Children with psoriasis and COVID-19: factors associated with an unfavourable COVID-19 course, and the impact of infection on disease progression (Chi-PsoCov registry).

BACKGROUND: The COVID-19 pandemic has raised questions regarding the management of chronic skin diseases, especially in patients on systemic treatments. Data concerning the use of biologics in adults with psoriasis are reassuring, but data specific to children are missing. Moreover, COVID-19 could impact the course of psoriasis in children. OBJECTIVES: The aim of this study was therefore to assess the impact of COVID-19 on the psoriasis of children, and the severity of the infection in relation to systemic treatments. METHODS: We set up an international registry of paediatric psoriasis patients. Children were included if they were under 18 years of age, had a history of psoriasis, or developed it within 1 month of COVID-19 and had COVID-19 with or without symptoms. RESULTS: One hundred and twenty episodes of COVID-19 in 117 children (mean age: 12.4 years) were reported. The main clinical form of psoriasis was plaque type (69.4%). Most children were without systemic treatment (54.2%); 33 (28.3%) were on biologic therapies, and 24 (20%) on non-biologic systemic drugs. COVID-19 was confirmed in 106 children (88.3%) and 3 children had two COVID-19 infections each. COVID-19 was symptomatic for 75 children (62.5%) with a mean duration of 6.5 days, significantly longer for children on non-biologic systemic treatments (P = 0.02) and without systemic treatment (P = 0.006) when compared with children on biologics. The six children who required hospitalization were more frequently under non-biologic systemic treatment when compared with the other children (P = 0.01), and particularly under methotrexate (P = 0.03). After COVID-19, the psoriasis worsened in 17 cases (15.2%). Nine children (8%) developed a psoriasis in the month following COVID-19, mainly a guttate form (P = 0.01). DISCUSSION: Biologics appear to be safe with no increased risk of severe form of COVID-19 in children with psoriasis. COVID-19 was responsible for the development of psoriasis or the worsening of a known psoriasis for some children.

Inflammatory bowel disease and psoriasis: modernizing the multidisciplinary approach.

Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohn's disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.

Circulating microRNAs in extracellular vesicles as potential biomarkers for psoriatic arthritis in patients with psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) develops in ~30% of patients with psoriasis. The diagnosis of PsA is challenging, and there are no reliable molecular markers in clinical use. MicroRNAs are short non-coding regulatory RNAs, which can be actively packaged into extracellular vesicles (EVs) and secreted to the circulation. OBJECTIVES: To explore whether plasma-derived EV microRNAs may serve as biomarkers for PsA in patients with psoriasis. METHODS: Plasma samples were obtained from patients with cutaneous-only psoriasis (PsC) and patients with psoriasis and PsA. Plasma EVs were isolated using miRCURY™ Exosome Isolation Kit. RNA sequencing was used to identify differentially expressed EV miRNAs in the discovery phase (PsC, n = 15; PsA, n = 14). In the validation phase (PsC, n = 29; PsA, n = 28), 41 selected miRNAs were analysed in plasma EVs by qPCR. The association of the identified miRNAs with PsA was assessed by logistic regression analysis. RESULTS: RNA sequencing identified 19 plasma EV miRNAs with significantly different levels between PsA and PsC in the discovery cohort. Significantly lower levels of plasma EV let-7b-5p and miR-30e-5p in PsA vs. PsC were confirmed in the validation cohort, and their decreased levels were found to be associated with the presence of PsA. ROC analysis revealed an AUC of 0.68 (95% CI 0.53-0.83) for let-7b-5p and 0.69 (95% CI 0.55-0.84) for miR-30e-5p. CONCLUSIONS: Circulating EV microRNA levels are altered in patients with PsA as compared with PsC. Findings of this exploratory study suggest that circulating EV microRNAs may serve as biomarkers for arthritis in psoriasis patients.

Changes in the level of serum microRNAs in patients with psoriasis after antitumour necrosis factor-α therapy.

