Lawrence Eichenfield, MD, reports on major developments in the changing field of pediatric dermatology.
Many exciting advancements are taking place in pediatric dermatology, especially in eczema/atopic dermatitis (AD), psoriasis, and patient management, according to Lawrence Eichenfield, MD, who recently updated attendees on developments in the specialty at The Fall Clinical Dermatology Conference at the Wynn Hotel in Las Vegas.
Dr Eichenfield, professor of dermatology and pediatrics, University of California, San Diego and Rady’s Children’s Hospital in San Diego, highlighted numerous trending topics in pediatric dermatology and offered pearls for dermatologists to take back to their clinic and implement.
Eczema/Atopic Dermatitis
“We are moving toward the concept of potential moisturizers being used early as preventative for AD. Two small number studies were conducted—one in Japan and one in the United States and the United Kingdom—with around 150 individuals using products. Those studies showed about a 50% decrease in the development of AD,” he said.
Simpson and colleagues1 performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for AD. Caregivers in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Caregivers in the control arm used no emollients. The primary clinical outcome was the cumulative incidence of AD at 6 months, as assessed by a trained investigator. Forty-two percent of eligible families agreed to be randomized into the trial and all participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of AD with a relative risk reduction of 50%. There were no emollient-related adverse events. The results demonstrated that emollient therapy from birth represents a feasible, safe, and effective approach for AD prevention.
Another study from Xu and colleagues2 looked at the cost-effectiveness of daily moisturizer as prevention against AD among high-risk newborns. In the analysis, the average cost of total-body moisturization using 7 common moisturizers from birth to 6 months of age was determined for male and female infants. The calculated amount of daily all-body moisturizer needed at birth was 3.6 g (0.12 oz) per application, which increased to 6.6 g (0.22 oz) at 6 months of age. Of the 7 products evaluated, the average price was $1.07/oz (range, $0.13-$2.96/oz). For a 6-month time window, the average incremental quality-adjusted life-years (QALYs) benefit was 0.021. A sensitivity analysis showed that the incremental gain of QALY ranged from 0.0041 to 0.030. Petrolatum was the most cost-effective moisturizer in the cohort. Even assuming the lowest incremental QALYs for the most expensive moisturizer, the intervention was still less than $45,000/QALY. The study researchers concluded daily moisturization may represent a cost-effective, preventive strategy to reduce the burden of AD.
Dr Eichenfield noted that this research has influenced him, and he now suggests early and regular use of moisturization as a potential preventive strategy to families in which there is a child with moderate to severe AD and the mother is pregnant again.
Crisaborole
Dr Eichenfield reviewed several recent studies that demonstrate the effectiveness of crisaborole (Eucrisa) for the treatment to AD.3,4 A study by Paller and colleagues3 assessed the efficacy and safety of crisaborole ointment, a phosphodiesterase-4 inhibitor, in 2 phase 3 AD studies. Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned patients aged 2 years or older with an Investigator’s Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary endpoint was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. More crisaborole- vs vehicle-treated patients achieved ISGA score success with a greater percentage with clear/almost clear. Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle. Treatment-related adverse events were infrequent and mild to moderate in severity. Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD. The short study duration was a limitation.
Dr Eichenfield shared that he and his colleagues recent study4 found that crisaborole data demonstrated significant improvements in quality of life and pruritus, with low incidence of adverse events. The study assessed the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N=517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, after completing a 28-day phase 3 pivotal study (AD-301, AD-302). Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. During the pivotal studies and AD-303, 65% of patients reported ≥1 treatment-emergent adverse events (TEAEs), most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related adverse events were AD (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs. Crisaborole ointment had a low frequency of treatment-related adverse events over 48 weeks of treatment of patients with AD. He added that many factors warrant continued study, including comparative efficacy and cost-efficiency.
Article continues on page 2
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Dupilumab
Dr Eichenfield highlighted several recent studies5,6 that evaluated the first biologic for AD dupilumab (Dupixent), the potent blocker of IL-4 and IL-13 (TH2) cytokines. A study by Simpson and colleagues5 enrolled adults with moderate to severe AD whose disease was inadequately controlled by topical treatment in 2 randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2). The study included 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo. The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo. In addition, in the 2 trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo. Dupilumab was also associated with reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab, he added.
