Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis

2010 ◽  
Vol 42A (4) ◽  
pp. 267-282 ◽  
Author(s):  
U. Ungethuem ◽  
T. Haeupl ◽  
H. Witt ◽  
D. Koczan ◽  
V. Krenn ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell Activation ◽  
Gene Networks ◽  
Cell Activation ◽  
Joint Disease ◽  
Disease Stage ◽  
Unknown Etiology ◽  
Coxa Vara ◽  
Molecular Signatures ◽  
Loss Of Function

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.

scholarly journals Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

2011 ◽  
Vol 30 (1) ◽  
pp. 25-29 ◽  
Author(s):  
I. Y. Ledezma-Lozano ◽  
J. J. Padilla-Martínez ◽  
S. D. Leyva-Torres ◽  
I. Parra-Rojas ◽  
M. G. Ramírez-Dueñas ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
Serum Levels ◽  
Unknown Etiology ◽  
Clinical Activity ◽  
Western Mexico

Objective:Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Methods:We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients.Results:RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p= 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p= 0.026). The RA patients showed higher sCD28 serum levels than HS (p= 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p= 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272;p= 0.016), was found.Conclusion:The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients.

scholarly journals AB1164 A COST PER RESPONDER ANALYSIS OF ABATACEPT VERSUS ADALIMUMAB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AMONG PATIENTS WITH SHARED EPITOPE (SE) POSITIVITY FROM A UNITED STATES PAYER PERSPECTIVE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1872.1-1873
Author(s):  
S. H. Park ◽  
X. Han ◽  
F. Lobo ◽  
S. Nanji ◽  
D. Patel
Keyword(s):  
Rheumatoid Arthritis ◽  
United States ◽  
T Cell Activation ◽  
Real World ◽  
Cell Activation ◽  
Shared Epitope ◽  
Pharmacy Cost ◽  
Controlled Clinical Trial ◽  
Payer Perspective ◽  
Cost Per Responder

Background:The shared epitope (SE) is a significant genetic risk factor for rheumatoid arthritis (RA), and it has been proposed to be associated with T-cell activation and the production of anti-citrullinated protein antibody (ACPA).1-3The results from the Early AMPLE trial, a head-to-head trial comparing the efficacy of abatacept versus adalimumab among early moderate-to-severe RA patients with positive ACPA (ACPA+) and rheumatoid factor (RF), showed that at week 24, patients with SE positivity (SE+) responded better to abatacept compared to adalimumab across all efficacy measures evaluated (ACR20 [American College of Rheumatology], ACR50, ACR70, DAS[disease activity score]28-CRP[C-reactive protein]).4Objectives:To compare the cost per responder (CPR) between abatacept and adalimumab among RA patients with SE+ at week 24 using the Early AMPLE trial data from a United States (US) payer perspective.Methods:A CPR analysis was conducted for RA patients with SE+, ACPA+, and RF. Responders were defined as patients achieving ACR20, ACR50, ACR70, or DAS28-CRP ≤2.6 and efficacy data was sourced from the trial (Figure 1).4Approved product labels were referenced for treatment dosing regimen and wholesale acquisition cost was used to calculate pharmacy cost.5A real-world rebate scenario was considered for adalimumab (30%) to reflect the real-world pricing in the US market. The CPR was calculated as the total pharmacy cost divided by the proportion of responders.Results:The total pharmacy cost at week 24 was $26,273 per patient for abatacept and $21,731 per patient for adalimumab. With achieving ACR70 as the definition of responder, the CPR at 24-week was $46,337 for abatacept and $74,935 for adalimumab, a difference of $28,598 (Table 1). The CPR was consistently lower for abatacept compared to adalimumab across all clinical measures, with difference ranging from $7,099 to $43,609.Table 1.Overall cost per responder resultsAbataceptAdalimumabDifferenceACR20$30,303.74$37,403.06-$7,099.32ACR50$34,254.68$48,077.83-$13,823.15ACR70$46,337.46$74,935.10-$28,597.64DAS28-CRP ≤2.6$52,546.68$96,155.65-$43,608.97Conclusion:While the pharmacy cost was higher for abatacept compared to adalimumab driven by the rebate, due to its higher clinical efficacy, the CPR was consistently lower for SE+ RA patients treated with abatacept. The results may be useful for US healthcare decision makers in understanding how to optimize treatment for SE+ RA patient while minimizing costs in today’s budget constrained environment.References:[1]Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.Arthritis and rheumatism. 1987;30(11):1205-13.[2]Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope.Curr Opin Rheumatol. 2010;22(3):293-8.[3]Sakkas LI, Bogdanos DP, Katsiari C, et al. Anti-citrullinated peptides as autoantigens in rheumatoid arthritis-relevance to treatment.Autoimmun Rev. 2014;13(11):1114-20.[4]Fleischmann R, Weinblatt M, Ahmad H, et al. Efficacy of abatacept and adalimumab in patientsn with early rheumatoid arthritis with multiple poor prognostic factors: post hoc analysis of a randomized controlled clinical trial (AMPLE).Rheumatol Ther. 2019;6(4): 559-571.[5]Truven Health Analytics. Redbook online. Accessed October 11, 2019.Disclosure of Interests:Sang Hee Park Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Xue Han Employee of: BMS, Francis Lobo Shareholder of: Bristol-Myers Squibb (US), Employee of: Bristol-Myers Squibb (US), Sakina Nanji Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study, Dipen Patel Consultant of: Pharmerit International, which received consultancy fees from Bristol-Myers Squibb (US), Inc. for this study

