Browsing by Author "Reolid, Alejandra"

Biological drugs targeting tumour necrosis factor are effective for psoriasis. However, 30-50% of patients do not respond to these drugs and may even develop paradoxical psoriasiform reactions. This study search-ed for DNA copy number variations that could predict anti-tumour necrotic factor drug response or the appearance of anti-tumour necrotic factor induced psoriasiform reactions. Peripheral blood samples were collected from 70 patients with anti-tumour necrotic factor drug-treated moderate-to-severe plaque psoriasis. Samples were analysed with an Illumina 450K methylation microarray. Copy number variations were obtained from raw methylation data using conumee and Chip Analysis Methylation Pipeline (ChAMP) R packages. One copy number variation was found, harbouring one gene (CPM) that was significantly associated with adalimumab response (Bonferroni-adjusted p-value < 0.05). Moreover, one copy number variation was identified harbouring 3 genes (ARNT2, LOC101929586 and MIR5572) related to the development of paradoxical psoriasiform reactions. In conclusion, this study has identified DNA copy number variations that could be good candidate markers to predict response to adalimumab and the development of anti-tumour necrotic factor paradoxical psoriasiform reactions.

While anti-TNF therapies are effective against psoriasis, 30%–50% of patients do not show an adequate response to these rugs. Different candidate-gene pharmacogenetics studies have identified single nucleotide polymorphisms that may predict anti-TNF drugs response in psoriasis. Nevertheless, only one paper has undertaken a pharmacogenomic approach failing to find significant biomarkers of biological drug response along the whole genome. Furthermore, most of the pharmacogenetic candidate biomarkers identified previously have not been confirmed in a different cohort of patients. The objective of this study was to find biomarkers that could predict anti-TNF drugs response along the whole genome and validate biomarkers identified previously. A genome-wide association study (GWAS) was performed using the Human Omni Express-8 v1.2 Beadchips in 243 psoriasis patients treated with anti-TNF drugs. This study was multicentric and did not interfere with clinical practice. Associations between single nucleotide polymorphisms (SNP) and PASI75 (a 75% reduction with respect to baseline PASI) at 3 months were evaluated. Imputation was performed using SNPs with R2 > 0.7. There were two SNPs located in NPFFR2 that were close to the significant threshold of 5 × 10−8. These data suggest that NPFFR2 might be associated with anti-TNF drug response. However, further studies involving a larger cohort of patients are needed in order to confirm these results.

Introduction: Epigenetic factors play an important role in psoriasis onset and development. Biological drugs are used to treat moderate-to-severe psoriasis patients resistant to conventional systemic drugs. Although they are safe and effective, some patients do not respond to them. Therefore, it is necessary to find biomarkers that could predict response to these therapies. Objective: To find epigenetic biomarkers that could predict response to biological drugs (ustekinumab, secukinumab, adalimumab, ixekizumab). Materials and methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 39 psoriasis patients treated with biological therapies before and after drug administration and from 42 healthy subjects. Afterwards, histones were extracted from PBMCs. Four histone modifications (H3 and H4 acetylation, H3K4 and H3K27 methylation) were determined by ELISA. Data were analysed by IBM-SPSS v.23. Results and conclusions: Psoriasis patients presented reduced levels of acetylated H3 and H4 and increased levels of methylated H3K4 compared to controls. Non-significant changes were observed after treatment administration in any of the histone modifications analysed. Nevertheless, significant changes in methylated H3K27 were found between responders and non-responders to biological drugs at 3 months. As 28% of these patients also presented psoriatic arthritis (PsA), the former analysis was repeated in the subsets of patients with or without PsA. In patients without PsA, significant changes in methylated H3K4 were found between responders and non-responders to biological drugs at 3 and 6 months. Although further studies should confirm these results, these findings suggest that H3K27 and H3K4 methylation may contribute to patients’ response to biological drugs in psoriasis.

Pharmacogenetics is the study of variations in DNA sequence related to drug response. Moreover, the evolution of biotechnology and the sequencing of human DNA have allowed the creation of pharmacogenomics, a branch of genetics that analyzes human genes, the RNAs and proteins encoded by them, and the inter-and intra-individual variations in expression and function in relation to drug response. Pharmacogenetics and pharmacogenomics are being used to search for biomarkers that can predict response to systemic treatments, including those for moderate-to-severe psoriasis. Psoriasis is a chronic inflammatory disease with an autoimmune contribution. Although its etiology remains unknown, genetic, epigenetic, and environmental factors play a role in its development. Diverse systemic and biologic therapies are used to treat moderate-to-severe psoriasis. However, these treatments are not curative, and patients exhibit a wide range of responses to them. Moderate-to-severe psoriasis is usually treated with systemic immunomodulators such as acitretin, ciclosporin, and methotrexate. Anti-tumor necrosis factor (TNF) drugs (adalimumab, etanercept, or infliximab) are the first-line treatment for patients resistant to conventional systemic therapies. Although these therapies are very efficient, around 30–50% of patients have inadequate response. Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 and is used for moderate-to-severe psoriasis. New drugs (apremilast, brodalumab, guselkumab, ixekizumab, and secukinumab) have recently been approved for psoriasis. However, response rates to systemic treatments for moderate-to-severe psoriasis range from 35 to 80%, so it is necessary to identify non-invasive biomarkers that could help predict treatment outcomes of these therapies and individualize care for patients with psoriasis. These biomarkers could improve patient quality of life and reduce health costs and potential side effects. Pharmacogenetic studies have identified potential biomarkers for response to biologic treatments for moderate-to-severe psoriasis. These biomarkers need to be validated in clinical trials involving large cohorts of patients before they can be translated to the clinic. We review pharmacogenetics and pharmacogenomics studies for the treatment of moderate-to-severe plaque psoriasis.

Aims-. This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. Materials and methods-. Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (N=95) and 6 months of treatment (N=90). Significant SNPs for univariate analysis were subjected to multivariate analysis. Results/Conclusions-. Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. Nevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice.