Signaling sphingolipids are biomarkers for atopic dermatitis prone to disseminated viral infections.

BACKGROUND: Life-threatening viral diseases such as eczema herpeticum (EH) and eczema vaccinatum (EV) occur in <5% of individuals with atopic dermatitis (AD). The diagnosis of AD, however, excludes all individuals with AD from smallpox vaccination. OBJECTIVES: We sought to identify circulatory and skin lipid biomarkers associated with EH and EV. METHODS: Stratum corneum and plasma samples from 15 subjects with AD and a history of EH, 13 age- and gender-matched subjects with AD and without EH history, and 13 healthy nonatopic (NA) controls were analyzed by liquid chromatography tandem mass spectrometry for sphingolipid content. Sphingosine-1-phosphate (S1P) and ceramide levels were validated in plasma samples from the Atopic Dermatitis Vaccinia Network/Atopic Dermatitis Research Network repository (12 NA, 12 AD, 23 EH) and plasma from 7 subjects with EV and 7 matched subjects with AD. S1P lyase was downregulated in human primary keratinocytes to evaluate its effect on herpes simplex virus 1 (HSV-1) replication in vitro. RESULTS: The stratum corneum of patients with EH demonstrated significantly higher levels of free sphingoid bases than those in patients who were NA, indicating enhanced sphingolipid turnover in keratinocytes (P < .05). Plasma from 2 independent cohorts of patients with EH had a significantly increased S1P/ceramide ratio in subjects with EH versus those with AD and or who were NA (P < .01). The S1P level in plasma from subjects with EV was twice the level in plasma from subjects with AD (mean = 1,533 vs 732 pmol/mL; P < .001). Downregulation of S1P lyase expression with silencing RNA led to an increased S1P level and doubled HSV-1 titer in keratinocytes. CONCLUSIONS: Our data point to long-term abnormalities in the S1P signaling system as a biomarker for previous disseminated viral diseases and a potential treatment target in recurring infections.

Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors.

BACKGROUND: While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. OBJECTIVES: This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. METHODS: AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. RESULTS: Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36). CONCLUSIONS: This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

Multiethnic genome-wide and HLA association study of total serum IgE level.

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. RESULTS: We identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8). CONCLUSION: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum.

BACKGROUND: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). METHODS: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. RESULTS: Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). CONCLUSION: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

BACKGROUND: Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis. METHODS: In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. RESULTS: Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group. CONCLUSIONS: In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933 .).

The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition.

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long-term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.

Nemolizumab in patients with moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study.

BACKGROUND: Nemolizumab, an anti-IL-31 receptor A mAb, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (part A; NCT01986933). OBJECTIVE: We sought to assess the long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week, double-blind extension (part B). METHODS: During part B, patients continued the previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B end points included percentage improvement from baseline in pruritus visual analog scale and dermatitis scores (including the Eczema Area and Severity Index). RESULTS: Overall, 216 of 264 patients completed part A, and 191 entered part B; 131 completed part B. In 153 patients randomized to nemolizumab in part A, improvement from baseline in pruritus visual analog scale score was maintained/increased from weeks 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at week 64: -73.0, -89.6, -74.7, and -79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to week 64 (percentage change in Eczema Area and Severity Index score: -68.5, -75.8, -78.9, and -69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83% to 89% had 1 or more adverse events, with no new safety concerns identified. CONCLUSION: Nemolizumab for up to 64 weeks was efficacious and overall well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.

A clinical trial of intradermal and intramuscular seasonal influenza vaccination in patients with atopic dermatitis.

