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Personalized medicine in psoriasis: developing a genomic classifier to predict histological response to Alefacept

ABSTRACT: Alefacept treatment is highly effective in a select group patients with moderate-to-severe psoriasis, and is an ideal candidate to develop systems to predict who will respond to therapy. A clinical trial of 22 patients with moderate to severe psoriasis treated with alefacept (7.5mg weekly i.v. x12 weeks) was conducted in 2002-2003, as a mechanism of action study. Patients were classified as responders or non-responders to alefacept based on histological criteria. Microarray data from PBMCs of 16 of these patients was analyzed to generate a treatment response classifier. We used a discriminant analysis method that performs sample classification from gene expression data, via nearest shrunken centroid method''. A disease response classifier using 23 genes was created to accurately predict response to alefacept (12.3% error rate in favour of responders). This preliminary study may provide a useful tool to predict response of psoriatic patients with alefacept. Keywords: class prediction

ORGANISM(S): Homo sapiens

PROVIDER: GSE18948 | GEO | 2009/12/01

SECONDARY ACCESSION(S): PRJNA120981

REPOSITORIES: GEO

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Personalized medicine in psoriasis: developing a genomic classifier to predict histological response to Alefacept

Project description:Alefacept treatment is highly effective in a select group patients with moderate-to-severe psoriasis, and is an ideal candidate to develop systems to predict who will respond to therapy. A clinical trial of 22 patients with moderate to severe psoriasis treated with alefacept (7.5mg weekly i.v. x12 weeks) was conducted in 2002-2003, as a mechanism of action study. Patients were classified as responders or non-responders to alefacept based on histological criteria. Microarray data from PBMCs of 16 of these patients was analyzed to generate a treatment response classifier. We used a discriminant analysis method that performs sample classification from gene expression data, via nearest shrunken centroid method''. A disease response classifier using 23 genes was created to accurately predict response to alefacept (12.3% error rate in favour of responders). This preliminary study may provide a useful tool to predict response of psoriatic patients with alefacept. Keywords: class prediction Microarray data from 16 patients was analyzed to generate a treatment response classifier. We used a discriminant analysis method that performs sample classification from gene expression data, via nearest shrunken centroid method.

2010-10-02 | E-GEOD-18948 | biostudies-arrayexpress

Genome-wide DNA methylation analysis of peripheral blood samples of moderate-to-severe psoriasis patients treated with anti-TNF drugs

Project description:Genome wide DNA methylation profiling of peripheral blood samples of moderate-to-severe psoriasis patients treated with anti-TNF drugs. Patients were distributed on Excellent Responders (ER) if they achieved PASI90 (a 90% reduction with respect to baseline PASI) at 3 and 6 months of treatment with anti-TNF drugs and Partial responders if they did not achieve a PASI75 (a 75% reduction with respect to baseline PASI) at 3 and 6 months of treatment. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 485,000 CpGs in 49 ER and 21 PR which were obtained from peripheral blood samples of anti-TNF drug treated patients. We have searched for pharmaoepigenetic biomarkers of anti-TNF response in moderate-to-severe psoriasis patients.

2020-05-28 | GSE151278 | GEO

Cellular and Molecular Changes in Psoriasis Lesions Induced by Ustekinumab: Distinct Differences in Responders vs. Non-Responders

Project description:A gene expression profiling sub-study was conducted in which skin biopsy samples (n=192) were collected for RNA extraction and hybridization to microarrays from patients with moderate-to-severe psoriasis who participated in ACCEPT, an IRB-approved Phase 3, multicenter, randomized trial. This analysis identified gene expressions significantly modulated in psoriasis lesions (LS) following ustekinumab or etanercept treatment at week 12 compared to baseline. Molecular expression of mRNA was found to be different in ustekinumab PASI75 responders vs. nonresponders. Differential modulation of selected mRNAs was also observed between ustekinumab and etanercept PASI75 responders.

2019-02-01 | GSE106992 | GEO

Expression data from skin biopsy samples from patients with moderate-to-severe psoriasis

Project description:A gene expression profiling sub-study was conducted in which skin biopsy samples were collected from 85 patients with moderate-to-severe psoriasis who were participating in ACCEPT, an IRB-approved Phase 3, multicenter, randomized trial. This analysis identified 4,175 probe-sets as being significantly modulated in psoriasis lesions (LS) compared with matched biopsies of non-lesional (NL) skin. Skin biopsy samples (n=170) were collected at baseline for RNA extraction and microarray analysis from 85 patients with moderate-to-severe psoriasis without receiving active psoriasis therapy.

2012-07-25 | E-GEOD-30999 | biostudies-arrayexpress

Guselkumab (interleukin-23-specific monoclonal antibody) demonstrates clinical and molecular response in moderate-to-severe psoriasis

Project description:A gene expression profiling study was conducted in which skin biopsy samples were collected for RNA extraction and hybridization to microarrays from patients with moderate-to-severe psoriasis who participated in the phase 1, guselkumab first-in-human randomized, double-blind, placebo-controlled trial. At week 12, significant reductions in psoriasis gene expression were observed in guselkumab-treated patients. Skin biopsy samples (n=59, LS: lesion, NL: non-lesion) were collected at baseline, weeks 1 and 12 following guselkumab treatment from patients with moderate-to-severe psoriasis for RNA extraction and microarray analysis.

