Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2017

Open Access 01-12-2017 | Research article

Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis

Authors: C. Derambure, G. Dzangue-Tchoupou, C. Berard, N. Vergne, M. Hiron, M. A. D’Agostino, P. Musette, O. Vittecoq, T. Lequerré

Published in: Arthritis Research & Therapy | Issue 1/2017

Login to get access

Abstract

Background

In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA.

Methods

Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX.

Results

From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response.

Conclusion

Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.
Appendix
Available only for authorised users
Literature
1.
Smolen JS, Aletaha D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat Rev Rheumatol. 2015;11(5):276–89.CrossRefPubMed
2.
Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014;73(3):516–28.CrossRefPubMed
3.
Orme ME, Macgilchrist KS, Mitchell S, Spurden D, Bird A. Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70. Biologics. 2012;6:429–64.PubMedPubMedCentral
4.
Ramiro S, Gaujoux-Viala C, Nam JL, Smolen JS, Buch M, Gossec L, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014;73(3):529–35.CrossRefPubMed
5.
Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ. 2009;181(11):787–96.CrossRefPubMedPubMedCentral
6.
Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2:CD008794.
7.
Gaujoux-Viala C, Gossec L, Cantagrel A, Dougados M, Fautrel B, Mariette X, et al. Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis. Joint Bone Spine. 2014;81(4):287–97.CrossRefPubMed
8.
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625–39.CrossRef
9.
Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2015;75(1):3–15.CrossRefPubMedPubMedCentral
10.
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313–23.CrossRefPubMed
11.
Suthanthiran M, Schwartz JE, Ding R, Abecassis M, Dadhania D, Samstein B, et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med. 2013;369(1):20–31.CrossRefPubMedPubMedCentral
12.
Markopoulos C, van de Velde C, Zarca D, Ozmen V, Masetti R. Clinical evidence supporting genomic tests in early breast cancer: do all genomic tests provide the same information? Eur J Surg Oncol. 2017;43:909–20.
13.
Burska AN, Roget K, Blits M, Soto Gomez L, van de Loo F, Hazelwood LD, et al. Gene expression analysis in RA: towards personalized medicine. Pharmacogenomics J. 2014;14(2):93–106.CrossRefPubMedPubMedCentral
14.
15.
Haupl T, Stuhlmuller B, Grutzkau A, Radbruch A, Burmester GR. Does gene expression analysis inform us in rheumatoid arthritis? Ann Rheum Dis. 2010;69(1):i37–42.CrossRefPubMed
16.
Folkersen L, Brynedal B, Diaz-Gallo LM, Ramskold D, Shchetynsky K, Westerlind H, et al. Integration of known DNA, RNA and protein biomarkers provides prediction of anti-TNF response in rheumatoid arthritis: results from the COMBINE study. Mol Med. 2016;22:322–8.
17.
Bansard C, Lequerre T, Derambure C, Vittecoq O, Hiron M, Daragon A, et al. Gene profiling predicts rheumatoid arthritis responsiveness to IL-1Ra (anakinra). Rheumatology (Oxford). 2010;50(2):283–92.CrossRef
18.
Lequerre T, Gauthier-Jauneau AC, Bansard C, Derambure C, Hiron M, Vittecoq O, et al. Gene profiling in white blood cells predicts infliximab responsiveness in rheumatoid arthritis. Arthritis Res Ther. 2006;8(4):R105.CrossRefPubMedPubMedCentral
19.
Krintel SB, Dehlendorff C, Hetland ML, Horslev-Petersen K, Andersen KK, Junker P, et al. Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. 2015;16(2):141–6.CrossRefPubMed
20.
Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, et al. Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheum. 2014;66(6):1421–31.CrossRef
21.
Sellam J, Marion-Thore S, Dumont F, Jacques S, Garchon HJ, Rouanet S, et al. Use of whole-blood transcriptomic profiling to highlight several pathophysiologic pathways associated with response to rituximab in patients with rheumatoid arthritis: data from a randomized, controlled, open-label trial. Arthritis Rheum. 2014;66(8):2015–25.CrossRef
22.
D'Agostino MA, Boers M, Wakefield RJ, Berner Hammer H, Vittecoq O, Filippou G, et al. Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid arthritis starting abatacept: results from the APPRAISE study. RMD Open. 2016;2(1):e000237.CrossRefPubMedPubMedCentral
23.
D'Agostino MA, Wakefield RJ, Berner-Hammer H, Vittecoq O, Filippou G, Balint P, et al. Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study. Ann Rheum Dis. 2016;75(10):1763–9.CrossRefPubMed
24.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.CrossRefPubMed
25.
van der Heijde DM, van’t Hof MA, Van Riel PL, Theunisse LA, Lubberts EW, van Leeuwen MA, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990;49(11):916–20.CrossRefPubMedPubMedCentral
