MicroRNA profiling of psoriatic skin identifies 11 miRNAs associated with disease severity.

MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as central regulators of gene expression and powerful biomarkers of disease. Much is yet unknown about their role in psoriasis pathology. To globally characterize the miRNAome of psoriatic skin, skin biopsies were collected from psoriatic cases (n = 75) and non-psoriatic controls (n = 46) and RNA sequenced. Count data were meta-analysed with a previously published dataset (cases, n = 24, controls, n = 20), increasing the number of psoriatic cases fourfold from previously published studies. Differential gene expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell-specific analyses were performed. Across all contrasts, we identified 439 significantly differentially expressed miRNAs (DEMs), of which 85 were novel for psoriasis and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in the constitution of all skin in psoriasis. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including "thyroid hormone signalling," "insulin resistance" and various infectious diseases. Cell-specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells. This study provides the most comprehensive overview of the miRNAome in psoriatic skin to date and identifies a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.

Rash during lamotrigine treatment is not always drug hypersensitivity: A retrospective cohort study among children and adults.

Purpose Cutaneous adverse drug reactions (cADRs) are a major cause of lamotrigine (LTG) discontinuation. Remarkable variation in their reported incidence suggests confounders and diverse terms and definitions. The aim of this study was to identify immunological cADRs and to throw light on classification and differential diagnoses in children and adults. Methods Hospital records of 2683 patients with epilepsy (1897 adults, 786 children) were retrospectively screened. Of these, 403 patients (236 adults, 167 children) with first time exposure to LTG were reviewed. Skin reactions were categorized into possible or probable cADRs due to LTG hypersensitivity, and other skin reactions (OSRs) unlikely to be caused by this mechanism. Results 29 of 403 patients (7.2%) reported emergent skin symptoms within 3 months of treatment with LTG of which 20 (5%: 5.9% adults, 3.6% children) were categorized as possible or probable cADRs. Concomitant infection appeared to be present in several cases, particularly in children. OSRs were found in 4.2% of the children using LTG, compared to 0.8% of the adults (p = 0.04). Conclusions Rash during the early phase of LTG treatment is not always drug hypersensitivity. Whenever skin symptoms occur, other potential causes should receive attention to avoid needless discontinuation, particularly in children. However, when early symptoms and signs of severe cADRs are suspected, LTG should promptly be discontinued.

Genetics of Atopic Dermatitis: From DNA Sequence to Clinical Relevance.

Atopic dermatitis (AD) is a complex disease that is thought to be triggered by environmental factors in genetically susceptible individuals. Twin studies have estimated the heritability of AD to be approximately 75%, with the null (loss-of-function) mutations of the gene encoding filaggrin (FLG) (chromosome 1q21.3) as the strongest known genetic risk factor. The discovery of the filaggrin gene was important in the emerging model for AD pathogenesis, combining skin barrier function with adaptive and innate immunity. Assisted by the recent development of large-scale high-throughput genomics, more than 30 genetic loci have been linked to AD across different populations. Identification of these loci, together with functional studies, has already provided new insights into disease biology and identified novel drug targets. Further, these susceptibility loci are laying the groundwork for phenome-wide association studies to test their multiple phenotype relationships and application of Mendelian randomization to investigate causal relationships. Despite many known genes, a majority of the genetic risk for AD is yet unexplored. Therefore, studies investigating refined phenotype groups, low-frequency and rare genetic variation, gene-gene and/or gene-environment interactions, epigenetic mechanisms and data from multi-omics technologies are warranted. In this review, we describe genetic discoveries for AD, including results from candidate gene studies, studies of AD-like genetic diseases, genome-wide association studies and genetic sequencing studies. We explain how some of these genetic discoveries have unraveled new mechanistic insights into the pathogenesis of AD and exemplify how personal genetic data could be used for preventive strategies and a tailored treatment regimen (i.e., precision medicine).

Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study.

BACKGROUND: Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis. METHODS AND FINDINGS: Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m2 (95% CI 1.02-1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m2 mean difference (95% CI 1.13-1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m2 increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03-1.04; P = 1.73 × 10(-60)). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06-1.12) per 1 kg/m2; P = 4.67 × 10(-9)). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m2 change in BMI per doubling odds of psoriasis (-0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied. CONCLUSIONS: Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship.

Obesity, Waist Circumference, Weight Change, and Risk of Incident Psoriasis: Prospective Data from the HUNT Study.

