AD. In a 2009 study, cutaneous hydration was quantified after various bathing and moisturizing regimens.¹⁸ The study showed clear benefits of emollient application on skin hydration, either after bathing or without bathing. Bathing followed by emollient applications did not decrease skin hydration in contrast to bathing without emollient application.¹⁸

There are limited studies evaluating bathing frequency in pediatric patients, and many families receive conflicting information regarding best practice. In one study that surveyed 354 parents, more than 75% of parents/guardians who had seen multiple providers for their child’s AD reported a substantial amount of confusion and frustration from conflicting advice on bathing frequency.¹⁹ Cardona et al²⁰ undertook a randomized clinical trial of frequent bathing and moisturizing vs less-frequent bathing and moisturizing in pediatric patients with AD aged 6 months to 11 years. Patients were divided into 2 groups: 1 being bathed twice daily with immediate moisturizer application and the other being bathed twice weekly followed by moisturization, then a switch to the other method. Patients used standardized topical corticosteroids (TCSs) in both groups. There were significant improvements in scoring AD and other objective measures during the frequent bathing time period vs infrequent bathing; in the group that bathed more frequently, SCORAD (SCORing Atopic Dermatitis) decreased by 21.2 compared with the group that bathed less frequently (95% confidence interval, 14.9-27.6; P<.0001). These findings suggest that more-frequent bathing with immediate moisturization is superior as an acute treatment intervention for improving AD disease severity in comparison to less-frequent bathing with immediate moisturization.²⁰

Expanding Treatment Options

Topical Phosphodiesterase Inhibitors
There are several new and evolving topical therapies in AD. Crisaborole ointment 2% is a steroid-free phosphodiesterase inhibitor approved in 2016 by the US Food and Drug Administration (FDA) for mild to moderate AD in patients aged 2 years and older. A recent multicenter, open-label, single-arm study in 137 infants (CrisADe CARE 1) evaluated the pharmacokinetics and efficacy of crisaborole ointment 2% applied twice daily for 4 weeks in pediatric patients aged 3 months to less than 24 months of age with mild to moderate AD.²¹ The study had 2 cohorts: one with a minimum of 5% body surface area involvement and another (the pharmacokinetic cohort) with a minimum of 35% body surface area involvement. Both cohorts demonstrated similar efficacy data. From baseline to day 29, the mean percentage change in eczema area and severity index (EASI) score was −57.5%, and an investigator global assessment (IGA) score of clear or almost clear with at least a 2-grade improvement was achieved in 30.2% of patients. Crisaborole systemic exposures in infants were comparable with those in patients aged 2 years or older. Patients tolerated crisaborole well, with a 4% rate of burning, which was similar to other studies in children and adults but perhaps lower than seen in clinical practice. Pharmacokinetic studies did not show any remarkable noticeable concern with accumulation of propylene glycol absorption.²¹

Based on the CrisADe CARE 1 study data, in March 2020 the FDA extended the indication of crisaborole ointment 2% from a prior lower age limit of 24 months to approval for use in treating mild to moderate AD in children as young as 3 months, making it the first nonsteroidal topical anti-inflammatory medication to be approved in children younger than 2 years in the United States.

Evolving Topical Therapies

Topical Janus Kinase Inhibitors
Ruxolitinib is a potent inhibitor of Janus kinase 1 (JAK-1) and Janus kinase 2 (JAK-2) and has been developed in topical formulations. In recent phase 3 clinical trials of patients with AD aged 12 years and older with mild to moderate disease (TRuE-AD1 and TRuE-AD2), more than half of the patients treated with either ruxolitinib cream in a 0.75% or 1.5% concentration reached EASI-75 after 8 weeks of treatment.²² Additionally, more patients treated with topical ruxolitinib reached an IGA score of clear to almost clear than patients treated with vehicle at the end of treatment. Thus far, it appears to be very well tolerated, significantly decreases EASI score (P<.0001), and improves overall pruritus.²²

Delgocitinib is a topical pan-JAK inhibitor that blocks several cytokine-signaling cascade pathways. It was first developed and approved in Japan in an ointment formulation for use in patients with AD aged 16 years and older.²³ The efficacy and safety profile of delgocitinib is currently being evaluated in pediatric patients with AD in Japan. In a recent phase 2 clinical study of 103 Japanese patients aged 2 to 15 years with moderate to severe AD, patients were randomized to receive either delgocitinib ointment in 0.25% or 0.5% concentrations or vehicle ointment twice daily for 4 weeks. The proportion of patients with a modified EASI-75 score was 38.2% (13/34) in the 0.25% group and 50.0% (17/34) in the 0.5% group vs 8.6% (3/35) in the placebo group. More patients treated with delgocitinib ointment received an IGA score of clear or almost clear than patients treated with vehicle at the end of treatment. Overall, both delgocitinib groups demonstrated superior improvement in clinical symptoms and signs without notable side effects.²⁴

Tapinarof
Tapinarof is a topical therapeutic aryl hydrocarbon receptor agonist. In a recent phase 2 randomized study of 2 concentrations and 2 frequencies of tapinarof cream vs vehicle in 247 randomized patients aged 12 to 65 years with moderate to severe disease, tapinarof demonstrated greater success with both concentrations than vehicle at all visits beyond week 2.²⁵ Additionally, in patients treated with tapinarof cream 1%, nearly 50% reached an IGA score of clear to almost clear with at least a 2-grade improvement. More than 50% of patients achieved EASI-75 improvement at 12 weeks of treatment with tapinarof cream 1% used daily. These findings suggest that tapinarof may be an efficacious and well-tolerated treatment for both adolescents and adults with AD; however, large confirmation trials are needed to further investigate.²⁵

Systemic Treatments

Oral JAK Inhibitors
Some of the most exciting novel therapies include several oral JAK inhibitors that target different combinations of kinases and have been shown to decrease AD severity and symptoms. Some of these agents have indications in other disease states, such as baricitinib and upadacitinib, which are both FDA approved for the treatment of rheumatoid arthritis, whereas others, such as abrocitinib, have been studied specifically for AD.

Although some agents have only been studied in adults to date, others have included adolescents in their core studies, such as abrocitinib, which received Breakthrough Therapy designation from the FDA for the treatment of patients with moderate to severe AD in February 2018. In recent phase 3 trials of patients aged 12 years and older with moderate to severe AD (JADE MONO-1 and JADE MONO-2), both doses of abrocitinib improved the IGA and EASI-75 outcomes compared with placebo.²⁶ Additional studies will be conducted to further investigate the relative efficacy and safety in patients younger than 18 years.

Biologics
Dupilumab is a fully human monoclonal antibody that inhibits IL-4 and IL-13 signaling without suppressing the immune system. It is approved for use in patients aged 12 years and older with moderate to severe asthma and in adults with chronic rhinosinusitis with nasal polyposis. It is the first biologic to show positive results in the moderate to severe pediatric AD population. There are now extended data available exhibiting sustained benefit in adolescent patients who were continued on dupilumab therapy, evidenced by further improvement in EASI scores at the 1-year mark.²⁷

Recently, dupilumab received approval for use in patients aged 6 to 11 years, making it the first biologic for AD to be approved for use in patients younger than 12 years. The expedited FDA approval was based on the phase 3 results in which the efficacy and safety of dupilumab combined with TCSs were compared to TCSs alone (N=367).²⁸ In this trial, more than twice as many children achieved clear or almost clear skin and more than 4 times as many achieved itch reduction with dupilumab plus TCSs than with TCSs alone. Three-quarters of patients receiving dupilumab at the subsequently approved dosing achieved at least a 75% improvement in overall disease.²⁸ An additional study is being conducted that includes pediatric patients aged 6 months to younger than 6 years (ClinicalTrials.gov Identifier NCT03346434).

Future Directions in Pediatric AD

Our review summarizes only some of the agents under clinical investigation for use in pediatric AD. Early treatment to establish excellent long-term disease control with aggressive topical regimens or with systemic agents may alter the course of AD and influence the development of comorbidities, though this has not yet been shown in clinical studies. The long-term impact of early treatment, along with many other intriguing issues, will be studied more in the near future.

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects many adolescents and adults. There has been a tremendous evolution of knowledge in AD, with insights into pathogenesis, epidemiology, impact of disease, and new therapies. A variety of studies examine the epidemiology of AD and associated comorbidities. The broad developments in disease state research are reflected in new publication numbers of AD citations on PubMed. A PubMed search of articles indexed for MEDLINE at the end of 2010 using the term atopic dermatitis would have shown 965 citations during the preceding 1-year period. In the 1-year period of June 2019 to June 2020, there were more than 2000 articles. The large body of research includes work of great significance in pediatric AD, and in this article we review recent findings that are important in understanding the progress being made in the field.

Epidemiology and Comorbidities

The epidemiology of AD has evolved over the last few decades, with emerging trends and novel insights into the burden of disease.¹ In a recent cross-sectional study on the epidemiology of AD in children aged 6 to 11 years, the 1-year diagnosed AD prevalence estimates worldwide included the following: United States, 10.0%; Canada, 13.3%; the EU5 Countries, 15.5%; Japan, 10.3%; and all countries studied, 12.2%.² Another recent paper that analyzed data from the Fragile Families and Child Wellbeing Study showed that the prevalence and persistence of AD in urban US children was 15.0%.³Although pediatric AD may spontaneously remit over time, disease continuing into adolescence and adulthood is common. Paternoster et al⁴ studied the longitudinal course of AD in children from 2 birth cohort prospective studies, showing distinct AD phenotypes having differing course trajectories over time. Disease subsets included patients with early-onset-persistent and early-onset-late-resolving disease.⁴ Whether phenotyping or subgroup analysis can be used to predict disease course or risk for development of comorbidities is unknown, but it is interesting to consider how such work could influence tailoring of specific therapies to early disease presentation.

Atopic dermatitis poses a serious public health burden owing to its high prevalence, considerable morbidity and disability, increased health care utilization, and cost of care.¹ Recent studies have found notably higher rates of multiple medical and mental health comorbidities in both children and adults with AD, including infections, atopic comorbidities (eg, allergic rhinitis, asthma, food allergies), eye diseases (eg, keratitis, conjunctivitis, keratoconus), and possible cardiovascular diseases and autoimmune disorders.^1,5-9 Allergic comorbidities are quite common in pediatric AD patients.¹⁰ In a recent study examining the efficacy and safety of dupilumab monotherapy in 251 adolescents with moderate to severe inadequately controlled AD, most had comorbid type 2 diseases including asthma (53.6%), food allergies (60.8%), and allergic rhinitis (65.6%).¹¹

Quality of Life/Life Impact of AD

Pediatric AD has a major impact on the quality of life of patients and their families.¹² The well-being and development of children are strongly influenced by the physical and psychosocial health of parents/guardians. Two studies by Ramirez and colleagues^13,14 published in 2019 examined sleep disturbances and exhaustion in mothers of children with AD. Data for the studies came from the Avon Longitudinal Study of Parents and Children. Children with active AD reported worse sleep quality than those without AD, with nearly 50% higher odds of sleep-quality disturbances. Analysis of the cohort data from 11,649 mother-child pairs who were followed up with a time-varying measure of child AD activity and severity as well as self-reported maternal sleep measures repeated at multiple time points for children aged 6 months to 11 years showed that mothers of children with AD reported difficulty falling asleep, subjectively insufficient sleep, and daytime exhaustion throughout the first 11 years of childhood.^13,14 These data suggest that sleep disturbance may be a family affair.

