Maryte Papadopoulos

The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort.

BACKGROUND Atopic dermatitis (AD) is a common skin disease that is characterized by recurrent episodes of itching. Filaggrin (FLG) loss-of-function (FLG null) mutations have been associated with an increased risk of AD. OBJECTIVE We sought to evaluate the effect of individual FLG null mutations on the persistence of AD over time. METHODS We evaluated a multiyear prospective cohort study of children with AD with respect to FLG null mutations (R501X, 2282del4, R2447X, and S3247X). We evaluated the association of these mutations with the persistence of AD symptoms over time with respect to reports of no symptoms of AD and whether topical medication was needed for symptom resolution. RESULTS Eight hundred fifty-seven subjects were followed for 3684 person-years. One or more FLG null mutations were noted in 16.3% of subjects and specifically in 27.5% of white subjects and 5.8% of African American subjects. Subjects with an FLG null mutation were less likely (odds ratio [OR], 0.54; 95% CI, 0.41-0.71) to report that their skin was symptom free at any time compared with those without an FLG null mutation. The effect of these mutations was similar in white subjects (OR, 0.42; 95% CI, 0.31-0.57) and African-American subjects (OR, 0.53; 95% CI, 0.25-1.12; P = .62). Children with the R501X mutation (OR, 0.44; 95% CI, 0.22-0.88) were the least responsive to therapy. CONCLUSIONS In a US cohort with AD, FLG null mutations were common. Children with FLG null mutations were more likely to have persistent AD. Although these mutations were more common in those of European ancestry, their effect on persistence was similar in those of African ancestry. Response to therapy was not uniform among children with FLG null mutations.

Thymic Stromal Lymphopoietin Variation, Filaggrin Loss of Function, and the Persistence of Atopic Dermatitis

IMPORTANCE Atopic dermatitis (AD) is a common chronic illness of childhood. OBJECTIVE To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation. MAIN OUTCOMES AND MEASURES Self-reported outcome of whether a childs skin had no symptoms of AD and required no medications for 6 months at 6-month intervals. RESULTS We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86). CONCLUSIONS AND RELEVANCE The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.

Phase I Study of H5.020CMV.PDGF-β to Treat Venous Leg Ulcer Disease

Venous leg ulcers are a prevalent nonhealing wound of the lower extremity. Although topically applied growth factors successfully improve wound repair in animal studies, similar studies on humans with venous leg ulcers have not been successful. This study was designed to evaluate the acute safety and biologic feasibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing platelet-derived growth factor-β (PDGF-β). In this phase I study, we demonstrate the initial safety, feasibility, and biologic plausibility of using H5.020CMV.PDGF-β to treat venous leg ulcer disease.Venous leg ulcers are a prevalent nonhealing wound of the lower extremity. Although topically applied growth factors successfully improve wound repair in animal studies, similar studies on humans with venous leg ulcers have not been successful. This study was designed to evaluate the acute safety and biologic feasibility of peri-ulcer injection of a replication-incompetent adenoviral construct expressing platelet-derived growth factor-beta (PDGF-beta). In this phase I study, we demonstrate the initial safety, feasibility, and biologic plausibility of using H5.020CMV.PDGF-beta to treat venous leg ulcer disease.

Exome Sequencing of Filaggrin and Related Genes in African-American Children with Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic relapsing disease. There is a considerable body of evidence supporting a genetic basis for AD (Bussman et al., 2011;Ellinghaus et al., 2013). Mutations in the Filaggrin (FLG) gene have been consistently found to be associated with AD in people of European and Asian ancestry (Brown and McLean, 2012). More than 40 FLG loss-of-function mutations have been described in Europeans and Asians, (Brown and McLean, 2012).However, FLG loss-of-function mutations have not commonly been found in Africans or African-Americans (Margolis et al., 2012;Brown and McLean, 2012;Winge et al., 2011a). Loss-of-function mutations in exon 3 of FLG result in diminished or absent filaggrin protein, most often due to a premature stop codon or a frameshift mutation resulting in a stop codon further downstream. Interestingly, the absence of profilaggrin protein (precursor of filaggrin) has also been noted in keratohyalin granules in the majority of those with ichthyosis vulgaris (IV) of European and Asian ancestry (Perusquia-Ortiz.A.M. et al., 2013;Thyssen et al., 2013;Fleckman and Brumbaugh, 2002).

