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At the time of this study, prior to the introduction of biologics in the US, systemic therapies used for the treatment of moderate-to-severe atopic dermatitis included off-label immunosuppressants and corticosteroids. Immunosuppressant therapy is associated with a substantial risk of side-effects, therefore needing clinical monitoring, and is likely to incur a significant healthcare burden for patients and payers. This retrospective cohort study based on claims data measured immunosuppressant use and its associated burden among US adult patients with atopic dermatitis covered under commercial or Medicare Supplemental insurance from January 01, 2010, to September 30, 2015. Overall, based on age, gender, region, and index year, 4201 control patients with atopic dermatitis without immunosuppressant use were matched with 4204 patients treated with immunosuppressants. The majority (68.5%) of patients using immunosuppressants were non-persistent with immunosuppressant treatment during the 12-month follow-up period after a mean (standard deviation) of 88.1 (70.7) days of immunosuppressant use; 72.3% required systemic steroid rescue treatment. Immunosuppressant users had higher incidence of immunosuppressant-related clinical events than controls; in addition, a larger proportion of immunosuppressant users versus controls developed cancer (0.28% vs 0.14%, respectively; P < 0.0001). Healthcare utilization and costs associated with clinical events and monitoring were also higher for immunosuppressant users compared with controls (total costs, $9516 vs $1630, respectively; P < 0.0001; monitoring costs, $363 vs $54, respectively; P < 0.0001). This study revealed that patients treated with systemic immunosuppressants often require systemic steroids or changes to treatment. The increase in immunosuppressant-related clinical events, including the need for increased monitoring with immunosuppressant treatment, compared with controls demonstrates a substantial treatment burden and highlights the unmet need for more effective long-term therapies for atopic dermatitis with improved safety profiles and reduced monitoring requirements. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to provide a long-term cost comparison of patients using additional homeopathic treatment (homeopathy group) with patients using usual care (control group) over an observation period of 33 months. Methods: Health claims data from a large statutory health insurance company were analysed from both the societal perspective (primary outcome) and from the statutory health insurance perspective (secondary outcome). To compare costs between patient groups, homeopathy and control patients were matched in a 1:1 ratio using propensity scores. Predictor variables for the propensity scores included health care costs and both medical and demographic variables. Health care costs were analysed using an analysis of covariance, adjusted for baseline costs, between groups both across diagnoses and for specific diagnoses over a period of 33 months. Specific diagnoses included depression, migraine, allergic rhinitis, asthma, atopic dermatitis, and headache. Results: Data from 21,939 patients in the homeopathy group (67.4% females) and 21,861 patients in the control group (67.2% females) were analysed. Health care costs over the 33 months were 12,414 EUR [95% CI 12,022–12,805] in the homeopathy group and 10,428 EUR [95% CI 10,036–10,820] in the control group (p<0.0001). The largest cost differences were attributed to productivity losses (homeopathy: EUR 6,289 [6,118–6,460]; control: EUR 5,498 [5,326–5,670], p<0.0001) and outpatient costs (homeopathy: EUR 1,794 [1,770–1,818]; control: EUR 1,438 [1,414–1,462], p<0.0001). Although the costs of the two groups converged over time, cost differences remained over the full 33 months. For all diagnoses, homeopathy patients generated higher costs than control patients. Conclusion: The analysis showed that even when following-up over 33 months, there were still cost differences between groups, with higher costs in the homeopathy group. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate osteoporosis risk in atopic dermatitis (AD) patients. This study included patients in the Taiwan National Health Insurance Research dataset. The population-based study included all patients aged 20–49 years who had been diagnosed with AD during 1996–2010. In total, 35,229 age and gender-matched patients without AD in a 1:1 ratio were randomly selected as the non-AD group. Cox proportional-hazards regression and Kaplan–Meier analyses were used to measure the hazard ratios and the cumulative incidences of osteoporosis, respectively. During the follow-up period, 360(1.02%) AD patients and 127(0.36%) non-AD patients developed osteoporosis. The overall incidence of osteoporosis was4.72-fold greater in the AD patients compared to the non-AD patients (1.82 vs. 0.24 per 1,000 person-years, respectively) after adjusting for potential confounding factors. Osteoporosis risk factors included female gender, age, advanced Charlson Comorbidity Index, depression and use of corticosteroids. The dataset analysis showed that AD was significantly associated with subsequent risk of osteoporosis. [ABSTRACT FROM AUTHOR]

The macrophage migration inhibitory factor (MIF) gene is located on human chromosome 22q11.2 and is linked to atopic phenotypes. Plasma MIF and log [total IgE] levels are significantly elevated in atopic dermatitis (AD) patients. The aim of this study was to evaluate the relationship between two MIF polymorphisms, −173 G to C and −794 CATT5–8, and total plasma IgE levels in AD patients in Korea. We performed PCR-RFLP analysis in 178 AD patients and 80 control subjects to determine whether MIF SNPs are associated with susceptibility to AD. Plasma total IgE and MIF levels were determined, and then logistic regression analyses were performed to determine the associations between a SNP or haplotype and plasma total IgE or MIF levels. The −173 G/C polymorphism, located in the MIF promoter, was significantly associated with AD; the odds ratios (ORs) for the CC homozygotes and GC heterozygotes were 9.3 and 2.5, respectively. The MIF C/5-CATT and the MIF C/7-CATT haplotypes were significantly associated with AD; the ORs for the MIF C/5-CATT and MIF C/7-CATT haplotypes were 9.7 and 4.5, respectively. Log [total IgE] levels were highly associated with the MIF −794 7-CATT polymorphism. Notably, the MIF C/7-CATT haplotype was associated with a decrease in plasma log [total IgE] levels in a gene dose-dependent manner. Although log [MIF] levels were not associated with the MIF polymorphisms, the frequencies of the MIF C/5-CATT haplotype-containing genotypes decreased in order of MIF levels. Our results demonstrate that MIF promoter polymorphisms in the −173 C allele and the MIF C/5-CATT and C/7-CATT haplotypes were significantly associated with an increased risk for AD. In particular, the −794 7-CATT locus and the MIF C/7-CATT haplotype were significantly associated with decreased total IgE levels in the plasma, suggesting that these polymorphisms might be a marker for intrinsic AD rather than extrinsic AD that shows high total IgE levels and presence of allergen-specific IgE. [ABSTRACT FROM AUTHOR]

Tight junction (TJ) dysfunction in the stratum granulosum leads to aberrant barrier function of the stratum corneum (SC) in the epidermis. However, it is unclear whether TJs are perturbed in atopic dermatitis (AD), a representative aberrant SC-related skin disease, and whether some factors related to AD pathogenesis induce TJ dysfunction. To address these issues, we investigated the alterations of TJs in AD skin and the effects of Th2 and Th17 cytokines on TJs in a skin-equivalent model. The levels of TJ proteins were determined in the epidermis of nonlesional and lesional skin sites of AD. Western blot and immunohistochemical analyses revealed that the levels of zonula occludens 1 were decreased in the nonlesional sites of AD, and the levels of zonula occludens 1 and claudin-1 were decreased in the lesional sites relative to the levels in skin from healthy subjects. Next, we examined the effects of interleukin (IL)-4, tumor necrosis factor-α, IL-17, and IL-22 on the TJ barrier in a skin-equivalent model. Only IL-17 impaired the TJ barrier. Furthermore, we observed a defect in filaggrin monomer degradation in the IL-17–treated skin model. Thus, TJs are dysfunctional in AD, at least partly, due to the effect of IL-17, which may result in an aberrant SC barrier. [ABSTRACT FROM AUTHOR]

It is well known that eccrine sweating is attenuated in patients with atopic dermatitis (AD). We have reported by using proteome analysis that gross cystic disease fluid protein 15 (GCDFP15), a substance secreted from eccrine sweat glands, is decreased in tape-stripped stratum corneum (SC) samples from AD patients. The aim of this study was to evaluate GCDFP15 production by eccrine glands with SC samples and to assess sweating in AD. SC samples were obtained from 51 healthy control (HC) and 51 AD individuals. Sweat samples were from 18 HC and 12 AD subjects. GCDFP15 was quantified by ELISA. By immunohistochemistry, the expression of GCDFP15 in eccrine glands was examined in normal and AD skin specimens. To identify GCDFP15-producing cells, double immunofluorescence staining for GCDFP15 and S100 protein was performed in frozen sections. To address the mechanism underlying the decreased eccrine sweating in AD patients, we examined the expression of cholinergic receptor M3 (CHRM3), a receptor for acetylcholine-induced sweating, in eccrine sweat glands. The amounts of GCDFP15 in the SC extracts were significantly lower in AD than HC (P < 0.0001). The sweat samples from AD patients also had lower levels of GCDFP15 concentration (P < 0.05). Immunohistochemistry showed positive GCDFP15 staining in the eccrine gland secretory cells and the ductal and acrosyringial lumen in normal skin, but AD lacked clear staining. Immunofluorescence staining revealed that GCDFP15 was co-expressed with S100 protein, suggesting that the clear cell of eccrine glands produces GCDFP15. Finally, we found that the expression of CHRM3 was depressed in AD, suggesting contribution to the low sweating. The SC of AD patients contains a low amount of GCDFP15 due to both low sweating and low GCDFP15 concentration in the sweat. GCDFP15 in SC is a potential marker for dysregulated sweating in AD. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10−36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10−8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring’s susceptibility to a common human disease. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of pimecrolimus cream 1% in the treatment of AD in the pediatric population. Methods: PubMed, EMBASE, Web of Science and Cochrane library databases were searched till July 2013. The randomized and nonrandomized blinded studies of pimecrolimus cream 1% applied twice daily with Jaded score ≥3 in pediatric patients with AD were included. The efficacy outcomes included investigator global assessment (IGA), eczema area and severity index (EASI) scores, pruritus and care giver's assessments and flares free period. Adverse events were reviewed to assess the safety. Results: Out of 81 studies, 7 were selected that enrolled 2,170 pediatric patients. The pooled analysis reported that pimecrolimus was no better to vehicle reducing eczema at day-8, day-26 and six weeks (OR 4.95, 95% CI 2.79–8.80), (OR 9.69, 95% CI 4.12–22.83) and (OR 3.83. 95% CI 1.94–7.56), respectively in children. Similarly, pimecrolimus did not show beneficial effects when analyzed for mild or absent pruritus at day 4 (OR 8.29, 95% CI 3.88–17.72 favoring vehicle), day 43 (OR 1.81 95% CI 1.13–2.89 favoring vehicle) and 1 week (OR 2.29, 95%CI 1.45 to 3.60 favoring vehicle) as compared with vehicle. One study comparing pimecrolimus with tacrolimus found no significant difference in achieving mild or absent pruritus (OR 0.94, 95% CI 0.44–1.99). More patients showed an improvement in overall disease in vehicle group at day 8 (OR 3.30, 95% CI 2.03–5.35), day 29 (OR 14.14, 95% CI 6.87–29.13) and day 43 (OR 4.11, 95% CI 2.59–6.52) as compared with pimecrolimus 1% group, as assessed by caregivers. No significant difference was seen between the total AEs in both groups (pimecrolimus vs vehicle/tacrolimus) (OR 1.19, 95% CI 0.85, 1.65) Conclusion: The results of the present meta-analysis showed that pimecrolimus cream 1% was not significantly better to vehicle for AD in pediatrics population. [ABSTRACT FROM AUTHOR]

Background: The fear of using topical corticosteroids, usually called topical corticophobia, is a frequent concern for atopic dermatitis patients and/or their parents. Assessing patients’ atopic dermatitis and their parents’ topical corticosteroid phobia is an essential step to improving adherence to treatment. Because topical corticophobia appears to be a complex phenomenon, its evaluation by binary responses (yes/no) is too simplistic. Thus, a scale is needed, which is capable of identifying the subtleties of topical corticosteroid phobia. Objectives: To develop and validate a scale, TOPICOP©, measuring worries and beliefs about topical corticosteroids among atopic dermatitis outpatients and their parents. Methods: An initial statistical validation of TOPICOP was carried out, collecting qualitative data about patients’ topical corticophobia behaviors and beliefs using focus-group methodology. Then, 208 outpatients or their parents from five French centers completed a self-administered questionnaire built from focus-group results. The scale-development process comprised an