A cross-sectional, real-world study on the burden of AD in children aged 6 to 11 years assessed by self-report demonstrated a substantial and multidimensional impact of AD, including itch, sleep disturbance, skin pain, and health-related quality-of-life impact, as well as comorbidities and school productivity losses. The burden associated with AD was remarkable and increased with disease severity.¹⁵

Drucker et al¹⁶ completed a comprehensive literature review on the burden of AD, summarized as a report for the National Eczema Association. Quality-of-life impact on pediatric patients included high rates of emotional distress; social isolation; depression; limitations in activities due to lesions with fear of triggers; and behavioral problems such as irritability, crying, and sleep disturbance resulting in difficulty performing at school.¹⁶ The psychological impact on children as well as emotional and behavioral difficulties may impact the ability for parents/guardians to implement treatment plans.¹⁷

There is a striking association between mental health disorders and AD in the US pediatric population, with a clear dose-dependent relationship that has been observed between the prevalence of a mental health disorder and the reported severity of the skin disease. Data suggest children with AD may be at increased risk for developing mental health disorders. The National Survey of Children’s Health found statistically significant increases in the likelihood of attention deficit hyperactivity disorder (odds ratio [OR], 1.87), depression (OR, 1.81), anxiety (OR, 1.77), conduct disorder (OR, 1.87), and autism (OR, 3.04).⁶

Evolving Practices and Therapies

Bathing Practices
There has long been much controversy regarding best bathing habits for patients with AD. In a 2009 study, cutaneous hydration was quantified after various bathing and moisturizing regimens.¹⁸ The study showed clear benefits of emollient application on skin hydration, either after bathing or without bathing. Bathing followed by emollient applications did not decrease skin hydration in contrast to bathing without emollient application.¹⁸

There are limited studies evaluating bathing frequency in pediatric patients, and many families receive conflicting information regarding best practice. In one study that surveyed 354 parents, more than 75% of parents/guardians who had seen multiple providers for their child’s AD reported a substantial amount of confusion and frustration from conflicting advice on bathing frequency.¹⁹ Cardona et al²⁰ undertook a randomized clinical trial of frequent bathing and moisturizing vs less-frequent bathing and moisturizing in pediatric patients with AD aged 6 months to 11 years. Patients were divided into 2 groups: 1 being bathed twice daily with immediate moisturizer application and the other being bathed twice weekly followed by moisturization, then a switch to the other method. Patients used standardized topical corticosteroids (TCSs) in both groups. There were significant improvements in scoring AD and other objective measures during the frequent bathing time period vs infrequent bathing; in the group that bathed more frequently, SCORAD (SCORing Atopic Dermatitis) decreased by 21.2 compared with the group that bathed less frequently (95% confidence interval, 14.9-27.6; P<.0001). These findings suggest that more-frequent bathing with immediate moisturization is superior as an acute treatment intervention for improving AD disease severity in comparison to less-frequent bathing with immediate moisturization.²⁰

Expanding Treatment Options

Topical Phosphodiesterase Inhibitors
There are several new and evolving topical therapies in AD. Crisaborole ointment 2% is a steroid-free phosphodiesterase inhibitor approved in 2016 by the US Food and Drug Administration (FDA) for mild to moderate AD in patients aged 2 years and older. A recent multicenter, open-label, single-arm study in 137 infants (CrisADe CARE 1) evaluated the pharmacokinetics and efficacy of crisaborole ointment 2% applied twice daily for 4 weeks in pediatric patients aged 3 months to less than 24 months of age with mild to moderate AD.²¹ The study had 2 cohorts: one with a minimum of 5% body surface area involvement and another (the pharmacokinetic cohort) with a minimum of 35% body surface area involvement. Both cohorts demonstrated similar efficacy data. From baseline to day 29, the mean percentage change in eczema area and severity index (EASI) score was −57.5%, and an investigator global assessment (IGA) score of clear or almost clear with at least a 2-grade improvement was achieved in 30.2% of patients. Crisaborole systemic exposures in infants were comparable with those in patients aged 2 years or older. Patients tolerated crisaborole well, with a 4% rate of burning, which was similar to other studies in children and adults but perhaps lower than seen in clinical practice. Pharmacokinetic studies did not show any remarkable noticeable concern with accumulation of propylene glycol absorption.²¹

Based on the CrisADe CARE 1 study data, in March 2020 the FDA extended the indication of crisaborole ointment 2% from a prior lower age limit of 24 months to approval for use in treating mild to moderate AD in children as young as 3 months, making it the first nonsteroidal topical anti-inflammatory medication to be approved in children younger than 2 years in the United States.

Evolving Topical Therapies

Topical Janus Kinase Inhibitors
Ruxolitinib is a potent inhibitor of Janus kinase 1 (JAK-1) and Janus kinase 2 (JAK-2) and has been developed in topical formulations. In recent phase 3 clinical trials of patients with AD aged 12 years and older with mild to moderate disease (TRuE-AD1 and TRuE-AD2), more than half of the patients treated with either ruxolitinib cream in a 0.75% or 1.5% concentration reached EASI-75 after 8 weeks of treatment.²² Additionally, more patients treated with topical ruxolitinib reached an IGA score of clear to almost clear than patients treated with vehicle at the end of treatment. Thus far, it appears to be very well tolerated, significantly decreases EASI score (P<.0001), and improves overall pruritus.²²

Delgocitinib is a topical pan-JAK inhibitor that blocks several cytokine-signaling cascade pathways. It was first developed and approved in Japan in an ointment formulation for use in patients with AD aged 16 years and older.²³ The efficacy and safety profile of delgocitinib is currently being evaluated in pediatric patients with AD in Japan. In a recent phase 2 clinical study of 103 Japanese patients aged 2 to 15 years with moderate to severe AD, patients were randomized to receive either delgocitinib ointment in 0.25% or 0.5% concentrations or vehicle ointment twice daily for 4 weeks. The proportion of patients with a modified EASI-75 score was 38.2% (13/34) in the 0.25% group and 50.0% (17/34) in the 0.5% group vs 8.6% (3/35) in the placebo group. More patients treated with delgocitinib ointment received an IGA score of clear or almost clear than patients treated with vehicle at the end of treatment. Overall, both delgocitinib groups demonstrated superior improvement in clinical symptoms and signs without notable side effects.²⁴

Tapinarof
Tapinarof is a topical therapeutic aryl hydrocarbon receptor agonist. In a recent phase 2 randomized study of 2 concentrations and 2 frequencies of tapinarof cream vs vehicle in 247 randomized patients aged 12 to 65 years with moderate to severe disease, tapinarof demonstrated greater success with both concentrations than vehicle at all visits beyond week 2.²⁵ Additionally, in patients treated with tapinarof cream 1%, nearly 50% reached an IGA score of clear to almost clear with at least a 2-grade improvement. More than 50% of patients achieved EASI-75 improvement at 12 weeks of treatment with tapinarof cream 1% used daily. These findings suggest that tapinarof may be an efficacious and well-tolerated treatment for both adolescents and adults with AD; however, large confirmation trials are needed to further investigate.²⁵

Systemic Treatments

Oral JAK Inhibitors
Some of the most exciting novel therapies include several oral JAK inhibitors that target different combinations of kinases and have been shown to decrease AD severity and symptoms. Some of these agents have indications in other disease states, such as baricitinib and upadacitinib, which are both FDA approved for the treatment of rheumatoid arthritis, whereas others, such as abrocitinib, have been studied specifically for AD.

Although some agents have only been studied in adults to date, others have included adolescents in their core studies, such as abrocitinib, which received Breakthrough Therapy designation from the FDA for the treatment of patients with moderate to severe AD in February 2018. In recent phase 3 trials of patients aged 12 years and older with moderate to severe AD (JADE MONO-1 and JADE MONO-2), both doses of abrocitinib improved the IGA and EASI-75 outcomes compared with placebo.²⁶ Additional studies will be conducted to further investigate the relative efficacy and safety in patients younger than 18 years.

Biologics
Dupilumab is a fully human monoclonal antibody that inhibits IL-4 and IL-13 signaling without suppressing the immune system. It is approved for use in patients aged 12 years and older with moderate to severe asthma and in adults with chronic rhinosinusitis with nasal polyposis. It is the first biologic to show positive results in the moderate to severe pediatric AD population. There are now extended data available exhibiting sustained benefit in adolescent patients who were continued on dupilumab therapy, evidenced by further improvement in EASI scores at the 1-year mark.²⁷

Recently, dupilumab received approval for use in patients aged 6 to 11 years, making it the first biologic for AD to be approved for use in patients younger than 12 years. The expedited FDA approval was based on the phase 3 results in which the efficacy and safety of dupilumab combined with TCSs were compared to TCSs alone (N=367).²⁸ In this trial, more than twice as many children achieved clear or almost clear skin and more than 4 times as many achieved itch reduction with dupilumab plus TCSs than with TCSs alone. Three-quarters of patients receiving dupilumab at the subsequently approved dosing achieved at least a 75% improvement in overall disease.²⁸ An additional study is being conducted that includes pediatric patients aged 6 months to younger than 6 years (ClinicalTrials.gov Identifier NCT03346434).

Future Directions in Pediatric AD

Our review summarizes only some of the agents under clinical investigation for use in pediatric AD. Early treatment to establish excellent long-term disease control with aggressive topical regimens or with systemic agents may alter the course of AD and influence the development of comorbidities, though this has not yet been shown in clinical studies. The long-term impact of early treatment, along with many other intriguing issues, will be studied more in the near future.

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children but also affects many adolescents and adults. There has been a tremendous evolution of knowledge in AD, with insights into pathogenesis, epidemiology, impact of disease, and new therapies. A variety of studies examine the epidemiology of AD and associated comorbidities. The broad developments in disease state research are reflected in new publication numbers of AD citations on PubMed. A PubMed search of articles indexed for MEDLINE at the end of 2010 using the term atopic dermatitis would have shown 965 citations during the preceding 1-year period. In the 1-year period of June 2019 to June 2020, there were more than 2000 articles. The large body of research includes work of great significance in pediatric AD, and in this article we review recent findings that are important in understanding the progress being made in the field.

Epidemiology and Comorbidities

The epidemiology of AD has evolved over the last few decades, with emerging trends and novel insights into the burden of disease.¹ In a recent cross-sectional study on the epidemiology of AD in children aged 6 to 11 years, the 1-year diagnosed AD prevalence estimates worldwide included the following: United States, 10.0%; Canada, 13.3%; the EU5 Countries, 15.5%; Japan, 10.3%; and all countries studied, 12.2%.² Another recent paper that analyzed data from the Fragile Families and Child Wellbeing Study showed that the prevalence and persistence of AD in urban US children was 15.0%.³Although pediatric AD may spontaneously remit over time, disease continuing into adolescence and adulthood is common. Paternoster et al⁴ studied the longitudinal course of AD in children from 2 birth cohort prospective studies, showing distinct AD phenotypes having differing course trajectories over time. Disease subsets included patients with early-onset-persistent and early-onset-late-resolving disease.⁴ Whether phenotyping or subgroup analysis can be used to predict disease course or risk for development of comorbidities is unknown, but it is interesting to consider how such work could influence tailoring of specific therapies to early disease presentation.

Atopic dermatitis poses a serious public health burden owing to its high prevalence, considerable morbidity and disability, increased health care utilization, and cost of care.¹ Recent studies have found notably higher rates of multiple medical and mental health comorbidities in both children and adults with AD, including infections, atopic comorbidities (eg, allergic rhinitis, asthma, food allergies), eye diseases (eg, keratitis, conjunctivitis, keratoconus), and possible cardiovascular diseases and autoimmune disorders.^1,5-9 Allergic comorbidities are quite common in pediatric AD patients.¹⁰ In a recent study examining the efficacy and safety of dupilumab monotherapy in 251 adolescents with moderate to severe inadequately controlled AD, most had comorbid type 2 diseases including asthma (53.6%), food allergies (60.8%), and allergic rhinitis (65.6%).¹¹

Quality of Life/Life Impact of AD

Pediatric AD has a major impact on the quality of life of patients and their families.¹² The well-being and development of children are strongly influenced by the physical and psychosocial health of parents/guardians. Two studies by Ramirez and colleagues^13,14 published in 2019 examined sleep disturbances and exhaustion in mothers of children with AD. Data for the studies came from the Avon Longitudinal Study of Parents and Children. Children with active AD reported worse sleep quality than those without AD, with nearly 50% higher odds of sleep-quality disturbances. Analysis of the cohort data from 11,649 mother-child pairs who were followed up with a time-varying measure of child AD activity and severity as well as self-reported maternal sleep measures repeated at multiple time points for children aged 6 months to 11 years showed that mothers of children with AD reported difficulty falling asleep, subjectively insufficient sleep, and daytime exhaustion throughout the first 11 years of childhood.^13,14 These data suggest that sleep disturbance may be a family affair.