Association of pharyngitis with oral antibiotic use for the treatment of acne: A cross sectional and prospective cohort study

OBJECTIVE To prospectively evaluate the association between antibiotics used to treat acne and pharyngitis. DESIGN Cross-sectional and 9-month prospective cohort. SETTING Urban university setting. PARTICIPANTS University students. INTERVENTION Participants were asked to fill out a survey form, were swabbed for culture, and had a visual examination for acne. MAIN OUTCOME MEASURE Report of pharyngitis. RESULTS In the cross-sectional study, 10 of the 15 students receiving oral antibiotics for acne reported an episode of pharyngitis in the previous 30 days, whereas 47 of the 130 students not receiving oral antibiotics, but who had acne, reported an episode of pharyngitis in the prior month. The unadjusted odds ratio (OR) (95% CI) associating current oral antibiotic use in acne patients with a self-reported episode of pharyngitis was 3.53 (95% CI, 1.14-10.95). In the cohort study, there were 358 female and 218 male participants; 36 (6.2%) received oral antibiotics for acne during the study, and 96 (16.6%) received topical antibiotics for acne. Using mixed model logistic regression, the OR was 4.34 (95% CI, 1.51-12.47) associating oral antibiotic use with pharyngitis. Less than 1% of participants were colonized by group A streptococcus, which was not associated with pharyngitis. CONCLUSIONS Our studies show that that the odds of reporting pharyngitis is more than 3 times baseline in patients receiving oral antibiotics for acne vs those who are not receiving oral antibiotics. The true clinical importance of these findings needs to be evaluated further by prospective studies, but this finding is not associated with group A streptococcus.

Obtaining DNA in the mail from a national sample of children with a chronic non-fatal illness

Post-marketing studies could be ideal post hoc sources of biologic materials. The US Food and Drug Administration (FDA) mandates post-approval/marketing studies that focus on the exploration of safety signals associated with new therapeutics. These studies are often disease-specific, are large, and are national in scope thereby improving the generalizability of their findings. Several post-marketing studies are currently being conducted evaluating treatments for psoriasis, atopic dermatitis (AD), and acne. We demonstrate the feasibility of obtaining DNA from a large national community-based population of children (PEER, www.thepeerprogram.com) who have AD (Kapoor et al., 2008). In addition, we assess the effectiveness of using a pre-notification letter and the use of monetary incentives to improve participation rates for obtaining buccal-DNA through the mail. Children with AD are being recruited nationwide (by dermatologists, pediatric dermatologists, pediatricians, allergists, and/or other treating physician’s offices) for the PEER study. After enrollment, subjects are contacted twice yearly, via mailed surveys, to inquire about their general health and the status of their AD. In order to obtain DNA from these subjects, we assessed the use of a pre-notification letter. All eligible subjects were contacted using a modification of the Dillman Tailored Design Method (Dillman, 2000) with a pre-notification letter describing our new, not PEER participation related, request for DNA. This process is detailed in the Figure S1 with supplemental Text. All subjects (whether they returned a pre-notification postcard indicating interest or not) were sent a study participation package. It included an Oragene DNA Self-Collection Kit; an incentive (

Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis

1,

Endothelial progenitor cell mobilization following acute wound injury

2, or

Reliability and validity of genotyping filaggrin null mutations.

5 bill, which was randomly allocated); return postage; and IRB approved consent and assent forms that described the study and use of DNA in future studies. Responses were evaluated with respect to the full PEER population, the sub-cohort that agreed to participate via the pre-notification letter (responders), those who did not respond to our pre-notification (non-responders), and then those who ultimately provided a sample (these individuals could have been part of either of the two preceding groups). Odds ratios with 95% confidence intervals (CI) estimated from unadjusted and adjusted logistic regression models are presented (Table 1). Table 1 The rate of submission of a sample and unadjusted odds ratio of a DNA sample based on basic demographics of the initial study population, those that agreed to participate via a postcard response, and those who did not respond to the pre-notification letter. ... Overall, there were 3,264 eligible participants of whom 46.4% were male, 48.7% African American, the average age was 7.1(SD: 4.0) years, and 732 (22.4%) provided sputum. Basic demographics and other variables of interest differed little between the overall sample, those who responded to our pre-notification letter agreeing to provide a saliva sample, those who did not respond to our request, and those who provided a sample (see Table S1). Actual sample providers included 402 of the 674 from the pre-notification group (402/674 or 59.6%) and 330 who did not respond to our pre-notification mailings (330/2590 or 12.7%)(Table 1). The odds ratio was 10.1 (8.4, 12.3) favoring individuals who returned their pre-notification postcard versus those who did not. Adjusting for sex, age at enrollment, African American, asthma, seasonal allergy, region of the country, severity of dermatitis, and family income had little effect (9.79 (8.04, 11.93)). Once a subject was mailed a DNA self-collection kit, the average time to the submission of a sample did not vary based on whether a subject had agreed to submit a sample (61.5 days, SD=80.5) or not (64.3 days, SD=78.8) (p=0.64). After processing the saliva specimens, on average 30 µg of DNA (SD 28 µg, median 20 µg, 25% percentile 12 µg, 75% percentile 38 µg) was obtained. Age (p<0.01) but no other factors influenced DNA quantity. By age category we obtained 20 µg (SD 14 µg) for those 3 to less than 6 years of age, 30 µg (26 µg) for those greater than 6 but less than 9 years of age, and 31 µg (31 µg) for those greater than 9 years. The incentive also influenced the response. As compared to the

Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.

1 incentive, the odds ratios were 1.01 (0.82, 1.24) for