BACKGROUND: MicroRNAs (miRNAs) are endogenous, nonprotein-coding, regulatory RNAs with important roles in health and disease. miRNAs are present in the circulation in a stable form and their levels are altered in diseases. OBJECTIVES: To determine whether antitumour necrosis factor (TNF)-α therapy affects serum miRNA levels in patients with psoriasis. METHODS: Serum samples were obtained from healthy donors and from patients with chronic plaque psoriasis before and 12 weeks after the initiation of treatment with the TNF-inhibitor etanercept or methotrexate. miRNA expression profiling was utilized to identify miRNAs with altered serum level in psoriasis, as well as anti-TNF-α-regulated miRNAs in patients' sera. The expression of five miRNAs regulated by etanercept was measured by quantitative polymerase chain reaction (qPCR) in sera from patients and controls. RESULTS: Etanercept significantly suppressed a panel of 38 miRNAs, which were found to be predominantly immune-cell derived and which have been implicated in inflammation and autoimmunity. Validation by qPCR showed that serum levels of miR-106b, miR-26b, miR-142-3p, miR-223 and miR-126 were significantly downregulated by etanercept in responders (Psoriasis Area and Severity Index change > 50%). By contrast, methotrexate did not significantly affect the levels of these miRNAs. Serum levels of these miRNAs were not upregulated in patients with psoriasis compared with healthy controls. The level of four circulating miRNAs was significantly different (increased: miR-128a; decreased: let-7d, miR-142-3p, miR-181a) in psoriasis and healthy serum. CONCLUSIONS: The level of circulating miRNAs is altered in psoriasis. Anti-TNF-α therapy has a profound effect on the serum level of miRNAs; however, these are not related to disease severity. Our results suggest that changes in the miRNA level may reflect a previously unknown effect of anti-TNF-α therapy. Our results suggest the involvement of miRNAs in pathways affected by anti-TNF-α therapy and warrant further investigation of serum miRNAs as potential biomarkers for therapy response in psoriasis.

MicroRNA-203 functions as a tumor suppressor in basal cell carcinoma.

Basal cell carcinoma (BCC) of the skin represents the most common malignancy in humans. MicroRNAs (miRNAs), small regulatory RNAs with pleiotropic function, are commonly misregulated in cancer. Here we identify miR-203, a miRNA abundantly and preferentially expressed in skin, to be downregulated in BCCs. We show that activation of the Hedgehog (HH) pathway, critically involved in the pathogenesis of BCCs, as well as the EGFR/MEK/ERK/c-JUN signaling pathway suppresses miR-203. We identify c-JUN, a key effector of the HH pathway, as a novel direct target for miR-203 in vivo. Further supporting the role of miR-203 as a tumor suppressor, in vivo delivery of miR-203 mimics in a BCC mouse model results in the reduction of tumor growth. Our results identify a regulatory circuit involving miR-203 and c-JUN, which provides functional control over basal cell proliferation and differentiation. We propose that miR-203 functions as a 'bona fide' tumor suppressor in BCC, whose suppressed expression contributes to oncogenic transformation via derepression of multiple stemness- and proliferation-related genes, and its overexpression could be of therapeutic value.

Advances in microRNAs: implications for immunity and inflammatory diseases.

Since their discovery in 1993 and the introduction of the term microRNA in 2001, it has become evident that microRNAs (miRNAs) involved in many biological processes, including development, differentiation, proliferation and apoptosis. The function of miRNA the control of protein production in cells by sequence-specific targeting of mRNAs for translational repression or mRNA degradati Interestingly, immune genes are apparently preferentially targeted by miRNAs compared to the average of the human genome, indicat the significance of miRNA-mediated regulation for normal immune responses. Here, we review what is known about the role of miRN in the pathogenesis of immune-related diseases such as chronic inflammatory skin diseases, autoimmunity and viral infections.

MicroRNAs: novel regulators in skin inflammation.

Compelling evidence indicates that microRNAs (miRNAs), short, non-protein coding RNAs, are critical for the development and survival of multicellular organisms. Recently, miRNAs were implicated in the pathogenesis of psoriasis and atopic eczema (AE), the two most common chronic inflammatory disorders in skin. In particular, miR-203, the first skin-specific miRNA, showing an intriguing expression profile being confined to skin epithelium, is specifically overexpressed in psoriasis. MiR-146a, another miRNA showing specific upregulation in psoriasis, is involved in the regulation of innate immune responses and the tumour necrosis factor (TNF)-alpha pathway. Interestingly, miR-125b, another miRNA involved in the TNF-alpha pathway, is also deregulated in psoriasis and AE. As skin inflammation may serve as a model for chronic inflammatory disorders, it is likely that miRNAs involved in skin inflammation will eventually emerge in other inflammatory or autoimmune disorders, and some of these may become disease markers and therapeutic targets. In this review we present an overview of what is currently known about the roles of miRNAs in chronic inflammatory skin disorders.