Although psoriasis has been associated with obesity, there are few prospective studies with objective measures. We prospectively examined the effect of body mass index, waist circumference, waist-hip ratio, and 10-year weight change on the risk of developing psoriasis among 33,734 people in the population-based Nord-Trøndelag Health Study (i.e., HUNT), Norway. During follow-up, 369 incident psoriasis cases occurred. Relative risk (RR) of psoriasis was estimated by Cox regression. One standard deviation higher body mass index, waist circumference, and waist-hip ratio gave RRs of 1.22 (95% confidence interval [CI] = 1.11-1.34), 1.26 (95% CI = 1.15-1.39), and 1.18 (95% CI = 1.07-1.31), respectively. Compared with normal weight participants, obese people had an RR of 1.87 (95% CI = 1.38-2.52), whereas comparing the fourth with the first quartile of waist circumference gave an RR of 1.95 (95% CI = 1.46-2.61). One standard deviation higher weight change gave an RR of 1.20 (95% CI = 1.07-1.35), and people who increased their body weight by 10 kg or more had an RR of 1.72 (95% CI = 1.15-2.58) compared with being weight stable. In conclusion, obesity and high abdominal fat mass doubles the risk of psoriasis, and long-term weight gain substantially increases psoriasis risk. Preventing weight gain and promoting maintenance of a normal body weight could reduce incidence of psoriasis.

Early eczema and the risk of childhood asthma: a prospective, population-based study.

BACKGROUND: Severe eczema in young children is associated with an increased risk of developing asthma and rhino-conjunctivitis. In the general population, however, most cases of eczema are mild to moderate. In an unselected cohort, we studied the risk of current asthma and the co-existence of allergy-related diseases at 6 years of age among children with and without eczema at 2 years of age. METHODS: Questionnaires assessing various environmental exposures and health variables were administered at 2 years of age. An identical health questionnaire was completed at 6 years of age. The clinical investigation of a random subsample ascertained eczema diagnoses, and missing data were handled by multiple imputation analyses. RESULTS: The estimate for the association between eczema at 2 years and current asthma at 6 years was OR=1.80 (95% CI 1.10-2.96). Four of ten children with eczema at 6 years had the onset of eczema after the age of 2 years, but the co-existence of different allergy-related diseases at 6 years was higher among those with the onset of eczema before 2 years of age. CONCLUSIONS: Although most cases of eczema in the general population were mild to moderate, early eczema was associated with an increased risk of developing childhood asthma. These findings support the hypothesis of an atopic march in the general population. TRIAL REGISTRATION: The Prevention of Allergy among Children in Trondheim study has been identified as ISRCTN28090297 in the international Current Controlled Trials database.

Agreement of specific IgE and skin prick test in an unselected cohort of two-year-old children.

UNLABELLED: The objective of this study was to evaluate the agreement between specific IgE (sIgE) and skin prick test (SPT), and the possible association between total IgE concentration and allergy-related disorders, when performed in an unselected cohort of 353 two-year olds. Median total IgE was within the reference value for two-year-old children regardless of the presence or absence of allergy-related disorders. 18.7% of the children had one or more positive reactions to SPT and/or sIgE in a panel of 12 allergens. Agreement between SPT and sIgE was variable, being best for peanut and poorest for milk. CONCLUSION: In young children total IgE is of limited value when evaluating allergy-related disorder. The lack of agreement among the positive tests of the sIgE and SPT for some allergens imply that these tests should not be used interchangeably, and both tests should probably be used complementarily when diagnosing atopic sensitization in small children.

Family eczema-history in 2-year-olds with eczema; a prospective, population-based study. The PACT-study, Norway.

BACKGROUND: A maternal line of inheritance regarding eczema has been described in several studies, whereas others find associations to both a maternal as well as a paternal line of inheritance. When studying family history of eczema symptoms, cohort studies including siblings are rare. Time point for assessing family eczema-history could be of importance when studying the associations between family eczema-history and children with eczema, as parents with unaffected children may not recall mild symptoms in other siblings or their own disease history. We therefore aimed to study the associations between reported eczema in mother, father and siblings and reported eczema in index child where information on family history was collected at two different ages of index child. METHODS: Parents/children participating in The Prevention of Allergy among Children in Trondheim (PACT) study were given questionnaires on reported eczema symptoms in mother, father and siblings at 6 weeks and 1 year. When index child was 2 years of age, a detailed questionnaire on different health issues with emphasize on different allergy related disorders were filled in. RESULTS: Both maternal and paternal reports on eczema were significantly associated with eczema in index child. Reporting family eczema-history at 1 year (N = 3087), "eczema sibling only" [adjusted odds ratio (aOR) = 3.13 (2.27-4.33)] as well as all other family-groups containing siblings with eczema were strongly associated with eczema 2 years. When family eczema-history was reported at 6 weeks (N = 2657), reporting of "eczema sibling only" was not associated to reported eczema at 2 years in index child [aOR = 1.31 (0.77-2.23)]. CONCLUSIONS: Having sibling(s) with eczema strengthened the associations between maternal and paternal reports on eczema with eczema in index child only when exposure was reported at 1 year. These findings indicate that results from questionnaires-based studies of family eczema-history depend on whether or not index child has yet developed eczema.

Allergy related disorders among 2-yrs olds in a general population. The PACT Study.

Allergic disorders represent a major health problem in most developed countries, but few population-based studies have focused on these disorders in early childhood. The aims of the present study were to investigate the prevalence, gender differences and distribution of allergy related disorders and their association to sensitization among unselected children, 2 yrs of age, in a general population. A population-based study with parental self reported questionnaire data involving allergy related symptoms and results from allergy tests from 4783 two-yr-old children was conducted, and skin prick tests (SPT) of a randomly selected sample comprising 390 children were performed. In the total population the prevalence of reported wheeze was 26%, doctor diagnosed asthma (DDAsthma) 7.0%, atopic dermatitis (AD) 17% and allergic rhinoconjunctivitis (ARC) 3%. Of the 1008 (21%) allergy tested children 59% reported a positive test, but of the randomly selected children only 8% had a positive SPT. Children with AD were most frequently sensitized and children with ARC were most likely to have other allergy related disorders (70%). More boys than girls had an allergy related disorder or a positive allergy test. In conclusion, two in five had an allergy related disorder, but less than 10% had a positive SPT. Having one allergic disorder, especially ARC, increased substantially the risk of having another, and having AD was most strongly associated to a positive allergy test. Moreover, boys were more likely than girls to have an allergy related disorder or a positive SPT indicating a gender difference in the natural history of allergy related disorders.

Cutaneous T cell lymphoma and graft-versus-host disease: a comparison of in vivo effects of extracorporeal photochemotherapy on Foxp3+ regulatory T cells.

Extracorporeal photochemotherapy (ECP) is a well established treatment for both cutaneous T cell lymphoma (CTCL) and graft-versus-host disease (GVHD). However, the general effector mechanism is not fully settled. Twenty-four patients with CTCL and 14 patients with GVHD were included to assess the relative numbers of regulatory T cells (Treg) and any change in the serum cytokine profile during 6 months of ECP therapy. The relative amount of Treg cells was twice as high in CTCL compared to GVHD and healthy controls. TGF-beta was on average three times higher in GVHD than in CTCL. Both patient groups had a small but significant increase in TGF-beta after treatment. Our results indicate a strengthened Treg function as a result of ECP. Elevated TGF-beta may indicate high Treg activation in GVHD, whereas an increased number of Treg cells in CTCL could be interpreted as a response that is involved in down-regulating the lymphoma cells.

Atopic dermatitis among 2-year olds; high prevalence, but predominantly mild disease--the PACT study, Norway.

Atopic dermatitis is often the first and most prevalent manifestation of atopic disease in preschool children. The objectives of the present study were to determine the prevalence and severity of atopic dermatitis in 2-year-old children. Questionnaire data from a total population of 4784 two-year olds and data from a clinical investigation of a sub-sample of 390 children were obtained from a comprehensive prospective study (Prevention of Atopy among Children in Trondheim). The severity of the atopic dermatitis was scored both according to the Nottingham Eczema Severity Score and the Severity Scoring of Atopic Dermatitis. In the total population the prevalence of this disease, defined as any eczema and itchy rash was 16.5% (95% CI: 15.5-17.6). In the subsample, the corresponding prevalence was 20.6% (95% CI: 16.6-24.6) and 15.9% (95% CI: 12.3-19.5) when diagnosed by the UK Working Party's Criteria. More than 70% of the children with UK-diagnosed atopic dermatitis had mild disease according to both the Nottingham Eczema Severity Score and the Severity Scoring of Atopic Dermatitis. The prevalence of atopic dermatitis among 2-year olds was high. However, more than two-thirds of the children had mild disease, which may imply that the impact of atopic dermatitis as a risk factor for future atopic disease is limited.