A cross-sectional, real-world study on the burden of AD in children aged 6 to 11 years assessed by self-report demonstrated a substantial and multidimensional impact of AD, including itch, sleep disturbance, skin pain, and health-related quality-of-life impact, as well as comorbidities and school productivity losses. The burden associated with AD was remarkable and increased with disease severity.¹⁵

Drucker et al¹⁶ completed a comprehensive literature review on the burden of AD, summarized as a report for the National Eczema Association. Quality-of-life impact on pediatric patients included high rates of emotional distress; social isolation; depression; limitations in activities due to lesions with fear of triggers; and behavioral problems such as irritability, crying, and sleep disturbance resulting in difficulty performing at school.¹⁶ The psychological impact on children as well as emotional and behavioral difficulties may impact the ability for parents/guardians to implement treatment plans.¹⁷

There is a striking association between mental health disorders and AD in the US pediatric population, with a clear dose-dependent relationship that has been observed between the prevalence of a mental health disorder and the reported severity of the skin disease. Data suggest children with AD may be at increased risk for developing mental health disorders. The National Survey of Children’s Health found statistically significant increases in the likelihood of attention deficit hyperactivity disorder (odds ratio [OR], 1.87), depression (OR, 1.81), anxiety (OR, 1.77), conduct disorder (OR, 1.87), and autism (OR, 3.04).⁶

Evolving Practices and Therapies

Bathing Practices
There has long been much controversy regarding best bathing habits for patients with AD. In a 2009 study, cutaneous hydration was quantified after various bathing and moisturizing regimens.¹⁸ The study showed clear benefits of emollient application on skin hydration, either after bathing or without bathing. Bathing followed by emollient applications did not decrease skin hydration in contrast to bathing without emollient application.¹⁸

There are limited studies evaluating bathing frequency in pediatric patients, and many families receive conflicting information regarding best practice. In one study that surveyed 354 parents, more than 75% of parents/guardians who had seen multiple providers for their child’s AD reported a substantial amount of confusion and frustration from conflicting advice on bathing frequency.¹⁹ Cardona et al²⁰ undertook a randomized clinical trial of frequent bathing and moisturizing vs less-frequent bathing and moisturizing in pediatric patients with AD aged 6 months to 11 years. Patients were divided into 2 groups: 1 being bathed twice daily with immediate moisturizer application and the other being bathed twice weekly followed by moisturization, then a switch to the other method. Patients used standardized topical corticosteroids (TCSs) in both groups. There were significant improvements in scoring AD and other objective measures during the frequent bathing time period vs infrequent bathing; in the group that bathed more frequently, SCORAD (SCORing Atopic Dermatitis) decreased by 21.2 compared with the group that bathed less frequently (95% confidence interval, 14.9-27.6; P<.0001). These findings suggest that more-frequent bathing with immediate moisturization is superior as an acute treatment intervention for improving AD disease severity in comparison to less-frequent bathing with immediate moisturization.²⁰

Expanding Treatment Options

Topical Phosphodiesterase Inhibitors
There are several new and evolving topical therapies in AD. Crisaborole ointment 2% is a steroid-free phosphodiesterase inhibitor approved in 2016 by the US Food and Drug Administration (FDA) for mild to moderate AD in patients aged 2 years and older. A recent multicenter, open-label, single-arm study in 137 infants (CrisADe CARE 1) evaluated the pharmacokinetics and efficacy of crisaborole ointment 2% applied twice daily for 4 weeks in pediatric patients aged 3 months to less than 24 months of age with mild to moderate AD.²¹ The study had 2 cohorts: one with a minimum of 5% body surface area involvement and another (the pharmacokinetic cohort) with a minimum of 35% body surface area involvement. Both cohorts demonstrated similar efficacy data. From baseline to day 29, the mean percentage change in eczema area and severity index (EASI) score was −57.5%, and an investigator global assessment (IGA) score of clear or almost clear with at least a 2-grade improvement was achieved in 30.2% of patients. Crisaborole systemic exposures in infants were comparable with those in patients aged 2 years or older. Patients tolerated crisaborole well, with a 4% rate of burning, which was similar to other studies in children and adults but perhaps lower than seen in clinical practice. Pharmacokinetic studies did not show any remarkable noticeable concern with accumulation of propylene glycol absorption.²¹

Based on the CrisADe CARE 1 study data, in March 2020 the FDA extended the indication of crisaborole ointment 2% from a prior lower age limit of 24 months to approval for use in treating mild to moderate AD in children as young as 3 months, making it the first nonsteroidal topical anti-inflammatory medication to be approved in children younger than 2 years in the United States.

Evolving Topical Therapies

Topical Janus Kinase Inhibitors
Ruxolitinib is a potent inhibitor of Janus kinase 1 (JAK-1) and Janus kinase 2 (JAK-2) and has been developed in topical formulations. In recent phase 3 clinical trials of patients with AD aged 12 years and older with mild to moderate disease (TRuE-AD1 and TRuE-AD2), more than half of the patients treated with either ruxolitinib cream in a 0.75% or 1.5% concentration reached EASI-75 after 8 weeks of treatment.²² Additionally, more patients treated with topical ruxolitinib reached an IGA score of clear to almost clear than patients treated with vehicle at the end of treatment. Thus far, it appears to be very well tolerated, significantly decreases EASI score (P<.0001), and improves overall pruritus.²²

Delgocitinib is a topical pan-JAK inhibitor that blocks several cytokine-signaling cascade pathways. It was first developed and approved in Japan in an ointment formulation for use in patients with AD aged 16 years and older.²³ The efficacy and safety profile of delgocitinib is currently being evaluated in pediatric patients with AD in Japan. In a recent phase 2 clinical study of 103 Japanese patients aged 2 to 15 years with moderate to severe AD, patients were randomized to receive either delgocitinib ointment in 0.25% or 0.5% concentrations or vehicle ointment twice daily for 4 weeks. The proportion of patients with a modified EASI-75 score was 38.2% (13/34) in the 0.25% group and 50.0% (17/34) in the 0.5% group vs 8.6% (3/35) in the placebo group. More patients treated with delgocitinib ointment received an IGA score of clear or almost clear than patients treated with vehicle at the end of treatment. Overall, both delgocitinib groups demonstrated superior improvement in clinical symptoms and signs without notable side effects.²⁴

Tapinarof
Tapinarof is a topical therapeutic aryl hydrocarbon receptor agonist. In a recent phase 2 randomized study of 2 concentrations and 2 frequencies of tapinarof cream vs vehicle in 247 randomized patients aged 12 to 65 years with moderate to severe disease, tapinarof demonstrated greater success with both concentrations than vehicle at all visits beyond week 2.²⁵ Additionally, in patients treated with tapinarof cream 1%, nearly 50% reached an IGA score of clear to almost clear with at least a 2-grade improvement. More than 50% of patients achieved EASI-75 improvement at 12 weeks of treatment with tapinarof cream 1% used daily. These findings suggest that tapinarof may be an efficacious and well-tolerated treatment for both adolescents and adults with AD; however, large confirmation trials are needed to further investigate.²⁵

Systemic Treatments

Oral JAK Inhibitors
Some of the most exciting novel therapies include several oral JAK inhibitors that target different combinations of kinases and have been shown to decrease AD severity and symptoms. Some of these agents have indications in other disease states, such as baricitinib and upadacitinib, which are both FDA approved for the treatment of rheumatoid arthritis, whereas others, such as abrocitinib, have been studied specifically for AD.

Although some agents have only been studied in adults to date, others have included adolescents in their core studies, such as abrocitinib, which received Breakthrough Therapy designation from the FDA for the treatment of patients with moderate to severe AD in February 2018. In recent phase 3 trials of patients aged 12 years and older with moderate to severe AD (JADE MONO-1 and JADE MONO-2), both doses of abrocitinib improved the IGA and EASI-75 outcomes compared with placebo.²⁶ Additional studies will be conducted to further investigate the relative efficacy and safety in patients younger than 18 years.

Biologics
Dupilumab is a fully human monoclonal antibody that inhibits IL-4 and IL-13 signaling without suppressing the immune system. It is approved for use in patients aged 12 years and older with moderate to severe asthma and in adults with chronic rhinosinusitis with nasal polyposis. It is the first biologic to show positive results in the moderate to severe pediatric AD population. There are now extended data available exhibiting sustained benefit in adolescent patients who were continued on dupilumab therapy, evidenced by further improvement in EASI scores at the 1-year mark.²⁷

Recently, dupilumab received approval for use in patients aged 6 to 11 years, making it the first biologic for AD to be approved for use in patients younger than 12 years. The expedited FDA approval was based on the phase 3 results in which the efficacy and safety of dupilumab combined with TCSs were compared to TCSs alone (N=367).²⁸ In this trial, more than twice as many children achieved clear or almost clear skin and more than 4 times as many achieved itch reduction with dupilumab plus TCSs than with TCSs alone. Three-quarters of patients receiving dupilumab at the subsequently approved dosing achieved at least a 75% improvement in overall disease.²⁸ An additional study is being conducted that includes pediatric patients aged 6 months to younger than 6 years (ClinicalTrials.gov Identifier NCT03346434).

Future Directions in Pediatric AD

Our review summarizes only some of the agents under clinical investigation for use in pediatric AD. Early treatment to establish excellent long-term disease control with aggressive topical regimens or with systemic agents may alter the course of AD and influence the development of comorbidities, though this has not yet been shown in clinical studies. The long-term impact of early treatment, along with many other intriguing issues, will be studied more in the near future.

Patients with cutaneous T-cell lymphoma (CTCL) often are diagnosed with atopic dermatitis (AD) or psoriasis before receiving their CTCL diagnosis. The effects of new biologic therapies for AD such as dupilumab, an IL-4/IL-13 antagonist, on CTCL are unknown. Dupilumab may be beneficial in CTCL given that helper T cell (T_H2) cytokines are increased in advanced CTCL.¹ We present a patient with definitive CTCL and concomitant AD who was safely treated with dupilumab and experienced improvement in both CTCL and AD.

Case Report

A 68-year-old man presented with increased itching from AD and a new rash on the arms, neck, chest, back, and lower extremities (Figures 1A and 2A). He had a medical history of AD and CTCL diagnosed by biopsy and peripheral blood flow cytometry (stage IVA1 [T4N0M0B2]) that was being treated with comprehensive multimodality therapy consisting of bexarotene 375 mg daily, interferon alfa-2b 3 mIU 3 times weekly, interferon gamma-1b 2 mIU 3 times weekly, total skin electron beam therapy followed by narrowband UVB twice weekly, and extracorporeal photopheresis every 4 weeks, which resulted in a partial clinical response for 6 months. A biopsy performed at the current presentation showed focal spongiosis and features of lichen simplex chronicus with no evidence suggestive of CTCL. Peripheral blood flow cytometry showed stable B₁-staged disease burden (CD4/CD8, 2.6:1); CD4⁺/CD7⁻, 12% [91/µL]; CD4⁺/CD26⁻, 21% [155/µL]). Treatment with potent and superpotent topical steroids was attempted for more than 6 months and was unsuccessful in relieving the symptoms.

Given the recalcitrant nature of the patient’s rash and itching, dupilumab was added to his CTCL regimen. Prior to initiating dupilumab, the patient reported a numeric rating scale itch intensity of 7 out of 10. After 4 weeks of treatment with dupilumab, the patient reported a numeric rating scale itch intensity of 1. Over a 3-month period, the patient’s rash improved dramatically (Figures 1B and 2B), making it possible to decrease CTCL treatments—bexarotene decreased to 300 mg, interferon alfa-2b to 3 mIU twice weekly, interferon gamma-1b to 2 mIU twice weekly, extracorporeal photopheresis every 5 weeks, and narrowband UVB was discontinued completely. A comparison of the patient’s flow cytometry analysis from before treatment to 3 months after dupilumab showed an overall slight reduction in CTCL B₁ blood involvement and normalization of the patient’s absolute eosinophil count and serum lactate dehydrogenase level. The patient tolerated the treatment well without any adverse events and has maintained clinical response for 6 months.

