Vitamin D deficiency and atopic dermatitis severity in a Bangladeshi population living in East London: A cross-sectional study.

Background: Atopic eczema is a common, chronic, inflammatory skin condition with considerable heterogeneity. South Asian people living in the UK frequently have low serum vitamin D3 (25(OH)D3), and those with atopic disease can present with severe eczema. The association between vitamin D deficiency and eczema severity, and the role of vitamin D supplementation in atopic eczema is inconsistent, and under-researched in people with Asian ancestry. Objectives: This cross-sectional study investigates the association between serum 25(OH)D3 and eczema severity in a cohort of South Asian children and young adults living in London. Methods: Eligible participants were Bangladeshi children and young adults aged 0-30 years with eczema, living in London and participating in the Tower Hamlets Eczema Assessment study. Data was collected via parent/patient self-reporting, clinical history and examination, and hospital databases. 25(OH)D3 levels were documented retrospectively, if available, from hospital databases. Eczema severity was classified by Eczema Area and Severity Index (EASI) score less than or greater than 10 (clear-mild vs. moderate-severe). Multivariate logistic regression was used to adjust for confounding factors. Results: 681 participants were included in analyses. 25(OH)D3 results were available for 49.6% (338/681), 84.3% of which had deficient or insufficient lowest 25(OH)D3. Lowest 25(OH)D3 was inversely correlated with EASI score (Spearman's rank R 2 = -0.24, p < 0.001). 26.1% (178/681) had EASI >10 and a lower median lowest and nearest 25(OH)D3. After adjustment for confounding EASI > 10 was significantly associated with a lowest 25(OH)D3 < 25 (OR 3.21, 95%CI 1.35, 8.60), use of mild-moderate potency topical steroid on the face and neck (OR 3.11, 95%CI 1.86, 5.31), calcineurin inhibitor on the face and neck (OR 2.79, 95% CI 1.26, 6.10) and potent - very potent topical steroid on the face and neck (OR2.23, 95%CI 1.02, 4.77) and body (OR 2.11, 95%CI 1.18, 3.87). Discussion: Vitamin D plays a role in modulation of proteins required for skin barrier function and regulation of the innate immune system, suggesting 25(OH)D3 deficiency contributes to skin inflammation. This study demonstrates a relationship between 25(OH)D3 deficiency and worse eczema severity in a cohort of South Asian children and young adults.

Loss of Function Filaggrin Mutations are Associated with Reduced History of Acne Vulgaris in a Cohort of Bangladeshi Atopic Eczema Patients in East London.

Acne vulgaris (AV) is the eighth most common non-fatal disease globally. Previous work identified an association between AV and increased Filaggrin (FLG) expression in the follicular epidermis, but further work did not find a clear link between loss of function (LoF) Filaggrin gene (FLG) mutations and protection from AV. In this work we aimed to explore any association between AV and FLG LoF mutations using a cohort of genotyped Bangladeshi patients with atopic eczema (AE) in East London. Retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone clinical assessment. The Chi squared or Fisher's exact test was used to determine differences between groups. We found a significant reduction in history of AV in AE patients with FLG LoF mutations relative to AE patients without FLG mutations (p = 0.02). We showed a non-significant reduction in AV diagnosis in patients with impaired barrier function (measured by trans epidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (p = 0.02). In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV.

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial.

BACKGROUND: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. OBJECTIVES: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. METHODS: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg-1 daily) or MTX (0.4 mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. RESULTS: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. CONCLUSIONS: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.

Deep palmar phenotyping in atopic eczema: patterns associated with filaggrin variants, disease severity and barrier function in a South Asian population.

BACKGROUND: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG). OBJECTIVES: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants. METHODS: A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants. RESULTS: There were 506 complete cases available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74-3.67], SH (ME 0.85, 95% CI 0.78-0.96) and TEWL (ME 1.32, 95% CI 1.11-1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91-80.73], improving to 77.99% (73.70-82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02-94.19). CONCLUSIONS: This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively.