A phase 2a pharmacokinetic study by Cork and colleagues6 looked at dupilumab’s performance in pediatric patients aged ≥6 to <18 years. Dupilumab administered both as single dose or as multiple weekly doses appeared safe and demonstrated preliminary efficacy in this open-label study. Overall the pharmacokinetic profile of dupilumab in the pediatric patients with AD is consistent with that observed in adults with moderate to severe AD; exposure was comparable between the 2 age groups studied at the same dose levels, according to the researchers. The 2 mg/kg and 4 mg/kg dose regimens showed similar improvements in efficacy endpoints. The 4 mg/kg dose was associated with more adverse events, but it did not lead to an increase in permanent discontinuations.
“The revolution is happening in systemic therapy in adults and we are on the edge of the revolution in children,” Dr Eichenfield noted. “Much needed new pediatric studies in the United States are being done in the 12 to 17 age group, and then they will continue in the 6 to 11 age group and then down to age 2. This is so very exciting and the field of atopic dermatitis is shockingly active (Tables 1 and 2). This will be an incredible change in care.”
Shared Decision Making
With the potential array of new treatment choices for patients, effective ways are needed to easily explain to patients their options and include them in the decision-making process, according to Dr Eichenfield. A study by Tan and colleagues7 noted that shared decision making combines individual patient interests and values with clinical best evidence under the guiding principle of patient autonomy. The study authors concluded that patient decision aids, such as easy to read and understand charts with treatment options and statistics, can support shared decision making and facilitate decisions that have multiple options with varying outcomes for which patients may attribute different values.
“As we start to collect our systemic medicines, and we have this calculus in our head about relative safety and relative efficacy in the population we may have to figure out ways to relate this to our patients so that they can understand and they will be as knowledgeable as we are about using newer therapies to control our case disease,” Dr Eichenfield said.
Another useful resource, the Curriculum United for Better Eczema Care (CUBE-C) by Guttman-Yassky and colleagues8 includes comprehensive multidisciplinary training for eczema care, he added.
Peanut Allergy
He also touched on the recent paradigm shift for the treatment of peanut exposure and allergy. “There is a new standard for us to take on for infantile atopic dermatitis. It has been shown that you can avoid peanut allergy, which is the most significant of allergy in terms of anaphylaxis and death, by giving early peanut product,” he said.
The 2017 Addendum to the 2010 guidelines for the diagnosis and management of food allergy9 identifies infants with severe AD (and/or egg allergy) as a group at risk to peanut allergy and provided guidelines for early introduction of peanut-containing foods into the diets of infants (as early as 4-6 months) at various risk levels for peanut allergy. Recommendations discuss direct referral to allergist and serum IgE-screening (if negative physicians can start the feed protocol, if positive refer to allergy specialist). “This is a total change in our management for children with AD,” he said.
Psoriasis
New pediatric indications have begun to roll out for pediatric psoriasis, including etanercept (Enbrel) and most recently ustekinumab (Stelara) for the treatment of adolescents (12 years of age or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. “The FDA with a new perspective really pushed for the work being done in AD and it is sort of opening the way for us to get systemic therapies [for children]. It should change our perspective on pediatric psoriasis, especially when you see the data on long-term impact of psoriasis in adults,” Dr Eichenfield said.
Recent research10, 11 has highlighted comorbidities and increased risk of cardiovascular disease (CVD) in people with psoriasis. Psoriasis is associated with risk of CVD and a major adverse CV event (MACE). A recent study by Egeberg and colleagues10 evaluated a human imaging study and a population-based study of CVD events to understand the effect of psoriasis duration on vascular disease and CV events. Patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography (duration effect reported as a β-coefficient). Then, MACE risk was examined by using nationwide registries (adjusted hazard ratios in patients with psoriasis (n=87,161) vs the general population (n=4,234,793). The researchers found detrimental effects of psoriasis duration on vascular inflammation and MACE, suggesting that cumulative duration of exposure to low-grade chronic inflammation may accelerate vascular disease development and MACEs. Providers should consider inquiring about duration of disease to counsel for heightened CVD risk in psoriasis, the authors concluded.