Comment

Cutaneous T-cell lymphomas represent a heterogeneous group of T-cell lymphoproliferative disorders involving the skin.² The definitive diagnosis of CTCL is challenging, as the clinical and pathologic features often are nonspecific in early disease. Frequently, undiagnosed patients are treated empirically with immunosuppressive agents. Tumor necrosis factor inhibitors and cyclosporine are both associated with progression or worsening of undiagnosed CTCL.^3,4 Dupilumab was the first US Food and Drug Administration–approved biologic for the treatment of moderate to severe AD. Cutaneous T-cell lymphoma has immunologic features, such as T_H2 skewing, that overlap with AD; however, the effects of dupilumab in CTCL are not yet known.^5,6 Our group has seen patients initially thought to have AD who received dupilumab without improvement and were subsequently diagnosed with CTCL, suggesting dupilumab did not affect CTCL tumor cells. Given these findings, there was concern that dupilumab might exacerbate undiagnosed CTCL. Our patient with definitive, severe, refractory CTCL noted marked improvement in both AD and underlying CTCL with the addition of dupilumab. No other treatments were added. The response was so dramatic that we were able to wean the doses and frequencies of several CTCL treatments. Our findings suggest that dupilumab may be beneficial in a certain subset of CTCL patients with a history of AD or known concomitant AD. Prospective studies are needed to fully investigate dupilumab safety and efficacy in CTCL and whether it has any primary effects on tumor burden in addition to benefit for itch and skin symptom relief.

Patients with cutaneous T-cell lymphoma (CTCL) often are diagnosed with atopic dermatitis (AD) or psoriasis before receiving their CTCL diagnosis. The effects of new biologic therapies for AD such as dupilumab, an IL-4/IL-13 antagonist, on CTCL are unknown. Dupilumab may be beneficial in CTCL given that helper T cell (T_H2) cytokines are increased in advanced CTCL.¹ We present a patient with definitive CTCL and concomitant AD who was safely treated with dupilumab and experienced improvement in both CTCL and AD.

Case Report

A 68-year-old man presented with increased itching from AD and a new rash on the arms, neck, chest, back, and lower extremities (Figures 1A and 2A). He had a medical history of AD and CTCL diagnosed by biopsy and peripheral blood flow cytometry (stage IVA1 [T4N0M0B2]) that was being treated with comprehensive multimodality therapy consisting of bexarotene 375 mg daily, interferon alfa-2b 3 mIU 3 times weekly, interferon gamma-1b 2 mIU 3 times weekly, total skin electron beam therapy followed by narrowband UVB twice weekly, and extracorporeal photopheresis every 4 weeks, which resulted in a partial clinical response for 6 months. A biopsy performed at the current presentation showed focal spongiosis and features of lichen simplex chronicus with no evidence suggestive of CTCL. Peripheral blood flow cytometry showed stable B₁-staged disease burden (CD4/CD8, 2.6:1); CD4⁺/CD7⁻, 12% [91/µL]; CD4⁺/CD26⁻, 21% [155/µL]). Treatment with potent and superpotent topical steroids was attempted for more than 6 months and was unsuccessful in relieving the symptoms.

Given the recalcitrant nature of the patient’s rash and itching, dupilumab was added to his CTCL regimen. Prior to initiating dupilumab, the patient reported a numeric rating scale itch intensity of 7 out of 10. After 4 weeks of treatment with dupilumab, the patient reported a numeric rating scale itch intensity of 1. Over a 3-month period, the patient’s rash improved dramatically (Figures 1B and 2B), making it possible to decrease CTCL treatments—bexarotene decreased to 300 mg, interferon alfa-2b to 3 mIU twice weekly, interferon gamma-1b to 2 mIU twice weekly, extracorporeal photopheresis every 5 weeks, and narrowband UVB was discontinued completely. A comparison of the patient’s flow cytometry analysis from before treatment to 3 months after dupilumab showed an overall slight reduction in CTCL B₁ blood involvement and normalization of the patient’s absolute eosinophil count and serum lactate dehydrogenase level. The patient tolerated the treatment well without any adverse events and has maintained clinical response for 6 months.

Comment

Cutaneous T-cell lymphomas represent a heterogeneous group of T-cell lymphoproliferative disorders involving the skin.² The definitive diagnosis of CTCL is challenging, as the clinical and pathologic features often are nonspecific in early disease. Frequently, undiagnosed patients are treated empirically with immunosuppressive agents. Tumor necrosis factor inhibitors and cyclosporine are both associated with progression or worsening of undiagnosed CTCL.^3,4 Dupilumab was the first US Food and Drug Administration–approved biologic for the treatment of moderate to severe AD. Cutaneous T-cell lymphoma has immunologic features, such as T_H2 skewing, that overlap with AD; however, the effects of dupilumab in CTCL are not yet known.^5,6 Our group has seen patients initially thought to have AD who received dupilumab without improvement and were subsequently diagnosed with CTCL, suggesting dupilumab did not affect CTCL tumor cells. Given these findings, there was concern that dupilumab might exacerbate undiagnosed CTCL. Our patient with definitive, severe, refractory CTCL noted marked improvement in both AD and underlying CTCL with the addition of dupilumab. No other treatments were added. The response was so dramatic that we were able to wean the doses and frequencies of several CTCL treatments. Our findings suggest that dupilumab may be beneficial in a certain subset of CTCL patients with a history of AD or known concomitant AD. Prospective studies are needed to fully investigate dupilumab safety and efficacy in CTCL and whether it has any primary effects on tumor burden in addition to benefit for itch and skin symptom relief.

Patients with cutaneous T-cell lymphoma (CTCL) often are diagnosed with atopic dermatitis (AD) or psoriasis before receiving their CTCL diagnosis. The effects of new biologic therapies for AD such as dupilumab, an IL-4/IL-13 antagonist, on CTCL are unknown. Dupilumab may be beneficial in CTCL given that helper T cell (T_H2) cytokines are increased in advanced CTCL.¹ We present a patient with definitive CTCL and concomitant AD who was safely treated with dupilumab and experienced improvement in both CTCL and AD.

Case Report

A 68-year-old man presented with increased itching from AD and a new rash on the arms, neck, chest, back, and lower extremities (Figures 1A and 2A). He had a medical history of AD and CTCL diagnosed by biopsy and peripheral blood flow cytometry (stage IVA1 [T4N0M0B2]) that was being treated with comprehensive multimodality therapy consisting of bexarotene 375 mg daily, interferon alfa-2b 3 mIU 3 times weekly, interferon gamma-1b 2 mIU 3 times weekly, total skin electron beam therapy followed by narrowband UVB twice weekly, and extracorporeal photopheresis every 4 weeks, which resulted in a partial clinical response for 6 months. A biopsy performed at the current presentation showed focal spongiosis and features of lichen simplex chronicus with no evidence suggestive of CTCL. Peripheral blood flow cytometry showed stable B₁-staged disease burden (CD4/CD8, 2.6:1); CD4⁺/CD7⁻, 12% [91/µL]; CD4⁺/CD26⁻, 21% [155/µL]). Treatment with potent and superpotent topical steroids was attempted for more than 6 months and was unsuccessful in relieving the symptoms.

Given the recalcitrant nature of the patient’s rash and itching, dupilumab was added to his CTCL regimen. Prior to initiating dupilumab, the patient reported a numeric rating scale itch intensity of 7 out of 10. After 4 weeks of treatment with dupilumab, the patient reported a numeric rating scale itch intensity of 1. Over a 3-month period, the patient’s rash improved dramatically (Figures 1B and 2B), making it possible to decrease CTCL treatments—bexarotene decreased to 300 mg, interferon alfa-2b to 3 mIU twice weekly, interferon gamma-1b to 2 mIU twice weekly, extracorporeal photopheresis every 5 weeks, and narrowband UVB was discontinued completely. A comparison of the patient’s flow cytometry analysis from before treatment to 3 months after dupilumab showed an overall slight reduction in CTCL B₁ blood involvement and normalization of the patient’s absolute eosinophil count and serum lactate dehydrogenase level. The patient tolerated the treatment well without any adverse events and has maintained clinical response for 6 months.

Comment

Cutaneous T-cell lymphomas represent a heterogeneous group of T-cell lymphoproliferative disorders involving the skin.² The definitive diagnosis of CTCL is challenging, as the clinical and pathologic features often are nonspecific in early disease. Frequently, undiagnosed patients are treated empirically with immunosuppressive agents. Tumor necrosis factor inhibitors and cyclosporine are both associated with progression or worsening of undiagnosed CTCL.^3,4 Dupilumab was the first US Food and Drug Administration–approved biologic for the treatment of moderate to severe AD. Cutaneous T-cell lymphoma has immunologic features, such as T_H2 skewing, that overlap with AD; however, the effects of dupilumab in CTCL are not yet known.^5,6 Our group has seen patients initially thought to have AD who received dupilumab without improvement and were subsequently diagnosed with CTCL, suggesting dupilumab did not affect CTCL tumor cells. Given these findings, there was concern that dupilumab might exacerbate undiagnosed CTCL. Our patient with definitive, severe, refractory CTCL noted marked improvement in both AD and underlying CTCL with the addition of dupilumab. No other treatments were added. The response was so dramatic that we were able to wean the doses and frequencies of several CTCL treatments. Our findings suggest that dupilumab may be beneficial in a certain subset of CTCL patients with a history of AD or known concomitant AD. Prospective studies are needed to fully investigate dupilumab safety and efficacy in CTCL and whether it has any primary effects on tumor burden in addition to benefit for itch and skin symptom relief.

Dupilumab is a novel medication that is approved by the US Food and Drug Administration to treat moderate to severe atopic dermatitis (AD) in patients 6 years and older. Dupilumab is an injectable fully human monoclonal antibody. It provides a giant leap toward a better quality of life for patients with AD. Dupilumab works by binding to the shared α subunit of the IL-4 receptor (IL-4R), thus inhibiting IL-4 and IL-13 from using that signaling pathway. The documented side-effect profile includes injection-site reaction, keratitis, nasopharyngitis, and headache.¹

We initiated off-label treatment with dupilumab in 3 adult patients who had a history of long-standing adult-onset dermatitis confirmed by histopathology. The 3 patients received a loading dose of 600 mg subcutaneously, followed by 300 mg every other week. Following treatment, the patients had expansion of their disease, with features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsies. These 3 cases demonstrate the well-known adage that the diagnosis of CTCL often requires multiple biopsies performed over time. Although dupilumab has proved efficacious and safe for treating AD, dermatologists should be cautious before starting this medication in an adult who has new-onset dermatitis and no history of atopy.

Case Reports

Patient 1
A 61-year-old man presented to dermatology after being lost to follow-up for several years and was started on dupilumab for long-standing nonspecific eczematous dermatitis based on histopathology. He had a pruritic rash of 10 years’ duration that had been biopsied multiple times and was found to be consistent with dermatitis and lichen simplex chronicus (Figure 1). He had been treated with triamcinolone ointment 0.1% and narrowband UVB as often as 3 times weekly over many years. The patient also had a history of idiopathic CD4 lymphopenia with consistently negative tests for human immunodeficiency virus.

At approximately the same time as dupilumab was initiated, he was started on 60 mg daily of prednisone by his pulmonologist because of a history of restrictive lung disease of unknown cause. While taking prednisone, he experienced notable improvement in his skin condition; however, as he was slowly tapered off prednisone, he noted remarkable worsening of the dermatitis. Dupilumab was discontinued. Two more biopsies were performed; findings on both were consistent with mycosis fungoides (MF)(Figure 2).

Upon initial evaluation in our clinic, there was concern for Sézary syndrome; however, peripheral blood studies were normal, and there was no monoclonal spike or irregularity in the patient’s Sézary flow cytometry panel. A biopsy demonstrated lichenoid dermatitis, possibly consistent with drug eruption. All supplements and likely medication culprits were discontinued without improvement.

Prior to follow-up in our clinic, the patient was again evaluated by an outside dermatologist and started on dupilumab. After 3 doses, she discontinued the medication because there was no improvement in the cutaneous symptoms. Findings on repeat biopsy following dupilumab treatment were consistent with MF.

Comment

Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.² In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.³ Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.

We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.

These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.^4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.

A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.⁷ IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.⁸

Dupilumab is a novel medication that is approved by the US Food and Drug Administration to treat moderate to severe atopic dermatitis (AD) in patients 6 years and older. Dupilumab is an injectable fully human monoclonal antibody. It provides a giant leap toward a better quality of life for patients with AD. Dupilumab works by binding to the shared α subunit of the IL-4 receptor (IL-4R), thus inhibiting IL-4 and IL-13 from using that signaling pathway. The documented side-effect profile includes injection-site reaction, keratitis, nasopharyngitis, and headache.¹

We initiated off-label treatment with dupilumab in 3 adult patients who had a history of long-standing adult-onset dermatitis confirmed by histopathology. The 3 patients received a loading dose of 600 mg subcutaneously, followed by 300 mg every other week. Following treatment, the patients had expansion of their disease, with features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsies. These 3 cases demonstrate the well-known adage that the diagnosis of CTCL often requires multiple biopsies performed over time. Although dupilumab has proved efficacious and safe for treating AD, dermatologists should be cautious before starting this medication in an adult who has new-onset dermatitis and no history of atopy.

