Dermatol Ther (Heidelb) (2018) 8:349–377 https://doi.org/10.1007/s13555-018-0243-4 REVIEW A Systematic Scoping Literature Review of Publications Supporting Treatment Guidelines for Pediatric Atopic Dermatitis in Contrast to Clinical Practice Patterns . . Elaine C. Siegfried Jennifer C. Jaworski Paola Mina-Osorio Received: April 20, 2018 / Published online: June 1, 2018 The Author(s) 2018 were disproportionately more publications for ABSTRACT topical calcineurin inhibitors (TCI) compared with topical corticosteroids (TCS); however, the Introduction: Treatment guidelines endorse a search interval may have biased the results variety of strategies for atopic dermatitis (AD) toward treatments approved near the beginning which may vary from published data and clin- of the time frame. In contrast, publications ical practice patterns. The objective of this documenting clinical practice patterns reﬂect review was to quantify the volume of available greater use of emollients and TCS (over TCI), as medical literature supporting pediatric AD well as systemic corticosteroids. Data is rela- treatments and compare these patterns to those tively limited for long-term and combination recommended by published guidelines and/or treatment, treatment of severe AD, and patients clinical practice patterns. younger than 2 years of age, and completely Methods: Searches of Embase (2005–2016) and lacking for systemic corticosteroids. abstracts from selected meetings (2014–2016) Conclusion: This scoping review demonstrates related to AD treatment in patients younger that available medical literature largely supports than 17 years of age yielded references that were published guidelines for topical therapy; how- assessed by study design, primary treatment, ever, clinical practice patterns are less aligned. age groups, and AD severity. There is a lack of data for older, more frequently Results: Published literature partially supports used generic treatments, including oral anti- clinical guidelines, with emollients and topical histamines, oral antibiotics, and systemic cor- medications being the most investigated. There ticosteroids. Overall, literature is lacking for Enhanced digital features To view enhanced digital long-term treatment, treatment for patients features for this article go to https://doi.org/10.6084/ younger than 2 years of age, and for systemic m9.ﬁgshare.6275408. treatment for severe disease. Funding: Regeneron Pharmaceuticals Inc. E. C. Siegfried Saint Louis University and Cardinal Glennon Children’s Hospital, St. Louis, MO, USA Keywords: Adolescents; Atopic dermatitis; Atopic eczema; Biologic agents; Children; J. C. Jaworski Infants; Systemic treatment; Topical Chicago, IL, USA calcineurin inhibitors; Topical corticosteroids; P. Mina-Osorio (&) Topical treatment Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA e-mail: email@example.com 350 Dermatol Ther (Heidelb) (2018) 8:349–377 included the American Academy of Dermatol- INTRODUCTION ogy (AAD; annual and summer meetings), the American Academy of Allergy, Asthma and Atopic dermatitis (AD) is a systemic immune- Immunology (AAAAI), the Society for Pediatric mediated disease which primarily affects chil- Dermatology (SPD)/World Congress of Pediatric dren with variably reported pediatric prevalence Dermatology (WCPD), the European Academy of 9–25% [1, 2]. There is a wide range of disease of Dermatology and Venereology (EADV), the severity, and a variety of approaches to treat- Society for Investigational Dermatology (SID)/ ment. There are few US Food and Drug International Investigational Dermatology Administration (FDA)-approved treatments for (IID), and the European Society for Pediatric AD, leaving many health care providers to pre- Dermatology (ESPD) meetings in the previous scribe off-label medications. 3 years. References from meetings other than Several recent treatment-speciﬁc systematic these were not included. reviews evaluate the efﬁcacy and/or safety of Results are reported as numbers of references topical calcineurin inhibitors (TCIs) [3, 4], by study design (interventional non-comparative, topical corticosteroids (TCS) , immunother- interventional non-randomized comparative, apy , immunosuppressants [6, 7], omal- randomized active-controlled, randomized pla- izumab , emollients [9, 10], phototherapy cebo/vehicle-controlled, randomized untreated- [11–14], and wet wraps . The goal of this controlled, observational prospective cohort, systematic scoping review was to quantitatively observational cross-sectional, observational and qualitatively assess the volume of medical comparative, registry, case report/series, pooled/ literature supporting guidelines-based treat- secondary/subgroup analysis of previously pub- ment as well as treatment with recently lished data, retrospective chart review, retrospec- approved and late-stage investigational phar- tive cohort, and survey/interview). On the basis of macologic and non-pharmacologic agents for keywords listed in Table 1, references were also AD in pediatric patients [1, 16–25]. Because identiﬁed by category of primary treatment there are no pediatric-speciﬁc AD treatment investigated [TCIs, TCS, systemic immunother- guidelines, we sought to evaluate how different apy, biologic, systemic immunosuppressant, treatment modalities have been investigated topical phosphodiesterase 4 (PDE4) inhibitor, across age groups and disease severities and how topical antibiotic, oral PDE4 inhibitor, topical these correspond to published guidelines and immunotherapy, pharmacologic combination studies of clinical practice patterns. The results treatment, emollient, phototherapy, wet wraps, of this analysis indicate gaps in evidence sup- bathing, dilute bleach baths, and non-pharma- porting current clinical management. cologic combination treatment]. When more than one active treatment was compared, only the METHODS primary treatment was used to categorize the ref- erence; if a combination of treatments was used as A literature search for ‘‘atopic dermatitis’’ and primary treatment, the reference was categorized speciﬁc drug-related keywords was performed as ‘‘combination treatment’’. The potency of TCS using Embase on 7 November, 2016. Search was determined on the basis of several sources terms are listed in Table 1. A review protocol [16, 26–28], and clinical judgment in the case of does not exist. This article is based on previ- non-marketed products; if a study included more ously conducted studies and does not contain than one TCS of different potency (e.g., medium any studies with human participants or animals potency for the body and low potency for face), it performed by any of the authors. was counted for the highest potency TCS used. Results were limited to those published in References that described clinical practice pat- English after 1 January, 2005 that included terns were summarized separately. References newborns, infants, children, and/or adoles- regarding new data (i.e., not pooled/sec- cents. The search was supplemented with ondary/subgroup analysis of previously published manual searches of selected meetings, which data) were further categorized by AD severity as Dermatol Ther (Heidelb) (2018) 8:349–377 351 Table 1 Search terms Treatment Search terms Corticosteroid ‘‘Topical corticosteroid*’’ OR ‘‘topical glucocorticoid*’’ OR ‘‘systemic corticosteroid*’’ OR ‘‘corticosteroid*’’ OR ‘‘glucocorticoid*’’ OR ‘‘hydrocortisone acetate’’ OR ‘‘alclometasone dipropionate’’ OR ‘‘clobetasone butyrate’’ OR ‘‘dexamethasone sodium phosphate’’ OR ‘‘dexamethasone valerate’’/de OR ‘‘dexamethasone valerate’’ OR ‘‘desonide’’ OR ‘‘ﬂuocortinbutylester’’ OR ‘‘beclomethasone dipropionate’’ OR ‘‘betamethasone benzoate’’ OR ‘‘betamethasone dipropionate’’ OR ‘‘budesonide’’ OR ‘‘desoximetasone’’ OR ‘‘diﬂucortolone valerate’’ OR ‘‘ﬂuocinolone acetonide’’ OR ‘‘ﬂuocinonide’’ OR ‘‘ﬂuocortolone’’ OR ‘‘ﬂuocortolone caproate’’ OR ‘‘ﬂuticasone propionate’’ OR ‘‘methylprednisolone aceponate’’ OR ‘‘mometasone furoate’’ OR ‘‘prednicarbate’’ OR ‘‘halcinonide’’ OR ‘‘clobetasol propionate’’ OR Calcineurin ‘‘Tacrolimus’’ OR ‘‘pimecrolimus’’ OR inhibitor Immunosuppressant ‘‘Cyclosporine’’ OR cyclosporin OR ‘‘azathioprine’’ OR ‘‘methotrexate’’ OR ‘‘mycophenolate mofetil’’ OR Oral antihistamine ‘‘Oral antihistamine*’’ OR Phototherapy ‘‘Phototherapy’’ OR Immunotherapy Immunotherapy OR Emollient ‘‘Emollient*’’ OR Wet wrap ‘‘Physical therap*’’ OR ‘‘wet wrap*’’ OR ‘‘wet dressing*’’ OR Bathing ‘‘Bath*’’ OR Dilute bleach baths ‘‘Hypochlorite sodium’’ OR Antibiotic ‘‘Antibiotic agent’’ OR ‘‘beta lactam antibiotic’’ OR ‘‘ﬂucloxacillin’’ OR ‘‘amoxicillin plus clavulanic acid’’ OR ‘‘cephalosporin’’ OR Biologic ‘‘Omalizumab’’ OR ‘‘ustekinumab’’ OR PDE4 inhibitor ‘‘Apremilast’’ OR ‘‘crisaborole’’ OR ‘‘e6005’’ OR ‘‘e-6005’’ OR ‘‘opa-15406’’ OR ‘‘opa15406’’ PDE4 phosphodiesterase 4 deﬁned within the reference (mild was analyzed RESULTS together with mild-to-moderate, and moderate was analyzed with moderate-to-severe/very sev- A total of 1579 references were retrieved from ere) and pediatric age groups included in Embase and screened for relevance (Fig. 1). The the study [newborns (up to 1 month), infants following references were excluded: those not (1–12 months), children (1–12 years), and/or focused on treatment (i.e., risk factors for AD), adolescents (13–17 years)]; studies that included those that did not specify treatment, duplicate patients from more than one age group were references, encore abstracts, abstracts present- counted in both groups. Interventional trials were ing data for which a manuscript has been pub- classiﬁed by duration of treatment, or duration of lished, abstracts from other meetings, non- follow-up for long-acting treatments like English articles, abstract supplements, retracted immunotherapy and biologics. articles, commentaries, review articles, and 352 Dermatol Ther (Heidelb) (2018) 8:349–377 Fig. 1 PRISMA ﬂow diagram. AD atopic dermatitis introductory articles. An additional 77 articles hydrocolloid dressing, homeopathy, applica- were not included in the analysis because they tion of human milk, and high altitude treat- focused on treatments that are not part of cur- ment (n = 1 each). In addition, references rent guideline-based management or new ther- focusing on adult patients, patient populations apies: pro/prebiotics (n = 14); clothing (n = 10); with mean age greater than 20 years, patient traditional Chinese medicine (n = 8); intra- populations that were less than 40% pediatric, venous immunoglobulin (n = 5); cleansing, or prevention of AD were also excluded leaving vitamin supplements, and educational inter- 231 articles. Manual searches of abstracts from ventions (n = 4 each); dietary elimination and selected meetings yielded an additional 24 ref- balneo/crenotherapy (n = 3 each); oral leuko- erences, added to the 51 identiﬁed in the triene inhibitors, water softeners, apheresis, and Embase search, for a total of 75 abstract refer- phytotherapy (n = 2 each); and acupuncture, ences. This yields a total of 255 references for topical antifungal, temperature-controlled inclusion. lamellar airﬂow, skin acidiﬁcation, peroxisome Of these, 17 assessed clinical practice patterns proliferator-activated receptor-alpha agonist via prospective analysis, claims data, retrospec- treatment, efalizumab, etanercept, chloroquine, tive analysis, or surveys/interviews [29–45], and lipoxins, adrenergic agonist treatment, documented a wide variety of treatments used in Dermatol Ther (Heidelb) (2018) 8:349–377 353 clinical practice (Fig. 2). Overall, 7 of 17 papers each). Other designs were utilized less often reported emollient use by up to 96% of patients. [randomized vehicle-controlled (n = 3), ran- Seven references also reported systemic corti- domized active-controlled (n = 2 and n =4, costeroid use in 1–25% of patients. respectively), and randomized active-/vehicle- The most frequently used study designs in controlled (n = 1 each)]. Studies that included this 11-year review were interventional non- infants were more often interventional non- comparative and randomized controlled. The comparative (n = 3) or randomized active-con- most frequently investigated medical treat- trolled (n = 3) compared with randomized ments were TCIs and emollients (Fig. 3). vehicle-controlled (n = 1). The single trial that included newborns was randomized, comparing different dosing regimens. Of the active-con- Treatments by AD Severity and Age Group trolled studies, 1 was once versus twice daily treatment, 1 was proactive versus reactive Published pharmacologic treatment trials varied treatment, 1 was soak-and-smear vs dry skin by AD severity (Fig. 4); however, AD severity application, and 1 was application before versus was not consistently deﬁned. A number of after emollient, all with the same TCS. The only studies did not prespecify severity (n = 48) or active- and vehicle-controlled trial compared used surrogate deﬁnitions (n = 8). The pattern different formulations of the same TCS. Among of severities studied was similar across age the 20 interventional TCS studies, 1 used lowest groups. Mild-to-moderate or not speciﬁed/other potency, 5 used low potency, 2 used lower- severity was included most