BACKGROUND: Antibody responses to the inactivated seasonal influenza vaccine in patients with atopic dermatitis (AD) have not been carefully characterized. OBJECTIVE: The primary objective of this study was to compare antibody responses to intradermal vaccination in participants with moderate/severe AD with those in nonatopic participants. Secondary objectives were to evaluate the effect of route of administration, Staphylococcus aureus skin colonization, and disease severity on vaccine response. METHODS: This was an open-label study conducted in the 2012-2013 influenza season at 5 US clinical sites. A total of 360 participants with moderate/severe AD or nonatopic subjects were assessed for eligibility, 347 of whom received intradermal or intramuscular vaccination per label and were followed for 28 days after vaccination. The primary outcome was the difference in the proportion of participants achieving seroprotection (hemagglutination-inhibition antibody titer ≥1:40 on day 28 after vaccination). RESULTS: Seroprotection rates for influenza B, H1N1, and H3N2 were not different (1) between participants with AD and nonatopic participants receiving intradermal vaccination and (2) between AD participants receiving intradermal and intramuscular vaccination. After intradermal, but not intramuscular, vaccination, participants with AD with S aureus colonization experienced (1) lower seroprotection and seroconversion rates and lower hemagglutination-inhibition antibody titer geometric mean fold increase against influenza B and (2) lower seroconversion rates against influenza H1N1 than noncolonized participants with AD. CONCLUSION: Participants with AD colonized with S aureus exhibited a reduced immune response to influenza vaccination compared with noncolonized participants after intradermal but not intramuscular vaccination. Because most patients with AD are colonized with S aureus, intramuscular influenza vaccination should be given preference in these patients.

Validation of a Parent-Reported Diagnostic Instrument in a U.S. Referral Population: The Childhood Eczema Questionnaire.

BACKGROUND/OBJECTIVES: There is a paucity of validated tools for diagnosing atopic dermatitis (AD) in very young children that do not rely on clinical evaluation. The Childhood Eczema Questionnaire (CEQ)-a diagnostic tool for AD in children younger than 2 years that a caretaker can complete-was recently validated in Sweden. The objective of this study was to validate the tool in a U.S. POPULATION: As a substudy, we added an additional question that was independently assessed. METHODS: Children younger than 2 years old were recruited from a dermatology clinic. Their caretakers completed a questionnaire containing the original tool's three questions as well as a fourth question that increased the time frame measured from 1 week to 6 months. Questionnaires with all "yes" answers were considered positive and were compared with a dermatologist diagnosis of AD. RESULTS: A total of 283 subjects were recruited. The first three questions (the original CEQ) predicted a positive diagnosis of AD with a sensitivity of 0.72 (95% confidence interval [CI] 0.58, 0.82) and a specificity of 0.93 (95% CI 0.87, 0.95). In a separate analysis we included the first two questions and the fourth question and found that the sensitivity increased to 0.82 (95% CI 0.69, 0.90) with a specificity of 0.89 (95% CI 0.83, 0.93). CONCLUSION: This study validates a novel parental questionnaire for the diagnosis of AD in children younger than 2 years in a U.S. clinic population.

OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study.

BACKGROUND: Peripheral leukocytes in patients with atopic dermatitis (AD) have elevated phosphodiesterase-4 activity, which is associated with production of proinflammatory mediators. OPA-15406 is a phosphodiesterase-4 inhibitor with high selectivity for phosphodiesterase-4-B. OBJECTIVES: We sought to assess effectiveness and tolerability of topical OPA-15406 in patients with AD. METHODS: This was a randomized, double-blind, vehicle-controlled, phase-II study. Patients 10 to 70 years of age with mild or moderate AD received topical OPA-15406 0.3% (n = 41), OPA-15406 1% (n = 43), or vehicle (n = 37) twice daily for 8 weeks. RESULTS: The primary end point, Investigator Global Assessment of Disease Severity score of 0 or 1 with greater than or equal to 2-grade reduction, was met at week 4 in the OPA-15406 1% group (P = .0165 vs vehicle). Mean percentage improvement from baseline Eczema Area and Severity Index score for OPA-15406 1% was notable in week 1 (31.4% vs 6.0% for vehicle; P = .0005), even larger in week 2 (39.0% vs 3.0%; P = .0001), and persisted for 8 weeks. Visual analog scale pruritus scores improved from moderate to mild within the first week in the OPA-15406 1% group (36.4% mean change; P = .0011). OPA-15406 levels in blood were negligible. Incidence of adverse events was low, with most events mild in intensity. LIMITATIONS: Further confirmatory phase-III studies are required. CONCLUSION: OPA-15406 ointment may provide an effective therapeutic modality for patients with mild to moderate AD.

