PEDIATRIC DERMATOLOGY A supplement to Pediatric News & Dermatology News JUNE 2020

Early onset of atopic dermatitis linked Patch testing in atopic dermatitis: When to poorer control, could signify more and how persistent disease Topical calcineurin inhibitors are an Patients with atopic dermatitis should be effective treatment option for periori cial routinely asked about conjunctivitis dermatitis Hope on the horizon: New cantharidin Psychology consults for children’s skin formulation alleviates molluscum issues can boost adherence, wellness contagiosum in pivotal trials Commentaries by Robert Sidbury, MD, MPH, & Lawrence F. Eichen eld, MD

PedDermASupp_Cover.indd 1 5/6/2020 7:38:35 AM 2 June 2020 • Pediatric Dermatology Dermatologic treatments can be complementary

BY ROBERT SIDBURY, MD, AND Topical calcineurin inhibitors such as high-risk infants will help better target LAWRENCE F. EICHENFIELD, MD tacrolimus and pimecrolimus have been prevention eorts as they continue to FDA-approved AD therapies for 2 de- evolve. he articles described herein con- cades, but Ollech et al. point to a poten- In a separate article, Wan et al. tain a variety of diagnostic and tial role treating periori cial dermatitis. demonstrate that earlier onset of AD Ttherapeutic updates, correlates with persistence, sometimes with complemen- increasing the importance of tary themes. The discussion early identi cation and inter- of patch testing is a good ex- vention for high-risk infants. ample. Jonathan I. Silverberg, Armed with risk strati cation MD, PhD, reminds us that data, pediatricians can inter- patients with atopic derma- vene earlier in infancy as rash titis (AD) are at greater risk and itch that might otherwise for allergic contact dermatitis be attributed to irritants may (ACD), and the culprit often sooner be labeled AD. is a product being used to New treatments for acne treat the disease itself. Tra- and molluscum as well as tips ditional IgE-based allergy for reducing procedural stress tests assessing immediate in pediatric patients compose Type 1 hypersensitivity such other ground covered in this as a prick test or radioaller- Dr. Robert Sidbury Dr. Lawrence F. Eichen eld wide-ranging sample of the lit- gosorbent test (RAST) will erature from the past year. not help; patch testing for Type IV de- We continue to learn more about layed-type hypersensitivity is indicated. the genetic basis, natural history, and Dr. Sidbury is chief of dermatology at Seattle Because ACD can be challenging to best care practices for AD. While a Children’s Hospital and professor, depart- uncouple from concomitant AD, most genetic basis for AD has long been ment of pediatrics, University of Washington, experts advise patch testing prior to known, studies such as that by Ayelet Seattle. He is a site principal investigator for consideration of systemic therapy, in- Ravn, MD, put a ner point on related dupilumab trials, for which the hospital has cluding newer biologic medications. questions. Does a maternal history of a contract with Regeneron. One such agent, omalizumab, typi- AD and atopy confer greater risk upon cally is indicated for chronic urticaria the child than a paternal history as Dr. Eichen eld is chief of pediatric and ad- or asthma, but Chan et al. demon- long suspected? This does not appear olescent dermatology at Rady Children’s strate bene t in AD. Dupilumab, the to be the case. Does a parental history Hospital-San Diego. He is vice chair of the only Food and Drug Administration– of AD as opposed to asthma or aller- department of dermatology and professor of approved nonsteroidal systemic med- gic rhinitis confer greater risk of AD dermatology and pediatrics at the University ication for AD, has revolutionized the to the child? Yes, it does. These are of California, San Diego. He disclosed that care of moderate to severe disease, important questions not only because he has served as an investigator and/or but providers should be alert to po- they are of great interest to parents, consultant to Abbvie, Lilly, P zer, Regeneron, tential ocular adverse eects. but because improved identi cation of Sano -Genzyme, and Verrica.

Editors Pediatric Dermatology is a supplement to Medical Communications Inc. will not Catherine Cooper Nellist Pediatric News and Dermatology News, assume responsibility for damages, loss, and Elizabeth Mechcatie independent newspapers that provide or claims of any kind arising from or Manager, Art Directors the practicing specialist with timely and related to the information contained in Elizabeth B. Lobdell relevant news and commentary about this publication, including any claims Creative Director Louise A. Koenig clinical developments in their respective related to the products, drugs, or services Director, Production/Manufacturing elds and about the impact of health mentioned herein. Rebecca Slebodnik care policy on the specialties and the ©Copyright 2020, by Frontline Medical Group Publisher physician’s practice. Communications Inc. All rights reserved. Sally Cioci Fischer The ideas and opinions expressed in [email protected] Pediatric Dermatology do not necessarily Cover: SolStock/E+/Getty Images reect those of the Publisher. Frontline

PedDermASupp_02_3_4.indd 2 5/6/2020 8:31:48 AM A Supplement to Pediatric News & Dermatology News 3 Which children are at greatest risk for AD?

BY BRUCE JANCIN It’s also information that clinicians a parental history of atopic dermatitis will nd helpful in appropriately tar- are a particularly high-risk group.” REPORTING FROM THE EADV CONGRESS geting primary prevention interven- Of note, the risk of pediatric atopic MADRID – A parental history of asthma tions if and when methods of proven dermatitis was the same regardless of or allergic rhinitis signi cantly increas- ecacy become available. That’s a like- whether the father or mother was the es the risk that a child will develop ly prospect, as this is now an extremely one with a history of atopic disease. If atopic dermatitis, and that risk dou- active eld of research, she noted. one parent had a history of an atopic bles if a parent has a history of atopic disease, the pediatric risk was increased dermatitis rather than another atopic 1.3-fold compared to when the paren- disease, Nina H. Ravn reported at a tal history was negative. If both par- meeting of the European Task Force ents had a history of atopic illness, the on Atopic Dermatitis held in conjunc- risk jumped to 2.08-fold. And if one tion with the annual congress of the parent had a history of more than one European Academy of Dermatology form of atopic disease, the pediatric and Venereology. risk of atopic dermatitis was increased She presented a comprehensive meta- 2.32-fold. analysis of 149 published studies ad- Dr. Ravn Dr. Wollenberg “A n interesting result that was new dressing the risk of developing atopic to me what that fathers’ and mothers’ dermatitis according to parental history The meta-analysis showed that a pa- contribution to risk is equal,” said ses- of atopic disease. rental history of atopic dermatitis was sion cochair Andreas Wollenberg, MD, The studies included more than associated with a 3.3-fold greater risk professor of dermatology at Ludwig 656,000 participants. The picture that of atopic dermatitis in the ospring Maximilian University of Munich. “For emerged from the meta-analysis was than in families without a parental the past 2 decades we were always one of a stepwise increase in the risk of history of atopy. A parental history of taught that the mother would have a pediatric atopic dermatitis according to asthma was associated with a 1.56-fold greater impact on that risk.” the type and number of parental atopic increased risk, while allergic rhinitis in “I was also surprised by our ndings,” diseases present. a parent was linked to a 1.68-fold in- Ms. Ravn replied. “But when we pooled “This is something that hopefully creased risk. all the data there really was no dier- can be useful when you talk with “It does matter what type of atopic ence, nor in any of our subanalyses.” parents or parents-to-be with atopic disease the parents have,” she ob- She reported having no nancial diseases and they want to know how served. “Those with a parental history conicts regarding her study. their disease might aect their child,” of asthma or allergic rhinitis can be [email protected] explained Ms. Ravn of the University considered as being at more of an in- of Copenhagen. termediate-risk level, while those with SOURCE: Ravn NH. THE EADV CONGRESS.

Commentary by Dr. Eichenfield including studies of twins, showing strong hereditary factors in AD development, as well as incredibly strong genetic in uences ATOPIC DERMATITIS (AD) continues to be the focus of much re- on the association of AD and asthma. search, including epidemiologic work and the development of new Others have postulated that different pathways could mediate therapies. some of the parental effects, including epigenetic modications, as The large meta-analysis by Nina H. Ravn from the University well as common “clustering” of environmental hazards. of Copenhagen presented several months ago included over Is this kind of research important? Absolutely! The individual 650,000 individuals in 149 published studies looking at the and global burden of AD is signicant, with its high prevalence in uence of parental eczema and other atopic conditions. It and association with the development of other atopic conditions. showed, as have other studies, that having parents with a history Can we prevent its development in high-risk children? Research of AD markedly increases a child’s risk of developing AD (3.3-fold to prevent its development includes emollient application studies increase), and that other atopic diseases (asthma, allergic rhini- in early life, pre- and probiotic supplementation, environmental tis) increased the odds of a child developing AD, but by less of modication studies, and others. While the answers are elusive an amount. Interestingly, this study found the effects were similar currently, we look forward to the time when we can decrease AD for both parents, not favoring maternal in uences as other studies onset rates in infants and young children, and studies to identify have shown. These ndings are consistent with other studies, risk factors may help us to do this.

PedDermASupp_02_3_4.indd 3 5/6/2020 8:31:51 AM 4 June 2020 • Pediatric Dermatology Early onset of AD linked to poorer control

BY BIANCA NOGRADY tive disease over time; however, wheth- ally declined with older age, and the dif- er these groups also dier in terms of ferences among the 3 onset age groups FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY the severity of AD is unknown.” were most pronounced from early ado- In this observational cohort study, lescence onward,” the authors wrote. arlier onset of atopic dermatitis 8,015 individuals with childhood-onset They noted that there was consid- (AD) in children could signify more AD – 53% of whom were female – were erable research currently focused on Edi cult to control and persistent assessed twice yearly for up to 10 years. identifying distinct AD phenotypes and disease, results of a study suggest. Nearly three-quarters (72%) of the group endotypes, and their evidence on the Atopic dermatitis most commonly had early-onset AD – dened as onset dierent disease course for early-, mid-, arises in infancy but also can emerge in before 2 years of age – while 19% had and late-onset disease supported this later childhood and even adolescence, mid-onset disease (3-7 years) and 9% had idea of disease subtypes. leading to a distinction between early- late-onset disease (8-17 years). “However, additional research is and late-onset disease, wrote Joy Wan, The study found that older age of needed to understand whether and how MD, of the University of Pennsylvania, onset was associated with better con- early-, mid-, and late-onset AD dier Philadelphia, and coauthors. “Early- trol, such that, for each additional year molecularly or immunologically, and onset, mid-onset, and late-onset AD of age at the onset of disease, there whether they respond dierentially to appear to dier in the presence of ac- was a 7% reduction in the odds of treatment,” they wrote. They also sug- poorer control of disease. Those who gested that the timing of onset could had mid-onset disease had a 29% lower help identify patients who were at great- odds of poorer control compared with er risk of persistent or poorly controlled those with early-onset disease, while disease, and who benets from more those with late-onset disease had a intensive monitoring or treatment. 49% lower odds of poorer control. The study was partly supported by The likelihood of AD persisting be- the National Institute of Arthritis and yond childhood also appeared to be Musculoskeletal and Skin Diseases and linked to the age of onset. Those with the Dermatology Foundation. Three mid-onset disease had a 55% lower odds authors declared links with the phar- of persistent AD, compared with those maceutical sector. No other conicts

HINKSTOCK with early-onset disease, while those of interest were declared. /T with late-onset disease had an 81% lower [email protected] odds. ORENZELLI L “In all 3 groups, the proportion of SOURCE: Wan J et al. J Am Acad Dermatol. UCA

L subjects reporting persistent AD gener- 2019 Dec;81(6):1292-9.