26.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7):RESEARCH0034.CrossRefPubMedPubMedCentral
27.
Gottenberg JE, Neto D, Gomez-Reino J, Iannone F, Lie E, Canhão H, et al. Positivity for rheumatoid factor and anti-cyclic citrullinated peptide is associated with a better drug retention of abatacept: data from a pan European analysis of RA registries. Ann Rheum Dis. 2014;73(supp 2):502–3.
28.
Gottenberg JE, Ravaud P, Cantagrel A, Combe B, Flipo RM, Schaeverbeke T, et al. Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry. Ann Rheum Dis. 2012;71(11):1815–9.CrossRefPubMed
29.
Nusslein HG, Alten R, Galeazzi M, Lorenz HM, Nurmohamed MT, Bensen WG, et al. Prognostic factors for abatacept retention in patients who received at least one prior biologic agent: an interim analysis from the observational, prospective ACTION study. BMC Musculoskelet Disord. 2015;16:176.CrossRefPubMedPubMedCentral
30.
Scarsi M, Ziglioli T, Airo P. Baseline numbers of circulating CD28-negative T cells may predict clinical response to abatacept in patients with rheumatoid arthritis. J Rheumatol. 2011;38(10):2105–11.CrossRefPubMed
31.
Toonen EJ, Gilissen C, Franke B, Kievit W, Eijsbouts AM, den Broeder AA, et al. Validation study of existing gene expression signatures for anti-TNF treatment in patients with rheumatoid arthritis. PLoS One. 2012;7(3):e33199.CrossRefPubMedPubMedCentral
32.
Serikawa KA, Jacobsen S, Lundsgaard D, Fox BA, Hummelshoj L, Poulsen LK, et al. Detection of gene expression signatures related to underlying disease and treatment in rheumatoid arthritis patients. Mod Rheumatol. 2012;23(4):729–40.CrossRefPubMed
33.
Nakamura S, Suzuki K, Iijima H, Hata Y, Lim CR, Ishizawa Y, et al. Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study. Arthritis Res Ther. 2016;18:159.CrossRefPubMedPubMedCentral
34.
35.
Scott I, Webster BR, Li JH, Sack MN. Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1. Biochem J. 2012;443(3):655–61.CrossRefPubMed
36.
Fornuskova D, Stiburek L, Wenchich L, Vinsova K, Hansikova H, Zeman J. Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem J. 2010;428(3):363–74.CrossRefPubMed
37.
Chang HY, Huang TC, Chen NN, Huang HC, Juan HF. Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells. Cell Death Dis. 2014;5:e1540.CrossRefPubMedPubMedCentral
38.
Leavy O. T cells: Mitochondria and T cell activation. Nat Rev Immunol. 2013;13(4):224.PubMed
39.
Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38(2):225–36.CrossRefPubMedPubMedCentral
40.
Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J Exp Med. 2002;195(1):59–70.CrossRefPubMedPubMedCentral
41.
Ledderose C, Bao Y, Lidicky M, Zipperle J, Li L, Strasser K, et al. Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling. J Biol Chem. 2014;289(37):25936–45.CrossRefPubMedPubMedCentral
42.
43.
Remans PH, Wijbrandts CA, Sanders ME, Toes RE, Breedveld FC, Tak PP, et al. CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell-induced inactivation of Rap1, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells. Arthritis Rheum. 2006;54(10):3135–43.CrossRefPubMed
44.
Remans PH, Gringhuis SI, van Laar JM, Sanders ME, der Papendrecht-van der Voort EA, Zwartkruis FJ, et al. Rap1 signaling is required for suppression of Ras-generated reactive oxygen species and protection against oxidative stress in T lymphocytes. J Immunol. 2004;173(2):920–31.CrossRefPubMed
45.
Aichler M, Elsner M, Ludyga N, Feuchtinger A, Zangen V, Maier SK, et al. Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria. J Pathol. 2013;230(4):410–9.CrossRefPubMed
46.
Zhu H, Chen L, Zhou W, Huang Z, Hu J, Dai S, et al. Over-expression of the ATP5J gene correlates with cell migration and 5-fluorouracil sensitivity in colorectal cancer. PLoS One. 2013;8(10):e76846.CrossRefPubMedPubMedCentral
47.
Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334(6059):1129–33.CrossRefPubMed
Metadata
Title
Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis
Authors
C. Derambure
G. Dzangue-Tchoupou
C. Berard
N. Vergne
M. Hiron
M. A. D’Agostino
P. Musette
O. Vittecoq
T. Lequerré
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-017-1319-8

Other articles of this Issue 1/2017

Arthritis Research & Therapy 1/2017 Go to the issue

Research article

Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study

Research article

Clinical and demographic factors associated with change and maintenance of disease severity in a large registry of patients with rheumatoid arthritis

Research article

Incretins in patients with rheumatoid arthritis

Research article

Resistin upregulates chemokine production by fibroblast-like synoviocytes from patients with rheumatoid arthritis

Research article

Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study

Review

Animal models of rheumatoid pain: experimental systems and insights

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits