scholarly journals POS0359 MOLECULAR PROFILING OF RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS PATIENTS REVEALS AN ASSOCIATION BETWEEN INNATE AND ADAPTIVE CELL POPULATIONS AND THERAPEUTIC RESPONSE TO ADALIMUMAB

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 410.1-410
Author(s):  
D. Sobral ◽  
A. F. Fernandes ◽  
A. Mashayekhi Sardoo ◽  
M. Bernardes ◽  
P. Pinto ◽  
...  
Keyword(s):  
Disease Activity ◽  
Immune Cell ◽  
Axial Spondyloarthritis ◽  
Therapeutic Option ◽  
Differential Expression Analysis ◽  
Differentially Expressed Gene ◽  
Molecular Profiling ◽  
Response To Therapy ◽  
Differentially Expressed ◽  
Response To Treatment

Background:The response to treatment in spondylarthropaties is heterogeneous, due to factors yet to be better described. For that reason, it is important to find tools that might help clinicians to decide what is the best available therapeutic option for each patient.Objectives:The goal of this study is to use comprehensive molecular profiling to characterize clinical response to therapy in a real-world setting. Specifically, to identify molecular biomarkers differentiating good responders and non-responders to TNF inhibitors (TNFi) treatment, using adalimumab, in radiographic axial spondyloarthritis | ankylosing spondylitis (r-axSpA|AS) patients context.Methods:Whole-blood mRNA and plasma proteins were measured in a cohort of biologic naïve r-axSpA|AS patients (n = 35) from the Bioefficacy study (Biomarkers identification of anti-TNF alpha agent efficacy in AS patients using RNA sequencing and mass spectrometry), pre and post (14 weeks) TNFi treatment using adalimumab. Response to treatment was categorized according to ASAS20. Results of differential expression analysis were used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi.Results:A treatment-related signature, independent of the type of response, suggests a reduction in inflammatory disease activity. We found genes and proteins robustly differentially expressed between baseline and week 14 in responders, including the GWAS AS-associated genes TNFRSF1A, FCGR2A, TYK2, TBKBP1, IL1R1, IL6R, ICOSLG, IL7R, HHAT and LTBR. Moreover, CRP and HP proteins showed strong and early decrease in the plasma of AS patients, while a cluster of apolipoproteins (APO1, APO2, APO3) showed an increased expression at week 14. Good responders to TNFi treatment tend to have higher expression of innate immunity genes at baseline, and lower expression of markers associated with adaptive immunity, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender and Gene x, the top differentially expressed gene at baseline between responders and non-responders, enabled an accurate prediction of response to adalimumab in our cohort (AUC=0.97).Conclusion:Differences in disease activity and/or innate/adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in r-axSpA|AS. Alternatively, a model including clinical and gene expression variables could be considered, particularly in patients with mild disease activity.Disclosure of Interests:None declared

scholarly journals Interleukin-6 and Related Proteins as Biomarkers in Systemic Sclerosis

2017 ◽  
Vol 2 (2_suppl) ◽  
pp. S13-S19 ◽  
Author(s):  
Christopher P. Denton ◽  
Voon H. Ong
Keyword(s):  
Systemic Sclerosis ◽  
Interleukin 6 ◽  
Cell Function ◽  
Immune Cell ◽  
Family Members ◽  
Surrogate Marker ◽  
Response To Therapy ◽  
Janus Kinase ◽  
Response To Treatment ◽  
Early Stage Disease