Case Reports

Patient 1
A 61-year-old man presented to dermatology after being lost to follow-up for several years and was started on dupilumab for long-standing nonspecific eczematous dermatitis based on histopathology. He had a pruritic rash of 10 years’ duration that had been biopsied multiple times and was found to be consistent with dermatitis and lichen simplex chronicus (Figure 1). He had been treated with triamcinolone ointment 0.1% and narrowband UVB as often as 3 times weekly over many years. The patient also had a history of idiopathic CD4 lymphopenia with consistently negative tests for human immunodeficiency virus.

At approximately the same time as dupilumab was initiated, he was started on 60 mg daily of prednisone by his pulmonologist because of a history of restrictive lung disease of unknown cause. While taking prednisone, he experienced notable improvement in his skin condition; however, as he was slowly tapered off prednisone, he noted remarkable worsening of the dermatitis. Dupilumab was discontinued. Two more biopsies were performed; findings on both were consistent with mycosis fungoides (MF)(Figure 2).

Upon initial evaluation in our clinic, there was concern for Sézary syndrome; however, peripheral blood studies were normal, and there was no monoclonal spike or irregularity in the patient’s Sézary flow cytometry panel. A biopsy demonstrated lichenoid dermatitis, possibly consistent with drug eruption. All supplements and likely medication culprits were discontinued without improvement.

Prior to follow-up in our clinic, the patient was again evaluated by an outside dermatologist and started on dupilumab. After 3 doses, she discontinued the medication because there was no improvement in the cutaneous symptoms. Findings on repeat biopsy following dupilumab treatment were consistent with MF.

Comment

Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.² In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.³ Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.

We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.

These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.^4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.

A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.⁷ IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.⁸

Dupilumab is a novel medication that is approved by the US Food and Drug Administration to treat moderate to severe atopic dermatitis (AD) in patients 6 years and older. Dupilumab is an injectable fully human monoclonal antibody. It provides a giant leap toward a better quality of life for patients with AD. Dupilumab works by binding to the shared α subunit of the IL-4 receptor (IL-4R), thus inhibiting IL-4 and IL-13 from using that signaling pathway. The documented side-effect profile includes injection-site reaction, keratitis, nasopharyngitis, and headache.¹

We initiated off-label treatment with dupilumab in 3 adult patients who had a history of long-standing adult-onset dermatitis confirmed by histopathology. The 3 patients received a loading dose of 600 mg subcutaneously, followed by 300 mg every other week. Following treatment, the patients had expansion of their disease, with features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsies. These 3 cases demonstrate the well-known adage that the diagnosis of CTCL often requires multiple biopsies performed over time. Although dupilumab has proved efficacious and safe for treating AD, dermatologists should be cautious before starting this medication in an adult who has new-onset dermatitis and no history of atopy.

Case Reports

Patient 1
A 61-year-old man presented to dermatology after being lost to follow-up for several years and was started on dupilumab for long-standing nonspecific eczematous dermatitis based on histopathology. He had a pruritic rash of 10 years’ duration that had been biopsied multiple times and was found to be consistent with dermatitis and lichen simplex chronicus (Figure 1). He had been treated with triamcinolone ointment 0.1% and narrowband UVB as often as 3 times weekly over many years. The patient also had a history of idiopathic CD4 lymphopenia with consistently negative tests for human immunodeficiency virus.

At approximately the same time as dupilumab was initiated, he was started on 60 mg daily of prednisone by his pulmonologist because of a history of restrictive lung disease of unknown cause. While taking prednisone, he experienced notable improvement in his skin condition; however, as he was slowly tapered off prednisone, he noted remarkable worsening of the dermatitis. Dupilumab was discontinued. Two more biopsies were performed; findings on both were consistent with mycosis fungoides (MF)(Figure 2).

Upon initial evaluation in our clinic, there was concern for Sézary syndrome; however, peripheral blood studies were normal, and there was no monoclonal spike or irregularity in the patient’s Sézary flow cytometry panel. A biopsy demonstrated lichenoid dermatitis, possibly consistent with drug eruption. All supplements and likely medication culprits were discontinued without improvement.

Prior to follow-up in our clinic, the patient was again evaluated by an outside dermatologist and started on dupilumab. After 3 doses, she discontinued the medication because there was no improvement in the cutaneous symptoms. Findings on repeat biopsy following dupilumab treatment were consistent with MF.

Comment

Mycosis fungoides is a rare chronic T-cell lymphoma that can smolder for decades as nonspecific dermatitis before declaring itself fully on skin biopsy.² In many cases, MF masquerades as eczema, psoriasis, contact dermatitis, or other dermatitides, and it often responds to the same medications, making diagnosis even more challenging. Treatment options include topical steroids, narrowband UVB, topical nitrogen mustard, topical carmustine, and bexarotene gel for early-stage disease.³ Although it cannot be determined which patients will progress, some do, and therapies must then be upgraded.

We reported 3 patients with adult-onset dermatitis and multiple biopsies demonstrating nondiagnostic findings, which, in retrospect, likely represented early smoldering CTCL. Each of these patients was treated with dupilumab because multiple biopsies demonstrated findings consistent with nondiagnostic dermatitis, along with a lack of response to standard therapies. In all 3 cases, however, the patients had no history of eczema or atopy. After starting dupilumab, each patient had an acute exacerbation of dermatitis; immediately thereafter, biopsies were consistent with CTCL.

These patients most likely had smoldering CTCL that expressed itself fully after dupilumab was started. Biologic medications and their effects on the immune system have been shown to have multiple unanticipated effects on the skin.^4-6 We are not insinuating that dupilumab was the cause of our patients having developed CTCL, but we do propose that the underlying interplay of dupilumab with the immune system might have accelerated progression of underlying CTCL, resulting in the lymphoma presenting itself clinically and histopathologically. We also must mention that all 3 cases could represent a “true, true, and unrelated” phenomenon.

A proposed mechanism for how dupilumab might hasten progression of CTCL is based on a functional increase of IL-13 available for binding at the IL-13 receptor (IL-13R) α2 site following blockade of the IL-13Rα1 site by dupilumab (Figure 3). The pathway that is blocked by dupilumab provides improvement in AD by blocking the α subunit of the IL-4R, making it a receptor antagonist for both IL-4 and IL-13. The IL-4R forms a heterodimer with both γ c and separately with IL-13Rα1. As a result, IL-4 and IL-13 cannot bind to their respective targets; thus, downstream signaling that is required for AD is halted.⁷ IL-13, in addition to IL-4R, also binds to an IL-13Rα2. IL-13 and both of its receptors are upregulated in CTCL, particularly IL-13Rα2.⁸

A large postmarketing surveillance study of topical calcineurin inhibitor exposure in adults with atopic dermatitis has found no increased risk of developing keratinocyte carcinomas overall or with basal cell or squamous cell carcinomas associated with treatment.

The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.

“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.

In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.

The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.

Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.

Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.

“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.

In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.

“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.

Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.

“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.

The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.

Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”

“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”

Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”

In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”

Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.

These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”

This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.

SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.

A large postmarketing surveillance study of topical calcineurin inhibitor exposure in adults with atopic dermatitis has found no increased risk of developing keratinocyte carcinomas overall or with basal cell or squamous cell carcinomas associated with treatment.

The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.

“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.

In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.

The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.

Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.

Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.

“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.

In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.

“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.

Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.

“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.

The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.

Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”

“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”

Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”

In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”

Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.

These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”

This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.

SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.

A large postmarketing surveillance study of topical calcineurin inhibitor exposure in adults with atopic dermatitis has found no increased risk of developing keratinocyte carcinomas overall or with basal cell or squamous cell carcinomas associated with treatment.

The results also suggest dose, frequency, and exposure duration to the topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus are not associated with an increased risk of keratinocyte carcinomas (KCs), basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) in patients with atopic dermatitis (AD), according to Maryam M. Asgari, MD, MPH, professor of dermatology, Harvard Medical School, Boston, and colleagues. In 2006, the Food and Drug Administration announced the addition of the boxed warning to the labeling of TCIs regarding a possible risk of cancer associated with use of pimecrolimus (Elidel) and with tacrolimus (Protopic), because of an increased risk of KCs associated with oral calcineurin inhibitors and reports of skin cancer in patients on TCIs.

“Controversy has surrounded the association between TCI exposure and KC risk since the black-box warning was issued by the FDA. A hypothesized mechanism of action for TCIs increasing KC risk includes a direct effect of calcineurin inhibition on DNA repair and apoptosis, which could influence keratinocyte carcinogenesis,” the authors of the study wrote in JAMA Dermatology. But, they added, there have been “conflicting results” in research exploring this association.

In the retrospective cohort study, Dr. Asgari and coauthors evaluated 93,746 adult patients with AD at Kaiser Permanente Northern California, diagnosed between January 2002 and December 2013, comparing skin cancer risk among 7,033 patients exposed to TCIs, 73,674 patients taking topical corticosteroids, and 46,141 patients who had not been exposed to TCIs or topical corticosteroids. Results were adjusted in a multivariate Cox regression analysis for age, gender, race/ethnicity, calendar year, number of dermatology visits per year, history of KCs, immunosuppression, prior systemic AD treatment, autoimmune disease, treatment with ultraviolet therapy, chemotherapy, and radiotherapy.

The researchers also examined how TCI dose, frequency and exposure duration impacted skin cancer risk. Patients were grouped by high-dose (0.1%) and low-dose (0.03%) formulations of tacrolimus; and the 1% formulation of pimecrolimus. Frequency of use was defined as low (once daily or less) or high (twice daily or more), and exposure duration was based on short- (less than 2 years), moderate- (2-4 years), and long-term (4 years or more) use. Patients were at least 40 years old (mean age, 58.5 years), 58.7% were women, 50.5% were White, 20.6% were Asian, 12.2% were Hispanic, and 7.9% were Black. They were followed for a mean of 7.70 years.

Compared with patients who were exposed to topical corticosteroids, there was no association between risk of KCs and exposure to TCIs in patients with AD (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93-1.13). There were also no significant differences in risk of BCCs and TCI exposure (aHR, 1.01; 95% CI, 0.90-1.14) and risk of SCCs and TCI exposure (aHR, 0.94; 95% CI, 0.82-1.08), compared with patients exposed to topical corticosteroids.

Results were similar for risk of KCs (aHR, 1.03; 95% CI, 0.92-1.14), BCCs (aHR, 1.04; 95% CI, 0.91-1.19), and SCCs (aHR, 0.91; 95% CI, 0.78-1.06) when patients exposed to TCIs were compared with those with AD who were unexposed to any medication. In secondary analyses, Dr. Asgari and coauthors found no association with overall risk of KCs, or risk of BCCs or SCCs, and the dose, frequency, or exposure duration to TCIs.

“Our findings appear to support those of smaller postmarketing surveillance studies of TCI and KC risk and may provide some reassurance about the safety profile of this class of topical agents in the treatment of AD,” they concluded.

In an interview, Jonathan Silverberg, MD, PhD, MPH, associate professor of dermatology, George Washington University, Washington, said initial concerns surrounding TCIs were based on high doses potentially increasing the risk of malignancy, and off-label use of TCIs for inflammatory skin diseases other than AD.

“However, the FDA’s concerns may not have been justified,” he said. The manufacturers of pimecrolimus and tacrolimus have published results of 10-year observational registries that assess cancer risk, which “found no evidence of any associations between TCIs and malignancy,” noted Dr. Silverberg, who is also director of clinical research and contact dermatitis at George Washington University.

Elizabeth Hughes, MD, a dermatologist in private practice in San Antonio, said in an interview that initial enthusiasm was “huge” for use of TCIs like tacrolimus in patients with AD when they first became available, especially in the pediatric population, for whom clinicians are hesitant to use long-term strong topical steroids. However, parents of children taking the medication soon became concerned about potential side effects.