Commentary by Dr. Eichenfield children, and that patients with earlier onset may have more long- standing disease, as well as more chance of having poorly controlled THE STUDY BY WAN ET AL. represents important work trying to “tease disease. This is a bit tricky to consider – that is, that younger-onset out” different aspects of atopic dermatitis (AD) onset and course. The patients experience disease resolution commonly, while others have classic teaching that AD is a childhood disease that starts very early persistent and poorly controlled disease. and “goes away” in a few years is an oversimpli cation, and several Of course, all studies have their limitations, as did this one, as it studies have shown that there are varying times of disease onset, was a long-term registry study of patients using a second-line, non- subsets of the pediatric AD that remit or seem to be “cured,” and steroid medication, and early-onset, early-resolving children may be other subsets that persist into adolescence or adulthood. In addition, underrepresented in the cohort study. later-childhood, adolescent, and adult-onset AD are increasingly My takeaway from a practice standpoint? Assess each child in- appreciated as part of our AD patient pool. The University of Penn- dependently. Query not just their age of onset, but their course and sylvania researchers have explored the different time courses of AD, severity: continuous versus intermittent, frequent versus infrequent using a long-term registry cohort study that was designed to assess ares, easily responsive to therapy versus hardly responsive. And long-term safety of pimecrolimus in pediatric patients. develop a therapeutic regimen that doesn’t treat just ares, but Major ndings of the group? That later-onset AD has less asso- allows long-term disease control with minimal rash, itch, and sleep ciated risks of asthma and seasonal allergies than younger-onset disturbance.

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PedDermASupp_05.indd 5 5/6/2020 8:30:18 AM 6 June 2020 • Pediatric Dermatology Patients with AD should routinely be asked about conjunctivitis

BY JEFF CRAVEN noted they had seen dupilumab-associ- eye ointment, or oral antihistamines ated conjunctivitis in both pediatric and from their dermatologists before an FROM THE JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY adult patients. ophthalmology referral, the IEC mem- AND VENEREOLOGY The IEC members recommended: bers said. Dermatologists also should • Patients should be informed about perform, or refer patients for, skin atients with atopic dermatitis the risks of conjunctivitis before be- prick testing or specic IgE testing for (AD) should regularly be asked ing prescribed dupilumab. aeroallergens in patients with AD who Pabout conjunctivitis and referred • AD patients should be asked “rou- have conjunctivitis, and patch testing to an ophthalmologist for diagnosis and tinely” about ocular complaints or Continued on following page } therapy, if they develop conjunctivitis, symptoms. according to a recent • AD patients with position statement from conjunctivitis should be Commentary by the International Ecze- referred to an ophthal- Dr. Sidbury ma Council. mologist for diagnosis Patients with AD who and treatment. EIGHT PERCENT OF PATIENTS with develop conjunctivitis • AD patients with atopic dermatitis have ocular patholo- during dupilumab treat- new-onset conjunctivitis gy including atopic keratoconjunctivitis, ment may experience during dupilumab treat- cataracts, and keratoconus; however, “bilateral in ammation WIKIMEDIA COMMONS/JOYHILL09 ment always should be re- clinicians do not always take a thorough of the anterior conjunctiva and hyper- ferred to an ophthalmologist, especially ocular review of systems and exam. It aemia of the limbus, which may cause in more severe cases such as when they has taken the new biologic medication nodular swelling,”according to the state- do not respond to treatment with anti- dupilumab to remind us that this should ment, which pertains to conjunctivitis histamine or articial tears. not be optional. The most notable dupi- in AD patients, “with and without dup- • Dermatologists also should rule out lumab-related adverse effect is conjunc- ilumab therapy” (J Eur Acad Dermatol keratoconjunctivitis before treating tivitis, occurring in up to 10% of treated Venereol. 2019 May 6. doi: 10.1111/ with dupilumab, as it may cause ker- patients in clinical trials and in an even jdv.15608). Currently, there are no pre- atitis and blindness. greater number in some postmarketing dictive factors of conjunctivitis and no • Patients who have had keratocon- cohorts. This has rightfully renewed em- guidance in the literature on how to junctivitis in the past should not be phasis on eye disease in AD patients. An manage conjunctivitis associated with precluded from treatment with dup- international consortium of AD experts dupilumab, which in some cases can ilumab, and those who develop con- (International Eczema Council) recom- make it necessary to stop treatment, the junctivitis during treatment should mended an ophthalmology consultation authors wrote. be referred to an ophthalmologist for new-onset conjunctivitis in dupilum- The International Eczema Council – but should stay on treatment while ab-treated patients. Arti cial tears and polled 86 dermatologists in 22 countries waiting for the consult. oral antihistamines should be consid- who are experts in AD; 46 members “It was stressed that at this moment ered, and if access to specialty care responded from 19 countries, including there are also no reliable data on the is delayed, prescription topical cortico- dermatologists from Australia, Canada, course of atopic keratoconjunctivitis and steroids or other immunosuppressants Denmark, France, Germany, Japan, vernal keratoconjunctivitis during dupi- like cyclosporine may be necessary. Al- Korea, the Netherlands, the United lumab treatment,” according to Jacob P. though the patho-mechanism of dup- Kingdom, and the United States. The Thyssen, MD, PhD, Herlev and Gentofte ilumab-induced conjunctivitis remains questions centered on the diagnosis and Hospital, Hellerup, Denmark, and coau- obscure, it is intriguing to note that such management of conjunctivitis in AD thors. These patients “should be carefully a signal has not been seen in asthma patients, and whether to refer cases to monitored by an ophthalmologist before patients treated with the same medica- an ophthalmologist. Consensus was and during treatment with dupilumab.” tion. This suggests that atopic dermatitis achieved if less than 30% of participants The recommendations also cen- patients may be uniquely susceptible disagreed with a statement. IEC mem- tered around which treatments should to dupilumab-induced conjunctivitis, bers then met in person at a European be initiated by dermatologists, and which further highlights the need for Academy of Dermatology and Venere- which should be referred to ophthal- ocular scrutiny for all AD patients on ology meeting in Paris to discuss the re- mologists. Those patients with con- the front end. sults of the survey. Survey respondents junctivitis should receive eye drops,

PedDermASupp_06thr10.indd 6 5/6/2020 8:55:20 AM A Supplement to Pediatric News & Dermatology News 7 New cantharidin formulation alleviates molluscum contagiosum in pivotal trials

BY ERIK GREB vehicle for 12 weeks. Treatment was ad- controls (P less than .0001). By day 84, ministered topically to each lesion every among treated patients, the lesion count REPORTING FROM AAD 2019 3 weeks for a maximum of four appli- had decreased by a mean of 69% in WASHINGTON – A novel, standardized cations, and washed o with soap and CAMP-1 and 83% in CAMP-2, compared preparation of topical cantharidin ef- warm water 24 hours after application. with 20% and 19%, respectively, among fectively cleared lesions in patients with The trials’ primary endpoint was the controls. Results among controls were molluscum contagiosum, compared percentage of patients with complete “probably consistent with natural histo- with placebo, according to the results clearance of their lesions. Secondary r y, ” Dr. Eicheneld observed. of two trials presented at the annual endpoints were the percentage of The researchers observed a high meeting of the American Academy of patients with complete clearance and incidence of treatment-emergent ad- Dermatology. decrease in lesions over time. verse events among patients receiving VP-102, a drug-device combination, In the two studies, 528 patients aged VP-102. “A n y crust or vesiculation was was well tolerated and was not associ- 2-60 years (mean age, approximately 7 considered to be a treatment-emergent ated with serious adverse events. years) were randomized to treatment adverse event,” he said. Pruritus and ap- No Food and Drug Administra- or vehicle. About 30% of participants plication-site pain were reported as well. tion–approved treatment is available had prior treatment. The baseline le- Most adverse events were mild. for treating molluscum contagiosum, sion count ranged from 1 to 184. Verrica Pharmaceuticals developed which is routinely treated with cantha- At day 84, the proportion of patients VP-102 and funded the study. Dr. ridin, a naturally occurring vesicant. in the VP-102 arm who achieved com- Eicheneld’s institution received fund- VP-102 is a novel formulation of 0.7% plete clearance of lesions was 46% in ing from the company; several other cantharidin solution, provided in a sin- CAMP-1 and 54% in CAMP-2, compared investigators are employees of Verrica. gle-use applicator, to provide consistent with 18% and 13%, respectively, among [email protected] delivery and long-term drug stability. To test the e cacy and safety of VP- 102, Lawrence F. Eicheneld, MD, chief Commentary by Dr. Sidbury of pediatric and adolescent dermatol- CANTHARIDIN HAS A STAR-CROSSED HISTORY as a therapeutic intervention for molluscum ogy at Rady Children’s Hospital–San contagiosum. It has been used for this purpose for decades without of cial FDA sanction. Diego, and his associates conducted the For reasons that are not entirely clear, accessing cantharidin has become dif cult even CAMP-1 (Cantharidin Application in though many pediatric dermatologists, myself included, prefer it to most, if not all, other Molluscum Patients) and CAMP-2 phase treatments. VP-102 is a single-use form of cantharidin that is working its way toward FDA 3 studies, which had similar designs. approval. Dr. Eichen eld describes results that show unsurprising bene t relative to pla- The studies enrolled patients with mol- cebo, and equally unsurprising adverse effects. Cantharidin is a chemovesicant, so some luscum contagiosum aged 2 years and crusting and vesiculation should be expected. These studies – and my own experience – older who had not received any treat- demonstrate that when used appropriately cantharidin can be a safe, effective intervention ment in the 2 weeks before enrollment. for molluscum contagiosum. Patients were randomized to VP-102 or

| Continued from previous page a short course of corticosteroid eye comitant asthma or other comorbidi- with an “ophthalmologic series, and drops without ophthalmological con- ties, as well as other treatment options, native eye drops/ointments to diag- sultations,” Dr. Thyssen and associates should be considered on an individual nose possible delayed type hypersensi- said. “However, persistent or recurrent patient basis,” the authors concluded. tivity reactions to topical ingredients.” conjunctivitis requiring repeated or The IEC survey was limited by the Among the treatments for conjunc- prolonged use of corticosteroid, tacro- small survey response and reliance on tivitis best left to ophthalmologists are limus, and ciclosporin-containing eye expert opinion. cyclosporine, tacrolimus, or corticoste- drops, must be managed by an ophthal- The authors reported personal and roid eye drops. mologist, given the risk of glaucoma, institutional relationships with a variety “Despite the more limited experience cataract, and infections.” of pharmaceutical companies, agencies, with eye drops by dermatologists, rap- “The AD severity, conjunctivitis sever- societies, and other organizations. No id access to ophthalmological service ity, possible contraindications, possible funding was obtained for the study. may be di cult, sometimes warranting eect of dupilumab therapy on con- [email protected]

PedDermASupp_06thr10.indd 7 5/6/2020 8:55:20 AM 8 June 2020 • Pediatric Dermatology Patch testing in atopic dermatitis: When and how