explanatory principal component analysis, Cronbach’s α-coefficients and structural equation modeling. Results: The validated questionnaire comprised 12 items, covering two important dimensions relative to “worries” (6 items) and “beliefs” (6 items). Psychometric properties showed that items had very good communality (>0.60) within their own dimension. The final two-factor solution accounted for 47.3% of the variance. Cronbach’s α-coefficients were, respectively, 0.79 and 0.78. Structural equation modeling strongly supported the possibility of calculating a global score. Conclusions: TOPICOP© is the first scale aimed at assessing topical corticophobia in adult patients and parents of children with eczema. TOPICOP® has excellent psychometric properties and should be easy to use in everyday clinical practice for clinicians and researchers. Further studies are needed to confirm our results and validate TOPICOP© in other cultures. [ABSTRACT FROM AUTHOR]

Background: Previous studies have extensively documented antimicrobial and chemotactic activities of beta-defensins. Human beta-defensin-2 (hBD-2) is strongly expressed in lesional psoriatic epidermis, and recently we have shown that high beta-defensin genomic copy number is associated with psoriasis susceptibility. It is not known, however, if biologically and pathophysiologically relevant concentrations of hBD-2 protein are present in vivo, which could support an antimicrobial and proinflammatory role of beta-defensins in lesional psoriatic epidermis. Methodology/Principal Findings: We found that systemic levels of hBD-2 showed a weak but significant correlation with beta defensin copy number in healthy controls but not in psoriasis patients with active disease. In psoriasis patients but not in atopic dermatitis patients, we found high systemic hBD-2 levels that strongly correlated with disease activity as assessed by the PASI score. Our findings suggest that systemic levels in psoriasis are largely determined by secretion from involved skin and not by genomic copy number. Modelling of the in vivo epidermal hBD-2 concentration based on the secretion rate in a reconstructed skin model for psoriatic epidermis provides evidence that epidermal hBD-2 levels in vivo are probably well above the concentrations required for in vitro antimicrobial and chemokine-like effects. Conclusions/Significance: Serum hBD-2 appears to be a useful surrogate marker for disease activity in psoriasis. The discrepancy between hBD-2 levels in psoriasis and atopic dermatitis could explain the well known differences in infection rate between these two diseases. [ABSTRACT FROM AUTHOR]

In the past decades, chronic inflammatory diseases such as psoriasis, atopic dermatitis, asthma, Crohn's disease and celiac disease were generally regarded as immune-mediated conditions involving activated T-cells and proinflammatory cytokines produced by these cells. This paradigm has recently been challenged by the finding that mutations and polymorphisms in epithelium-expressed genes involved in physical barrier function or innate immunity, are risk factors of these conditions. We used a functional genomics approach to analyze cultured keratinocytes from patients with psoriasis or atopic dermatitis and healthy controls. First passage primary cells derived from non-lesional skin were stimulated with pro-inflammatory cytokines, and expression of a panel of 55 genes associated with epidermal differentiation and cutaneous inflammation was measured by quantitative PCR. A subset of these genes was analyzed at the protein level. Using cluster analysis and multivariate analysis of variance we identified groups of genes that were differentially expressed, and could, depending on the stimulus, provide a disease-specific gene expression signature. We found particularly large differences in expression levels of innate immunity genes between keratinocytes from psoriasis patients and atopic dermatitis patients. Our findings indicate that cell-autonomous differences exist between cultured keratinocytes of psoriasis and atopic dermatitis patients, which we interpret to be genetically determined. We hypothesize that polymorphisms of innate immunity genes both with signaling and effector functions are coadapted, each with balancing advantages and disadvantages. In the case of psoriasis, high expression levels of antimicrobial proteins genes putatively confer increased protection against microbial infection, but the biological cost could be a beneficial system gone awry, leading to overt inflammatory disease. [ABSTRACT FROM AUTHOR]