frequently, and the medium potency, 11 used medium potency, 13- to 17-year age range was investigated most none used high potency, and 1 used very high often (Fig. 5). potency TCS. Of these, two of the medium Publications more often investigated topical potency TCS studies included a low potency treatments for mild-to-moderate AD and sys- TCS for the face and other sensitive skin areas temic treatments for more severe AD (Fig. 4). (Table 2). More studies of mild-to-moderate Non-pharmacologic treatments were investi- disease focused on older age groups (Table 2). gated primarily in mild-to-moderate AD (Fig. 4). There were 59 references with TCIs as pri- Across age groups, TCIs and emollients were mary treatment [73–131]; an additional 5 ref- the treatments most frequently investigated erences used TCIs as an active comparator. Of (Fig. 6). The number of treatment modalities the 59 references, 9 were pooled/secondary/post investigated in children (1–12 years) was greater hoc analyses of previously published studies than any other age group (Fig. 6). Few studies and 7 studies did not assess clinical efﬁcacy. The included treatment in infants and newborns greatest numbers of TCI clinical efﬁcacy studies (Fig. 6). Despite the frequency of systemic cor- in adolescents, children, and/or infants were ticosteroid use in clinical practice, this analysis interventional non-comparative (n = 12, n = 16, failed to identify any publications supporting n = 6, respectively) or randomized vehicle-con- use of this treatment. trolled (n =8, n = 12, n = 3) compared with randomized active-controlled (n =9, n = 10, Supporting Evidence by Treatment n = 3). Of the active-controlled studies, 9 were versus TCS, 1 was versus the same TCI using Topical Pharmacologic Treatments different doing regimen, 1 was versus another There were 27 references that studied TCS as TCI, and 2 were versus emollient/device cream. primary treatment [46–72]; an additional 16 The majority of references (10/16, 63%) used TCS as an active comparator. Of the 27 supporting topical PDE4 inhibitors were pooled references focusing on TCS, 2 were pooled or post hoc analyses [132–147]. Of the remain- analyses of previously published studies, 5 were ing references, 3 were randomized vehicle-con- case reports/series, and 3 did not assess clinical trolled, 2 were interventional non-comparative, efﬁcacy. TCS clinical efﬁcacy studies were pri- and 1 was randomized active-controlled versus marily interventional non-comparative (n =7 354 Dermatol Ther (Heidelb) (2018) 8:349–377 Fig. 2 Clinical practice patterns. AD atopic dermatitis, ICD international classiﬁcation of diseases, NOS not otherwise speciﬁed, NR not reported, PIM pimecrolimus, RoA route of administration, TAC tacrolimus, TCI topical calcineurin inhibitor Dermatol Ther (Heidelb) (2018) 8:349–377 355 Fig. 2 continued 356 Dermatol Ther (Heidelb) (2018) 8:349–377 Fig. 2 continued Dermatol Ther (Heidelb) (2018) 8:349–377 357 Fig. 3 Number of references by primary investigated treatment (a) and study design (b; n = 238). The same color coding used in a was used to indicate primary treatment investigated in b, and in all other ﬁgures. PDE4 phosphodiesterase 4 Fig. 4 Number of references investigating pharmacologic x-axis; pattern ﬁlled bars represent the ‘‘mild’’ (n =4) or (a) and non-pharmacologic (b) treatments by AD severity ‘‘moderate’’ (n = 8) subset of the indicated ranges. PDE4 (n = 215). Solid ﬁlled bars represent ranges listed on the phosphodiesterase 4 358 Dermatol Ther (Heidelb) (2018) 8:349–377 Fig. 5 Number of references by AD severity and age group (n = 215). Solid ﬁlled bars represent ranges listed on the x-axis; pattern ﬁlled bars represent the ‘‘mild’’ (n = 4) or ‘‘moderate’’ (n = 8) subset of the indicated ranges Fig. 6 Number of references investigating pharmacologic (a) and non-pharmacologic (b) treatments by age group (n = 215). PDE4 phosphodiesterase 4 the same topical PDE4 inhibitor using a differ- interventional non-comparative (n = 3), ran- ent dosing regimen. domized vehicle-controlled (n = 3), or random- Topical combination treatments included ized active-controlled (n = 9; 8 were vs TCS–antibiotic (n = 4), TCI–phototherapy monotherapy and 1 was vs emollient) and (n = 1), TCS–TCI (n = 6), TCS–emollient (n =3), included adolescents (n = 11), children (n = 13), and TCS–wet wrap (n =2) [148–163]. There was and infants (n =4). 