The integration of large-scale public data and network analysis uncovers molecular characteristics of psoriasis

In recent years, a growing interest in the characterization of the molecular basis of psoriasis has been observed. However, despite the availability of a large amount of molecular data, many pathogenic mechanisms of psoriasis are still poorly understood. In this study, we performed an integrated analysis of 23 public transcriptomic datasets encompassing both lesional and uninvolved skin samples from psoriasis patients. We defined comprehensive gene co-expression network models of psoriatic lesions and uninvolved skin. Moreover, we curated and exploited a wide range of functional information from multiple public sources in order to systematically annotate the inferred networks. The integrated analysis of transcriptomics data and co-expression networks highlighted genes that are frequently dysregulated and show aberrant patterns of connectivity in the psoriatic lesion compared with the unaffected skin. Our approach allowed us to also identify plausible, previously unknown, actors in the expression of the psoriasis phenotype. Finally, we characterized communities of co-expressed genes associated with relevant molecular functions and expression signatures of specific immune cell types associated with the psoriasis lesion. Overall, integrating experimental driven results with curated functional information from public repositories represents an efficient approach to empower knowledge generation about psoriasis and may be applicable to other complex diseases.Peer reviewe

Biomarkers of disease progression in people with psoriasis: a scoping review

peer reviewed[en] BACKGROUND: Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. OBJECTIVES: To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. RESULTS: Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. CONCLUSIONS: This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area

Biomarkers of systemic treatment response in people with psoriasis: a scoping review

Background Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. Objectives To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. Methods A systematic search of CENTRAL, Embase, LILACS, and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving the psoriasis population (any age, n≥50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data was extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multi-stakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. Results Of 71 included studies (n=64 effectiveness outcomes and n=8 safety outcomes), most reported genomic or proteomic biomarkers associated with response to biologics (n=48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key prognostic factors, lack of adjustment for multiple testing and selective outcome reporting. We identified candidate biomarkers of efficacy to TNF inhibitors (variation in CARD14, CDKAL1, IL1B, IL12B, IL17RA loci and LPS-induced phosphorylation of NF-kB in Type 2 dendritic cells) and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, Th17 cell differentiation, positive regulation of NF-kB and Th17 cell activation. Conclusions This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. Candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use