“The TCIs can be absorbed to a small extent through body surface area, so it was not a big leap to become concerned that infants and small children could absorb enough ... into the bloodstream to give a similar side effect profile as oral tacrolimus,” she said.

The addition of the boxed warning in 2006 was frustrating for dermatologists “because a medication we needed very much for a young population now was ‘labeled’ and parents were scared to use it,” Dr. Hughes explained.

Dr. Silverberg noted that, while the results of the new study are unlikely to change clinical practice, they are reassuring, and provide real-world data and “further confirmation of previous studies showing no associations between AD and malignancy.”

“Since AD and skin cancer are both commonly managed by dermatologists, there is potential for increased surveillance and detection of skin cancers in AD patients. So, the greatest chance of seeing a false-positive signal for malignancy would likely occur with skin cancers,” he pointed out. “Yet, even in the case of skin cancers, there were no demonstrable signals.”

Based on the results, “I think it is definitely reasonable to reconsider” the TCI boxed warning, but there isn’t much precedent for boxed warnings to be removed from labeling, Dr. Silverberg commented. “Unfortunately, the black-box warning may persist despite a lot of reassuring data.”

In a related editorial, Aaron M. Drucker, MD, ScM, and Mina Tadrous, PharmD, PhD, of the University of Toronto, said the boxed warning “had the intent of helping patients and clinicians understand possible risks,” but also carried the “potential for harm” if patients discontinued or did not adhere to treatment. “Safety warnings on topical medications could lead to undertreatment of atopic dermatitis, reduced quality of life and, potentially, increased use of more toxic systemic medications.”

Long-term studies of medications and cancer risk are challenging to perform, having to account for dose-response relationships, confounding by indication, and time bias, among other factors, and this study “recognizes and attempts to address many of these challenges,” Dr. Drucker and Dr. Tadrous wrote.

These results are similar to previous studies that have “consistently reported no or minimal association between TCI use and skin cancer,” they noted, adding that, “if an association exists, it is likely very small, meaning that skin cancer attributable to TCI use is rare. Clinicians can use this evidence to counsel and reassure patients for whom the benefits of ongoing treatment with TCIs may outweigh the harms.”

This study was funded by a grant from Valeant Pharmaceuticals. Dr. Asgari reported receiving grants from Valeant during the study, and from Pfizer not related to the study. The other authors reported no relevant conflicts of interest. Dr. Drucker reported relationships with the Canadian Agency for Drugs and Technology in Health, CME Outfitters, Eczema Society of Canada, Sanofi, Regeneron, and RTI Health Solutions in the form of paid fees, consultancies, honoraria, educational grants, and other compensation paid to him and/or his institution. Dr. Tadrous reported no relevant disclosures. Dr. Silverberg reported receiving honoraria for advisory board, speaker, and consultant services from numerous pharmaceutical manufacturers, and research grants for investigator services from GlaxoSmithKline and Galderma. Dr. Hughes Tichy reported no relevant financial disclosures. Dr. Silverberg is a member of the Dermatology News editorial advisory board.

SOURCE: Asgari MM et al. JAMA Dermatol. 2020 Aug 12. doi: 10.1001/jamadermatol.2020.2240.

Collecting cells from the skin surface with adhesive tape strips is demonstrating a level of accuracy that is rivaling skin biopsies for atopic dermatitis and psoriasis, promising a minimally invasive approach for monitoring these and potentially other dermatologic diseases, according to the latest advances with this approach.

Courtesy Mount Sinai Health System

“Tape strips are not going to fully replace biopsies, but we think they will have an important role in diagnosing and monitoring response to therapy by avoiding the potential scarring and pain of biopsy,” reported Emma Guttman-Yassky, MD, PhD, professor of dermatology and director of the laboratory inflammatory skin diseases at the Icahn School of Medicine at Mount Sinai Medical Center, New York.

The concept of using adhesive strips to remove surface skin cells for clinical study has been around for more than 20 years, but there has been recent progress. A newly published study, which compared skin from patients with atopic dermatitis (AD) or psoriasis with that of controls, was characterized as “the most comprehensive tape strip molecular profiling in any inflammatory skin disease to date and the first to fully characterize and compare AD to psoriasis,” wrote Dr. Guttman-Yassky, the senior author, and coauthors.

It also appears to be a leap forward. RNA sequencing detected thousands of differentially expressed genes reflecting immune and barrier biomarkers characteristic of the molecular phenotypes of atopic dermatitis and psoriasis. These were not only found to be consistent with biopsy studies but identified additional unique genes and pathways relevant to their pathological signature.

“In the past, the success rate for transcriptome sequencing even for a more limited panel of proteins was approaching 50% when considering both lesional, nonlesional skin, and healthy skin, but we are now approaching 100% for sample recovery and for analysis of RNA and genes,” Dr. Guttman-Yassky said in an interview.

Tissue samples were obtained with tape strips from lesional and nonlesional skin from 20 patients with AD and 20 patients with psoriasis. Compared with 20 tape strips from controls, they were evaluated with RNA sequencing followed by quantitative real-time polymerase chain reaction of immune and barrier biomarkers.

The sample recovery rate was 96% overall and 95% or better regardless of whether the skin was lesional or nonlesional.

With RNA sequencing of more than 20,000 transcripts, including multiple cellular, immune, and barrier biomarkers, an enormous amount of data was generated, but the key finding is that these diseases are readily distinguished with profiling based on tape strips.

Although numerous biomarkers were shared, “tape strips completely discriminate between atopic dermatitis and psoriasis with a degree of reliability that is comparable to skin biopsy,” Dr. Guttman-Yassky said.

One of the biomarkers, expression of nitric oxide synthase 2/inducible nitric oxide synthase, distinguished AD from psoriasis with 100% accuracy. As previously reported in biopsy studies, other biomarkers collectively associated AD with a profile related to a Th2-type inflammatory response and psoriasis with a Th17-type inflammatory response.

Tape strips also confirmed significant pathology in the nonlesional as well as the lesional skin of patients with AD or psoriasis. This included an increase in Th2-type products, such as interleukin-4 and IL-13, in nonlesional skin of atopic dermatitis and Th17-type products, such as IL-17, in nonlesional skin of psoriasis.

Some biomarkers of AD and psoriasis had an even greater differentiation in tape strips than previously reported from biopsy studies, according to Dr. Guttman-Yassky. In this study, tape strips also captured more differentially expressed genes than previously reported with biopsies.

One potential limitation of tape strips is that the RNA isolation process is time consuming, but this might be less of an issue in routine clinical use if there is a more refined number of biomarkers that are targeted or if technological improvements simplify processing, Dr. Guttman-Yassky pointed out.

To develop clinical utility for tape strips beyond AD and psoriasis, more work is needed to standardize the depth of sampling, which is variable with tape strips, she noted. Depth is relevant to the analysis of gene expression and mRNA activity of each dermatologic disease.

“Tape strips remain a research tool for now, but we do think that this technique can be refined and employed for clinical purposes, including diagnosis and monitoring response to treatment,” she said.

Relative to biopsy, the advantages are not difficult to envision. Dr. Guttman-Yassky, who recently published a study of tape strips for evaluating AD in children emphasized that tape strips are generally painless.

“Patients really do not mind tape strips,” she said. Although she believes that tape strips are providing unique insight into the pathology of inflammatory diseases not necessarily available with biopsy, she emphasized the practical value. Not least, “these could really help when the goal is to evaluate response to therapy over time.”

Another investigator who has conducted studies with tape strips, Maja-Lisa Clausen, MD, PhD, also thinks tape strips are likely to become routine clinical tools.

“Once the basis research, validation, and data are out, I think numerous companies will be ready to develop machines for more quick and easy processing, compared to the more labor intensive process that is used today for research,” explained Dr. Clausen, who is in the department of dermatology, Bispebjerb Hospital, University of Copenhagen.

She considers tape strips particularly promising for children, but she thinks the biomarker profiling made possible by these strips might be leading to personalized treatment programs for dermatologic diseases.

“What we need is further validation; which tape to use, how deep, and the importance of storage, which is a big issue in the clinic,” Dr. Clausen said in an interview.

Dr. Guttman-Yassky has financial relationships with multiple pharmaceutical companies, including those with therapies for psoriasis.

SOURCE: Guttman-Yassky E et al. J Allergy Clin Immunol. 2020 Jul 9. doi: 10.1016/j.jaci.2020.05.048.

Collecting cells from the skin surface with adhesive tape strips is demonstrating a level of accuracy that is rivaling skin biopsies for atopic dermatitis and psoriasis, promising a minimally invasive approach for monitoring these and potentially other dermatologic diseases, according to the latest advances with this approach.

Courtesy Mount Sinai Health System

“Tape strips are not going to fully replace biopsies, but we think they will have an important role in diagnosing and monitoring response to therapy by avoiding the potential scarring and pain of biopsy,” reported Emma Guttman-Yassky, MD, PhD, professor of dermatology and director of the laboratory inflammatory skin diseases at the Icahn School of Medicine at Mount Sinai Medical Center, New York.

The concept of using adhesive strips to remove surface skin cells for clinical study has been around for more than 20 years, but there has been recent progress. A newly published study, which compared skin from patients with atopic dermatitis (AD) or psoriasis with that of controls, was characterized as “the most comprehensive tape strip molecular profiling in any inflammatory skin disease to date and the first to fully characterize and compare AD to psoriasis,” wrote Dr. Guttman-Yassky, the senior author, and coauthors.

It also appears to be a leap forward. RNA sequencing detected thousands of differentially expressed genes reflecting immune and barrier biomarkers characteristic of the molecular phenotypes of atopic dermatitis and psoriasis. These were not only found to be consistent with biopsy studies but identified additional unique genes and pathways relevant to their pathological signature.

“In the past, the success rate for transcriptome sequencing even for a more limited panel of proteins was approaching 50% when considering both lesional, nonlesional skin, and healthy skin, but we are now approaching 100% for sample recovery and for analysis of RNA and genes,” Dr. Guttman-Yassky said in an interview.

Tissue samples were obtained with tape strips from lesional and nonlesional skin from 20 patients with AD and 20 patients with psoriasis. Compared with 20 tape strips from controls, they were evaluated with RNA sequencing followed by quantitative real-time polymerase chain reaction of immune and barrier biomarkers.

The sample recovery rate was 96% overall and 95% or better regardless of whether the skin was lesional or nonlesional.

With RNA sequencing of more than 20,000 transcripts, including multiple cellular, immune, and barrier biomarkers, an enormous amount of data was generated, but the key finding is that these diseases are readily distinguished with profiling based on tape strips.

Although numerous biomarkers were shared, “tape strips completely discriminate between atopic dermatitis and psoriasis with a degree of reliability that is comparable to skin biopsy,” Dr. Guttman-Yassky said.

One of the biomarkers, expression of nitric oxide synthase 2/inducible nitric oxide synthase, distinguished AD from psoriasis with 100% accuracy. As previously reported in biopsy studies, other biomarkers collectively associated AD with a profile related to a Th2-type inflammatory response and psoriasis with a Th17-type inflammatory response.

Tape strips also confirmed significant pathology in the nonlesional as well as the lesional skin of patients with AD or psoriasis. This included an increase in Th2-type products, such as interleukin-4 and IL-13, in nonlesional skin of atopic dermatitis and Th17-type products, such as IL-17, in nonlesional skin of psoriasis.

Some biomarkers of AD and psoriasis had an even greater differentiation in tape strips than previously reported from biopsy studies, according to Dr. Guttman-Yassky. In this study, tape strips also captured more differentially expressed genes than previously reported with biopsies.

One potential limitation of tape strips is that the RNA isolation process is time consuming, but this might be less of an issue in routine clinical use if there is a more refined number of biomarkers that are targeted or if technological improvements simplify processing, Dr. Guttman-Yassky pointed out.

To develop clinical utility for tape strips beyond AD and psoriasis, more work is needed to standardize the depth of sampling, which is variable with tape strips, she noted. Depth is relevant to the analysis of gene expression and mRNA activity of each dermatologic disease.

“Tape strips remain a research tool for now, but we do think that this technique can be refined and employed for clinical purposes, including diagnosis and monitoring response to treatment,” she said.

Relative to biopsy, the advantages are not difficult to envision. Dr. Guttman-Yassky, who recently published a study of tape strips for evaluating AD in children emphasized that tape strips are generally painless.