The search for biomarkers in systemic sclerosis (SSc) is driven by a goal to stratify patients, identify potential subgroups for treatment, and help assess response to therapy. Emerging evidence indicates that interleukin-6 (IL-6) and some family members are key biomarkers involved in SSc pathogenesis and therefore suitable targets for therapy. Recent studies evaluating IL-6 and its canonical Janus kinase/signal transducers and activators of transcription downstream pathways in modulating fibrotic response and immune cell function suggest a pivotal role for IL-6 in SSc pathogenesis. Although the significance and effect of local tissue expression of IL-6 and its family members are less well established, high levels of circulating IL-6 may identify subgroups of patients with early-stage disease, particularly those at risk for progressive lung fibrosis. In addition, higher disease activity may portend poor prognostic outcome in terms of survival and skin disease. Longitudinal assessment of serum levels of IL-6 and its signaling associates may prove valuable in monitoring response to treatment. As an IL-6–dependent surrogate marker, C-reactive protein may assist cohort enrichment if targeted treatment for IL-6 demonstrates efficacy, especially in subgroups with high IL-6 levels. Although IL-6 appears to be a key factor in the hierarchy of the complex network of disease-associated molecules, the systemic or autocrine/paracrine manner in which IL-6 asserts its profibrotic effects—particularly its interaction with other key pathogenic factors in SSc—is unknown. Ongoing clinical trials will help to delineate the mechanisms of IL-6 in SSc pathogenesis and inform on the role of these biomarkers.

scholarly journals The Sex Influence on Response to Tumor Necrosis Factor-α Inhibitors and Remission in Axial Spondyloarthritis

2017 ◽  
Vol 45 (2) ◽  
pp. 195-201 ◽  
Author(s):  
Ennio Lubrano ◽  
Fabio Massimo Perrotta ◽  
Maria Manara ◽  
Salvatore D’Angelo ◽  
Olga Addimanda ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Disease Activity ◽  
Axial Spondyloarthritis ◽  
Response To Treatment ◽  
Inactive Disease ◽  
Disease Remission ◽  
Female Patients ◽  
Patient Reported ◽  
Factor Α ◽  
Necrosis Factor

Objective.The aim of this study was to evaluate the influence of sex on response to treatment and disease remission in patients with axial spondyloarthritis (axSpA).Methods.In this retrospective multicenter study, patients with axSpA, according to the Assessment of Spondyloarthritis international Society (ASAS) criteria for axSpA, and treated with adalimumab, etanercept, golimumab, or infliximab, were studied. We compared clinical characteristics, patient-reported outcomes, disease activity, function, and response to treatment in male and female patients with this disease.Results.Three hundred forty patients with axSpA (270 with ankylosing spondylitis, 19 with psoriatic arthritis with axial involvement, and 51 with nonradiographic axSpA) were studied. Male subjects had a significantly higher prevalence of grade IV sacroiliitis, higher levels of serum C-reactive protein, lower Maastricht Ankylosing Spondylitis Enthesitis Score, and fatigue when compared with females. Further, Kaplan-Meier survival curves showed that the rate of partial remission, ASAS40 response, and Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement, but not ASDAS inactive disease, were significantly lower in female patients.Conclusion.Our data suggest that female sex was associated with a lower rate of response to treatment and of disease remission in patients with axSpA treated with antitumor necrosis factor-α drugs.

scholarly journals Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Victor Farutin ◽  
Thomas Prod’homme ◽  
Kevin McConnell ◽  
Nathaniel Washburn ◽  
Patrick Halvey ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cell ◽  
Clinical Laboratory ◽  
Cell Types ◽  
Molecular Profiling ◽  
Response To Treatment ◽  
Cell Type ◽  
Inflammatory Conditions ◽  
Cell Type Specific ◽  
High Level

Abstract Background The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). Methods Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. Results A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p < 0.01) between the two cohorts. A baseline, response signature of increased innate cell types in responders compared to increased adaptive cell types in non-responders was identified in both cohorts. This result was further assessed by applying the cell type-specific analysis to five other publicly available RA datasets. Evaluation of the neutrophil-to-lymphocyte ratio at baseline in the remaining patients (n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03–1.41, p = 0.02]). Conclusion Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

scholarly journals Clinically Relevant Biomarker Discovery in High-Risk Recurrent Neuroblastoma