scholarly journals Immune Suppressive Effects of Plasma-Derived Exosome Populations in Head and Neck Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1997 ◽  
Author(s):  
Inga J. Beccard ◽  
Linda Hofmann ◽  
Jan C. Schroeder ◽  
Sonja Ludwig ◽  
Simon Laban ◽  
...  
Keyword(s):  
T Cells ◽  
Head And Neck ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Cell Activation ◽  
Disease Stage ◽  
High Stage ◽  
Treg Differentiation ◽  
The Impact

Plasma-derived exosomes of head and neck squamous cell carcinoma (HNSCC) patients carry inhibitory factors mediating immune suppression. Separation of tumor-derived exosomes (TEX) and non-TEX may assist in a better understanding of their respective parental cells. Here, we evaluate the impact of TEX or hematopoietic-derived exosomes on immune suppression. We evaluated apoptosis in CD8+ T cells, conversion of CD4+ T cells to regulatory T cells (Treg), and adenosine production by TEX, non-TEX, or total exosomes. Exosome protein cargo was significantly higher in total and CD45(−) exosomes from high stage compared to low stage patients. Furthermore, total and CD45(−) exosomes of high stage patients induced more apoptosis in CD8+ T cells than their low stage counterparts. CD69 suppression, a marker of reduced CD8+ T cell activation, was only mediated by CD45(−) exosomes. All fractions induced Treg differentiation, defined by CD39 expression, but only CD45(−) exosomes showed a stage-dependent conversion. CD45(−) exosomes produced higher adenosine concentrations than CD45(+) exosomes, concluding that adenosine production measured in total exosomes mainly derives from TEX. The presented results show significant induction of immune suppression by TEX in HNSCC. This immunosuppressive effect supports the potential role of exosomes as liquid biomarkers for disease stage and level of immune suppression.

scholarly journals Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis

2007 ◽  
Vol 179 (4) ◽  
pp. 2609-2615 ◽  
Author(s):  
Won-Woo Lee ◽  
Zhi-Zhang Yang ◽  
Guangjin Li ◽  
Cornelia M. Weyand ◽  
Jörg J. Goronzy
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation

scholarly journals Aberrant Regulation of Synovial T Cell Activation by Soluble Costimulatory Molecules in Rheumatoid Arthritis

2006 ◽  
Vol 177 (12) ◽  
pp. 8844-8850 ◽  
Author(s):  
Bing Wan ◽  
Hong Nie ◽  
Ailian Liu ◽  
Guozhang Feng ◽  
Dongyi He ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecules

scholarly journals Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2x2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1455-1455 ◽  
Author(s):  
Peter Westervelt ◽  
Gail J. Roboz ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dose Level ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Activation ◽  
Phase 1 ◽  
Disease Stage ◽  
Molecular Abnormalities ◽  
Grade 3

Abstract Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38). Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR. Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level. Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. Disclosures Roboz: Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

scholarly journals Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

2018 ◽  
Author(s):  
Jianping Guo ◽  
Tao Zhang ◽  
Hongzhi Cao ◽  
Xiaowei Li ◽  
Hao Liang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell Activation ◽  
Genetic Risk ◽  
Cell Activation ◽  
Disease Risk ◽  
Interaction Analysis ◽  
Hla Typing ◽  
Han Population ◽  
Hla Dqa1 ◽  
Citrullinated Protein

ABSTRACTThe strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the ‘real’ or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQα1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 × 10−36, OR=2.29). Further stepwise conditional analysis revealed that DRβ1:37N has an independent protective effect on ACPA–positive RA (P = 5.81 × 10−16, OR=0.49). The DQα1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 × 10−5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQα1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DRβ1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.In this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

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