1 case series. The remaining studies were Dermatol Ther (Heidelb) (2018) 8:349–377 359 Table 2 Number of references investigating topical corticosteroids by potency, AD severity, and age group a b Topical corticosteroid AD severity Age group (TCS) potency Mild-to- Moderate-to-severe/ Mild-to-severe/ Severe Not Adolescents Children Infants Newborns moderate very severe very severe speciﬁed/ other Lowest/class VII (n =5) 1 1 3 2 2 2 Low/class VI (n =5) 3 2 3 5 5 Lower–medium/class V (n =3) 1 2 2 3 3 Medium class III–IV (n =6) 1 2 1 1 1 3 6 1 1 High/class II (n =0) Very high/class I (n =6) 2 3 1 6 4 1 AD atopic dermatitis Mild-to-moderate includes ‘‘mild’’ (n = 4), moderate-to-severe/very severe includes ‘‘moderate’’ (n =8) Studies that spanned more than one age group are counted more than once If a study included[ 1 TCS of different potency (e.g., medium potency for the body and low potency for face), it was counted for the highest potency TCS used; lowest includes methylprednisolone aceponate 0.1% (formulation not speciﬁed), methylprednisolone aceponate 0.1% cream, prednisolone valerate 0.3% ointment, triamcinolone acetonide 0.0025% cream; low, desonide 0.05% foam, desonide 0.05% hydrogel, ﬂuocinolone acetonide 0.01% oil; lower-medium, hydrocortisone butyrate 0.1% cream, ﬂuticasone propionate 0.05% lotion; medium, betamethasone valerate 0.1% ointment, clobetasone butyrate 0.05% cream, clocortolone pivalate 0.1% cream, ﬂuticasone propionate 0.005% ointment, triamcinolone acetonide 0.1% ointment; very high, clobetasol propionate 0.05% cream/lotion, ﬂuocinonide 0.1% cream 360 Dermatol Ther (Heidelb) (2018) 8:349–377 In addition, topical antibiotic treatment was were versus conventional multimodal therapy. the subject of a randomized vehicle-controlled There were no immunotherapy trials in infants study in children and adolescents , and or newborns. topical immunotherapy with Streptococcus pyo- There were 10 references that included genes ointment was the topic of a case study in a omalizumab (n = 9) or ustekinumab (n =1) child . biologic treatment [200–209]. Of these, only 3 Topical pharmacologic treatments were the were interventional: 2 non-comparative (1 in most frequently investigated. Overall, evidence adolescents, 1 in children and adolescents) and was high level and covered a wide range of age 1 randomized placebo-controlled in children groups. Notably, the only reference to include and adolescents. The other 7 were case reports/ newborns was a TCS trial. series. Systemic combination treatments included immunotherapy–immunomodulator (n =3) and Systemic Pharmacologic Treatments immunotherapy–immunosuppressant (n =1) There were 15 references that included one or combinations [210–213]. They were interven- more systemic immunosuppressant agents as tional non-comparative (n = 2) and interven- primary treatment [166–180]; 1 additional ref- tional non-randomized comparative (n =2) and erence used a systemic immunosuppressant as included children and adolescents (n =3) or an active comparator. Medications included adolescents alone (n =1). azathioprine (n = 7), cyclosporine (n =6), In addition, there was a case report of oral cyclosporine–glucosamine combination (n =2), PDE4 inhibitor treatment in a child . methotrexate (n = 3), and mycophenolate Systemic treatments were investigated less mofetil (n = 3). Of the 15 references, 2 were case frequently than topical treatments. The level of reports/series, 6 were retrospective chart re- evidence in these references was lower than views/cohorts, and 1 was a registry. Of the those in references about topical treatments. remaining 6 studies, all assessed clinical efﬁ- There was only 1 paper among 60 that included cacy—1 was interventional non-comparative infants; none included newborns. (including children and adolescents), 2 were randomized placebo-controlled (1 in adoles- cents, 1 in children), 2 were randomized active- Non-pharmacologic Management controlled (1 versus a different systemic There were 53 references addressing ﬁrst-line immunosuppressant in children and 1 combi- skin care as primary treatment [215–267], nation systemic immunosuppressant therapy including 42 papers assessing emollients (an versus monotherapy in adolescents). additional 4 used emollient as an active com- There were 19 references that used systemic parator), 4 assessing bathing (an additional 2 immunotherapy as primary treatment references used