2019 ◽  
Vol 18 ◽  
pp. 117693511983291 ◽  
Author(s):  
Peter Utnes ◽  
Cecilie Løkke ◽  
Trond Flægstad ◽  
Christer Einvik
Keyword(s):  
High Risk ◽  
Cell Lines ◽  
Target Genes ◽  
Biomarker Discovery ◽  
Expression Profiles ◽  
Response To Therapy ◽  
Gene Set Enrichment Analysis ◽  
Favorable Outcome ◽  
Differentially Expressed ◽  
Response To Treatment

Neuroblastoma is a pediatric cancer of the developing sympathetic nervous system. High-risk neuroblastoma patients typically undergo an initial remission in response to treatment, followed by recurrence of aggressive tumors that have become refractory to further treatment. The need for biomarkers that can select patients not responding well to therapy in an early phase is therefore needed. In this study, we used next generation sequencing technology to determine the expression profiles in high-risk neuroblastoma cell lines established before and after therapy. Using partial least squares-discriminant analysis (PLS-DA) with least absolute shrinkage and selection operator (LASSO) and leave-one-out cross-validation, we identified a panel of 55 messenger RNAs and 17 long non-coding RNAs (lncRNAs) which were significantly altered in the expression between cell lines isolated from primary and recurrent tumors. From a neuroblastoma patient cohort, we found 20 of the 55 protein-coding genes to be differentially expressed in patients with unfavorable compared with favorable outcome. We further found a twofold increase or decrease in hazard ratios in these genes when comparing patients with unfavorable and favorable outcome. Gene set enrichment analysis (GSEA) revealed that these genes were involved in proliferation, differentiation and regulated by Polycomb group (PcG) proteins. Of the 17 lncRNAs, 3 upregulated ( NEAT1, SH3BP5-AS1, NORAD) and 3 downregulated lncRNAs ( DUBR, MEG3, DHRS4-AS1) were also found to be differentially expressed in favorable compared with unfavorable outcome. Moreover, using expression profiles on both miRNAs and mRNAs in the same cohort of cell lines, we found 13 downregulated and 18 upregulated experimentally observed miRNA target genes targeted by miR-21, -424 and -30e, -29b, -138, -494, - 181a, -34a, -29b, respectively. The advantage of analyzing biomarkers in a clinically relevant neuroblastoma model system enables further studies on the effect of individual genes upon gene perturbation. In summary, this study identified several genes, which may aid in the prediction of response to therapy and tumor recurrence.

scholarly journals Quantifying the relative immune cell activation from whole tissue/organ-derived differentially expressed gene data

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Edward Wijaya ◽  
Yoshinobu Igarashi ◽  
Noriyuki Nakatsu ◽  
Yasunari Haseda ◽  
Joel Billaud ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Differentially Expressed Gene ◽  
Differentially Expressed ◽  
Immune Cell Activation ◽  
Gene Data

Impaired response to treatment with tumour necrosis factor α inhibitors in smokers with axial spondyloarthritis

2015 ◽  
Vol 75 (3) ◽  
pp. 532-539 ◽  
Author(s):  
Adrian Ciurea ◽  
Almut Scherer ◽  
Ulrich Weber ◽  
Pascale Exer ◽  
Jürg Bernhard ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Disease Activity ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Axial Spondyloarthritis ◽  
Smoking Status ◽  
Response To Treatment ◽  
Asas Classification Criteria ◽  
The Impact ◽  
Necrosis Factor

ObjectivesTo investigate the impact of smoking on the response to treatment with a first tumour necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (axSpA) in a real-life cohort.MethodsPatients fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA in the Swiss Clinical Quality Management Cohort were included in this study. The potential association between smoking status and differential response to TNFi in terms of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) was analysed using multiple adjusted longitudinal mixed effect models. Binary response rates at 1 year were assessed with multiple adjusted logistic analyses.ResultsA first TNFi was initiated in 698 patients with axSpA with available smoking status and a baseline or follow-up BASDAI assessment, of which 490 (70%) had complete covariate data. In comparison to non-smokers, current smokers demonstrated significantly smaller reductions in BASDAI and ASDAS scores upon treatment with TNFi (0.75 BASDAI units and 0.69 ASDAS units less, p=0.005 and 0.001, respectively) for patients with elevated baseline C-reactive protein (CRP) level. This effect was numerically smaller in patients with normal CRP. The odds for reaching a 50% improvement in BASDAI response or the ASAS criteria for 40% improvement after 1 year were significantly lower in current smokers than in non-smokers (0.54, 95% CI 0.31 to 0.95, p=0.03 and 0.43, 95% CI 0.24 to 0.76, p=0.004, respectively).ConclusionsCurrent smoking is associated with an impaired response to TNFi in axSpA.

Circulating immune complexes in childhood malignancies: a Pediatric Oncology Group study.

1983 ◽  
Vol 1 (12) ◽  
pp. 799-803
Author(s):  
R P Castleberry ◽  
M R Duncan ◽  
S Stagno ◽  
D J Fernbach ◽  
V Land
Keyword(s):  
Disease Activity ◽  
Immune Complexes ◽  
Stage Iv ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Circulating Immune Complexes ◽  
Response To Treatment ◽  
Serum Samples ◽  
Pediatric Malignancies ◽  
Childhood Malignancies

Pretreatment serum samples obtained at diagnosis from 89 children with various pediatric malignancies were examined for circulating immune complexes (CIC) using the [125I]Clq binding assay. The study population consisted of 35 children with acute lymphocytic leukemia (ALL), 22 children with acute non-lymphocytic leukemia (ALL), 24 with neuroblastoma (NB), and eight with osteosarcoma (OS). Concomitant quantitation of immunoglobulins was performed in 55 patients, revealing normal values for age. Increased levels of CIC at diagnosis were found in 9%, 22%, 42%, and 50% of children with ALL, AML, NB, and OS, respectively. Except for a higher proportion of CIC-positive patients observed in stage IV NB (nine of 17) compared to stage I-III NB (one of seven), no correlation was observed between initial CIC level and presenting clinical features, response to treatment, prognosis, or presence of infection. Longitudinal sampling of six NB and two OS patients did not reveal a clear relationship between disease activity and quantity of CIC. For the pediatric malignancies studied, these data demonstrate minimal value in quantitating CIC as a means of assessing disease activity or predicting response to treatment and are in contrast to the apparently adverse effect of elevated pretreatment CIC on response to therapy and survival observed in adults with ALL, AML, and OS.

The rheumatoid arthritis gene expression signature among women who improve or worsen during pregnancy – a pilot study

2020 ◽  
pp. jrheum.201128
Author(s):  
Amogh Pathi ◽  
Matthew Wright ◽  
Mette Kiel Smed ◽  
J. Lee Nelson ◽  
Jørn Olsen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Disease Activity ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Gene Expression Signature ◽  
Differentially Expressed ◽  
Expression Signature ◽  
Healthy Women ◽  
Gene Expression Signatures

Objective To assess whether gene expression signatures associated with rheumatoid arthritis (RA) before pregnancy differ between women who improve or worsen during pregnancy, and determine whether these expression signatures are altered during pregnancy when RA improves or worsens. Methods Clinical data and blood samples were collected before pregnancy (T0) and at the third trimester (T3) from 11 RA and 5 healthy women. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI). At each time-point, RA-associated gene expression signatures were identified using differential expression analysis of RNA sequencing profiles between RA and healthy women. Results Of the women with RA, 6 improved by T3 (RAimproved), 3 worsened (RAworsened) and 2 were excluded. At T0, mean CDAI scores were similar in both groups (RAimproved: 11.2±9.8; RAworsened: 13.8±6.7; Wilcoxon-rank test: p=0.6). In the RAimproved group, 89 genes were differentially expressed at T0 (q<0.05 and fold-change (FC)≥2) compared to healthy women. When RA improved at T3, 65 of 89 (73%) of these no longer displayed RA-associated expression. In the RAworsened group, a largely different RA gene expression signature (429 genes) was identified at T0. When RA disease activity worsened at T3, 207 of 429 (48%) lost their differential expression, while an additional 157 genes became newly differentially expressed. Conclusion In our pilot dataset, pre-pregnancy RA expression signatures differed between women who subsequently improved or worsened during pregnancy, suggesting that inherent genomic differences perhaps influence how pregnancy impacts disease activity. Further, these RA signatures were altered during pregnancy, as disease activity changed.