BY BRUCE JANCIN Northwestern’s patch test clinic with than 90% of the positive reactions. the purpose of identifying the com- “You can patch test them directly to EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR mon oending allergens in patients their personal care products and make with AD. The key nding: The patients that connection beautifully and see WAIKOLOA, HAWAII – The prevalence of with AD were signi cantly more likely how they’re reacting to them,” he said. allergic contact dermatitis is elevated to have positive patch test reactions to among patients with atopic dermatitis ingredients in their repetitively used When to patch test atopic (AD) – and it pays to know their major personal care products, topical corti- dermatitis patients sources of risk, according to costeroids, and topical anti- Dr. Silverberg was a coauthor of Jonathan I. Silverberg, MD, biotics than the individuals multidisciplinary expert consensus PhD. without AD. The probable guidelines on when to consider patch “What are atopic derma- explanation for this results is testing in AD (Dermatitis. 2016 Jul- titis patients allergic to? It’s that the skin barrier disrup- Aug;27[4]:186-92). “We had to go all coming from their per- tion inherent in AD allows consensus because we don’t have sonal care products and the for easier passage of weak nearly enough studies to provide true things being used to treat allergens through the skin evidence-based recommendations,” he their atopic dermatitis,” Dr. (J Am Acad Dermatol. 2018 explained. Silverberg said at the Hawaii Dr. Silverberg Dec;79[6]:1028-33.e6). Because allergic contact dermatitis Dermatology Seminar pro- Lanolin was identi ed as is a potentially curable comorbid con- vided by the Global Academy for Med- a particularly common allergen in the dition in AD patients, it’s important to ical Education/Skin Disease Education AD group. “Lanolin is found in one of recognize the scenarios in which patch Foundation. the most commonly used moisturizers testing should be considered. These in- Dr. Silverberg, of the department we recommend to patients: Aquaphor. clude AD refractory to topical therapy; of dermatology at Northwestern It’s also found in tons of lip balms and adolescent- or adult-onset atopic derma- University, Chicago, coauthored a sys- emollients. Pretty much every soft titis; and in AD patients with an atypical tematic review and meta-analysis that soap out there contains lanolin, and or evolving lesional distribution, such as examined the association between AD it’s in a variety of other personal care localized dermatitis on the eyelids, head and contact sensitization. In their ex- products,” Dr. Silverberg noted. and neck, or hands and feet. Patch test- amination of 74 published studies, the Other common oenders in the AD ing is also warranted before initiating investigators found that the likelihood population included fragrance mix II, systemic therapy for AD. of allergic contact dermatitis was 1.5- cinnamal, quaternium-15, budesonide, “If you’re about to put a patient on fold greater in adults and children with tixocortol, carba mix, neomycin, baci- a biologic or phototherapy and step AD than in healthy individuals from tracin, rubber mix, and chlorhexidine. them up to a whole new class of risk the general population (J Am Acad Relevance was established in more Continued on following page } Dermatol. 2017 Jul;77[1]:70-8). This nding is at odds with an earli- er widespread belief that AD patients Commentary by Dr. Sidbury should not be at increased risk because the immune pro le of their primarily FOR PATIENTS WITH ATOPIC DERMATITIS, it is important to remember that sometimes Th2-mediated disease would have a friend can be foe. Dr. Silverberg and colleagues remind us that allergic contact dermatitis is suppressant eect on Th1-mediated more common in AD patients, and is often caused by personal care products including the hypersensitivity. emollients and topical steroids that are foundations of their care. Important points highlighted “Recent data are calling into ques- include the fact that many such relevant allergens in this population are not represented on tion old dogmas and reshaping the way the T.R.U.E. test; the more complete NAACD (North American Allergic Contact Dermatitis) tray we think about this. And this is not is indicated if accessible. Indications for patch testing can include atypical presentations just an academic exercise, this is highly or distribution, refractory disease, or a suggestive history. Dr. Silverberg notes anecdotally clinically relevant,” the dermatologist that extensive nummular eczema also should raise suspicion for allergic contact dermatitis. asserted. He echoes the American Academy of Dermatology management guidelines when he ad- The results of the meta-analysis vises strong consideration be given to patch testing prior to initiation of systemic therapy. prompted Dr. Silverberg and col- For primary care providers, it is also worth noting that a skin biopsy is not helpful in the leagues to conduct a retrospective discrimination of allergic contact dermatitis from atopic dermatitis: Both share an identical study of more than 500 adults patch spongiotic histopathology. tested to an expanded allergen series at

PedDermASupp_06thr10.indd 8 5/6/2020 8:55:21 AM A Supplement to Pediatric News & Dermatology News 9 Fast, aggressive eczema treatment linked to fewer food allergies by age 2 years

BY JENNIE SMITH individual food allergies, only chicken tween-group dierences at baseline, egg was associated with a statistically with characteristics such as Staphylo- FROM THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY: IN PRACTICE signi cant dierence in prevalence (15% coccus aureus infections and some in- vs 36%, P equal to .006). ammatory biomarkers higher in the esearchers in Japan report that “Our present study may be the rst early-treatment group. infants with atopic dermatitis to demonstrate that early aggressive The Japan Agency for Medical Re- Rwho are treated early and aggres- topical corticosteroid treatment to search and Development supported the sively with corticosteroids develop few- shorten the duration of eczema in in- study, and the investigators disclosed er food allergies by age 2 years. fants was signi cantly associated with a no relevant conicts of interest. Yumiko Miyaji, MD, PhD, of Japan’s decrease in later development of [food [email protected] National Center for Child Health and allergies],” Dr. Miyaji and colleagues Development in Tokyo and colleagues wrote in their analysis. SOURCE: Miyaji Y et al. J Allergy Clin looked at 3 years’ worth of records for The investigators acknowledged as Immunol Pract. 2019. doi: 10.1016/j. 177 infants younger than 1 year of age limitations of their study some be- jaip.2019.11.036. seen at a hospital allergy center for ec- zema. Of these infants, 89 were treated with betamethasone valerate within 4 Commentary by Dr. Sidbury months of disease onset, and 88 were treated after 4 months of onset. Most THE CONCEPT OF THE ATOPIC MARCH – the idea that some affected individuals will develop (142) were followed up at 22-24 months, food allergies and eczema as babies, asthma as children, and hay fever as adults in an orderly when all were in complete remission or sequence – is well described. Recent work has raised the question whether early aggressive near remission from eczema. intervention in susceptible infants may prevent eczema and possibly other comorbidities along At follow-up, clinicians collected in- this “march.” Miyaji and colleagues have compared infants treated with a topical steroid within formation about anaphylactic reactions 4 months of onset with those treated later and found that indeed the early-treatment group to food, administered speci c food chal- developed fewer food allergies. This idea aligns with lessons learned from the LEAP studies lenges, and tested serum immunoglobin of peanut allergy prevention, in which it seemed that the abnormal atopic skin barrier was a E levels for food allergens. Dr. Miyaji point of allergic vulnerability. These are early data, and comparative groups were not identical, and colleagues found a signi cant dif- but it is exciting to contemplate that successful atopic dermatitis treatment might not only ference in the prevalence of allergies confer great physical relief, decrease the risk of skin infection, and improve quality of life, but between the early-treated and late-treat- also possibly prevent the development of food allergies. Risks and bene ts of therapy always ed groups to chicken egg, cow’s milk, must be considered, but the benign neglect often demonstrated because a child’s itchy rash wheat, peanuts, s oy, or sh (25% vs. is “just eczema” is increasingly obsolete. 46%, respectively; P equal to .013). For

| Continued from previous page How to patch test atopic of that, but clean means having the of adverse events, that’s an ideal time dermatitis patients fewest ingredients possible and trying to think about reversible options,” Dr. Most of the common topical allergens to steer clear of those really common Silverberg advised. in AD patients are not included in the allergens that patients are highly likely Another situation in which he con- T.R.U.E. Test. An expanded allergen to have been exposed to and potentially siders patch testing advisable, although series, such as the American Contact sensitized to over the many years of this one isn’t covered in the consen- Dermatitis Society core 80 series, is their tenure of atopic dermatitis.” sus guidelines, is in AD patients with the better way to go. Dr. Silverberg reported receiving prominent nummular eczema lesions. Once the dermatologist determines research grants from Galderma and “Widespread nummular eczema le- that a patient’s positive patch test reac- GlaxoSmithKline and serving as a con- sions may be a sign of allergic contact tion is relevant, it’s important to recom- sultant to more than a dozen pharma- dermatitis in atopic dermatitis patients. mend the use of personal care products ceutical companies. I’m not saying everyone with nummu- that are “pretty clean,” he said. SDEF/Global Academy for Medical lar lesions is going to have a positive “Clean in my opinion is not a matter Education and this news organization patch test, but it’s de nitely a situation of ‘It should be all organic and all natu- are owned by the same parent company. you want to think about,” he said. ral,’ ” he emphasized. “I’m not anti- any [email protected]

PedDermASupp_06thr10.indd 9 5/6/2020 8:55:22 AM 10 June 2020 • Pediatric Dermatology Topical calcineurin inhibitors are effective treatment option for periori cial dermatitis

BY DOUG BRUNK POD, treatment(s) prescribed, duration 64% of those treated with TCI and of therapy, clinical response, recurrences, metronidazole, and in 70% of those REPORTING FROM SPD 2019 and side e ects. In an e ort to capture treated with TCI and a systemic antibi- AUSTIN, TEX. – Topical calcineurin in- missing data, the researchers performed otic. Adverse events attributed to TCI hibitors (TCIs) are an e ective ther- follow-up via telephone for all patients were rare and mild in severity. apeutic option for pediatric patients who lacked appropriate follow-up docu- “We were surprised that there were with perioricial dermatitis (POD), as mentation in the medical record. almost no reported side e ects from monotherapy or as part of a Of the 132 patients, the fe- the usage of TCIs as it is known that combination regimen, results male:male ratio was 1.2:1 and these agents can cause a burning or from a retrospective cohort the median age at diagnosis stinging sensation,” Dr. Ollech said. study showed. was 4.2 years. About one- “Only one case described this side The mainstays of treatment third of patients (33%) had e ect. We found 30% of the patients for POD include topical and involvement of one region, to have associated atopic dermatitis as oral antibiotics. In an interview 38% had involvement of two well as a few patients with irritant der- prior to the annual meeting regions, 26% had involvement matitis. We were also surprised how of the Society for Pediatric of three regions, and 3% pa- convenient the TCI treatment was for Dermatology, Ayelet Ollech, Dr. Ollech tients had involvement of all a patient who had POD and concomi- MD, said that the most regions. The most common tant facial AD or even irritant dermati- common systemic agents used include disorders on medical history were atop- tis as an agent that can treat both. This erythromycin, azithromycin, and, in ic dermatitis (AD) and asthma (in 29% can be very helpful for the parents that patients older than 8-10 years of age, mi- and 17% of patients, respectively). apply the medication to have a single nocycline or doxycycline. Topical agents, Dr. Ollech reported that 72 of the solution to more than one rash.” which are often used as monotherapy 132 patients (55%) had evaluable fol- The researchers noted recurrence of in mild disease, include metronidazole, low-up data via either medical record POD in 14% of patients overall, including clindamycin, erythromycin, sodium sul- documentation or the phone question- 6% of patients treated with TCI alone, facetamide, and, less often, azelaic acid, naire. Of these, 67% were treated with 29% of patients treated with TCI and topical retinoids, and ivermectin. “TCIs TCI alone, 19% were treated with a metronidazole, and 30% of patients treat- (pimecrolimus 1% cream and tacrolim- combination of TCI and topical met- ed with TCI and a systemic antibiotic. us 0.03% or 0.1% ointment) are a good ronidazole, and 10% were treated with Dr. Ollech and her colleagues report- steroid-sparing option for POD,” said Dr. a combination of TCI and a systemic ed having no nancial disclosures. Ollech, a pediatric dermatology fellow at antibiotic. The median duration of [email protected] Ann & Robert H. Lurie Children’s Hospi- treatment was 60 days. The researchers tal of Chicago. “In the adult population, observed complete response in 65% SOURCE: Ollech A et al. SPD 2019, Poster two randomized controlled studies of of patients treated with TCI alone, in 23. pimecrolimus 1% cream showed good results. In the pediatric population, there are only a few case series and case reports Commentary by Dr. Sidbury of TCIs for the treatment of POD.” In what is believed to be the largest PERIORAL DERMATITIS IS NOTORIOUSLY STUBBORN, necessitating a well-stocked thera- study of its kind, Dr. Ollech, Anthony peutic toolkit. Topical calcineurin inhibitors (TCIs) have been used off label to treat perioral J. Mancini, MD, and colleagues assessed dermatitis for nearly the entire 20 years they have been on the market; Dr. Ollech and col- the clinical utility of TCI in 132 pediatric leagues characterize their experience over the past decade. In their cohort of young children patients with POD who were treated in (mean age = 4 years), they demonstrated just why this drug class has been an enduring the division of dermatology at Children’s weapon against perioral dermatitis: It can work! As monotherapy, roughly 65% of patients Hospital of Chicago between 2008 and cleared. This means of course that over a third of patients will not clear with this medication 2018. The researchers made note of alone, a gure that jibes with my own experience; practitioners utilizing this option should epidemiologic variables, personal and have a plan B in mind at the outset. Insurance coverage can be another barrier for this family medical histories, possible trig- off-label indication; however, Dr. Ollech’s secondary nding that one in three patients in her gers, duration of illness, previous treat- cohort had comorbid atopic dermatitis, for which TCIs are indicated, suggests coverage may ments, distribution (periocular, perinasal, be easier for some. perioral, extra facial regions), severity of Pages 10a—10d u

PedDermASupp_06thr10.indd 10 5/6/2020 8:55:23 AM APPROVED FOR PATIENTS AGED 12 YEARS AND OLDER WITH UNCONTROLLED MODERATE-TO-SEVERE ATOPIC DERMATITIS

Not an actual patient. INDICATION DUPIXENT is indicated for the treatment of patients aged 12 years and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. DUPIXENT can be used with or without topical corticosteroids.