2014-05-14 | E-GEOD-51440 | biostudies-arrayexpress

Transcription profiling of human whole blood from rheumatoid arthritis patients

Project description:The whole blood was collected pre-treatment from rheumatoid arthritis patients starting the anti_TNF therapy. All patients were naïve to anti_TNFs. The disease activity was measured using the DAS28 score at the pre-treatment visit1 (DAS28_v1) and 14 weeks after treatment visit3 (DAS28_v3). The response to the therapy was evaluated using the EULAR [European League Against Rheumatism] definition of the response. The objective of the data analysis was to identify gene expression coorelating with response as well as to identify genes that differentiate responders versus non-responders pre-treatment. The results of this investigation identified 8 trainscripts that predict responders vs. non-responders with 89% accuracy. Experiment Overall Design: Patients' response to anti-TNF was assessed using EULAR score and patients were classified as responders, moderate responders and non-responders. Genes correlating with the response status have been identified.

2009-09-18 | E-GEOD-15258 | biostudies-arrayexpress

Transcription profiling of CD34 positive mononuclear cells from drug naive, chronic myeloid leukemia (CML) patients to determine an expression signature predictive of a major cytogenic response in CML patients treated with Imatinib.

Project description:Newly diagnosed chronic phase chronic myeloid leukemia (CML) patients with a major cytogenetic response (MCyR) after 12 months of imatinib therapy have an excellent long-term outcome, while patients without MCyR have a high progression risk. Since patients with primary cytogenetic resistance may benefit from more intensive therapy up-front, we sought to identify biomarkers to predict MCyR. Keywords: Two group comparison to identify trasncriptomic signature that predicts response to therapy CD34+ cells were isolated from cryopreserved mononuclear cells of chronic phase CML patients with a complete cytogenetic response (CCyR) or >65% Ph-positive metaphases after 12 months of imatinib therapy (training set N=36). Gene expression profiles generated on amplified RNA using Affymetrix HG-U133 Plus 2.0 arrays were compared between responders and non-responders, using the criteria ANOVA p<0.1 and fold difference >I1.5I. A minimal response classifier derived from the comparison was used to predict response in a prospectively collected validation set using same criteria for responders/nonresponders (N=23).

2009-12-31 | E-GEOD-14671 | biostudies-arrayexpress

Molecular and cellular profilling of scalp psoriasis reveals differences and similarities compared to skin psoriasis

Project description:Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis on other skin areas. We sought to determine the cellular and mollecular phenotype of scalp psoriasis by performing a comparative analysis of scalp vs skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement, and 10 control subjects without psoriasis. Our results suggest that even in the scalp psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprinting were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with skin psoriasis which was mainly associated with activation of TNFâµ/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes. To define the transcriptomic profile of scalp skin, punch biopsies (6 mm diameter) were obtained from 20 Caucasian patients with untreated moderate to severe psoriasis with significative scalp involvement and 10 control subjects without psoriasis (N). Lesional (LS) samples were isolated from the infiltrated border of a plaque of psoriasis. Non lesional (NL) samples were taken from scalp areas with no visible psoriasis between the infiltrated plaques.

2015-11-25 | E-GEOD-75343 | biostudies-arrayexpress

Specific molecular signatures underlie response to decitabine in CMML [RNA-seq]

Project description:Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable with few means to predict which patients will benefit. To develop a molecular means of predicting response at diagnosis, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients responsive and resistant to decitabine (DAC). While somatic mutations did not differentiate responders and non-responders, we were able to identify for the first time 158 differentially methylated regions (DMRs) at baseline between responders and non-responders using next-generation sequencing. These DMRs were primarily localized to non-promoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. We also found 53 differentially expressed genes between responders and non-responders. Genes up-regulated in responders were enriched in the cell cycle, potentially contributing to effective DAC incorporation. Two chemokines overexpressed in non-responders -- CXCL4 and CXCL7 -- were able to block the effect of DAC on normal CD34+ and primary CMML cells in vitro, suggesting their up-regulation contributes to primary DAC resistance. mRNA profiling in bone marrow mononuclear cells (BM MNC) from 14 CMML patients (8 decitabine responders vs. 6 non-responders).

2015-03-31 | E-GEOD-61162 | biostudies-arrayexpress

Specific molecular signatures underlie response to decitabine in CMML [ERRBS]

Project description:Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable with few means to predict which patients will benefit. To develop a molecular means of predicting response at diagnosis, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients responsive and resistant to decitabine (DAC). While somatic mutations did not differentiate responders and non-responders, we were able to identify for the first time 158 differentially methylated regions (DMRs) at baseline between responders and non-responders using next-generation sequencing. These DMRs were primarily localized to non-promoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. We also found 53 differentially expressed genes between responders and non-responders. Genes up-regulated in responders were enriched in the cell cycle, potentially contributing to effective DAC incorporation. Two chemokines overexpressed in non-responders -- CXCL4 and CXCL7 -- were able to block the effect of DAC on normal CD34+ and primary CMML cells in vitro, suggesting their up-regulation contributes to primary DAC resistance. DNA methylation profiling in bone marrow mononuclear cells (BM MNC) from 39 CMML patients (19 decitabine responders vs. 20 non-responders).

2015-03-31 | E-GEOD-61161 | biostudies-arrayexpress

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