DIFFERENTIALLY EXPRESSED GENE SIGNATURES OF ULCERATIVE COLITIS DETERMINE NOVEL REGULATORS AND PREDICT RESPONSE TO BIOLOGIC THERAPY

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S28-S29
Author(s):  
Harrison Penrose ◽  
Eman Toraih ◽  
Emmanuelle Ruiz ◽  
Rida Iftikhar ◽  
Morgan Collins ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Differentially Expressed Genes ◽  
Immune Cell ◽  
Biologic Therapy ◽  
Function Analysis ◽  
Differentially Expressed Gene ◽  
Differentially Expressed ◽  
Diagnostic Tools ◽  
Gene Signatures ◽  
Large Patient

Abstract Disease heterogenicity among Ulcerative colitis (UC) patients and their variable responses to therapy is not well understood. Previously, using publicly available transcriptomes from colonic tissue of UC patients, we demonstrated the immune cell landscape and pathways that are common and distinct among patients and for non-responders to biologic therapy. Here, we AIM to determine differentially expressed gene signatures specific to inflamed UC tissue and for non-responders to biologic anti-TNFa and anti-a4b7 therapy in large patient cohorts. Methods: Transcriptomes from 210 UC patient samples from inflamed and matched uninflamed tissue (GSE4183, GSE14580, GSE38713, GSE107593) and from UC patients prior to and while receiving anti-TNFa (infliximab) and anti-a4b7 integrin (vedolizumab) (GSE12251, GSE73661) treatment were analyzed. Generating and analyzing differentially expressed genes (DEGs), transcriptional signatures, and hierarchical clustering were performed using the limma Bioconductor R package and Cluster3/JavaTree software. Disease/function analysis was performed by Ingenuity Pathway Analysis (IPA) and predicting outcomes to therapy by receiver operating characteristic (ROC) curve analysis and area under the curve (AUC). Transcripts were validated in primary UC tissue samples using qPCR. Results: In three UC cohorts, we identified a specific transcriptional signature of 100 DEGs (UC100) common among patients (Figure 1A-D). The UC100 signature was validated in an independent cohort, demonstrating the ability to distinctly separate inflamed from matched uninflamed transcriptomes (p=4.65e-08). The UC100 DEGs encode protein involved in inflammation, immunity, antimicrobial response, growth, cellular movement, metabolism (lipid, amino acid), and energy production. Among them are many DEGs with unexamined roles in UC, including PCK1, HMGCS2, ACAT1, HCAR3, LPCAT1, and LIPG. Their differential expression was further validated in primary UC tissue by qPCR. Moreover, we identified twenty DEGs in UC patients resistant to anti-TNFa and anti-a4b7 therapy (UCR20) (Figure 2A-C). The UC20R DEGs encode protein involved in inflammation, immune cell trafficking, antimicrobial responses, lipid metabolism, and mitochondrial dysfunction. Four of the top DEGs predicted resistance to both therapies with a sensitivity of 73.3% and specificity 85.7%; AUC for IGFBP5: 0.86±0.008, p=0.008; STC1: 0.83±0.09, p=0.015; VNN2: 0.81±0,10, p=0.022; and SELE: 0.77±0.11, p=0.045. Conclusion: This study demonstrates differentially expressed genes in UC common across cohorts and those with predictive power to biologic therapy outcome. This provides a platform for development of more precise diagnostic tools and personally tailored therapeutic regimens for UC patients.

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