IMPORTANT SAFETY INFORMATION CONTRAINDICATION: DUPIXENT is contraindicated in patients with known hypersensitivity to dupilumab or any of its excipients. WARNINGS AND PRECAUTIONS Hypersensitivity: Hypersensitivity reactions, including generalized urticaria, rash, erythema nodosum, anaphylaxis and serum sickness or serum sickness-like reactions, were reported in <1% of subjects who received DUPIXENT in clinical trials. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue DUPIXENT. Conjunctivitis and Keratitis: Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received DUPIXENT. Conjunctivitis was the most frequently reported eye disorder in these patients. Advise patients to report new onset or worsening eye symptoms to their healthcare provider. Reduction of Corticosteroid Dosage: Do not discontinue systemic, topical or inhaled corticosteroids abruptly upon initiation with DUPIXENT. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. Atopic Dermatitis Patients with Comorbid Asthma: Advise patients not to adjust or stop their asthma treatments without consultation with their physicians. Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages. AD, atopic dermatitis.

191265_L01_Adult.indd 1 4/29/20 7:40 PM SHARED RESULTS

TRIAL DESIGNS: A total of 917 adult patients in Trials 1 and 2 (16-week trials), 251 adolescent patients in Trial 6 (16-week trial), and 421 adult patients in Trial 3 (52-week trial) with moderate-to-severe atopic dermatitis not adequately controlled with topical prescription treatments were randomized to DUPIXENT or placebo. For all patients in Trial 3, lesions were treated with concomitant TCS. All adults received 300 mg Q2W following a 600 mg loading dose. Adolescents ≥60 kg also received this dose, while adolescents <60 kg received 200 mg Q2W following a 400 mg loading dose. Eligible patients had an IGA score ≥3 (overall atopic dermatitis lesion severity scale of 0 to 4), an EASI score ≥16 on a scale of 0 to 72, and body surface area involvement of ≥10%. At baseline, 52% of adults and 46% of adolescents had an IGA score of 3 (moderate atopic dermatitis), 48% of adults and 54% of adolescents had an IGA of 4 (severe atopic dermatitis), mean EASI score was 33 for adults and 36 for adolescents, and weekly averaged peak pruritus NRS was 7 on a scale of 0 to 10 for adults and 8 for adolescents. 1

TRIAL RESULTS: The primary endpoint was the change from baseline in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and ≥2-point improvement at Week 16 (38% and 36% of adults treated with DUPIXENT vs 10% and 9% with placebo in Trials 1 and 2, respectively, P<0.001; 24% of adolescents treated with DUPIXENT vs 2% with placebo in Trial 6, P<0.001; 39% of adults treated with DUPIXENT + TCS vs 12% with placebo + TCS in Trial 3, P<0.0001). Other endpoints included change from baseline in the proportion of subjects with EASI-75 at Week 16 (improvement of ≥75%; 51% and 44% of adults treated DUPIXENT vs 15% and 12% with placebo in Trials 1 and 2, respectively, P<0.001; 42% of adolescents treated with DUPIXENT vs 8% with placebo in Trial 6, P<0.001; 69% of adults treated with DUPIXENT + TCS vs 23% with placebo + TCS in Trial 3, P<0.0001) and reduction in itch as defined by ≥4-point improvement in the Peak Pruritus NRS at Week 16 (41% and 36% of adults treated with DUPIXENT vs 12% and 10% with placebo in Trials 1 and 2, respectively, P<0.001; 37% of adolescents treated with DUPIXENT vs 5% with placebo in Trial 6, P<0.001; 59% of adults with DUPIXENT + TCS vs 20% with placebo + TCS in Trial 3, P<0.0001).1-5 EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; NRS, numerical rating scale; Q2W, once every 2 weeks; TCS, topical corticosteroids. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (cont’d) Parasitic (Helminth) Infections: It is unknown if DUPIXENT will influence the immune response against helminth infections. Treat patients with pre-existing helminth infections before initiating therapy with DUPIXENT. If patients become infected while receiving treatment with DUPIXENT and do not respond to anti-helminth treatment, discontinue treatment with DUPIXENT until the infection resolves.

© 2019 Sanofi and Regeneron Pharmaceuticals, Inc. All Rights Reserved. DUP.19.11.0087

191265_L01_Adult.indd 2 4/29/20 7:41 PM Not an actual patient. SHARED RELIEF Itch reduction1 Clear or almost-clear skin1 A biologic—not a steroid treatment No requirement for initial lab testing or or an immunosuppressant1 ongoing lab monitoring, according to the full Prescribing Information1 IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS: The most common adverse reactions (incidence ≥1% at Week 16) in adult patients with atopic dermatitis are injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, and dry eye. The safety profile in adolescents through Week 16 was similar to that of adults with atopic dermatitis. In an open-label extension study, the long-term safety profile observed in adolescents through Week 52 was consistent with that seen in adults with atopic dermatitis. DRUG INTERACTIONS: Avoid use of live vaccines in patients treated with DUPIXENT. USE IN SPECIFIC POPULATIONS • Pregnancy: Available data from case reports and case series with DUPIXENT use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, DUPIXENT may be transmitted from the mother to the developing fetus. • Lactation: There are no data on the presence of DUPIXENT in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUPIXENT and any potential adverse effects on the breastfed child from DUPIXENT or from the underlying maternal condition.

Please see brief summary of full Prescribing Information on the following pages.

VISIT DUPIXENTHCP.COM/ATOPICDERMATITIS TO LEARN MORE

191265_L01_Adult.indd 3 4/29/20 7:41 PM DUPIXENT® (dupilumab) injection, for subcutaneous use Rx only Table 1: Adverse Reactions Occurring in ≥1% of the DUPIXENT Monotherapy Group or the DUPIXENT + TCS Group in the Atopic Brief Summary of Prescribing Information Dermatitis Trials through Week 16 1 INDICATIONS AND USAGE 1.1 Atopic Dermatitis DUPIXENT Monotherapya DUPIXENT + TCSb DUPIXENT is indicated for the treatment of patients aged 12 years and Adverse Reaction DUPIXENT Placebo DUPIXENT Placebo older with moderate-to-severe atopic dermatitis whose disease is not 300 mg Q2Wc N=517 300 mg Q2Wc + TCS adequately controlled with topical prescription therapies or when those N=529 n (%) + TCS N=110 N=315 therapies are not advisable. DUPIXENT can be used with or without topical n (%) n (%) n (%) corticosteroids. Injection site reactions 51 (10) 28 (5) 11 (10) 18 (6) 4CONTRAINDICATIONS Conjunctivitisd 51 (10) 12 (2) 10 (9) 15 (5) DUPIXENT is contraindicated in patients who have known hypersensitivity to dupilumab or any of its excipients [see Warnings and Precautions (5.1)]. Blepharitis 2 (<1) 1 (<1) 5 (5) 2 (1) 5WARNINGS AND PRECAUTIONS Oral herpes 20 (4) 8 (2) 3 (3) 5 (2) 5.1 Hypersensitivity Keratitise 1 (<1) 0 4 (4) 0 Hypersensitivity reactions, including generalized urticaria, rash, erythema nodosum and serum sickness or serum sickness-like reactions, were Eye pruritus 3 (1) 1 (<1) 2 (2) 2 (1) reported in less than 1% of subjects who received DUPIXENT in clinical Other herpes simplex virus 10 (2) 6 (1) 1 (1) 1 (<1) trials. Two subjects in the atopic dermatitis development program infectionf experienced serum sickness or serum sickness-like reactions that were associated with high titers of antibodies to dupilumab. If a clinically Dry eye 1 (<1) 0 2 (2) 1 (<1) significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue DUPIXENT [see Adverse Reactions (6.1, 6.2)]. aPooled analysis of Trials 1, 2, and 4. 5.2 Conjunctivitis and Keratitis bAnalysis of Trial 3 where subjects were on background TCS therapy. Conjunctivitis and keratitis occurred more frequently in atopic dermatitis c DUPIXENT 600 mg at Week 0, followed by 300 mg every two weeks. subjects who received DUPIXENT. Conjunctivitis was the most frequently d Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, reported eye disorder. Most subjects with conjunctivitis recovered or were bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye recovering during the treatment period. Keratitis was reported in <1% of the irritation, and eye inflammation. DUPIXENT group (1 per 100 subject-years) and in 0% of the placebo group e Keratitis cluster includes keratitis, ulcerative keratitis, allergic keratitis, (0 per 100 subject-years) in the 16-week atopic dermatitis monotherapy atopic keratoconjunctivitis, and ophthalmic herpes simplex. trials. In the 52-week DUPIXENT + topical corticosteroids (TCS) atopic f dermatitis trial, keratitis was reported in 4% of the DUPIXENT + TCS group Other herpes simplex virus infection cluster includes herpes simplex, (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 genital herpes, herpes simplex otitis externa, and herpes virus infection, subject-years). Most subjects with keratitis recovered or were recovering but excludes eczema herpeticum. during the treatment period [see Adverse Reactions (6.1)]. Safety through Week 52 (Trial 3) Advise patients to report new onset or worsening eye symptoms to their In the DUPIXENT with concomitant TCS trial (Trial 3) through Week 52, healthcare provider. the proportion of subjects who discontinued treatment because of adverse 5.5 Reduction of Corticosteroid Dosage events was 1.8% in DUPIXENT 300 mg Q2W + TCS group and 7.6% in the Do not discontinue systemic, topical, or inhaled corticosteroids abruptly placebo + TCS group. Two subjects discontinued DUPIXENT because of upon initiation of therapy with DUPIXENT. Reductions in corticosteroid adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis dose, if appropriate, should be gradual and performed under the direct (1 subject). supervision of a physician. Reduction in corticosteroid dose may be The safety profile of DUPIXENT + TCS through Week 52 was generally associated with systemic withdrawal symptoms and/or unmask conditions consistent with the safety profile observed at Week 16. previously suppressed by systemic corticosteroid therapy. Adolescents with Atopic Dermatitis 5.6 Patients with Comorbid Asthma The safety of DUPIXENT was assessed in a trial of 250 subjects 12 to 17 Advise patients with atopic dermatitis or CRSwNP who have co-morbid years of age with moderate-to-severe atopic dermatitis (Trial 6). The safety asthma not to adjust or stop their asthma treatments without consultation profile of DUPIXENT in these subjects through Week 16 was similar to the with their physicians. safety profile from studies in adults with atopic dermatitis. 5.7 Parasitic (Helminth) Infections The long-term safety of DUPIXENT was assessed in an open-label Patients with known helminth infections were excluded from participation extension study in subjects 12 to 17 years of age with moderate-to-severe in clinical studies. It is unknown if DUPIXENT will influence the immune atopic dermatitis (Trial 7). The safety profile of DUPIXENT in subjects response against helminth infections. followed through Week 52 was similar to the safety profile observed at Treat patients with pre-existing helminth infections before initiating therapy Week 16 in Trial 6. The long-term safety profile of DUPIXENT observed in with DUPIXENT. If patients become infected while receiving treatment adolescents was consistent with that seen in adults with atopic dermatitis. with DUPIXENT and do not respond to antihelminth treatment, discontinue Specific Adverse Reactions treatment with DUPIXENT until the infection resolves. Conjunctivitis 6ADVERSE REACTIONS During the 52-week treatment period of concomitant therapy atopic The following adverse reactions are discussed in greater detail elsewhere dermatitis trial (Trial 3), conjunctivitis was reported in 16% of the in the labeling: DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in • Hypersensitivity [see Warnings and Precautions (5.1)] 9% of the placebo + TCS group (10 per 100 subject-years). [see Warnings • Conjunctivitis and Keratitis [see Warnings and Precautions (5.2)] and Precautions (5.2)]. 6.1 Clinical Trials Experience Eczema Herpeticum and Herpes Zoster Because clinical trials are conducted under widely varying conditions, The rate of eczema herpeticum was similar in the placebo and DUPIXENT adverse reaction rates observed in the clinical trials of a drug cannot be groups in the atopic dermatitis trials. directly compared to rates in the clinical trials of another drug and may not Herpes zoster was reported in <0.1% of the DUPIXENT groups (<1 per reflect the rates observed in practice. 100 subject-years) and in <1% of the placebo group (1 per 100 subject- Adults with Atopic Dermatitis years) in the 16-week atopic dermatitis monotherapy trials. In the 52-week Three randomized, double-blind, placebo-controlled, multicenter trials DUPIXENT + TCS atopic dermatitis trial, herpes zoster was reported in (Trials 1, 2, and 3) and one dose-ranging trial (Trial 4) evaluated the safety 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the of DUPIXENT in subjects with moderate-to-severe atopic dermatitis. placebo + TCS group (2 per 100 subject-years). The safety population had a mean age of 38 years; 41% of subjects were Hypersensitivity Reactions female, 67% were white, 24% were Asian, and 6% were black; in terms of Hypersensitivity reactions were reported in <1% of DUPIXENT-treated comorbid conditions, 48% of the subjects had asthma, 49% had allergic subjects. These included serum sickness reaction, serum sickness-like rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In reaction, generalized urticaria, rash, erythema nodosum, and anaphylaxis these 4 trials, 1472 subjects were treated with subcutaneous injections of [see Contraindications (4), Warnings and Precautions (5.1), and Adverse DUPIXENT, with or without concomitant topical corticosteroids (TCS). Reactions (6.2)]. A total of 739 subjects were treated with DUPIXENT for at least 1 year in Eosinophils the development program for moderate-to-severe atopic dermatitis. DUPIXENT-treated subjects had a greater initial increase from baseline Trials 1, 2, and 4 compared the safety of DUPIXENT monotherapy to in blood eosinophil count compared to subjects treated with placebo. In placebo through Week 16. Trial 3 compared the safety of DUPIXENT + TCS subjects with atopic dermatitis, the mean and median increases in blood to placebo + TCS through Week 52. eosinophils from baseline to Week 4 were 100 and 0 cells/mcL respectively. Weeks 0 to 16 (Trials 1 to 4) Across all indications, the incidence of treatment-emergent eosinophilia In DUPIXENT monotherapy trials (Trials 1, 2, and 4) through Week 16, the (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. Treatment- proportion of subjects who discontinued treatment because of adverse emergent eosinophilia (≥5,000 cells/mcL) was reported in <2% of events was 1.9% in both the DUPIXENT 300 mg Q2W and placebo groups. DUPIXENT-treated patients and <0.5% in placebo-treated patients. Blood eosinophil counts declined to near baseline levels during study treatment Table 1 summarizes the adverse reactions that occurred at a rate of at [see Warnings and Precautions (5.3)]. least 1% in the DUPIXENT 300 mg Q2W monotherapy groups, and in the DUPIXENT + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment.

191265_L01_Adult.indd 4 4/29/20 7:41 PM Cardiovascular (CV) Data In the 1-year placebo controlled trial in subjects with atopic dermatitis Animal Data (Trial 3), CV thromboembolic events (CV deaths, non-fatal MIs, and In an enhanced pre- and post-natal development toxicity study, pregnant non-fatal strokes) were reported in 1 (0.9%) of the DUPIXENT + TCS cynomolgus monkeys were administered weekly subcutaneous doses 300 mg Q2W group, 0 (0.0%) of the DUPIXENT + TCS 300 mg QW group, of homologous antibody against IL-4Rα up to 10 times the MRHD (on a and 1 (0.3%) of the placebo + TCS group. mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to 6.2 Immunogenicity parturition. No treatment-related adverse effects on embryofetal toxicity As with all therapeutic proteins, there is a potential for immunogenicity. The or malformations, or on morphological, functional, or immunological detection of antibody formation is highly dependent on the sensitivity and development were observed in the infants from birth through 6 months specificity of the assay. Additionally, the observed incidence of antibody of age. (including neutralizing antibody) positivity in an assay may be influenced 8.2 Lactation by several factors, including assay methodology, sample handling, timing Risk Summary of sample collection, concomitant medications, and underlying disease. There are no data on the presence of dupilumab in human milk, the effects For these reasons, comparison of the incidence of antibodies to dupilumab on the breastfed infant, or the effects on milk production. Maternal IgG is in the studies described below with the incidence of antibodies in other known to be present in human milk. The effects of local gastrointestinal studies or to other products may be misleading. and limited systemic exposure to dupilumab on the breastfed infant are Approximately 5% of subjects with atopic dermatitis, asthma, or CRSwNP unknown. The developmental and health benefits of breastfeeding should who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies be considered along with the mother’s clinical need for DUPIXENT and any to dupilumab; ~2% exhibited persistent ADA responses, and ~2% had potential adverse effects on the breastfed child from DUPIXENT or from the neutralizing antibodies. underlying maternal condition. Approximately 4% of subjects in the placebo groups in the 52-week studies 8.4 Pediatric Use were positive for antibodies to DUPIXENT; ~2% exhibited persistent ADA Atopic Dermatitis responses, and ~1% had neutralizing antibodies. The safety and efficacy of DUPIXENT have been established in Approximately 16% of adolescent subjects with atopic dermatitis who pediatric patients 12 years of age and older with moderate-to-severe received DUPIXENT 300 mg or 200 mg Q2W for 16 weeks developed atopic dermatitis. A total of 251 adolescents ages 12 to 17 years old antibodies to dupilumab; ~3% exhibited persistent ADA responses, and with moderate-to-severe atopic dermatitis were enrolled in Trial 6. The ~5% had neutralizing antibodies. safety and efficacy were generally consistent between adolescents and Approximately 4% of adolescent subjects with atopic dermatitis in the adults [see Adverse Reactions (6.1) and Clinical Studies (14.2) in the full placebo group were positive for antibodies to DUPIXENT; ~1% exhibited prescribing information]. Safety and efficacy in pediatric patients (<12 years persistent ADA responses, and ~1% had neutralizing antibodies. of age) with atopic dermatitis have not been established. The antibody titers detected in both DUPIXENT and placebo subjects were 8.5 Geriatric Use mostly low. In subjects who received DUPIXENT, development of high Of the 1472 subjects with atopic dermatitis exposed to DUPIXENT in a titer antibodies to dupilumab was associated with lower serum dupilumab dose-ranging study and placebo-controlled trials, 67 subjects were concentrations [see Clinical Pharmacology (12.3) in the full prescribing 65 years or older. Although no differences in safety or efficacy were information]. observed between older and younger subjects, the number of subjects Two subjects who experienced high titer antibody responses developed aged 65 and over is not sufficient to determine whether they respond serum sickness or serum sickness-like reactions during DUPIXENT therapy differently from younger subjects [see Clinical Pharmacology (12.3) in the [see Warnings and Precautions (5.1)]. full prescribing information]. 7 DRUG INTERACTIONS 10 OVERDOSE 7.1 Live Vaccines There is no specific treatment for DUPIXENT overdose. In the event of Avoid use of live vaccines in patients treated with DUPIXENT. overdosage, monitor the patient for any signs or symptoms of adverse 7.2 Non-Live Vaccines reactions and institute appropriate symptomatic treatment immediately. Immune responses to vaccination were assessed in a study in which 17 PATIENT COUNSELING INFORMATION subjects with atopic dermatitis were treated once weekly for 16 weeks with Advise the patients and/or caregivers to read the FDA-approved patient 300 mg of dupilumab (twice the recommended dosing frequency). After labeling (Patient Information and Instructions for Use). 12 weeks of DUPIXENT administration, subjects were vaccinated with Pregnancy Registry a Tdap vaccine (Adacel®) and a meningococcal polysaccharide vaccine ® There is a pregnancy exposure registry that monitors pregnancy (Menomune ). Antibody responses to tetanus toxoid and serogroup C outcomes in women exposed to DUPIXENT during pregnancy. Encourage meningococcal polysaccharide were assessed 4 weeks later. Antibody participation in the registry [see Use in Specific Populations (8.1)]. responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated subjects. Administration Instructions Immune responses to the other active components of the Adacel and Provide proper training to patients and/or caregivers on proper Menomune vaccines were not assessed. subcutaneous injection technique, including aseptic technique, and the preparation and administration of DUPIXENT prior to use. Advise patients 8 USE IN SPECIFIC POPULATIONS to follow sharps disposal recommendations [see Instructions for Use]. 8.1 Pregnancy Hypersensitivity Pregnancy Exposure Registry Advise patients to discontinue DUPIXENT and to seek immediate medical There is a pregnancy exposure registry that monitors pregnancy outcomes attention if they experience any symptoms of systemic hypersensitivity in women exposed to DUPIXENT during pregnancy. reactions [see Warnings and Precautions (5.1)]. Please contact 1-877-311-8972 or go to https://mothertobaby.org/ongoing- Conjunctivitis and Keratitis study/dupixent/ to enroll in or to obtain information about the registry. Advise patients to consult their healthcare provider if new onset or Risk Summary worsening eye symptoms develop [see Warnings and Precautions (5.2)]. Available data from case reports and case series with DUPIXENT use in Reduction in Corticosteroid Dosage pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Human IgG Inform patients to not discontinue systemic, topical, or inhaled antibodies are known to cross the placental barrier; therefore, DUPIXENT corticosteroids except under the direct supervision of a physician. Inform may be transmitted from the mother to the developing fetus. In an enhanced patients that reduction in corticosteroid dose may be associated with pre- and post-natal developmental study, no adverse developmental effects systemic withdrawal symptoms and/or unmask conditions previously were observed in offspring born to pregnant monkeys after subcutaneous suppressed by systemic corticosteroid therapy [see Warnings and administration of a homologous antibody against interleukin-4-receptor Precautions (5.5)]. alpha (IL-4Rα) during organogenesis through parturition at doses up to Patients with Comorbid Asthma 10-times the maximum recommended human dose (MRHD) (see Data). Advise patients with atopic dermatitis or CRSwNP who have comorbid The estimated background risk of major birth defects and miscarriage for asthma not to adjust or stop their asthma treatment without talking to their the indicated populations are unknown. All pregnancies have a background physicians [see Warnings and Precautions (5.6)]. risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