Pediatric Psoriasis Comorbidity Screening Guidelines were published in 2017.11 For the study, a literature review was performed using PubMed from January 1999 through December 2015. An expert panel in psoriasis, pediatric dermatology, pediatric rheumatology, pediatric gastroenterology, pediatric endocrinology, and adult and pediatric cardiology used the patient-centered Strength of Recommendation Taxonomy (SORT) method to evaluate and grade the quality of evidence. (Because of the limited number of pediatric studies published on these topics, the strength of the panel’s recommendations is classified as SORT level C expert consensus recommendations.) The panel concluded that patients with pediatric psoriasis should receive routine screening and identification of risk factors for associated comorbidities. The guidelines were for all health care providers caring for patients with pediatric psoriasis, including primary care clinicians, dermatologists, and pediatric specialists.
“If you have young children or adolescents with psoriasis as patients it is reasonable to assess their cardiovascular risk factors and get them to understand that aggressive intervention may be very important in the future,” he said.
Disclosures: During his talk, Dr Eichenfield listed disclosures including Anacor/Pfizer, Cutanea, Genentech, Galderma Labratories, Eil Lilly, Medimetrics, Novan, Otsuka, Regeneron/Sanofi, and Ortho Dermatologics (formerly Valeant Pharmaceuticals).
References
1. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134(4):818-823.
2. Xu S, Immaneni S, Hazen GB, Silverberg JI, Paller AS, Lio PA. Cost-effectiveness of prophylactic moisturization for atopic dermatitis. JAMA Pediatr. 2017;171(2):e163909.
3. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.e6.
4. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2017;77(4):641-649.e5.
5. Simpson EL, Bieber T, Guttman-Yassky E, et al; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.
6. Cork MJ. Pharmacokinetics, safety and efficacy of dupilumab in a pediatric population with moderate-to-severe atopic dermatitis: results from an open-label phase 2a trial evaluation of the safety, efficacy and pharmacokinetics of dupilumab in pediatric patients with moderate-to-severe AD. Presented at: The Annual Meeting of the American Academy of Dermatology; March 3-7, 2017; Orlando, FL.
7. Tan J, Linos E, Sendelweck MA, et al. Shared decision making and patient decision aids in dermatology. Br J Dermatol. 2016;175(5):1045-1048.
8. Guttman-Yassky E, Waldman A, Ahluwalia J, Ong PY, Eichenfield LF. Atopic dermatitis: pathogenesis. Semin Cutan Med Surg. 2017;36(3):100-103.
9. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel [published online January 6, 2017]. Allergy Asthma Clin Immunol. https://doi.org/10.1186/s13223-016-0175-4.
10. Egeberg A, Skov L, Joshi AA, et al. The relationship between duration of psoriasis, vascular inflammation, and cardiovascular events. J Am Acad Dermatol. 2017;77(4):650-656.e3.
11. Osier E, Wang AS, Tollefson MM, et al. Pediatric psoriasis comorbidity screening guidelines. JAMA Dermatol. 2017;153(7):698-704.
Lawrence Eichenfield, MD, reports on major developments in the changing field of pediatric dermatology.
Many exciting advancements are taking place in pediatric dermatology, especially in eczema/atopic dermatitis (AD), psoriasis, and patient management, according to Lawrence Eichenfield, MD, who recently updated attendees on developments in the specialty at The Fall Clinical Dermatology Conference at the Wynn Hotel in Las Vegas.
Dr Eichenfield, professor of dermatology and pediatrics, University of California, San Diego and Rady’s Children’s Hospital in San Diego, highlighted numerous trending topics in pediatric dermatology and offered pearls for dermatologists to take back to their clinic and implement.
Eczema/Atopic Dermatitis
“We are moving toward the concept of potential moisturizers being used early as preventative for AD. Two small number studies were conducted—one in Japan and one in the United States and the United Kingdom—with around 150 individuals using products. Those studies showed about a 50% decrease in the development of AD,” he said.
Simpson and colleagues1 performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for AD. Caregivers in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Caregivers in the control arm used no emollients. The primary clinical outcome was the cumulative incidence of AD at 6 months, as assessed by a trained investigator. Forty-two percent of eligible families agreed to be randomized into the trial and all participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of AD with a relative risk reduction of 50%. There were no emollient-related adverse events. The results demonstrated that emollient therapy from birth represents a feasible, safe, and effective approach for AD prevention.