bathing as an active compara- [181–199] including subcutaneous (n = 12), tor), 2 assessing dilute bleach baths, and 5 sublingual (n = 4), or oral antigen administra- assessing emollient–cleanser combinations. Of tion (n = 1), and intradermal (n = 1) or subcu- these 53 references, 2 were case reports/series taneous Mycobacterium vaccae (n = 1). Of these, and 2 were pooled/secondary/subgroup analy- 1 was a case report and 2 were retrospective ses of previously published data. All but one of chart reviews. Of the remaining 16 studies, 15 the remaining papers assessed efﬁcacy including assessed clinical efﬁcacy. Of these, 6 were 2 retrospective chart reviews/cohorts, 6 obser- interventional non-comparative (1 in adoles- vational studies, 17 interventional non-com- cents, 1 in children, 4 included both groups), 3 parative studies, 10 randomized untreated/ were randomized placebo-controlled (1 in ado- vehicle-controlled studies, 12 randomized lescents, 1 in children, 1 included both groups), active-controlled studies, and 1 randomized 4 were untreated-controlled (all included chil- active- and untreated-controlled study. Of the dren and adolescents), and 2 were active-con- trials that included an active comparator, 2 were trolled (1 in adolescents, 1 included both versus TCS, 5 were versus a different emollient, groups). Of the active controlled trials, both 2 were versus bathing, and 3 were versus Dermatol Ther (Heidelb) (2018) 8:349–377 361 Fig. 7 Duration of treatment for short-acting treat- treatment/follow-up could not be determined for 1 study ments/duration of follow-up for long-acting treatments published as an abstract. PDE4 phosphodiesterase 4, w in interventional studies (n = 162). Duration of weeks, y years monotherapy. First-line skin care efﬁcacy stud- investigating emollients and other skin care ies primarily included children (n = 48). included high level evidence, while references A total of 5 references assessed wet wrap investigating wet wrap therapy and photother- therapy as primary treatment [268–272]. Of apy had lower level evidence. these 1 was a retrospective chart review, 1 was an observational prospective cohort, and 2 were interventional non-comparative. The remain- Treatments and Interventional Trial ing reference was a randomized active-con- Evidence by Duration of Treatment trolled study versus conventional treatment in children and infants. Out of the 162 interventional studies, 106 There were 11 references assessing pho- (65%) were less than 12 weeks in duration totherapy as primary treatment [273–283]. The (Fig. 7). Only TCIs, TCS, systemic majority (7/11, 64%) were retrospective immunotherapy, and pharmacologic combina- chart reviews. One additional reference inclu- tion treatment have been investigated for more ded phototherapy as an active comparator. than 52 weeks (Fig. 7). All TCS and TCI studies Emollients were the second most investi- that were 24 weeks or longer used intermittent gated treatment. Overall, published studies of (less than daily treatment) or proactive (treating non-pharmacologic treatments included all age at ﬁrst signs or symptoms of a ﬂare) treatment groups, except newborns. References (Fig. 7). 362 Dermatol Ther (Heidelb) (2018) 8:349–377 literature, although the number of references DISCUSSION identiﬁed and level of evidence in those refer- ences are low (Fig. 3). This is not unexpected as The results of our analysis largely reﬂect current these treatments are associated with safety AD treatment guidelines [1, 16–21], and the concerns and limited to use in a subset of quality of evidence supporting the use of these patients with severe AD. However, the high treatments is high (including randomized con- impact of severe AD represents a signiﬁcant trolled trials). The relatively large number of unmet need that deserves additional study. references investigating emollient treatment Systemic antimicrobials, topical antibiotics, and the high prevalence of emollient use and other antiseptic measures are discussed but reported in clinical practice (up to 96%; Fig. 2) not recommended by the guidelines, except for are indirect indicators that ﬁrst-line manage- oral antivirals/antibiotics and dilute bleach ment recommendations are being widely baths in patients with AD who have clinical implemented. signs of secondary infection. For patients who The highest proportion of published litera- experience frequent