References: 1. DUPIXENT Prescribing Information. 2. 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. 3. Data on file, Regeneron Pharmaceuticals, Inc. 4. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389(10086):2287-2303. 5. Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial [published online November 6, 2019]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.3336

Manufactured by: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 U.S. License # 1760; Marketed by sanofi-aventis U.S. LLC, (Bridgewater, NJ 08807) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591). DUPIXENT® is a registered trademark of Sanofi Biotechnology/© 2019 Regeneron Pharmaceuticals, Inc./sanofi-aventis U.S. LLC. All rights reserved. Issue Date: June 2019 DUP.19.12.0053

PedDermASupp_11.indd 11 5/4/2020 3:48:57 PM

191035_L01_Adult.indd 5 1/23/20 6:15 PM 12 June 2020 • Pediatric Dermatology New mechanisms, therapies for acne considered

BY JIM KLING said. “And we also know that papules courage patients, she leans in. “I tell that develop into scars do so because patients they’re going to have some EXPERT ANALYSIS FROM COASTAL DERM they’re there for a longer period of sloughing of the skin the rst 2 weeks. SEATTLE – It used to be thought that time. Those that develop scars are I tell them that people pay money for acne begins with microcomedones, present about 10.5 days, compared that. It’s called a chemical peel,” said which go on to develop either in am- with 6.6 days for those that don’t de- Dr. Stein Gold, noting that patients re- matory lesions or nonin ammatory velop into scars.” spond well to this information. lesions, but more recent evidence has She went on to review some of the If patients nd the treatments too changed that perception, ac- new treatments for acne irritating, she advises them to avoid cording to Linda Stein Gold, that can be brought to bear applying it to wet skin. They can also MD, director of dermatology in such cases. These include apply it every other night, or even less research at Henry Ford Hos- developments with topical frequently, and then work up to more pital, Detroit. retinoids that are aimed at frequent use, she said at the meeting, Biopsies of acne-prone improving delivery and re- jointly presented by the University of areas have found that, be- ducing skin irritation. Louisville and Global Academy for fore the development of A new topical retinoid, Medical Education. microcomedones, “it appears trifarotene cream, 0.005%, Tazarotene is another topical ret- that there is in ammation Dr. Stein Gold showed ecacy and tolera- inoid that can be very irritating. A around the hair follicles,” Dr. bility for both the face and new lotion formulation of tazarotene Stein Gold said at the annual Coastal trunk in a recent phase 3 trial of pa- 0.045% contains a lower dose than the Dermatology Symposium. “All acne is tients with moderate facial and trun- 0.1% typically used in creams, and has in ammation acne,” and in ammation cal acne and was recently approved similar ecacy but reduced irritation, also persists, she added. Biopsies of for patients aged 9 years and older. In Dr. Stein Gold said. In August, the scarred lesions, once considered post- the study, about 30%-40% of people manufacturer submitted an application in ammatory, also have revealed per- aged 9 years and older treated with for approval with the Food and Drug sistent in ammation, she noted. once-daily trifarotene cream (Aklief ) Administration for treatment of acne. One study found that persistent scars achieved clear or almost-clear status Dr. Stein Gold also talked about can evolve from closed comedones, of the face at 12 weeks, vs. about using retinoids to minimize scarring, papules, and pustules, but the most 20% and 26%, of those on the vehicle referring to a study of patients with common was a papule that turned into cream (J Am Acad Dermatol. 2019 moderate and severe facial acne, a postin ammatory lesion (J Drugs Jun;80[6]:1691-9). and atrophic acne scars, comparing Dermatol. 2017 Jun 1;16[6]:566-72). The drug can also treat papules and adapalene 0.3% plus benzoyl peroxide “So when patients come in and they pustules, nearly as well as it treats 2.5% gel on one side of the face and have these red spots on their face, it’s blackheads and whiteheads, according vehicle on the other side of the face not over. There’s still time to be ag- to the dermatologist. for 24 weeks, followed by application gressive because those in ammatory Like other retinoids, it produces of the active treatment to both sides of lesions are more likely to lead to scars some redness and scaling, and rather the face for 24 weeks. Treatment was than anything else,” Dr. Stein Gold than letting these adverse events dis- Continued on following page }

Commentary by Dr. Sidbury Stein Gold also described a weaker strength tazarotene preparation (0.045% lotion) that also has shown promise, with similar efcacy DR. STEIN GOLD ADVISES NOT BEING COMPLACENT on either end but decreased irritation, compared with available 0.05% and 0.1% of the acne spectrum. In early microcomedonal acne, historically tazarotene products. dubbed “nonin ammatory,” in ammation is present and can be del- Dr. Stein Gold wisely prepares patients for expected retinoid-in- eterious; similarly, “old” red macules thought to represent resolved duced dryness and expertly repurposes this expected adverse effect acne also can have a residual in ammatory component that can as a benefit (e.g., like a chemical peel patients pay lots of money affect outcome. Her principal message is this: All acne is in am- for!). Finally, Dr. Stein Gold describes clascoterone, a pipeline top- matory, and topical retinoids can benet all phenotypes. Trifarotene ical androgen receptor antagonist that among other things inhibits 0.005% cream is a new topical retinoid approved down to 9 years of sebum production. This is the principal mechanism underpinning the age. This agent continues a trend of acne drug approval at younger efficacy of isotretinoin, so having a novel topical agent achieve this ages, mirroring the decreasing average age of acne presentation. Dr. same effect is exciting.

PedDermASupp_12thr15.indd 12 5/6/2020 8:24:56 AM A Supplement to Pediatric News & Dermatology News 13 Destress dermatologic procedures with honesty, distraction, and relaxation

BY HEIDI SPLETE concerns should be addressed. CBT-based techniques include deep FROM PEDIATRIC DERMATOLOGY breathing and positive coping state- educing fear and anxiety in chil- ments such as “I can do this” for older dren undergoing dermatologic children, or encouraging them to talk Rprocedures is possible with tech- about a family pet or listen to music. niques based on cognitive-behavioral Younger children may be distracted therapy, according to a report pub- with pinwheels, rattles, or songs. “Addi- lished in Pediatric Dermatology. tionally, in recent years, virtual reality For many children, the anticipation headsets have even proved to be eec- MAGES

of pain and the anxiety about a proce- tive distractors, resulting in an overall I

dure results in a more painful experi- reduction in both pain and fear,” Dr. ETTY ence, wrote Andrew M. Armenta, MD, Armenta and his associates noted. /G of the University of Texas, Galveston, Other useful strategies include

and colleagues. allowing children to choose their po- FOTOSTORM Preparing children in advance and sition and location for an injection or using cognitive-behavioral therapy procedure when possible. Small chil- is being done and why “not only makes (CBT) strategies in the moment can dren may be able to sit on the lap of practicing pediatric dermatology easier, help reduce their anxiety. an adult, and older children may prefer but also can improve patient adherence “CBT is a skill‐based approach that sitting up to lying down. Avoid physi- to painful procedures,” they said. focuses on the present and aims to teach cal restraint unless it is absolutely nec- No disclosure information was given. ecient ways of identifying distorted essary for safety, they emphasized. [email protected] thinking, modifying beliefs, and chang- Incorporating CBT-based strategies ing behaviors for a more favorable out- of breathing and distraction with hon- SOURCE: Armenta AM et al. Pediatr Dermatol. come of real‐life situations,” they wrote. esty and respectful disclosure of what 2019. doi: 10.1111/pde.13739. First, Dr. Armenta and his associates advised, be honest with children about what to expect from a procedure. Ev- Commentary by Dr. Sidbury idence does not support phrases such as, “It won’t hurt,” or “It will be over PROCEDURES – INCLUDING NEEDLE STICKS – are stressful for children. Dr. Armenta soon,” to reduce anxiety. reminds us that tepid reassurance like “it will be over soon” or white lies like “it won’t Timing the disclosure of a procedure hurt” are not the best way to decompress anxious children. He uses cognitive-behavioral and creating the appropriate setting also therapy to help children modify their beliefs and behaviors to decrease procedure-related can help reduce anxiety. For very young anxiety. One size will not t all, as younger children may do best with short notice to min- children, short notice of a procedure is imize anticipation, whereas an older child may do better with time to mentally prepare. often best, with the promise of a small When possible, allowing children a modicum of control (e.g., sit up or lie down) can be reward or outing afterward. Older chil- helpful. Physical restraint, the ultimate loss of control, should be avoided unless absolutely dren may want some advance notice so necessary. And sometimes it is. they can feel prepared, but their specic

| Continued from previous page a novel androgen receptor antagonist, Stein Gold said. A 1% cream formula- associated with a reduction of atrophic which inhibits sebum production and tion is being studied for acne. acne scars at 24 weeks, which was prevents colonization by Cutibacterium Dr. Stein Gold is a consultant, inves- maintained for up to 48 weeks (Am J acnes (formerly called Propionibacterium tigator, and/or speaker for Galderma, Clin Dermatol. 2019 Oct[5];20:725-32). acnes) and subsequent inammation. Ortho Derm, Sol Gel, Foamix, Cassi- “We can now say to patients, ‘Not “It does a lot of good things in terms opea, and Almirall. This publication only can I help you with your acne, of the pathogenesis of acne, but more and Global Academy for Medical Ed- but I can potentially even improve your importantly, it is one of the rst drugs ucation are owned by the same parent atrophic scarring,’ ” she said. that topically has been shown to de- company. Finally, she discussed clascoterone, crease the production of sebum,” Dr. [email protected]

PedDermASupp_12thr15.indd 13 5/6/2020 8:24:59 AM 14 June 2020 • Pediatric Dermatology Omalizumab proves effective for treating patients with severe pediatric atopic dermatitis

BY STEVE CIMINO index between the two groups was acknowledged that “omalizumab is –6.9 (95% confidence interval, –12.2 a costly intervention” but said atopic FROM JAMA PEDIATRICS to –1.5; P = .01) and significantly fa- dermatitis is also costly, raising the new study has found that omali- vored omalizumab therapy. question as to whether the high costs zumab (Xolair) reduced severity The adjusted mean difference for of both justify treatment. Aand improved quality of life in the Eczema Area and Severity Index In addition, omalizumab as treat- pediatric patients with severe atopic (–6.7; 95% CI, –13.2 to –0.1) also ment can come with both benets and dermatitis. favored omalizumab. In regard to harms. Severe atopic dermatitis can “Future work with an even larger decrease quality of life, and though sample size, a longer duration, and omalizumab appears to be safe, there higher-a nity versions of omalizum- “Future work with an even larger are adverse eects and logistical bur- ab would clarify the precise role of dens to overcome, she said. anti-IgE therapy and its ideal target sample size, a longer duration, More than anything, she recognized population,” wrote Susan Chan, MD, and higher-affinity versions of the need to prioritize, wondering what of Guy’s and St. Thomas’ NHS Foun- omalizumab would clarify the level of atopic dermatitis patients dation Trust in London and her co- would truly benet from this level of authors. The study was published in precise role of anti-IgE therapy treatment. “Is using a $100,000-per- JAMA Pediatrics. and its ideal target population.” year medication for an itchy condition To determine the benefits of an overtreatment,” she asked, “or a omalizumab in reducing immu- lifesaver?” noglobulin E levels and thereby The study was funded by the Na- treating severe childhood eczema, quality of life, after 24 weeks the tional Institute for Health Research the researchers launched the Atopic Children’s Dermatology Life Quality Efficacy and Mechanism Evalua- Dermatitis Anti-IgE Pediatric Trial Index/Dermatology Life Quality In- tion Programme and Guy’s and St. (ADAPT). dex favored the omalizumab group Thomas’ Charity. The authors had This randomized clinical trial re- with an adjusted mean difference of numerous financial disclosures, in- cruited 62 patients between the ages –3.5 (95% CI, –6.4 to –0.5). cluding receiving grants from the of 4 and 19 years with severe ecze- In an accompanying editorial, Ann NIHR EME Programme and Guy’s ma, which was defined as a score Chen Wu, MD, of Harvard Medical and St. Thomas’ Charity along with over 40 on the objective Scoring School in Boston noted that the re- active and placebo drugs from No- Atopic Dermatitis (SCORAD) index. sults of the study from Chan et al. vartis for use in the study. Dr. Wu They received 24 weeks of treat- were promising but “more questions reported receiving a grant from ment with either omalizumab (n = need to be answered before the drug GlaxoSmithKline. 30) or placebo (n = 32) followed by 24 can be used to treat atopic dermatitis [email protected] weeks of follow-up. Participants had a in clinical practice” (JAMA Pediatr. mean age of 10.3 years. 2019 Nov 25. doi: 10.1001/jamapediat- SOURCE: Chan S et al. JAMA Pediatr. After 24 weeks, the adjusted mean rics.2019.4509). 2019 Nov 25. doi: 10.1001/jamapediat- difference in objective SCORAD Her initial concern was price; she rics.2019.4476.

Commentary by Dr. Sidbury marked bene t across several metrics including severity indices and quality of life reports. THE CAUSAL ROLE OF IgE in atopic dermatitis (AD) is not clear. Most As Dr. Wu pointed out in her editorial, we will need to learn AD patients have elevated interleukin-4 and IL-5 which would lead to more before this expensive biologic (redundant?) medication elevated IgE and eosinophil levels, but which is the chicken and which can assume its place in the AD armamentarium. Do IgE levels the egg is less clear. An available therapy targeting IL-4 signaling, matter? Are specific dosing schedules necessary? Are certain AD dupilumab, has proven very effective. However, prior to the work by subtypes more amenable? Until these questions are answered, or Chan et al., treatments directed at IgE have been largely ineffective. trials with more than 62 patients at a single center yield similar My own experience with omalizumab for AD has not been encourag- results, I will reserve omalizumab for other conditions such as ing. In Dr. Chan’s cohort, however, children with severe eczema show chronic urticaria.

PedDermASupp_12thr15.indd 14 5/6/2020 8:25:00 AM A Supplement to Pediatric News & Dermatology News 15 Review looks at alopecia areata’s natural course

BY JAKE REMALY with a history of atopic dermatitis, and calculated that, for those with more 4% had an autoimmune disease (vitil- than 50% hair loss at the initial pre- FROM PEDIATRIC DERMATOLOGY igo, celiac disease, or type 1 diabetes). sentation, the likelihood of being in a ost children who develop alo- Twenty-eight percent of patients had high category of hair loss, as measured pecia areata before age 4 years a family history of alopecia areata, by increasing SALT scores, was sig- Mhave mild disease with less than 27.2% had a family history of other nicantly higher at 1 year (odds ratio, 50% hair loss, and present between autoimmune diseases, and 32% had a 1.85; P =.033) and at 2 or more years ages 2 and 4, according to a retrospec- family history of hypothyroidism. (OR, 2.29; P = .038). “While there is a tive chart review of 125 children. At the rst visit, 57.6% had patch‐stage likelihood of increasing disease severi- Almost 90% of the children presented alopecia and SALT scores in the mild t y, those with higher severity at initial between ages 2 and 4 years, compared range (0%‐24% hair loss), which was pres- presentation are likely to stay severe af- with 11.9% between ages 1 and 2 years, ent in a high proportion of these patients ter one or 2 years,” the authors noted. and 1.6% aged under 1 year, “in keeping at follow-up: 49.4% at 3-6 months, 39.5% They had no conicts of interest to with the existing literature,” the study at 1 year, and 42.9% at 2 or more years. disclose. authors reported in Pediatric Derma- At the rst visit, 28% had high SALT [email protected] tology. “A high percentage of patients scores (50%-100% hair loss), increasing continued to have mild, patchy alopecia to 36% at 3-6 months, 41.8% at 1 year, SOURCE: Rangu S et al. Pediatr Dermatol. at their follow‐up visits,” they added. and 46.4% at 2 or more years. They 2019 Aug 29. doi: 10.1111/pde.13990. Epidemiologic studies of children with alopecia areata are few and have not focused on the youngest patients, Commentary by Dr. Eichenfield said Sneha Rangu, of the section of dermatology at Children’s Hospital ALOPECIA AREATA (AA) is a not uncommon in ammatory autoimmune skin disorder of Philadelphia, and coauthors. They manifesting as focal nonscarring hair loss. It is highly variable in the extent of hair loss performed a retrospective chart review and course of the disease over time and can be very distressing for involved children of 125 patients, who initially present- and adolescents as well as their families. Rangu and colleagues at Children’s Hospital of ed at the hospital with alopecia areata Philadelphia have made a great contribution to our knowledge base by investigating 125 between Jan. 1, 2016, and June 1, 2018, children presenting with AA at age 4 years or younger. How did this relatively young group when they were younger than 4 years. present and were there associated autoimmune or other diseases? Did they have mild Patients who received systemic therapy or more severe disease? Was their course worse than older children diagnosed with AA? or topical Janus kinase (JAK) inhibitors The study showed that AA was quite rare under 2 years, with almost 90% of the children for alopecia were excluded. Severity was being aged 2-4 years when presenting. Female predominance, seen in other studies, was measured with the Severity of Alopecia significant (about 70%), but it is impossible to assess how this is affected by referral bias Tool (SALT) score, to monitor progres- or differential parental concern for boys versus girls. Only 4% of patients had an autoim- sion of hair loss, analyzing scores at the mune disease history (vitiligo, celiac disease, type 1 diabetes), while more than 40% had initial presentation, at 3-6 months, at 1 a history of atopic dermatitis. Family history of AA was seen in 28%, with about 27% and year, and at 2 or more years. 32% having family history of other autoimmune conditions or hypothyroidism. Alopecia Almost 70% were female, and 86.6% totalis (all of the scalp involved) or universalis (all hair bearing surfaces involved) was were between ages 2 and 4 years when seen in just less than 30% of patients, a higher number than I would expect, but probably they rst presented. The initial diag- affected by referral patterns into a specialty pediatric hair center. Most importantly to me, nosis was alopecia areata in 72.0%, the study showed in a 2-year observation period that those patients who did not have alopecia totalis in 8.8%, and alopecia high percentage loss (50%+) generally did well, while those who had more severe disease universalis in 19.2%. Of the 41 boys, initially had more of a chance of remaining more severe over time. This is consistent with 39% had alopecia totalis or alopecia other studies in older children and consistent with our experience at Rady Children’s Hos- universalis, as did 22% of the girls, pital, in San Diego. I often counsel families that, when a young child has focal hair loss, if which suggested that boys presenting they don’t reach the 50%-plus hair loss threshold, the prognosis is generally quite good, under aged 4 years were more likely with it being uncommon for them to progress to very severe losses. to have more severe disease, or that Finally, there are many studies ongoing for alopecia areata, including new therapeutic “guardians of boys are more likely to studies evaluating Janus kinase inhibitors and other systemic and possible topical agents. present for therapy when disease is There are no approved drugs for treating AA, and there is great interest in these studies more severe.” both for adults and pediatric patients. About 40% of the children presented

PedDermASupp_12thr15.indd 15 5/6/2020 8:25:00 AM 16 June 2020 • Pediatric Dermatology Psychology consult for children’s skin issues can boost adherence, wellness

BY DOUG BRUNK

EXPERT ANALYSIS FROM SPD 2019 AUSTIN, TEX. – One day each week, Sa- sha D. Jaquez, PhD, visits with patients in the dermatology clinic at Dell Chil- dren’s Medical Center of Central Texas who wrestle with some aspect of their skin condition, from noncompliance to a recommended treatment regimen to fear of needles when an injection of medicine is required to keep them well.

“Our goal is to help promote the AQUEZ

health and development of children, D. J

adolescents, and families through the ASHA . S

use of evidence-based methods like R cognitive-behavioral therapy,” said Dr. D Jaquez, who is a pediatric psychologist OURTESY

at the University of Texas, Austin. “We C do assessment and treatment of behav- Pediatric psychologist Sasha D. Jaquez (center) consults with two pediatric ioral and emotional di culties related dermatologists at Dell Children’s Medical Center, Austin: Dr. Lucia Diaz (left) and to their skin condition or medical con- chief of pediatric dermatology, Dr. Moise Levy (right). dition. So if they’re depressed but it’s not related to their skin condition, we focus on how to move forward in the to come from.’ Sometimes patients will likely refer the patient to a com- most e cient way possible by teach- aren’t ready to work on feeling better, munity mental health system.” ing skills, practicing those skills with and that is good for us to know.” During 1-hour visits at the derma- them in the o ce, and sending them During consultations, she often tology clinic, Dr. Jaquez uses a mixed home to use those skills. I don’t have talks with children and adolescents approach that includes cognitive-be- 100% compliance on this, so if I notice about how thoughts, feelings, and be- havioral therapy and motivational in- that they’re not doing what I asked of haviors are related. She’ll use phrasing terviewing to help patients and family them, we’ll have a conversation about like, “The way that you think about members cope with their problematic what the barrier is. ‘What is getting something changes the way that behavior or negative thought patterns in the way?’ I’ll ask. ‘Is this something you feel, and it changes the way that related to their skin conditions. “We you’re really wanting, or do you want you act. We have control over our do not have magic wands; we focus on a magic pill? If you want a magic pill, thoughts and behaviors, so if we think the here and now,” she explained. “We then our o ce isn’t where that’s going Continued on following page }

Commentary by Dr. Sidbury are complex, and solutions come gradually. Second, she focuses on positive, collaborative, realistic suggestions to help not just THE PSYCHOSOCIAL IMPACT OF CHRONIC SKIN DISEASE is appar- the affected child but the entire family to better cope. ent to anyone who cares for children with dermatologic issues. Her approach is grounded in empathy and seeks to destigma- For those who do not, a raft of recent literature rams this point tize the psychological comorbidities that can accompany chronic home: Adolescents with severe atopic dermatitis are more likely skin disease. to consider suicide; psoriasis patients more often suffer anxiety; She acknowledges that a staff psychologist is a luxury most depression is overrepresented among hidradenitis suppurativa dermatology practices do not have, and certainly none have hour- sufferers. Dr. Jaquez, a pediatric psychologist working at Dell Chil- long visits, but all providers can be alert to red ags; proactively dren’s Hospital in Austin, highlighted her approach to helping such probe for concerns; and offer appropriate support where it may individuals. First, she has 1-hour appointments. These problems best be found.