Another study from Xu and colleagues2 looked at the cost-effectiveness of daily moisturizer as prevention against AD among high-risk newborns. In the analysis, the average cost of total-body moisturization using 7 common moisturizers from birth to 6 months of age was determined for male and female infants. The calculated amount of daily all-body moisturizer needed at birth was 3.6 g (0.12 oz) per application, which increased to 6.6 g (0.22 oz) at 6 months of age. Of the 7 products evaluated, the average price was $1.07/oz (range, $0.13-$2.96/oz). For a 6-month time window, the average incremental quality-adjusted life-years (QALYs) benefit was 0.021. A sensitivity analysis showed that the incremental gain of QALY ranged from 0.0041 to 0.030. Petrolatum was the most cost-effective moisturizer in the cohort. Even assuming the lowest incremental QALYs for the most expensive moisturizer, the intervention was still less than $45,000/QALY. The study researchers concluded daily moisturization may represent a cost-effective, preventive strategy to reduce the burden of AD.
Dr Eichenfield noted that this research has influenced him, and he now suggests early and regular use of moisturization as a potential preventive strategy to families in which there is a child with moderate to severe AD and the mother is pregnant again.
Crisaborole
Dr Eichenfield reviewed several recent studies that demonstrate the effectiveness of crisaborole (Eucrisa) for the treatment to AD.3,4 A study by Paller and colleagues3 assessed the efficacy and safety of crisaborole ointment, a phosphodiesterase-4 inhibitor, in 2 phase 3 AD studies. Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned patients aged 2 years or older with an Investigator’s Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary endpoint was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. More crisaborole- vs vehicle-treated patients achieved ISGA score success with a greater percentage with clear/almost clear. Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle. Treatment-related adverse events were infrequent and mild to moderate in severity. Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD. The short study duration was a limitation.
Dr Eichenfield shared that he and his colleagues recent study4 found that crisaborole data demonstrated significant improvements in quality of life and pruritus, with low incidence of adverse events. The study assessed the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N=517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, after completing a 28-day phase 3 pivotal study (AD-301, AD-302). Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. During the pivotal studies and AD-303, 65% of patients reported ≥1 treatment-emergent adverse events (TEAEs), most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related adverse events were AD (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs. Crisaborole ointment had a low frequency of treatment-related adverse events over 48 weeks of treatment of patients with AD. He added that many factors warrant continued study, including comparative efficacy and cost-efficiency.
Article continues on page 2
{{pagebreak}}
Dupilumab
Dr Eichenfield highlighted several recent studies5,6 that evaluated the first biologic for AD dupilumab (Dupixent), the potent blocker of IL-4 and IL-13 (TH2) cytokines. A study by Simpson and colleagues5 enrolled adults with moderate to severe AD whose disease was inadequately controlled by topical treatment in 2 randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2). The study included 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo. The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo. In addition, in the 2 trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo. Dupilumab was also associated with reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab, he added.
A phase 2a pharmacokinetic study by Cork and colleagues6 looked at dupilumab’s performance in pediatric patients aged ≥6 to <18 years. Dupilumab administered both as single dose or as multiple weekly doses appeared safe and demonstrated preliminary efficacy in this open-label study. Overall the pharmacokinetic profile of dupilumab in the pediatric patients with AD is consistent with that observed in adults with moderate to severe AD; exposure was comparable between the 2 age groups studied at the same dose levels, according to the researchers. The 2 mg/kg and 4 mg/kg dose regimens showed similar improvements in efficacy endpoints. The 4 mg/kg dose was associated with more adverse events, but it did not lead to an increase in permanent discontinuations.
“The revolution is happening in systemic therapy in adults and we are on the edge of the revolution in children,” Dr Eichenfield noted. “Much needed new pediatric studies in the United States are being done in the 12 to 17 age group, and then they will continue in the 6 to 11 age group and then down to age 2. This is so very exciting and the field of atopic dermatitis is shockingly active (Tables 1 and 2). This will be an incredible change in care.”
Shared Decision Making
With the potential array of new treatment choices for patients, effective ways are needed to easily explain to patients their options and include them in the decision-making process, according to Dr Eichenfield. A study by Tan and colleagues7 noted that shared decision making combines individual patient interests and values with clinical best evidence under the guiding principle of patient autonomy. The study authors concluded that patient decision aids, such as easy to read and understand charts with treatment options and statistics, can support shared decision making and facilitate decisions that have multiple options with varying outcomes for which patients may attribute different values.
“As we start to collect our systemic medicines, and we have this calculus in our head about relative safety and relative efficacy in the population we may have to figure out ways to relate this to our patients so that they can understand and they will be as knowledgeable as we are about using newer therapies to control our case disease,” Dr Eichenfield said.
Another useful resource, the Curriculum United for Better Eczema Care (CUBE-C) by Guttman-Yassky and colleagues8 includes comprehensive multidisciplinary training for eczema care, he added.
Peanut Allergy
He also touched on the recent paradigm shift for the treatment of peanut exposure and allergy. “There is a new standard for us to take on for infantile atopic dermatitis. It has been shown that you can avoid peanut allergy, which is the most significant of allergy in terms of anaphylaxis and death, by giving early peanut product,” he said.
The 2017 Addendum to the 2010 guidelines for the diagnosis and management of food allergy9 identifies infants with severe AD (and/or egg allergy) as a group at risk to peanut allergy and provided guidelines for early introduction of peanut-containing foods into the diets of infants (as early as 4-6 months) at various risk levels for peanut allergy. Recommendations discuss direct referral to allergist and serum IgE-screening (if negative physicians can start the feed protocol, if positive refer to allergy specialist). “This is a total change in our management for children with AD,” he said.
Psoriasis
New pediatric indications have begun to roll out for pediatric psoriasis, including etanercept (Enbrel) and most recently ustekinumab (Stelara) for the treatment of adolescents (12 years of age or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. “The FDA with a new perspective really pushed for the work being done in AD and it is sort of opening the way for us to get systemic therapies [for children]. It should change our perspective on pediatric psoriasis, especially when you see the data on long-term impact of psoriasis in adults,” Dr Eichenfield said.
Recent research10, 11 has highlighted comorbidities and increased risk of cardiovascular disease (CVD) in people with psoriasis. Psoriasis is associated with risk of CVD and a major adverse CV event (MACE). A recent study by Egeberg and colleagues10 evaluated a human imaging study and a population-based study of CVD events to understand the effect of psoriasis duration on vascular disease and CV events. Patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography (duration effect reported as a β-coefficient). Then, MACE risk was examined by using nationwide registries (adjusted hazard ratios in patients with psoriasis (n=87,161) vs the general population (n=4,234,793). The researchers found detrimental effects of psoriasis duration on vascular inflammation and MACE, suggesting that cumulative duration of exposure to low-grade chronic inflammation may accelerate vascular disease development and MACEs. Providers should consider inquiring about duration of disease to counsel for heightened CVD risk in psoriasis, the authors concluded.
Pediatric Psoriasis Comorbidity Screening Guidelines were published in 2017.11 For the study, a literature review was performed using PubMed from January 1999 through December 2015. An expert panel in psoriasis, pediatric dermatology, pediatric rheumatology, pediatric gastroenterology, pediatric endocrinology, and adult and pediatric cardiology used the patient-centered Strength of Recommendation Taxonomy (SORT) method to evaluate and grade the quality of evidence. (Because of the limited number of pediatric studies published on these topics, the strength of the panel’s recommendations is classified as SORT level C expert consensus recommendations.) The panel concluded that patients with pediatric psoriasis should receive routine screening and identification of risk factors for associated comorbidities. The guidelines were for all health care providers caring for patients with pediatric psoriasis, including primary care clinicians, dermatologists, and pediatric specialists.
“If you have young children or adolescents with psoriasis as patients it is reasonable to assess their cardiovascular risk factors and get them to understand that aggressive intervention may be very important in the future,” he said.
Disclosures: During his talk, Dr Eichenfield listed disclosures including Anacor/Pfizer, Cutanea, Genentech, Galderma Labratories, Eil Lilly, Medimetrics, Novan, Otsuka, Regeneron/Sanofi, and Ortho Dermatologics (formerly Valeant Pharmaceuticals).
References
1. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134(4):818-823.
2. Xu S, Immaneni S, Hazen GB, Silverberg JI, Paller AS, Lio PA. Cost-effectiveness of prophylactic moisturization for atopic dermatitis. JAMA Pediatr. 2017;171(2):e163909.
3. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.e6.
4. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2017;77(4):641-649.e5.
5. Simpson EL, Bieber T, Guttman-Yassky E, et al; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.
6. Cork MJ. Pharmacokinetics, safety and efficacy of dupilumab in a pediatric population with moderate-to-severe atopic dermatitis: results from an open-label phase 2a trial evaluation of the safety, efficacy and pharmacokinetics of dupilumab in pediatric patients with moderate-to-severe AD. Presented at: The Annual Meeting of the American Academy of Dermatology; March 3-7, 2017; Orlando, FL.
7. Tan J, Linos E, Sendelweck MA, et al. Shared decision making and patient decision aids in dermatology. Br J Dermatol. 2016;175(5):1045-1048.
8. Guttman-Yassky E, Waldman A, Ahluwalia J, Ong PY, Eichenfield LF. Atopic dermatitis: pathogenesis. Semin Cutan Med Surg. 2017;36(3):100-103.
9. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel [published online January 6, 2017]. Allergy Asthma Clin Immunol. https://doi.org/10.1186/s13223-016-0175-4.
10. Egeberg A, Skov L, Joshi AA, et al. The relationship between duration of psoriasis, vascular inflammation, and cardiovascular events. J Am Acad Dermatol. 2017;77(4):650-656.e3.
11. Osier E, Wang AS, Tollefson MM, et al. Pediatric psoriasis comorbidity screening guidelines. JAMA Dermatol. 2017;153(7):698-704.
Lawrence Eichenfield, MD, reports on major developments in the changing field of pediatric dermatology.
Many exciting advancements are taking place in pediatric dermatology, especially in eczema/atopic dermatitis (AD), psoriasis, and patient management, according to Lawrence Eichenfield, MD, who recently updated attendees on developments in the specialty at The Fall Clinical Dermatology Conference at the Wynn Hotel in Las Vegas.
Dr Eichenfield, professor of dermatology and pediatrics, University of California, San Diego and Rady’s Children’s Hospital in San Diego, highlighted numerous trending topics in pediatric dermatology and offered pearls for dermatologists to take back to their clinic and implement.
Eczema/Atopic Dermatitis
“We are moving toward the concept of potential moisturizers being used early as preventative for AD. Two small number studies were conducted—one in Japan and one in the United States and the United Kingdom—with around 150 individuals using products. Those studies showed about a 50% decrease in the development of AD,” he said.
Simpson and colleagues1 performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for AD. Caregivers in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Caregivers in the control arm used no emollients. The primary clinical outcome was the cumulative incidence of AD at 6 months, as assessed by a trained investigator. Forty-two percent of eligible families agreed to be randomized into the trial and all participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of AD with a relative risk reduction of 50%. There were no emollient-related adverse events. The results demonstrated that emollient therapy from birth represents a feasible, safe, and effective approach for AD prevention.
Another study from Xu and colleagues2 looked at the cost-effectiveness of daily moisturizer as prevention against AD among high-risk newborns. In the analysis, the average cost of total-body moisturization using 7 common moisturizers from birth to 6 months of age was determined for male and female infants. The calculated amount of daily all-body moisturizer needed at birth was 3.6 g (0.12 oz) per application, which increased to 6.6 g (0.22 oz) at 6 months of age. Of the 7 products evaluated, the average price was $1.07/oz (range, $0.13-$2.96/oz). For a 6-month time window, the average incremental quality-adjusted life-years (QALYs) benefit was 0.021. A sensitivity analysis showed that the incremental gain of QALY ranged from 0.0041 to 0.030. Petrolatum was the most cost-effective moisturizer in the cohort. Even assuming the lowest incremental QALYs for the most expensive moisturizer, the intervention was still less than $45,000/QALY. The study researchers concluded daily moisturization may represent a cost-effective, preventive strategy to reduce the burden of AD.
Dr Eichenfield noted that this research has influenced him, and he now suggests early and regular use of moisturization as a potential preventive strategy to families in which there is a child with moderate to severe AD and the mother is pregnant again.
Crisaborole
Dr Eichenfield reviewed several recent studies that demonstrate the effectiveness of crisaborole (Eucrisa) for the treatment to AD.3,4 A study by Paller and colleagues3 assessed the efficacy and safety of crisaborole ointment, a phosphodiesterase-4 inhibitor, in 2 phase 3 AD studies. Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned patients aged 2 years or older with an Investigator’s Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary endpoint was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. More crisaborole- vs vehicle-treated patients achieved ISGA score success with a greater percentage with clear/almost clear. Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle. Treatment-related adverse events were infrequent and mild to moderate in severity. Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD. The short study duration was a limitation.
Dr Eichenfield shared that he and his colleagues recent study4 found that crisaborole data demonstrated significant improvements in quality of life and pruritus, with low incidence of adverse events. The study assessed the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N=517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, after completing a 28-day phase 3 pivotal study (AD-301, AD-302). Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. During the pivotal studies and AD-303, 65% of patients reported ≥1 treatment-emergent adverse events (TEAEs), most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related adverse events were AD (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs. Crisaborole ointment had a low frequency of treatment-related adverse events over 48 weeks of treatment of patients with AD. He added that many factors warrant continued study, including comparative efficacy and cost-efficiency.
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Dupilumab
Dr Eichenfield highlighted several recent studies5,6 that evaluated the first biologic for AD dupilumab (Dupixent), the potent blocker of IL-4 and IL-13 (TH2) cytokines. A study by Simpson and colleagues5 enrolled adults with moderate to severe AD whose disease was inadequately controlled by topical treatment in 2 randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2). The study included 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo. The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo. In addition, in the 2 trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo. Dupilumab was also associated with reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab, he added.
A phase 2a pharmacokinetic study by Cork and colleagues6 looked at dupilumab’s performance in pediatric patients aged ≥6 to <18 years. Dupilumab administered both as single dose or as multiple weekly doses appeared safe and demonstrated preliminary efficacy in this open-label study. Overall the pharmacokinetic profile of dupilumab in the pediatric patients with AD is consistent with that observed in adults with moderate to severe AD; exposure was comparable between the 2 age groups studied at the same dose levels, according to the researchers. The 2 mg/kg and 4 mg/kg dose regimens showed similar improvements in efficacy endpoints. The 4 mg/kg dose was associated with more adverse events, but it did not lead to an increase in permanent discontinuations.
“The revolution is happening in systemic therapy in adults and we are on the edge of the revolution in children,” Dr Eichenfield noted. “Much needed new pediatric studies in the United States are being done in the 12 to 17 age group, and then they will continue in the 6 to 11 age group and then down to age 2. This is so very exciting and the field of atopic dermatitis is shockingly active (Tables 1 and 2). This will be an incredible change in care.”
Shared Decision Making
With the potential array of new treatment choices for patients, effective ways are needed to easily explain to patients their options and include them in the decision-making process, according to Dr Eichenfield. A study by Tan and colleagues7 noted that shared decision making combines individual patient interests and values with clinical best evidence under the guiding principle of patient autonomy. The study authors concluded that patient decision aids, such as easy to read and understand charts with treatment options and statistics, can support shared decision making and facilitate decisions that have multiple options with varying outcomes for which patients may attribute different values.
“As we start to collect our systemic medicines, and we have this calculus in our head about relative safety and relative efficacy in the population we may have to figure out ways to relate this to our patients so that they can understand and they will be as knowledgeable as we are about using newer therapies to control our case disease,” Dr Eichenfield said.
Another useful resource, the Curriculum United for Better Eczema Care (CUBE-C) by Guttman-Yassky and colleagues8 includes comprehensive multidisciplinary training for eczema care, he added.
Peanut Allergy
He also touched on the recent paradigm shift for the treatment of peanut exposure and allergy. “There is a new standard for us to take on for infantile atopic dermatitis. It has been shown that you can avoid peanut allergy, which is the most significant of allergy in terms of anaphylaxis and death, by giving early peanut product,” he said.
The 2017 Addendum to the 2010 guidelines for the diagnosis and management of food allergy9 identifies infants with severe AD (and/or egg allergy) as a group at risk to peanut allergy and provided guidelines for early introduction of peanut-containing foods into the diets of infants (as early as 4-6 months) at various risk levels for peanut allergy. Recommendations discuss direct referral to allergist and serum IgE-screening (if negative physicians can start the feed protocol, if positive refer to allergy specialist). “This is a total change in our management for children with AD,” he said.
