Efficacy of Ustekinumab Followed by Abatacept for the Treatment of Psoriasis Vulgaris (PAUSE)
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PROVIDER: PRJNA1006804 | ENA |
REPOSITORIES: ENA
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Project description:Ustekinumab provides clinical benefit to psoriasis patients, but precise cellular and molecular changes underlying its therapeutic utility are not yet fully understood. To assess differences between ustekinumab responders vs. non responders in modulating specific inflammatory pathways and provide reference data for exploring molecular effects of next-generation interleukin(IL)-17 and IL-23-antagonists in psoriasis.
2019-02-01 | GSE117239 | GEO
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
Project description:ImportancePsoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept.ObjectiveTo determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal.Design, setting, and participantsPsoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021.InterventionsParticipants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ≤100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39.Main outcomes and measuresThe primary end point was the proportion of participants with psoriasis relapse (loss of ≥50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated.ResultsA total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased.Conclusions and relevanceThis parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse.Trial registrationClinicalTrials.gov Identifier: NCT01999868.
| S-EPMC8515260 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) primarily affects the respiratory system but extrapulmonary manifestations, including the skin, have been well documented. However, transcriptomic profiles of skin lesions have not been performed thus far. Here, we present a single-cell RNA sequencing analysis in a patient with COVID-19 infection with a maculopapular skin rash while on treatment with the interleukin (IL)-12/IL-23 blocker ustekinumab for underlying psoriasis. Results were compared with healthy controls and untreated psoriasis. We found the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry receptors ACE2 and TMPRSS2 in keratinocytes of the patient with COVID-19, while ACE2 expression was low to undetectable in psoriasis lesions and healthy skin. Among all cell types, ACE2+ keratinocyte clusters showed the highest levels of transcriptomic dysregulation in COVID-19, expressing type 1–associated immune markers such as CXCL9 and CXCL10. In line with a generally type 1–skewed immune microenvironment, cytotoxic lymphocytes showed increased expression of the IFNG gene and other T-cell effector genes, while type 2, type 17, or type 22 T-cell activation was largely absent. Conversely, downregulation of several anti-inflammatory mediators was observed. This first transcriptomic description of a COVID-19-associated rash identifies ACE2+ keratinocytes displaying profound transcriptional changes, and inflammatory immune cells that might help to improve the understanding of SARS-CoV-2-associated skin conditions.
2023-03-27 | GSE206147 | GEO
Project description:To explore markers which predict the efficacy of abatacept in rheumatoid arthritis, peripheral blood mononuclear cells were obtained before abatacept treatment.
2023-04-10 | GSE224842 | GEO
Project description:The objective of this study was to identify specific gene expression profiles able to predict the response of rheumatoid arthritis patients treated with methotrexate /abatacept (Aba). Thirty six RA patients were received Abatacept. The drug efficacy was evaluated with the DAS28 score after 6 months of treatment according to the EULAR response criteria. Among 36 Aba RA patients, 17 were responders and 19 were classified as no-responders. A blood sample was carried out in patients just before the first injection of treatment in PaxGene tubes. Two color experiments : patient(Cy5)/Control pool (Cy3).
2017-05-17 | E-GEOD-68215 | biostudies-arrayexpress
Project description:Our goal was to assess for the histological and transcriptomic effects of Abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: Tocilizumab, Rituximab, Methotrexate and Adalimumab.
2021-08-23 | GSE172188 | GEO
Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.
2014-10-30 | PXD001387 | Pride
Project description:Analysis of transcriptome data identified 96, 64 and 3 genes that were differentially expressed (DE, adj. P value < 0.05) following abatacept treatment in Tfh, Treg and CD4+CD45RO+PD1+CXCR5- T cells, respectively. We determined if abatacept treatment altered the core transcriptional profiles of Tfh and Treg lineages by comparing gene expression of bulk sorted Treg and Tfh cells from cryopreserved PBMCs at baseline, week 24, and after abatacept withdrawal. Analysis of differentially expressed (DE) genes in Tfh was performed using Gene Ontology (GO) term enrichment analysis. This analysis revealed 9 significantly enriched GO categories, which were related to processes involved in cell division and proliferation. DE genes in the enriched GO categories showed a highly significant correlation in Tfh and Treg cells, further highlighting the similarity in the response of these two populations to abatacept. In contrast to Tfh and Treg, acatacept had a minimal impact on CD4+CD45RO+PD1+CXCR5- T cells.
2018-12-27 | GSE121827 | GEO
Project description:Cellular and Molecular Changes in Psoriasis Lesions Inducedby Ustekinumab: Distinct Differences in Responders vs. Non responders
| PRJNA481519 | ENA