PedDermASupp_16thr19.indd 16 5/6/2020 8:23:03 AM A Supplement to Pediatric News & Dermatology News 17

| Continued from previous page with the stress of a chronic illness like chological and mental health issues for it’s going to be a bad d ay, it’s going psoriasis or atopic dermatitis. “Let’s their patients. “Psychological comor- to be a bad d ay. If we think it’s going gure out, ‘How do we accept that bidities such as depression and anxiety to be a good d ay, then we’re going this is how it is, and that they’re going can be associated with certain skin to nd the positive aspects in the day to have to nd their own ‘normal?’ ” conditions,” she said. “Let them know and we might let those bad aspects go she said. “I don’t know how many that this is stressful stu. Have discus- away. If I do something dierent [for sions early, so if the time comes for a my skin condition], then I’m going to “Give him something to do referral they won’t think you’re giving feel dierent.” besides scratch, because if those up on them. Don’t be afraid to say She recalled the case of a 3-year-old you have a psychologist that you want boy with atopic dermatitis who was hands are busy, he won’t be to refer to. S ay, ‘I have an added team referred for excessive scratching. His scratching. Let’s change the way member I would love for you to meet. mom stays at home, while dad works this behavior happens. Let’s give She’s our psychologist. She works with and travels frequently. “The parents patients who are having diculties.’ ” had diering views on how to treat his him attention all the time instead Giving patients perceived control medical condition. Mom wanted to of just when he’s scratching. of their care could also help improve do wet wraps while dad wanted to do the behavior of concern. For example, bleach baths. Their son was getting no That will work very quickly.” when patients with needle phobia treatment because the parents couldn’t require an injection, ask if they would agree on anything. Mom noticed that times someone comes into my oce like to lay down, or sit down for the her son scratches when he wants atten- and says, ‘I just want to be normal.’ I injection. “Giving them this tiny bit of tion and when he’s angry.” like to ask patients, ‘what is your nor- control is going to help them feel more When Dr. Jaquez met with his par- mal?’ These kids might have a lower empowered,” she said. ents, she encouraged them to agree quality of life than a child without a Dr. Jaquez also recommends that cli- on a plan to implement at home so chronic illness, but we want to make nicians pay attention to nonverbal cues that their son would gain some relief. sure that they’re living their lives to and steer clear of using scare tactics to She also advised them to ignore when the fullest. You want to monitor not change their behavior. “Use positive their son scratches or when he gets only adherence [to medication] but behavioral strategies and try to avoid angry. “Give him something else to do also quality of life. Sleep concerns are punishment. Children don’t want to besides scratch, because if those hands big. A lot of our kids might not being hear ‘stop’ all the time. Parents are are busy, he won’t be scratching. Let’s going to school, or they’re afraid to tired of saying it, and kids are tired change the way this behavior happens. go to school because they get picked of hearing it. We focus on praising Let’s give him attention all the time on because people don’t understand the things that are going well. I advise instead of just when he’s scratching. their skin condition.” parents all the time: ‘Catch them being That will work very quickly. And it Dr. Jaquez acknowledged that not all good.’ ” did.” dermatologists have a psychologist on Dr. Jaquez reported having no nan- She makes it a point to talk with sta or in their referral network, but cial disclosures. patients and their families about living all are capable of destigmatizing psy- [email protected] Frequent soaks ease pediatric atopic dermatitis

BY HEIDI SPLETE parents, according to Ivan D. Cardona, MD, of Maine Medical Research Insti- FROM THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY: IN PRACTICE tute, Portland, and colleagues. In a study published in the Journal regimen of twice-daily baths fol- of Allergy and Clinical Immunology: lowed by occlusive moisturizer In Practice, the researchers random- Aimproved atopic dermatitis in ized 42 children aged 6 months to 11 children with moderate to severe disease years with moderate to severe atopic more eectively than did a twice-weekly dermatitis to a routine of twice-week-

protocol, based on data from 42 children. ly “soak and seal” (SS) procedures HINKSTOCK /T Guidelines for bathing frequency consisting of soaking baths for 10 for children with atopic dermatitis are minutes or less, followed by an oc-

inconsistent and often confusing for Continued on following page } ANIAOSTUDIO

PedDermASupp_16thr19.indd 17 5/6/2020 8:23:03 AM 18 June 2020 • Pediatric Dermatology Acne before puberty: When to treat, when to worry

BY RANDY DOTINGA Dr. Friedlander, who is professor of cialist if there are other signs of hyper- dermatology and pediatrics at the Uni- androgenism. However, “the likelihood REPORTING FROM SDEF WOMEN’S & PEDIATRIC DERMATOLOGY SEMINAR versity of California, San Diego, talked is very low,” and she’s never needed to about treating acne in the following refer a neonate with acne for evaluation. NEWPORT BEACH, CALIF. – Acne – which prepubertal age groups: As for treatment, she said, “Mainly, can appear anytime from the neonatal I’m using tincture of time.” However, period to puberty – is most worrisome Neonatal acne (ages birth to 4 weeks) “many of my mothers have told me when it appears during the Acne appears in this popula- that topical yogurt application will midchildhood years, from tion up to 20% of the time, work.” Why yogurt? It’s possible that ages 1 to 7 years, according to according to research, and its bacteria could play a role in combat- Sheila Fallon Friedlander, MD. it is much more common in ing acne, she said. “This is something you are males than in females, at a Masquerader alert! Beware of neona- going to see in your prac- ratio of ve to one. tal cephalic pustulosis, Dr. Friedlander tice,” said Dr. Friedlander, a The cause is “most likely the cautioned, which may be an inamma- pediatric dermatologists at relationship between placental tory response to yeast. Ketoconazole Rady Children’s Hospital– androgens and the baby’s ad- cream may be helpful. San Diego. It’s important to Dr. Friedlander renal glands,” Dr. Friedlander know when it’s time to be said. However, something Infantile acne (ages 0-12 months) concerned and when another condi- more serious could be going on. “Look This form of acne is more common in tion may be masquerading as acne, she at the child and see if he’s sick. If he males and may hint at the future devel- said at the at Skin Disease Education looks sick, then we need to worry.” opment of severe adolescent acne. It Foundation’s Women’s & Pediatric Hormonal abnormalities also could be does resolve but it may take months or Dermatology Seminar. a cause, she said. Refer a baby to a spe- Continued on following page }

| Continued from previous page (SCORAD) compared with the less can be time consuming, making adher- clusive emollient, or to twice-daily frequent bathing (“dry method”). Im- ence dicult for families.” However, the SS with baths of 15-20 minutes fol- provements in SCORAD (the primary results suggest that the frequent bathing lowed by emollient. The groups were outcome) correlated with a secondary protocol was safe and eective at im- treated for 2 weeks, then switched outcome of improved scores on the par- proving symptoms of atopic dermatitis, protocols. The study included a total ent-rated Atopic Dermatitis Quickscore. and may reduce steroid use. of four clinic visits over 5 weeks. All The ndings were limited by factors The researchers had no nancial patients also received standard of care including small sample size, lack of data conicts to disclose. low-potency topical corticosteroids on environmental factors such as water [email protected] and moisturizer. temperature and quality, and the lack of Overall, the frequent bathing (“wet a washout period between the treatment SOURCE: Cardona ID et al. J Allergy Clin Im- method”) led to a decrease of 21.2 on protocols. They acknowledged that munol Pract. 2019 Nov 13. doi: 10.1016/j. the SCORing Atopic Dermatitis Index “twice-daily SS bathing in the real world jaip.2019.10.042.

Commentary by Dr. Eichenfield soaking baths for 15-20 minutes, followed by emollient. After 2 weeks, patients were changed to the other regimen, and throughout the 4 THERE HAVE BEEN VARIABLE APPROACHES to recommendations weeks, all received standard low-potency topical corticosteroids and on bathing practices for individuals with atopic dermatitis (AD), with moisturizer. The “wet method” won! Frequent bathing improved the one older methodology stressing avoidance of bathing to “minimize objective eczema scores much more than the “dry method.” drying of the skin.” Studies have clearly shown that moisturizing after It’s uncertain if the bathing is helping by impacting on skin mois- bathing obviates any drying effect of bathing and evaporation, which ture content, debriding the skin of antigens and impacting bacteria, can occur without moisturizers. However, there is still inconsistency in or by changing the utility of the topical medications and moisturiz- advice about how frequent someone with AD should bathe. Dr. Car- ers. My takeaway from this study? While twice-a-day bathing might dona and colleagues from the Maine Research Institute carried out a be hard to do in “real-life” eczema care, bathing can be a helpful well-designed, prospective study of 42 children randomized to 2 weeks intervention, and avoidance of bathing has no justi cation from an of infrequent (twice-weekly) 10-minute or less baths, or to twice-daily eczema standpoint.

PedDermASupp_16thr19.indd 18 5/6/2020 8:23:04 AM A Supplement to Pediatric News & Dermatology News 19

Commentary by Dr. Sidbury DR. FRIEDLANDER NOTES THAT acne can span the pediatric age spectrum from 0 to 18 years of age, and different concerns may be appropriate depending on the age of presentation. Neonatal acne does not generally cause alarm if the infant is otherwise well. Parents often suffer dissonance as they strident- ly wish for resolution yet eschew any

OURCE potentially harmful interventions at this S age. Yogurt to the rescue! There is an-

CIENCE ecdotal evidence (oxymoron?) that top- /S ically applied yogurt may treat neonatal

ARAZZI acne, and parents feel very comfortable with its use; at the very least it may . P. M . P. R

D safely bide time for this spontaneously Infantile acne does resolve but it may take months to years. resolving af iction. Dr. Friedlander also calls out midchildhood acne (affecting | Continued from previous page if the child is on medication. “You need children aged 1-7 years) as a context in years, Dr. Friedlander said. to look carefully,” she said, adding that which underlying pathology must more In general, this acne isn’t a sign of it’s important to check for signs of pre- carefully be considered. Such children something more serious. “You do not mature puberty such as giant spikes in always should have their growth plotted, need to go crazy with the work-up,” growth, abnormally large hands and and examination should screen for signs she said. “With mild to moderate dis- feet, genital changes, and body odor. of androgenization such as pubic hair ease, with nothing else suspicious, I Check blood pressure if you’re worried or body odor. Distinctive clinical mimics don’t do a big work-up.” about an adrenal tumor. such as facial angiobromas in tuberous However, do consider whether the It’s possible for children to develop sclerosis always should be considered child is undergoing precocious puberty, precocious puberty – with acne – be- when the pieces do not t. Dr. Friedlander said. Signs include axil- cause of exposure to testosterone gel lary hair, pubic hair, and body odor. used by a father. Dehydroepiandroste- As for treatment of infantile acne, rone (DHEA) creams also may cause investigate further if there’s signi cant “start out topically” and consider op- the condition. “The more creams out inammation and signs of early sexual tions such as Bactrim (sulfamethoxaz- there with androgenic eects, the more development or virilization. ole/trimethoprim) and erythromycin. we may see it,” Dr. Friedlander said. Benzoyl peroxide wash may be Masquerader alert! Idiopathic facial “This is something to ask about because enough to help the condition initially, aseptic granuloma can be mistaken families may not be forthcoming.” and consider topical clindamycin or a for acne and abscess, and ultrasound is Masquerader alert! Perioral dermatitis combination product. “Start out slow,” helpful to con rm it. “It’s not so easy may look like acne, and it may be linked she said. Twice a week to start might to treat,” she said. “Ivermectin may be to inhaled or topical steroids, she said. be appropriate. Moisturizers can be helpful. Sometimes you do cultures Other masqueraders include demo- helpful, as can topical adapalene. and make sure something else isn’t dex folliculitis, angio bromas (think Also, keep in mind that even mild going on.” tuberous sclerosis), and keratosis pi- acne can be emotionally devastating to laris (the most common type of bump a child in this age group and worthy of Midchildhood (ages 1-7 years) on a children aged 1-7 years). The treatment. “Your assessment may be “It’s not as common to have acne de- latter condition “is not the end of the very dierent than hers,” she said. It’s velop in this age group, but when it world,” said Dr. Friedlander, who add- possible that “she has a few lesions, but develops you need to be concerned,” ed that “I’ve never cured anyone of it.” she feels like an outcast.” Dr. Friedlander said. “This is the age Dr. Friedlander reported no relevant period when there is more often some- Prepubertal acne (ages nancial disclosures. SDEF and this thing really wrong.” 7 years to puberty) news organization are owned by the Be on the lookout for a family history Acne in this group is generally not same parent company. of hormonal abnormalities, and check worrisome, Dr. Friedlander said, but [email protected]

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