Psoriasis
New pediatric indications have begun to roll out for pediatric psoriasis, including etanercept (Enbrel) and most recently ustekinumab (Stelara) for the treatment of adolescents (12 years of age or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. “The FDA with a new perspective really pushed for the work being done in AD and it is sort of opening the way for us to get systemic therapies [for children]. It should change our perspective on pediatric psoriasis, especially when you see the data on long-term impact of psoriasis in adults,” Dr Eichenfield said.
Recent research10, 11 has highlighted comorbidities and increased risk of cardiovascular disease (CVD) in people with psoriasis. Psoriasis is associated with risk of CVD and a major adverse CV event (MACE). A recent study by Egeberg and colleagues10 evaluated a human imaging study and a population-based study of CVD events to understand the effect of psoriasis duration on vascular disease and CV events. Patients with psoriasis (N=190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography (duration effect reported as a β-coefficient). Then, MACE risk was examined by using nationwide registries (adjusted hazard ratios in patients with psoriasis (n=87,161) vs the general population (n=4,234,793). The researchers found detrimental effects of psoriasis duration on vascular inflammation and MACE, suggesting that cumulative duration of exposure to low-grade chronic inflammation may accelerate vascular disease development and MACEs. Providers should consider inquiring about duration of disease to counsel for heightened CVD risk in psoriasis, the authors concluded.
Pediatric Psoriasis Comorbidity Screening Guidelines were published in 2017.11 For the study, a literature review was performed using PubMed from January 1999 through December 2015. An expert panel in psoriasis, pediatric dermatology, pediatric rheumatology, pediatric gastroenterology, pediatric endocrinology, and adult and pediatric cardiology used the patient-centered Strength of Recommendation Taxonomy (SORT) method to evaluate and grade the quality of evidence. (Because of the limited number of pediatric studies published on these topics, the strength of the panel’s recommendations is classified as SORT level C expert consensus recommendations.) The panel concluded that patients with pediatric psoriasis should receive routine screening and identification of risk factors for associated comorbidities. The guidelines were for all health care providers caring for patients with pediatric psoriasis, including primary care clinicians, dermatologists, and pediatric specialists.
“If you have young children or adolescents with psoriasis as patients it is reasonable to assess their cardiovascular risk factors and get them to understand that aggressive intervention may be very important in the future,” he said.
Disclosures: During his talk, Dr Eichenfield listed disclosures including Anacor/Pfizer, Cutanea, Genentech, Galderma Labratories, Eil Lilly, Medimetrics, Novan, Otsuka, Regeneron/Sanofi, and Ortho Dermatologics (formerly Valeant Pharmaceuticals).
References
1. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014;134(4):818-823.
2. Xu S, Immaneni S, Hazen GB, Silverberg JI, Paller AS, Lio PA. Cost-effectiveness of prophylactic moisturization for atopic dermatitis. JAMA Pediatr. 2017;171(2):e163909.
3. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.e6.
4. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2017;77(4):641-649.e5.
5. Simpson EL, Bieber T, Guttman-Yassky E, et al; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.
6. Cork MJ. Pharmacokinetics, safety and efficacy of dupilumab in a pediatric population with moderate-to-severe atopic dermatitis: results from an open-label phase 2a trial evaluation of the safety, efficacy and pharmacokinetics of dupilumab in pediatric patients with moderate-to-severe AD. Presented at: The Annual Meeting of the American Academy of Dermatology; March 3-7, 2017; Orlando, FL.
7. Tan J, Linos E, Sendelweck MA, et al. Shared decision making and patient decision aids in dermatology. Br J Dermatol. 2016;175(5):1045-1048.
8. Guttman-Yassky E, Waldman A, Ahluwalia J, Ong PY, Eichenfield LF. Atopic dermatitis: pathogenesis. Semin Cutan Med Surg. 2017;36(3):100-103.
9. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel [published online January 6, 2017]. Allergy Asthma Clin Immunol. https://doi.org/10.1186/s13223-016-0175-4.
10. Egeberg A, Skov L, Joshi AA, et al. The relationship between duration of psoriasis, vascular inflammation, and cardiovascular events. J Am Acad Dermatol. 2017;77(4):650-656.e3.
11. Osier E, Wang AS, Tollefson MM, et al. Pediatric psoriasis comorbidity screening guidelines. JAMA Dermatol. 2017;153(7):698-704.
