We identified clinically relevant biomarkers of AD, including novel markers, easily sampled and typed in infants. These markers may provide objective assessment of disease severity and suggest new therapeutic targets, or response measurement targets for AD. Future studies will be required to determine whether these biomarkers, seen in very early AD, can predict disease outcomes or comorbidities.

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Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear.Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood.Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity.Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema1wheeze1rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2-to 3-fold, rs7216389 risk variant by 1.4-to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity.Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Summary Background MicroRNAs (miRNAs), important regulators of gene expression, have been implicated in a variety of disorders. The expression pattern of miRNAs in paediatric atopic dermatitis (AD) has not been well studied. Objectives We sought to investigate miRNA expression profiles in different blood compartments of infants with AD. Methods Small RNA and analysis with the HTG EdgeSeq system were performed to identify differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) and plasma of infants with AD vs. age‐matched healthy controls, with reverse transcription quantitative real‐time polymerase chain reaction (RT‐qPCR) used for validation and measurement of miRNA targets. Logistic regression models with area under the receiving operating characteristic estimation was used to evaluate the diagnostic potential of chosen miRNAs for AD. Results RNA sequencing was performed to access miRNA expression profiles in paediatric AD. We identified 10 differentially expressed miRNAs in PBMCs and eight dysregulated miRNAs in plasma of infants with AD compared with controls. Upregulated miRNAs in PBMCs included miRNAs known to be involved in inflammation: miR‐223‐3p, miR‐126‐5p and miR‐143‐3p. Differential expression of only one miRNA, miR‐451a, was observed in both PBMCs and plasma of children with AD. Dysregulation of three miRNAs (miR‐451a, miR‐143‐3p and miR‐223‐3p) was validated in larger numbers of samples and miR‐451a was identified as a predictive biomarker for the early diagnosis of the disease. Experimentally verified targets of miR‐451a, interleukin 6 receptor (IL6R) and proteasome subunit beta type‐8 (PSMB8), were increased in patients with AD, negatively correlated with miR‐451a levels and upregulated following inhibition of miR‐451a in PBMCs. Conclusions In infants with AD, a distinct peripheral blood miRNA signature is seen, highlighting the systemic effects of the disease. miR‐451a is uniquely expressed in different blood compartments of patients with AD and may serve as a promising novel biomarker for the early diagnosis of AD.

Background Atopic dermatitis (AD) presents with the wide spectrum of clinical phenotypes within and between various populations. Recent study showed low frequency of filaggrin loss-of-function (FLG LOF) mutations in Croatian AD patients. At present, there are no data on biomarkers of immune response in Croatian AD patients that might be useful in the selection and monitoring of novel immune therapies. Objectives To investigate levels of cytokines of various signature in the stratum corneum (SC) collected from lesional and non-lesional skin of AD patients and healthy controls and to evaluate their relationship with the severity of disease and skin barrier function.Methods SC samples were collected from 100 adult patients with moderate-to-severe AD and 50 healthy controls. The levels of 21 cytokines were measured by multiplex immunoassay. We conducted machine learning analysis to assess whether a small number of cytokine measurements can discriminate between healthy controls and AD patients and can predict AD severity (SCORAD). ResultsThe SC levels of thirteen cytokines representing innate immunity, Th-1, Th-2 and Th-17/22 immune response showed significant differences between healthy and AD skin. Our analysis demonstrated that as few as three cytokines measured in lesional skin can discriminate healthy controls and AD with an accuracy of 99% and that the predictive models for SCORAD did not achieve a high accuracy. Cytokine levels were highly correlated with the levels of filaggrin degradation products and skin barrier function.Conclusions Stratum corneum analysis revealed aberrant levels of cytokines representing innate immunity, Th-1-, Th-2-and Th-17/22-mediated immune response in Croatian AD patients. Increased Th-2 cytokines and their strong association with natural moisturizing factor (NMF) can explain low NMF levels despite of low frequency of FLG LOF mutations in Croatian population. Predictive models for SCORAD identified cytokines associated with SCORAD but warrants further investigation.