Dermatology Quality of Life Index scores in Bangladeshi patients with atopic eczema and their families in East London.

BACKGROUND: Atopic eczema (AE) is a chronic relapsing, pruritic disease that greatly affects the child and family's quality of life (QoL). It is usually common and severe among children of Bangladeshi ethnicity. OBJECTIVES: This is a cross-sectional quantitative study in patients with AE of Bangladeshi origin, which aims to analyse different components of the family, children and adult quality-of-life indices and their relationship to patient age, sex, eczema severity and distribution, other allergic associations, parental education and socioeconomic level. METHODS: Children and young adults of Bangladeshi origin aged 0-30 years, clinically diagnosed with AE were recruited as part of the Tower Hamlets Eczema Assessment project, a clinical phenotyping study of AE in the Bangladeshi population living in East London. Questionnaires completed by children/parents included the Family Dermatology Life Quality Index (FDLQI), Infant's Dermatology Quality of Life (IDQOL) and the Children's Dermatology Life Quality Index (CDLQI). Young adults completed the Dermatology Life Quality Index (DLQI). The disease severity was assessed objectively using the Eczema Area Severity Index (EASI). Patients and parents who did not read or speak English were aided by Bengali/Sylheti-speaking research assistants. RESULTS: Overall, 460 Bangladeshi children and 98 adults with AE were recruited. Burden of care, extra housework and emotional distress were the highest affected domains in parental QoL, while itching and sleep were the highest for children. Significant factors influencing FDLQI score were EASI [marginal effect (ME) 1.01, 95% confidence interval (CI) 1.00-1.03; P = 0.004], age (ME 0.98, 95% CI 0.97-0.99; P = 0.004), extensor eczema distribution (ME 1.25, 95% CI 1.03-1.52; P = 0.023), parental English fluency (ME 1.29, 95% CI 1.10-1.52; P = 0.002) and atopic comorbidities (ME 1.10, 95% CI 1.04-1.17; P = 0.001). Parental socioeconomic class was a nonsignificant factor. IDQOL/CDLQI was influenced significantly by the child's age (ME 0.99, 95% CI 0.97-1.00, P = 0.023), 'nonclear' eczema distribution clusters especially the 'severe extensive' cluster (ME 1.46, 95% CI 1.15-1.84; P = 0.002) and nonsignificantly by EASI and parental English literacy and socioeconomic levels. DLQI was affected significantly by nonclear eczema distribution groups especially 'severe extensive' (ME 2.49, 95% 1.76-3.53; P < 0.001) and nonsignificantly by patient age, and female sex. CONCLUSIONS: AE is a chronic disease where many external factors other than disease severity affect QoL of patients and their families, -especially in under-represented minority groups who face different linguistic and cultural barriers.

Modeling of Temporal Exposure to the Ambient Environment and Eczema Severity.

Atopic eczema is a common and complex disease. Missing genetic hereditability and increasing prevalence in industrializing nations point toward an environmental driver. We investigated the temporal association of weather and pollution parameters with eczema severity. This cross-sectional clinical study was performed between May 2018 and March 2020 and is part of the Tower Hamlets Eczema Assessment. All participants had a diagnosis of eczema, lived in East London, were of Bangladeshi ethnicity, and were aged <31 years. The primary outcome was the probability of having an Eczema Area and Severity Index score > 10 after previous ambient exposure to commonly studied meteorological variables and pollutants. There were 430 participants in the groups with Eczema Area and Severity Index ≤ 10 and 149 in those with Eczema Area and Severity Index > 10. Using logistic generalized additive models and a model selection process, we found that tropospheric ozone averaged over the preceding 270 days was strongly associated with eczema severity alongside the exposure to fine particles with diameters of 2.5 µm or less (fine particulate matter) averaged over the preceding 120 days. In our models and analyses, fine particulate matter appeared to largely act in a supporting role to ozone. We show that long-term exposure to ground-level ozone at high levels has the strongest association with eczema severity.

Diagnosis and Management of Inherited Palmoplantar Keratodermas.

Inherited monogenic palmoplantar keratodermas are a heterogeneous group of conditions characterised by persistent epidermal thickening of the palmoplantar skin. Palmoplantar keratodermas are grouped depending on the morphology of the keratoderma into diffuse, focal/striate or papular/punctate. Some palmoplantar keratodermas just affect the skin of the palms and soles and others have associated syndromic features which include changes in hair, teeth, nails, hearing loss or cardiomyopathy. Next generation sequencing has helped discover genes involved in many of these conditions and has led to reclassification of some palmoplantar keratodermas. In this review, we discuss the diagnostic features of palmoplantar keratodermas and management options.

Independent Loss of Methylthioadenosine Phosphorylase (MTAP) in Primary Cutaneous T-Cell Lymphoma.

Methylthioadenosine phosphorylase (MTAP) and the tumor suppressor genes CDKN2A-CDKN2B are frequently deleted in malignancies. The specific role of MTAP in cutaneous T-cell lymphoma subgroups, mycosis fungoides (MF) and Sézary syndrome (SS), is unknown. In 213 skin samples from patients with MF/SS, MTAP copy number loss (34%) was more frequent than CDKN2A (12%) in all cutaneous T-cell lymphoma stages using quantitative reverse transcription PCR. Importantly, in early stage MF, MTAP loss occurred independently of CDKN2A loss in 37% of samples. In peripheral blood mononuclear cells from patients with SS, codeletion with CDKN2A occurred in 18% of samples but loss of MTAP alone was uncommon. In CD4(+) cells from SS, reduced MTAP mRNA expression correlated with MTAP copy number loss (P < 0.01) but reduced MTAP expression was also detected in the absence of copy number loss. Deep sequencing of MTAP/CDKN2A-CDKN2B loci in 77 peripheral blood mononuclear cell DNA samples from patients with SS did not show any nonsynonymous mutations, but read-depth analysis suggested focal deletions consistent with MTAP and CDKN2A copy number loss detected with quantitative reverse transcription PCR. In a cutaneous T-cell lymphoma cell line, promoter hypermethylation was shown to downregulate MTAP expression and may represent a mechanism of MTAP inactivation. In conclusion, our findings suggest that there may be selection in early stages of MF for MTAP deletion within the cutaneous tumor microenvironment.

Positive relationship-intensity of response to p-phenylenediamine on patch testing and cross-reactions with related allergens.

BACKGROUND: Hair dye exposure is the most common cause of sensitization to p-phenylenediamine (PPD). Cross-reactions with structurally related allergens occur. OBJECTIVES: It is suggested that a stronger patch test reaction (3+ rather than 1+) to PPD (usually tested as 1% petrolatum) is associated with an increased propensity for cross-reactions. In this article we will demonstrate this association. METHODS: Of 230 patients with allergic reactions to PPD on patch testing identified during 2007-2012 from clinical records, notes for 221 were available for review. Data were collected regarding age, sex, and grade of reaction [International Contact Dermatitis Research Group (ICDRG) criteria] to PPD. Cross-reactions with the following allergens, found in our baseline series, were recorded: Disperse Yellow 3, N-isopropyl-N'-phenyl-p-phenylenediamine (IPPD), and caine mix. Having excluded 23 doubtful reactions, the reactions from 198 patients were further considered. RESULTS: Of the patients, 75.3% (n = 149) were female, and the mean age was 48.6 years (12-82 years). Of the patients allergic to PPD, 16.6% (n = 33) showed cross-reactions with one or more related allergens. Cross-reactions were seen in 16% with a grade of 1+, 14.5% with a grade of 2+, 28.6% with a grade of 3+ when PPD was tested 1% pet., and 50.0% when PPD was tested at 0.1-0.001%, arbitrarily considered to be 4+ (p = 0.02; Cramér's V = 0.23). CONCLUSION: An increasing likelihood of reactions to Disperse Yellow 3, IPPD or caine mix was seen with increasing strength of patch test reaction to PPD. The clinical relevance of these cross-reactions is unclear.