“Patients really do not mind tape strips,” she said. Although she believes that tape strips are providing unique insight into the pathology of inflammatory diseases not necessarily available with biopsy, she emphasized the practical value. Not least, “these could really help when the goal is to evaluate response to therapy over time.”

Another investigator who has conducted studies with tape strips, Maja-Lisa Clausen, MD, PhD, also thinks tape strips are likely to become routine clinical tools.

“Once the basis research, validation, and data are out, I think numerous companies will be ready to develop machines for more quick and easy processing, compared to the more labor intensive process that is used today for research,” explained Dr. Clausen, who is in the department of dermatology, Bispebjerb Hospital, University of Copenhagen.

She considers tape strips particularly promising for children, but she thinks the biomarker profiling made possible by these strips might be leading to personalized treatment programs for dermatologic diseases.

“What we need is further validation; which tape to use, how deep, and the importance of storage, which is a big issue in the clinic,” Dr. Clausen said in an interview.

Dr. Guttman-Yassky has financial relationships with multiple pharmaceutical companies, including those with therapies for psoriasis.

SOURCE: Guttman-Yassky E et al. J Allergy Clin Immunol. 2020 Jul 9. doi: 10.1016/j.jaci.2020.05.048.

Collecting cells from the skin surface with adhesive tape strips is demonstrating a level of accuracy that is rivaling skin biopsies for atopic dermatitis and psoriasis, promising a minimally invasive approach for monitoring these and potentially other dermatologic diseases, according to the latest advances with this approach.

Courtesy Mount Sinai Health System

“Tape strips are not going to fully replace biopsies, but we think they will have an important role in diagnosing and monitoring response to therapy by avoiding the potential scarring and pain of biopsy,” reported Emma Guttman-Yassky, MD, PhD, professor of dermatology and director of the laboratory inflammatory skin diseases at the Icahn School of Medicine at Mount Sinai Medical Center, New York.

The concept of using adhesive strips to remove surface skin cells for clinical study has been around for more than 20 years, but there has been recent progress. A newly published study, which compared skin from patients with atopic dermatitis (AD) or psoriasis with that of controls, was characterized as “the most comprehensive tape strip molecular profiling in any inflammatory skin disease to date and the first to fully characterize and compare AD to psoriasis,” wrote Dr. Guttman-Yassky, the senior author, and coauthors.

It also appears to be a leap forward. RNA sequencing detected thousands of differentially expressed genes reflecting immune and barrier biomarkers characteristic of the molecular phenotypes of atopic dermatitis and psoriasis. These were not only found to be consistent with biopsy studies but identified additional unique genes and pathways relevant to their pathological signature.

“In the past, the success rate for transcriptome sequencing even for a more limited panel of proteins was approaching 50% when considering both lesional, nonlesional skin, and healthy skin, but we are now approaching 100% for sample recovery and for analysis of RNA and genes,” Dr. Guttman-Yassky said in an interview.

Tissue samples were obtained with tape strips from lesional and nonlesional skin from 20 patients with AD and 20 patients with psoriasis. Compared with 20 tape strips from controls, they were evaluated with RNA sequencing followed by quantitative real-time polymerase chain reaction of immune and barrier biomarkers.

The sample recovery rate was 96% overall and 95% or better regardless of whether the skin was lesional or nonlesional.

With RNA sequencing of more than 20,000 transcripts, including multiple cellular, immune, and barrier biomarkers, an enormous amount of data was generated, but the key finding is that these diseases are readily distinguished with profiling based on tape strips.

Although numerous biomarkers were shared, “tape strips completely discriminate between atopic dermatitis and psoriasis with a degree of reliability that is comparable to skin biopsy,” Dr. Guttman-Yassky said.

One of the biomarkers, expression of nitric oxide synthase 2/inducible nitric oxide synthase, distinguished AD from psoriasis with 100% accuracy. As previously reported in biopsy studies, other biomarkers collectively associated AD with a profile related to a Th2-type inflammatory response and psoriasis with a Th17-type inflammatory response.

Tape strips also confirmed significant pathology in the nonlesional as well as the lesional skin of patients with AD or psoriasis. This included an increase in Th2-type products, such as interleukin-4 and IL-13, in nonlesional skin of atopic dermatitis and Th17-type products, such as IL-17, in nonlesional skin of psoriasis.

Some biomarkers of AD and psoriasis had an even greater differentiation in tape strips than previously reported from biopsy studies, according to Dr. Guttman-Yassky. In this study, tape strips also captured more differentially expressed genes than previously reported with biopsies.

One potential limitation of tape strips is that the RNA isolation process is time consuming, but this might be less of an issue in routine clinical use if there is a more refined number of biomarkers that are targeted or if technological improvements simplify processing, Dr. Guttman-Yassky pointed out.

To develop clinical utility for tape strips beyond AD and psoriasis, more work is needed to standardize the depth of sampling, which is variable with tape strips, she noted. Depth is relevant to the analysis of gene expression and mRNA activity of each dermatologic disease.

“Tape strips remain a research tool for now, but we do think that this technique can be refined and employed for clinical purposes, including diagnosis and monitoring response to treatment,” she said.

Relative to biopsy, the advantages are not difficult to envision. Dr. Guttman-Yassky, who recently published a study of tape strips for evaluating AD in children emphasized that tape strips are generally painless.

“Patients really do not mind tape strips,” she said. Although she believes that tape strips are providing unique insight into the pathology of inflammatory diseases not necessarily available with biopsy, she emphasized the practical value. Not least, “these could really help when the goal is to evaluate response to therapy over time.”

Another investigator who has conducted studies with tape strips, Maja-Lisa Clausen, MD, PhD, also thinks tape strips are likely to become routine clinical tools.

“Once the basis research, validation, and data are out, I think numerous companies will be ready to develop machines for more quick and easy processing, compared to the more labor intensive process that is used today for research,” explained Dr. Clausen, who is in the department of dermatology, Bispebjerb Hospital, University of Copenhagen.

She considers tape strips particularly promising for children, but she thinks the biomarker profiling made possible by these strips might be leading to personalized treatment programs for dermatologic diseases.

“What we need is further validation; which tape to use, how deep, and the importance of storage, which is a big issue in the clinic,” Dr. Clausen said in an interview.

Dr. Guttman-Yassky has financial relationships with multiple pharmaceutical companies, including those with therapies for psoriasis.

SOURCE: Guttman-Yassky E et al. J Allergy Clin Immunol. 2020 Jul 9. doi: 10.1016/j.jaci.2020.05.048.

The use of topical corticosteroids does not significantly increase fracture risk in young children diagnosed with atopic dermatitis, results from a large population-based study suggest.

LucaLorenzelli/Thinkstock

“Little has been published about the risk of fracture in children with atopic dermatitis on topical corticosteroids specifically,” one of the study authors, Reese L. Imhof, said in an interview following the virtual annual meeting of the Society for Pediatric Dermatology. “There are concerns, particularly among parents, regarding potential bone side effects through possible corticosteroid percutaneous absorption. Fears related to topical corticosteroid use likely stem from the fact that prolonged systemic corticosteroid use is associated with an increased risk of bone fractures.”

In an effort to determine the fracture risk in children who were diagnosed with atopic dermatitis (AD) prior to age 4 years and received topical corticosteroid treatment, Mr. Imhof, from Mayo Medical School, Rochester, Minn., and his associates used the Rochester Epidemiology Project records-linkage system to identify patients in Olmstead County, Minn., who received their first AD diagnosis prior to age 4 years between Jan. 1, 2004, through Dec. 31, 2017. Those who received topical corticosteroids listed in National Drug File-Reference Terminology class 8952 (anti-inflammatory, topical) or 8954 (anti-infective/anti-inflammatory combinations, topical) between Jan. 1, 2004, and Dec. 31, 2018 were included in the analysis and were followed to identify new bone fractures, excluding pathological fractures in neoplastic disease and skull or facial bone fractures.

The researchers conducted two analyses of the data. For the primary statistical analysis, they evaluated topical corticosteroid exposure as a binary time-dependent covariate in a Cox proportional hazard model using age as the time scale, with patients entering the risk set at the age of the first clinic visit rather than the age of their first AD diagnosis. Next, the researchers performed a landmark analysis as a sensitivity analysis. For this, each patient’s fourth birthday was defined as the starting point, since all included patients were diagnosed with AD prior to age 4 years.

Of the 7,505 patients first identified with AD, 3,542 were included in the primary analysis and 2,499 were included in the landmark analysis. In the primary analysis, 2,384 patients (67%) received a topical prescription for a topical corticosteroid prior to age 4 years, and an additional 190 (5%) received their first prescription after age 4 years. The researchers observed that 451 patients (13%) had a fracture after AD diagnosis at a median age of 7.4 years. The median age at last follow-up for the remaining 3,091 patients was 6.6 years. Evaluated as a time-dependent covariate, the use of a topical corticosteroid was associated with a nonsignificant 17% increased risk of fracture (hazard ratio, 1.17; P = .16).

In the landmark analysis, 1,722 patients (69%) were prescribed a topical corticosteroid prior to age 4 years. Of these patients, 333 (13%) had their first fracture after AD diagnosis, at a median age of 8.7 years. The median age at last follow-up for the remaining patients was 9.3 years. The researchers observed that, starting at 4 years of age, there was no association between topical corticosteroid use and risk of fracture (HR, 1.00; P = 1.00).

“Our findings suggest that topical corticosteroids do not significantly increase fracture risk in this pediatric population with atopic dermatitis,” Mr. Imhof said. “Dermatologists can use the results of this study to reassure parents of infants and young children, as most patients in our study received their first topical corticosteroid prescription prior to age 4.”

He acknowledged certain limitations of the study, such as its retrospective design and study population, which was predominantly white and resided in the upper Midwest. “Also, our study examined prescription data with the assumption made that topical corticosteroids were used as prescribed,” he said. “An additional limitation is that we evaluated ever versus never exposure to topical corticosteroids rather than cumulative duration of use and/or potency.”

Mr. Imhof and his colleagues reported having no financial disclosures.

dbrunk@mdedge.com

The use of topical corticosteroids does not significantly increase fracture risk in young children diagnosed with atopic dermatitis, results from a large population-based study suggest.

LucaLorenzelli/Thinkstock

“Little has been published about the risk of fracture in children with atopic dermatitis on topical corticosteroids specifically,” one of the study authors, Reese L. Imhof, said in an interview following the virtual annual meeting of the Society for Pediatric Dermatology. “There are concerns, particularly among parents, regarding potential bone side effects through possible corticosteroid percutaneous absorption. Fears related to topical corticosteroid use likely stem from the fact that prolonged systemic corticosteroid use is associated with an increased risk of bone fractures.”

In an effort to determine the fracture risk in children who were diagnosed with atopic dermatitis (AD) prior to age 4 years and received topical corticosteroid treatment, Mr. Imhof, from Mayo Medical School, Rochester, Minn., and his associates used the Rochester Epidemiology Project records-linkage system to identify patients in Olmstead County, Minn., who received their first AD diagnosis prior to age 4 years between Jan. 1, 2004, through Dec. 31, 2017. Those who received topical corticosteroids listed in National Drug File-Reference Terminology class 8952 (anti-inflammatory, topical) or 8954 (anti-infective/anti-inflammatory combinations, topical) between Jan. 1, 2004, and Dec. 31, 2018 were included in the analysis and were followed to identify new bone fractures, excluding pathological fractures in neoplastic disease and skull or facial bone fractures.

The researchers conducted two analyses of the data. For the primary statistical analysis, they evaluated topical corticosteroid exposure as a binary time-dependent covariate in a Cox proportional hazard model using age as the time scale, with patients entering the risk set at the age of the first clinic visit rather than the age of their first AD diagnosis. Next, the researchers performed a landmark analysis as a sensitivity analysis. For this, each patient’s fourth birthday was defined as the starting point, since all included patients were diagnosed with AD prior to age 4 years.

Of the 7,505 patients first identified with AD, 3,542 were included in the primary analysis and 2,499 were included in the landmark analysis. In the primary analysis, 2,384 patients (67%) received a topical prescription for a topical corticosteroid prior to age 4 years, and an additional 190 (5%) received their first prescription after age 4 years. The researchers observed that 451 patients (13%) had a fracture after AD diagnosis at a median age of 7.4 years. The median age at last follow-up for the remaining 3,091 patients was 6.6 years. Evaluated as a time-dependent covariate, the use of a topical corticosteroid was associated with a nonsignificant 17% increased risk of fracture (hazard ratio, 1.17; P = .16).