Strategies used for measuring long-term control in atopic dermatitis trials: A systematic review.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. There are no standardized methods for capturing long-term control of AD. OBJECTIVE: We sought to identify how long-term control has been captured in published randomized controlled trials (RCTs). Results will initiate consensus discussions on how best to measure long-term control in the core outcome set for AD. METHODS: We conducted a systematic review of RCTs of AD treatments published between 2000 and 2013, with a follow-up period of 3 months or longer, at least 1 outcome measure recorded at 3 or more time points, full article available, and published in English. RESULTS: In all, 101 of 353 RCTs were eligible. Methods to capture long-term control included: repeated measurement of AD outcomes (92 RCTs; 91%), use of AD medication (29 RCTs; 28.7%), and AD flares/remissions (26 RCTs; 25.7%). Repeated measurements of AD outcomes were typically collected 3 to 5 times during a trial, but analysis methods often failed to make best use of the data. Time to first flare was most commonly used for trials including flare data (21/52). Medication use was recorded based on quantity, potency, and frequency of application. LIMITATIONS: We included RCT data only. CONCLUSION: This review illustrates the difficulties in measuring long-term control, and points to the need for improved harmonization of outcomes.

Study of the Atopic March: Development of Atopic Comorbidities.

BACKGROUND: Atopic dermatitis (AD) is often the first step in the atopic march leading to the development of asthma or allergic rhinitis. The goal of this study was to determine whether early intervention with pimecrolimus limits the atopic march in infants with AD and to evaluate its efficacy and safety. METHODS: This was a 3-year double-blind study in which patients were randomized to pimecrolimus or vehicle and then open-label pimecrolimus for a planned further 3 years. Rescue topical corticosteroid was permitted if 3 days of study medication led to no improvement; investigators made decisions on rescue medication until week 14 and caregivers thereafter. Efficacy assessments included disease-free days, Eczema Area and Severity Index, and body surface area affected. RESULTS: Infants ages 3 to 18 months with recent-onset AD (≤3 months) were observed for a mean of 2.8 years (N = 1,091). No significant differences between pimecrolimus- and placebo-treated groups were found in the percentage of patients with AD who developed asthma (10.7%) or other allergic conditions (allergic rhinitis, 22.4%; food allergy, 15.9%; allergic conjunctivitis, 14.1%; one or more atopic comorbidities, 37.0%) by study end. Allergic rhinitis, food allergy, and having one or more atopic comorbidities (but not asthma or allergic conjunctivitis alone) developed significantly more often in infants with greater AD severity at baseline. Pimecrolimus was significantly more effective than vehicle for AD treatment at week 14. Adverse event incidences were similar. CONCLUSIONS: This longitudinal observation of infants with AD provides evidence of the atopic march. Pimecrolimus was safe and effective in infants with mild to moderate AD.

Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum.

BACKGROUND: A subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype. OBJECTIVE: We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+. METHODS: We performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis. RESULTS: We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency <5%), and 86 (17.4%) novel variants, of which 2.8% were coding synonymous, 93.3% were noncoding (64.6% intronic), and 3.8% were missense. We identified 6 rare IFNGR1 missense variants, including 3 damaging variants (Val14Met [V14M], Val61Ile, and Tyr397Cys [Y397C]) conferring a higher risk for ADEH+ (P = .031). Variants V14M and Y397C were confirmed to be deleterious, leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2-7 SNPs), conferred a reduced risk of ADEH+ (P = .015-.002 and P = .0015-.0004, respectively), and both SNP and haplotype associations were replicated in an independent African American sample (P = .004-.0001 and P = .001-.0001, respectively). CONCLUSION: Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.

A systematic review of topical corticosteroid withdrawal ("steroid addiction") in patients with atopic dermatitis and other dermatoses.

BACKGROUND: The National Eczema Association has received increasing numbers of patient inquiries regarding "steroid addiction syndrome," coinciding with the growing presence of social media dedicated to this topic. Although many of the side effects of topical corticosteroids (TCS) are addressed in guidelines, TCS addiction is not. OBJECTIVE: We sought to assess the current evidence regarding addiction/withdrawal. METHODS: We performed a systematic review of the current literature. RESULTS: Our initial search yielded 294 results with 34 studies meeting inclusion criteria. TCS withdrawal was reported mostly on the face and genital area (99.3%) of women (81.0%) primarily in the setting of long-term inappropriate use of potent TCS. Burning and stinging were the most frequently reported symptoms (65.5%) with erythema being the most common sign (92.3%). TCS withdrawal syndrome can be divided into papulopustular and erythematoedematous subtypes, with the latter presenting with more burning and edema. LIMITATIONS: Low quality of evidence, variability in the extent of data, and the lack of studies with rigorous steroid addiction methodology are limitations. CONCLUSIONS: TCS withdrawal is likely a distinct clinical adverse effect of TCS misuse. Patients and providers should be aware of its clinical presentation and risk factors.

Atopic Dermatitis Is Associated With Cervical High Risk Human Papillomavirus Infection.

OBJECTIVE: High-risk human papillomavirus (hrHPV) infection is more likely to persist and cause cervical cancer in immunosuppressed women. Atopic dermatitis, which is known to affect cell-mediated immunity and skin barrier function, is associated with recalcitrant warts; therefore, we hypothesized that women with atopic dermatitis may be more likely to be positive for hrHPV infection and progress to high-grade cervical dysplasia. MATERIALS AND METHODS: A retrospective case-control study of 1,160 women who were either positive or negative for hrHPV in their index cervical cytology. Patient age, race, history of atopic dermatitis, allergic rhinitis, smoking, body mass index, socioeconomic status, marital status, hormone contraceptive use, and 2-year clinical outcomes (follow-up hrHPV testing and cervical biopsy results) were recorded. All cases with atopic dermatitis (n = 74) were confirmed by a dermatologist. Analyses were restricted to females with documented clinical follow-up, which yielded 577 hrHPV-positive and 583 hrHPV-negative cases for comparison. Associations were examined by t test, χ test, and multivariate logistic regression. RESULTS: Atopic dermatitis was more common in the hrHPV-positive cases (48/577, 8.3%) compared with HPV-negative controls (26/583, 4.5%, p = .007). Multivariate logistic regression analysis revealed an adjusted odds ratio of 3.75 (95% CI = 1.3-10.9, p = .02) after controlling for significant covariates, such as age and marital status. Smoking was not associated with hrHPV infection, persistence, or high-grade cervical dysplasia in these cases. CONCLUSIONS: Atopic dermatitis is associated with cervical hrHPV infection in adult women.

Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. OBJECTIVE: We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. METHODS: In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. RESULTS: YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4(+) T-cell responses was observed. CONCLUSIONS: YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.

Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention.

BACKGROUND: Atopic dermatitis (atopic eczema) is a chronic inflammatory skin disease that has reached epidemic proportions in children worldwide and is increasing in prevalence. Because of the significant socioeconomic effect of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on disease prevention, with limited success. Recent advances in cutaneous biology suggest skin barrier defects might be key initiators of atopic dermatitis and possibly allergic sensitization. OBJECTIVE: Our objective was to test whether skin barrier enhancement from birth represents a feasible strategy for reducing the incidence of atopic dermatitis in high-risk neonates. METHODS: We performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for atopic dermatitis. Parents in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. RESULTS: Forty-two percent of eligible families agreed to be randomized into the trial. All participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of atopic dermatitis with a relative risk reduction of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). There were no emollient-related adverse events and no differences in adverse events between groups. CONCLUSION: The results of this trial demonstrate that emollient therapy from birth represents a feasible, safe, and effective approach for atopic dermatitis prevention. If confirmed in larger trials, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases.

Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches.

Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence.

Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents.

Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option.

Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.

Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.