bacterial infections, guide- ture in this analysis focused on the use of TCIs, lines suggest that dilute bleach baths be con- likely reﬂecting the search interval. Topical sidered as a maintenance treatment. The range tacrolimus was approved by the FDA in 2000, of systemic antibiotic use among reports of and pimecrolimus in 2001, 3 years prior to the clinical practice was wide (16–63%; Fig. 2). This search start date. One year into the search likely reﬂects the lack of well-accepted clinical interval, substantial controversy focused on the and laboratory biomarkers to deﬁne infection, theoretical risk of TCI-related lymphoma and a rather than colonization, as well as the short- Boxed Warning. The number of references term improvement commonly observed after supporting the use of TCS is smaller than treatment with systemic anti-staphylococcal expected and more focused on mild-to-moder- antibiotics . However, high-level evidence ate disease and older age groups (Fig. 3). This supporting the use of systemic antibiotics is may also be related to the search interval, lacking, and a small meta-analysis recommends beginning decades after widespread, ‘‘grandfa- against this treatment . thered’’ use of these medications. It could also Guidelines also suggest that sedating oral reﬂect comparatively limited funding for clini- antihistamines may be useful, especially in the cal research to study older, generic drugs, or context of interrupted sleep. Like use of sys- changes in treatment patterns over time . temic antibiotics, the range of published prac- The potencies of TCS and durations of tice patterns is wide (7–84%; Fig. 2), possibly treatment used in clinical trials reﬂect guideline reﬂecting lack of evidence and potential adverse recommendations to use the lowest potency effects . agent for the shortest time period that will The AAD guidelines recommend avoiding control symptoms, but long-term studies of TCS systemic corticosteroids for AD, while the are lacking. Published studies of TCIs focus AAAAI/American College of Allergy, Asthma, more on the safety and efﬁcacy of monotherapy and Immunology (ACAAI), and European than as guidelines-directed long-term mainte- guidelines caution against their use, especially nance, but include data on intermittent use for on a long-term basis. In accordance with these up to 5 years [119, 285]. guidelines, our search strategy did not identify Current guidelines also recommend other any studies that speciﬁcally investigated the use options for moderate-to-severe AD including of systemic corticosteroids, although surpris- wet wrap therapy (with or without TCS), pho- ingly their use ranged from 1–25% in reports of totherapy, or systemic immunosuppressants clinical practice (Fig. 2). (cyclosporine, azathioprine, or methotrexate, Several references focused on the use of sys- with mycophenolate mofetil as an alternative). temic immunotherapy, many of which use higher These recommendations are also reﬂected in level interventional evidence. The AAD guidelines reports of clinical practice and the medical do not recommend allergen-speciﬁc immunother- Dermatol Ther (Heidelb) (2018) 8:349–377 363 apy because of insufﬁcient evidence, while the chart reviews, case reports, and other non-ran- AAAAI/ACAAI and European guidelines suggest domized data) because in the absence of high that it canbeusefulinselectedpatients. level evidence in pediatric patients, dermatolo- Biologic therapy is discussed but not recom- gists often rely on these primary data sources mended by any current guideline because of when making clinical decisions regarding their insufﬁcient evidence. There were a few refer- patients. Including this diversity of publication ences regarding use of biologic agents in pedi- types reﬂects ‘‘real-world’’ clinical practice, but atric patients, with only one reporting higher limits our ability to assess the quality and out- level evidence. comes of the references included in this analysis. Regarding patient age groups and AD sever- However, the lack of a central database of con- ity, there was only one reference on AD treat- ference abstracts precludes inclusion of data ment in newborns and few references with high from all possibly relevant meetings, and some quality evidence to support treatment of severe important meetings may have been inadver- AD using systemic agents. Although recent tently overlooked in our search. publications