In the landmark analysis, 1,722 patients (69%) were prescribed a topical corticosteroid prior to age 4 years. Of these patients, 333 (13%) had their first fracture after AD diagnosis, at a median age of 8.7 years. The median age at last follow-up for the remaining patients was 9.3 years. The researchers observed that, starting at 4 years of age, there was no association between topical corticosteroid use and risk of fracture (HR, 1.00; P = 1.00).

“Our findings suggest that topical corticosteroids do not significantly increase fracture risk in this pediatric population with atopic dermatitis,” Mr. Imhof said. “Dermatologists can use the results of this study to reassure parents of infants and young children, as most patients in our study received their first topical corticosteroid prescription prior to age 4.”

He acknowledged certain limitations of the study, such as its retrospective design and study population, which was predominantly white and resided in the upper Midwest. “Also, our study examined prescription data with the assumption made that topical corticosteroids were used as prescribed,” he said. “An additional limitation is that we evaluated ever versus never exposure to topical corticosteroids rather than cumulative duration of use and/or potency.”

Mr. Imhof and his colleagues reported having no financial disclosures.

dbrunk@mdedge.com

The use of topical corticosteroids does not significantly increase fracture risk in young children diagnosed with atopic dermatitis, results from a large population-based study suggest.

LucaLorenzelli/Thinkstock

“Little has been published about the risk of fracture in children with atopic dermatitis on topical corticosteroids specifically,” one of the study authors, Reese L. Imhof, said in an interview following the virtual annual meeting of the Society for Pediatric Dermatology. “There are concerns, particularly among parents, regarding potential bone side effects through possible corticosteroid percutaneous absorption. Fears related to topical corticosteroid use likely stem from the fact that prolonged systemic corticosteroid use is associated with an increased risk of bone fractures.”

In an effort to determine the fracture risk in children who were diagnosed with atopic dermatitis (AD) prior to age 4 years and received topical corticosteroid treatment, Mr. Imhof, from Mayo Medical School, Rochester, Minn., and his associates used the Rochester Epidemiology Project records-linkage system to identify patients in Olmstead County, Minn., who received their first AD diagnosis prior to age 4 years between Jan. 1, 2004, through Dec. 31, 2017. Those who received topical corticosteroids listed in National Drug File-Reference Terminology class 8952 (anti-inflammatory, topical) or 8954 (anti-infective/anti-inflammatory combinations, topical) between Jan. 1, 2004, and Dec. 31, 2018 were included in the analysis and were followed to identify new bone fractures, excluding pathological fractures in neoplastic disease and skull or facial bone fractures.

The researchers conducted two analyses of the data. For the primary statistical analysis, they evaluated topical corticosteroid exposure as a binary time-dependent covariate in a Cox proportional hazard model using age as the time scale, with patients entering the risk set at the age of the first clinic visit rather than the age of their first AD diagnosis. Next, the researchers performed a landmark analysis as a sensitivity analysis. For this, each patient’s fourth birthday was defined as the starting point, since all included patients were diagnosed with AD prior to age 4 years.

Of the 7,505 patients first identified with AD, 3,542 were included in the primary analysis and 2,499 were included in the landmark analysis. In the primary analysis, 2,384 patients (67%) received a topical prescription for a topical corticosteroid prior to age 4 years, and an additional 190 (5%) received their first prescription after age 4 years. The researchers observed that 451 patients (13%) had a fracture after AD diagnosis at a median age of 7.4 years. The median age at last follow-up for the remaining 3,091 patients was 6.6 years. Evaluated as a time-dependent covariate, the use of a topical corticosteroid was associated with a nonsignificant 17% increased risk of fracture (hazard ratio, 1.17; P = .16).

In the landmark analysis, 1,722 patients (69%) were prescribed a topical corticosteroid prior to age 4 years. Of these patients, 333 (13%) had their first fracture after AD diagnosis, at a median age of 8.7 years. The median age at last follow-up for the remaining patients was 9.3 years. The researchers observed that, starting at 4 years of age, there was no association between topical corticosteroid use and risk of fracture (HR, 1.00; P = 1.00).

“Our findings suggest that topical corticosteroids do not significantly increase fracture risk in this pediatric population with atopic dermatitis,” Mr. Imhof said. “Dermatologists can use the results of this study to reassure parents of infants and young children, as most patients in our study received their first topical corticosteroid prescription prior to age 4.”

He acknowledged certain limitations of the study, such as its retrospective design and study population, which was predominantly white and resided in the upper Midwest. “Also, our study examined prescription data with the assumption made that topical corticosteroids were used as prescribed,” he said. “An additional limitation is that we evaluated ever versus never exposure to topical corticosteroids rather than cumulative duration of use and/or potency.”

Mr. Imhof and his colleagues reported having no financial disclosures.

dbrunk@mdedge.com

Racial differences in the rates of atopic dermatitis appear to arise early in life, results from a single-center retrospective study found.

©Radist/Thinkstock

“Atopic dermatitis is a very common pediatric skin condition with significant morbidity for patients and their families,” lead study author Reesa L. Monir, MD, said during the virtual annual meeting of the Society for Pediatric Dermatology. “Existing studies show increased disease prevalence in Black and Asian children relative to White children, with conflicting data for Hispanic children. The methodology behind many of these existing studies, however, is somewhat questionable. Many were survey-based studies asking parents to remember a diagnosis of eczema or even asking parents to just report an itchy rash and using that as a diagnosis.”

For the current study, Dr. Monir and colleagues reviewed the records of 4,016 infants born between June 1, 2011, and April 30, 2017, who were followed in the University of Florida’s health care system. The researchers defined this as having two or more well-child visits after birth and at least one visit at 300 days of life or later, and the used documentation of specific ICD-9 or ICD-10 codes to capture an objective diagnosis of atopic dermatitis (AD). Of the 4,016 patients, 39.2% were Black, 38.5% were White, 7.1% were Hispanic, 5.3% were Asian, 6.5% were from other racial backgrounds, and 3.4% were multiracial.

Dr. Monir, who is a resident in the department of dermatology at the University of Florida, Gainesville, reported that Black infants had the highest prevalence of AD at 37%, followed by Asian infants (25.8%), Hispanic infants (24.1%), multiracial infants (23%), infants from other racial backgrounds (19.1%), and non-Hispanic White infants (17.9%). Compared with White infants, the odds ratio estimates for AD was highest for Black infants (OR, 2.62), followed by Asian infants (OR, 1.55), multiracial infants (OR, 1.42), Hispanic infants (OR, 1.41), and infants from other racial backgrounds (OR, .97).

On unadjusted analysis, the following factors were significantly associated with race: delivery mode (P = .006), insurance type (P less than .001), NICU stay (P less than .001), and gestational age (P less than .0001). However, on multivariate logistic regression, only two factors were significantly associated with the diagnosis of AD: race (P less than .0001) and NICU stay (P = .0385).

“When we looked at the early childhood period specifically, we found striking racial differences in the rates of AD arising early in life,” Dr. Monir concluded. “The diagnosis was independently associated with race and NICU stay. We suggest that further investigation into these disparities and ways we can mitigate them should focus on this early childhood period.”

The researchers reported having no relevant financial disclosures.

dbrunk@mdedge.com

Racial differences in the rates of atopic dermatitis appear to arise early in life, results from a single-center retrospective study found.

©Radist/Thinkstock

“Atopic dermatitis is a very common pediatric skin condition with significant morbidity for patients and their families,” lead study author Reesa L. Monir, MD, said during the virtual annual meeting of the Society for Pediatric Dermatology. “Existing studies show increased disease prevalence in Black and Asian children relative to White children, with conflicting data for Hispanic children. The methodology behind many of these existing studies, however, is somewhat questionable. Many were survey-based studies asking parents to remember a diagnosis of eczema or even asking parents to just report an itchy rash and using that as a diagnosis.”

For the current study, Dr. Monir and colleagues reviewed the records of 4,016 infants born between June 1, 2011, and April 30, 2017, who were followed in the University of Florida’s health care system. The researchers defined this as having two or more well-child visits after birth and at least one visit at 300 days of life or later, and the used documentation of specific ICD-9 or ICD-10 codes to capture an objective diagnosis of atopic dermatitis (AD). Of the 4,016 patients, 39.2% were Black, 38.5% were White, 7.1% were Hispanic, 5.3% were Asian, 6.5% were from other racial backgrounds, and 3.4% were multiracial.

Dr. Monir, who is a resident in the department of dermatology at the University of Florida, Gainesville, reported that Black infants had the highest prevalence of AD at 37%, followed by Asian infants (25.8%), Hispanic infants (24.1%), multiracial infants (23%), infants from other racial backgrounds (19.1%), and non-Hispanic White infants (17.9%). Compared with White infants, the odds ratio estimates for AD was highest for Black infants (OR, 2.62), followed by Asian infants (OR, 1.55), multiracial infants (OR, 1.42), Hispanic infants (OR, 1.41), and infants from other racial backgrounds (OR, .97).

On unadjusted analysis, the following factors were significantly associated with race: delivery mode (P = .006), insurance type (P less than .001), NICU stay (P less than .001), and gestational age (P less than .0001). However, on multivariate logistic regression, only two factors were significantly associated with the diagnosis of AD: race (P less than .0001) and NICU stay (P = .0385).

“When we looked at the early childhood period specifically, we found striking racial differences in the rates of AD arising early in life,” Dr. Monir concluded. “The diagnosis was independently associated with race and NICU stay. We suggest that further investigation into these disparities and ways we can mitigate them should focus on this early childhood period.”

The researchers reported having no relevant financial disclosures.

dbrunk@mdedge.com

Racial differences in the rates of atopic dermatitis appear to arise early in life, results from a single-center retrospective study found.

©Radist/Thinkstock

“Atopic dermatitis is a very common pediatric skin condition with significant morbidity for patients and their families,” lead study author Reesa L. Monir, MD, said during the virtual annual meeting of the Society for Pediatric Dermatology. “Existing studies show increased disease prevalence in Black and Asian children relative to White children, with conflicting data for Hispanic children. The methodology behind many of these existing studies, however, is somewhat questionable. Many were survey-based studies asking parents to remember a diagnosis of eczema or even asking parents to just report an itchy rash and using that as a diagnosis.”

For the current study, Dr. Monir and colleagues reviewed the records of 4,016 infants born between June 1, 2011, and April 30, 2017, who were followed in the University of Florida’s health care system. The researchers defined this as having two or more well-child visits after birth and at least one visit at 300 days of life or later, and the used documentation of specific ICD-9 or ICD-10 codes to capture an objective diagnosis of atopic dermatitis (AD). Of the 4,016 patients, 39.2% were Black, 38.5% were White, 7.1% were Hispanic, 5.3% were Asian, 6.5% were from other racial backgrounds, and 3.4% were multiracial.

Dr. Monir, who is a resident in the department of dermatology at the University of Florida, Gainesville, reported that Black infants had the highest prevalence of AD at 37%, followed by Asian infants (25.8%), Hispanic infants (24.1%), multiracial infants (23%), infants from other racial backgrounds (19.1%), and non-Hispanic White infants (17.9%). Compared with White infants, the odds ratio estimates for AD was highest for Black infants (OR, 2.62), followed by Asian infants (OR, 1.55), multiracial infants (OR, 1.42), Hispanic infants (OR, 1.41), and infants from other racial backgrounds (OR, .97).

On unadjusted analysis, the following factors were significantly associated with race: delivery mode (P = .006), insurance type (P less than .001), NICU stay (P less than .001), and gestational age (P less than .0001). However, on multivariate logistic regression, only two factors were significantly associated with the diagnosis of AD: race (P less than .0001) and NICU stay (P = .0385).

“When we looked at the early childhood period specifically, we found striking racial differences in the rates of AD arising early in life,” Dr. Monir concluded. “The diagnosis was independently associated with race and NICU stay. We suggest that further investigation into these disparities and ways we can mitigate them should focus on this early childhood period.”

The researchers reported having no relevant financial disclosures.

dbrunk@mdedge.com