have investigated the role of emollients in preventing atopic dermatitis in CONCLUSIONS newborns, they did not meet the inclusion cri- teria for this systematic review and were not In summary, treatments investigated in pub- included in this analysis [288, 289]. lished medical literature include those recom- We and others  have found that the mended in current treatment guidelines; deﬁnitions of mild, moderate, and severe used however, clinical practice pattern publications in clinical trials often overlap and many trials include a scope of therapies not supported by use a range of severity (i.e., mild-to-moderate or high level evidence or current treatment moderate-to-severe). This lack of standardiza- guidelines. This may be related to the fact that tion precludes comparative effectiveness analy- clinical practice patterns are often not com- sis of available data. There is a general need for a pletely evidence-based, but driven by medical better deﬁnition of AD severity to guide clinical training, individual experience, and institu- use. For example, topical tacrolimus is FDA-ap- tional ‘‘norms’’. This makes change difﬁcult and proved for moderate-to-severe AD ; how- also delays and interferes with introduction of ever, severe AD often requires systemic therapy. innovative treatments into guidelines and There is also a striking lack of medical liter- practice . Finally, standardized data are ature for long-term use of many of the treat- needed to support the treatments that are ments included in this analysis. The only actually used in clinical practice, especially topical treatment that has been studied for those used in younger children and for long- longer than 1 year is TCI and the only systemic term treatment and severe disease. treatment is immunotherapy, which is not rec- ommended by current guidelines for routine treatment. Given the chronic nature of AD and the need for ongoing maintenance treatment, ACKNOWLEDGEMENTS long-term data is critical for making sound treatment decisions, especially for pediatric patients who are more susceptible to develop- Funding. This work was funded by Regen- mental effects and systemic exposure to topical eron Pharmaceuticals Inc. Article processing charges were funded by Regeneron Pharmaceu- treatments. This scoping review expands on the results of ticals Inc. Data collection and analysis, manu- script development, and the decision to submit a recent related publication; Nankervis et al.  assessed the quality of systematic reviews the manuscript were independent of the fund- and randomized controlled trials for AD treat- ing source. ments in patients of all ages. Our analysis inclu- ded additional primary data sources (abstracts, 364 Dermatol Ther (Heidelb) (2018) 8:349–377 Medical Writing and/or Editorial Assis- presented is not related to any of the company’s tance. Ferdinando Giacco, PhD, of Excerpta investigational or approved products. She Medica, performed the Embase search and ini- designed the searches, provided substantial tial reference screening under the direction of contributions to the analysis and interpretation Ronald van Olffen, PhD, also of Excerpta Med- of data, critically reviewed each draft, and ica, and with ﬁnancial support from Regeneron approved the ﬁnal version for submission. Pharmaceuticals Inc. The authors thank Yufang Compliance with Ethics Guidelines. This Lu, MD, PhD, Executive Director, Immunology article is based on previously conducted studies Medical Affairs at Regeneron Pharmaceuticals and does not contain any studies with human Inc, for her assistance with the development participants or animals performed by any of the and review of the manuscript and Lucy Musie- authors. lak-Stevanovic for her graphic design assistance. Data Availability. Data sharing not appli- Authorship. All named authors meet the cable to this article as no datasets were gener- International Committee of Medical Journal ated or analyzed during the current study. Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of Open Access. This article is distributed the work as a whole, and have given their under the terms of the Creative Commons approval for this version to be published. Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/ Disclosures. Elaine Siegfried is an employee by-nc/4.0/), which permits any noncommer- of Saint Louis University. 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